OA20989A - Macrocyclic azolopyridine derivatives as EED and PRC2 modulators. - Google Patents

Macrocyclic azolopyridine derivatives as EED and PRC2 modulators. Download PDF

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OA20989A
OA20989A OA1202100428 OA20989A OA 20989 A OA20989 A OA 20989A OA 1202100428 OA1202100428 OA 1202100428 OA 20989 A OA20989 A OA 20989A
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heterocyclyl
heteroaryl
fluoro
pyrido
tetrahydro
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OA1202100428
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Ivan Viktorovich Efremov
Steven KAZMIRSKI
Qingyi Li
III Lorin A THOMPSON
Owen Brendan Wallace
Shawn Donald Johnstone
Peter RAHL
Feng Zhou
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Fulcrum Therapeutics, Inc.
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Publication of OA20989A publication Critical patent/OA20989A/en

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Abstract

The invention relates to modulators of Embryonic Ectoderm Development (EED) and/or Polycomb Repressive Complex 2 (PRC2) useful in the treatment of disorders and diseases associated with EEC and PRC2, being macrocyclic azolopyridine derivatives and compositions thereof of Formula I: or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, enantiomer, isomer, or tautomer thereof, wherein X1, X2, X3, A1, A2, Y, R1, R2, R3, and R4 are as described herein.

Description

Description of the Text File Submitted Electronically
The présent application contains a Sequence Listing, which has been submitted in ASCII format via EFS-Web and is hereby incorporât ed b y reference in its entirety. Said ASCII copy, créât ed on March 11, 2020, is named “FULC-034-01WO_SeqList.txt” and is 6 KB in size.
Field of Invention
The présent disclosure relates to macrocyclic azolopyridine dérivatives, compositions comprising these compounds, methods of treating dïseases or disorders associated with Embryonic Ectoderm Development (EED) and/or Polycomb Répressive Complex 2 (PRC2), e.g., by modulating gene expression, and methods of synthesis of these compounds.
Background of the Invention
Polycomb group (PcG) proteins are a family of chromatin modifying enzymes that play a key rôle in gene expression and are dysregulated in many human diseases. The PcG family includes two classes of Polycomb Répressive Complexes (PRCs), namely Polycomb Répressive Complex 1 (PRC1) and Polycomb Répressive Complex 2 (PRC2). PRC2 includes SUZ12 (suppressor of zeste 12), EED (embryonic ectoderm development) and the catalytic subunit, EZH2 (enhancer of zeste homolog 2), and represses genes by methylatîng histone H3 lysine 27 (H3K27me3) at and around the promoter régions of genes. This critical component of chromatin régulation is involved in modulation of gene transcription and plays crucial function in development, différentiation, and régénération. Although EZH2 is the catalytic subunit, PRC2 minimal 1 y requires EED and SUZ12 for îts methyltransferase activity. EED, SUZI2 and EZH2 hâve been found to be overexpressed in many cancers, which include but are not limited to hepatocellular carcinoma, breast cancer, prostate cancer, etc. Activating mutations in EZH2 hâve been found in FL (follicular lymphoma) and DLBCL (diffuse large B cell lymphoma) patients. EED normally médiates repression of gene activity by binding to di- and trimethylated lysine 27 of histone 3 where it allosterically activâtes EZH2 activity of PRC2. EED has also been reported to recruit PRC1 to H3K27me3 loci and to enhance PRC1 mediated H2A ubiquitin E3 ligase activity.
Taken together, 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 fêtai orthologues (i.e. gamma globin), Hox genes, X chromosome inactivation, etc. Thus, EED provides a pharmacologie target for the treatment of diseases or disorders to impact transcription of spécifie target genes in blood and other tissues. The need exists for small molécules that modulate EED and/or PRC2.
Summary of the Invention
A first aspect of the invention relates to compounds of Formula I:
Ri and pharmaceutically acceptable salts, prodrugs, solvatés, hydrates, enantiomers, isomers, and tautomers thereof, wherein:
Xb X2î and X3 are independently N or C(Rs), provided that Xi, X2, and Xj are not ail N and at least one of Xj, X2, or X3 is N;
A, is a bond, -C(R8)(R9)-, -O-, -NR8, -S-, -S(O)-, or -SO2-;
A? and Y are independently at each occurrence -C(R8)(R9)- -O-, -NR8, -S-, -S(O)-, or SO2-;
R) is H, halogen, -NRsRq, -P(O)(OR8)(OR9), -C(O)Rs, -C(O)NR8R9, -CN, CrC6 alkyl, Cr C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, Cj-Ci0 cycloalkyl, Cs-Cs cycloalkenyl, Cj-C8 spirocycloaikyl, spiroheterocyclyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, spirocycloaikyl, spiroheterocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R6;
R2 and Rj are independently at each occurrence H, halogen, -OH, -NH2, -CN, CrC6 alkyl, CrC6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R?;
R4 is H, halogen, —OH, —NH2, —CN, Ci-C& alkyl, Ci-Cg alkoxy, C2-C6 alkenyl, 01 C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl îs optionally substituted with one or more R7, or R4 and Rg when taken together can form C3-C10 cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl, wherein the cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Rio;
R5 is H, halogen, —CN, —ORg, —NR8R9, —C(O)Rg, —C(O)OR8, — C(O)NR8R9, —NRgC(O)R9, S(O)R8, -S(O)2R8, -NR8S(O)2R9j -S(O)2NR8R9, Ci-C6 alkyl, CrC6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R7;
Ri, is independently at each occurrence oxo, halogen, -CN, OH, -NR8R9, -ORg, -C(O)Rg, C(O)OR8, - C(O)NR8R9, -NR8C(O)R9, -S(O)R8, -S(O)2R8, -NR8S(O)2R9, -S(O)2NR8R9, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cj-Cs cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Rio; or two R6 can combine to form C3-C10 cycloalkyl, C3-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl, wherein the cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Rio;
R? is independently at each occurrence oxo, halogen, -CN, -ORg, -C(O)Rg, -C(O)OR8, C(O)NR8R9, -NR8C(O)R9î -S(O)R8, -S(O)2R8, -NR8S(O)2R9, -S(O)2NR8R9, Ci-C6 alkyl, CrC6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl;
R8 is independently at each occurrence H, OH, halogen, Ci-C^ alkyl, Cj-Cè alkoxy, C2-Ce alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Rio;
R9 is independently at each occurrence H, halogen, Ct-C6 alkyl, Cj-Ce alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Cg cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Rio;
or Rs and R9 when taken together form a C3-C6 cycloalkyl or heterocyclyl, wherein ihe cycloalkyl or heterocyclyl is optionally substituted with Rio; and
Rio is independently at each occurrence oxo, halogen, -CN, -ORj h -C(O)Rn, -C(O)ORn, C(O)NRuRi2,-NRnRi2,-NRnC(O)Ri2, -S(O)Rn, -S(O)2Ru, -NRuS(O)2Ri2, -S(O)2NRnRi2, CjC6 alkyl, CrC6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, CrC8 cycloalkyl, heterocyclyl, aryl, or heteroaryl; and
Rj ] and Ri2 are independently H, Ci-C^ alkyl, Ci-C& haloalkyl, C1-C& alkoxy, C2-Ce alkenyl, C2-C(, alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl.
Another aspect of the invention relates to a pharmaceutical composition comprising a compound of Formula I and a pharmaceuticaliy acceptable carrier. The pharmaceuticaliy acceptable carrier may further inciude an excipient, diluent, or surfactant.
Another aspect of the invention is directed to a method of treating a disease or disorder associated with modulation of embryonic ectoderm development (EED). The method involves administering to a patient in need thereof an effective amount of the compound of Formula 1.
Another aspect of the invention relates to a method of treating a disease or disorder associated with modulation of Polycomb Répressive Complex 2 (PRC2). The method comprises administering to a patient in need thereof an effective amount of the compound of Formula I.
The présent invention further provides methods of treating a cancer selected from diffused large B cell lymphoma, follicular lymphoma, other lymphomas, leukemia, multiple myeloma, mesothelioma, gastric cancer, malignant rhabdoid tumor, hepatocellular carcinoma, prostate cancer, breast carcinoma, bile du et and gallbladder cancers, bladder carcinoma, biain tumois including neuroblastoma, schwannoma, glioma, glioblastoma and astrocytoma, cervical cancer, colon cancei, melanoma, endométrial cancer, esophageal cancer, head and neck cancer, lung cancer, nasopharyngeal carcinoma, ovarian cancer, pancreatic cancer, rénal cell carcinoma, rectal cancer, thyroid cancers, parathyroid tumors, uterine tumors, and soft tissue sarcomas.
The présent invention further provides methods of a blood disorder selected from Acute lymphoblaslic leukemia (ALL), Acute myeloid leukemia (AML) (e.g., acute promyelocytic leukemia, APL), Amyloidosis, Anémia, Aplastic anémia, Bone marrow failure syndromes, Chronic lymphocytic leukemia (CLL), Chronic myeloid leukemia (CML), Deep vein thrombosis (DVT), Diamond-Blackfan anémia, Dyskeratosis congenita (DKC), Eosinophilie disorder, Essential thrombocythemia. Fanconi anémia, Gaucher disease, Hemochromatosis, Hemolytic anémia, Hemophîlia, Flereditary spherocytosis, Hodgkin’s lymphoma, Idiopathîc thrombocytopénie purpura (ITP), Inherited bone marrow failure syndromes, Iron-deficiency anémia, Langerhans cell histiocytosis, Large granular lymphocytîc (LGL) leukemia, Leukemia, Leukopenia, Mastocytosis, Monoclonal gammopathy, Multiple myeloma, Myelodysplastic syndromes (MDS), Myelofibrosis, Myeloproliferative neoplasms (MPN), Non-Hodgkin’s lymphoma, Paroxysmal noctumal hemoglobinuria (PNH), Pemicious anémia (B 12 deficiency), Polycythemia vera, Porphyria, Posttransplant lymphoproliférative disorder (PTLD), Puimonary embolism (PE), Shwachman-Diamond syndrome (SDS), sickle cell disease (SCD), Thalassemia (e.g., β-thalassemîa), Thrombocytopenia, Thrombotic thrombocytopénie purpura (TTP), Venons thromboembolism. Von Willebrand disease, and Waldenstrom’s macroglobulinemia (lymphoplasmacytic lymphoma).
The présent invention further provides methods of treating sickle cell disease (SCD) oi β-thalassemia. The method comprises administering to a patient in need thereof an effective amount of the compound of Formula I.
The présent invention further provides methods of treating thoracic aortic aneurysm, coronary heart disease, stenotic disease, puimonary artery hypertension (PAH), liver fibrosis, allergie inflammation, retinitis pigmentosa, septic shock, herpes simplex virus, human cytomégalovirus, a-thalassemia, familial atrial fibrillation, common variable immunodeficiency, aneurysm-osteoarthritis syndrome, and acquired immunodeficiency syndrome. The method comprises administering to a patient in need thereof an effective amount of the compound of Formula I.
The présent invention further provides use of a compound of Formula 1 for treating a disease or disorder associated with the modulation of embryonic ectoderm development (EED).
The présent invention further provides use of a compound of Formula I for treating a disease or disorder associated with the modulation of Polycomb Répressive Complex 2 (PRC2).
The présent invention further provides a compound of Formula I for use in the manufacture of a médicament for treating a disorder or disease associated with embryonic ectoderm development (EED).
The présent invention further provides a compound of Formula I for use in the manufacture of a médicament for treating a disorder or disease associated with Polycomb Répressive Complex 2 (PRC2).
Detailed Description of the Invention
EED médiates repression of gene activity by binding to di- and trimethylated lysine 27 of histone 3 where it allosterically activâtes the methyltransferase activity of PRC2, fonctions to recruit PRC1 to H3K27me3 loci, enhances PRC1 medîated H2A ubiquitin E3 ligase activity and régulâtes PRC2 in the silencing of expression of genes and gene clusters involved în development, Le., Hox genes, and in X chromosome inactivation. Thus, EED and/or PRC2 provides a pharmacological target for the diseases or disorders, including cancers, to impact transcription.
Hemoglobin is the critical protein involved in oxygen transport throughout the body of vertebrates. It is found in red blood cells and consists of two a subunits and two β subunits. The composition of hemoglobin is developmentally regulated where the human genome encodes multiple versions of these pro teins that are expressed during distinct stages of development (Blobel étal., Exp. Hematol. 2015, incorporated herein by référencé; Stamatoyannopoulos G, Exp. Hematol. 2005, incorporated herein by reference). In general, fêtai hemoglobin (HbF) is composed of two subunits of hemoglobin γ (ΗΒγ) and two subunits of hemoglobin a (HBa) and adult hemoglobin (HbA) is composed of two subunits of hemoglobin β (ΗΒβ) and two subunits of HBa. Thus, the β subumt utilized during the fêtai stage of development is (ΗΒγ) and switches to hemoglobin β (ΗΒβ) after birth. Red blood cell disorders like sickle cell disease (SCD) and β-thalassemias are caused by alterations within the gene for the hemoglobin β (ΗΒβ) subunit. SCD is an autosomal récessive disease caused by a single mutation in both copies of the HBB gene (E6V). A fêtai ortholog of ΗΒβ, hemoglobin γ (ΗΒγ) can reverse disease-related pathophysiology in these disorders by also forming complexes with the required hemoglobin a subunit (Paikari and Sheehan, Bi. J. Haematol. 2018, incorporated herein by reference; Lettre and Bauer, Lancet 2016, incoiporated herein by reference). Because β-like globin expression is developmentally regulated, with a réduction in the fêtai ortholog (γ) occumng shortly after birth concomitantly with an increase in the adult ortholog (β), it has been postulated that maintaining expression of the anti-sickling γ ortholog may be of therapeutic benefit in children and adults.
The developmental régulation of the expression of β-like subunits has been the focus of intense studies for décades (Li et al. Blood 2002, incoiporated herein by reference). Ail five β-like subunits in humans résidé on chromosome 11 where their genomic location corresponds to their temporal expression pattern. A distal cluster of enhancer éléments, called the locus control région (LCR), coordinates the expression pattern at the β globin locus where multiple transcription factors including GATAI, GATA2, KLF1, KLF2, and MYB and T ALI bind at spécifie locations within the LCR at spécifie times in development. The five human β-like subunits are epsilon {HBE1\ ε), gammaG (HBG2-, γ), gammaA (HBGl; γ), delta (HBD; O) and beta (HBB; β). HBEI is expressed during embryonic development, HBGl and HBG2 are expressed during fêtai development, and HBD and HBB are expressed in adults. The HBGl and HBG2 genes encode identical proteins except for a single amino acid change at residue 136 (HBGÎ = gly; HBG2 = ala). Functionally, however, upregulation of either gene can compensate for mutant or defect adult ΗΒβ.
Sickle cell disease (SCD) is caused by homozygous mutations in the HBB gene product (E6V) that results in a mutant hemoglobin protein (HbS). Under deoxygenated conditions, the HbS protein polymerizes which leads to abnonnal red blood cell morphology. This abnormal morphology can lead to multiple pathologie symptoms including vaso-occlusion, pain crises, pulmonary hypertension, organ damage, and stroke. Expression of the fêtai hemoglobin protein can reverse the SCD pathophysiology through inhibiting HbS polymerization and moiphologically defective red blood cells. SCD affects millions of pcopie worldwide and is the most common inherited blood disorder in the United States (70,000-80,000 Americans). SCD has a high incidence in African Americans where it is estimated to occur in 1 in 500 individuals. β-thalassemia is caused by mutations in the HBB gene and is the resuit of reduced hemoglobin production. The mutations in the HBB gene typically reduce the production of adult β-globin protein which leads to low leveis of adult hemoglobin. HbA. This leads to a shortage of red blood cells and a lack of oxygen distribution throughout the body. Patients with β-thalassemias can hâve weakness, fatigue and are at risk of developing abnonnal blood clots. Thousands of infants are bom with β—thalassemia each year where symptoms are typically detected within the first two years of liie. Ί he identification of factois that regulate the expression of fêtai hemoglobin could be useful targets for the treatment of SCD and β—thalassemias as upregulation of fêtai hemoglobin could compensate for mutant HbS protein in SCD or a lack of HbA in β-thalassemias.
Based on clinical and preclinical studies, upregulation of hemoglobin γ (ΗΒγ) is the proposed mechanism for compounds including Palmolidomide and Hydroxyurea and targets including EHMT1/EHMT2 and LSD1 (Moutouh-de Parseval étal. J. Clin. Invest. 2008, incorporated herein by reference; Letvin et al. NEJM 1984, incorporated herein by reference; Renneville et al. Blood 2015, incorporated herein by reference; Shi et al. Nature Med. 2015, incorporated herein by reference). We discovered that treatment with inhibitors of Polycomb Répressive Complex 2 (PRC2) lùnction through targeting the EED subunit leads to ΗΒγ upregulation.
The PRC2 complex is an evolutionarily conserved multi-subunit chromatin regulatory complex that functîons in repression of gene expression (Margueron and Reinberg, Nature 2011, incorporated herein by reference). The four core PRC2 subunits are EED, SUZ12, RbAp48 and EZH1 or EZH2. EZH1 and EZH2 contain methyltransferase activity and catalyze trimethylation of lysine 27 on histone H3 (H3K27roe3). The EED subunit can bind to the H3K27me3 mark and stimulate EZH2 methyltransferase activity. Additional subunits can associate with P RC 2 that may impact complex localisation on chromatin in spécifie régions of the genome which leads to the formation of H3K27me3-marked chromatin domains. The déposition of the H3K27me3 modification is typically associated with the repression of gene expression.
The présent invention provides, inter alia, modulators of EED and/or PRC2, and prophylactic measures to treat diseases and disorders associated with EED and/or PRC2.
In a First aspect, the invention provides compounds of Formula I:
and pharmaceutically acceptable salts, prodrugs, solvatés, hydrates, enantiomers, isomers, and tautomers thereof, wherein Xi, X2, X3, Ai, A2, Y, Ri, Rj, Rs; and R4 are as described above. The details of the invention are set forth in the accompanying description below. Although méthode and materials similar or équivalent to those described herein can be used in the practice or testing of the présent invention, illustrative methods and materials are now described. Other features, objects, and advantages of the invention will be apparent from the description and from the daims. In the spécification and the appended daims, the singular forms also include the plural unless the context dearly dictâtes otherwise. Unless defïned otherwise, ail technical and scientific terms used herein hâve the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. AH patents and publications cited in this spécification are încorporated herein by reference in their entireties.
Définitions
The articles a and an are used in this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article. By way of example, an element means one élément or more than one element.
The tenu and/or is used in this disclosure to mean either and or or unless indicated otherwise.
The tenu “optionally substituted” is understood to mean that a given Chemical moiety (e.g., an alkyl group) can (but is not required to) be bonded to other substituents (e.g., heteroatoms). For instance, an alkyl group that is optionally substituted can be a fully saturated alkyl chain (e.g., a pure hydrocarbon). Altematively, the saine optionally substituted alkyl group can hâve substituents different from hydrogen. For instance, it can, at any point along the chain be bounded to a halogen atom, a hydroxyl group, or any other substituent described herein. Thus the tenu “optionally substituted” means that a given Chemical moiety has the potential to contain other fiinctional groups, but does not necessarily hâve any further fiinctional groups. Suitable substituents used in the optional substitution of the described groups include, without limitation, halogen, oxo, CN, -COOH, -CH2CN, -O-Ci-C6 alkyl, CrC6alkyl, -OC2-C6 alkenyl, -OC2-C6 alkynyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -OH, -OP(O)(OH)Z, -OC(O)Ci-C6 alkyl, -C(O)C(-C6 alkyl, -OC(O)OCrC6 alkyl, NH2, NH(Ci-C6 alkyl), N(Ci-C6 alkyl)2, -NHC(O)Ci-C6alkyl, -C(O)NHCrC6 alkyl, -S(O)2-Ci-C6 alkyl, S(O)NHCi-C6 alkyl, and S(O)N(Ci-C6 alkyl)2.
Unless otherwise specifically defined, the terni aryl reiers to cyclic, aromatic hydrocaibon gioups that hâve 1 to 2 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl. Where containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl). The aryl group may be optionally substituted by one or more substituents, e.g., 1 to 5 substituents, at any point of attachment. Exemplary substituents include, but are not limited to, -H, -halogen, -O-Ci-C6 alkyl, Cr C6 alkyl, -OC2-C6 alkenyl, -OC2-C6 alkynyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -OH, -OP(O)(OH)2, OC(O)C,-C6 alkyl, -C(O)CrC6 alkyl, -OC(O)OCi-C6 alkyl, NH2, NH(Ci-C6 alkyl), N(CrC6 alkyl)2, -S(O)2-Ci-C6alkyl, -S(O)NHCrC6alkyl, and S(O)N(CrC6 alkyl)2. The substituents can themselves be optionally substituted. Furthermore when containing two fused rings the aryl groups herein defined may hâve an unsaturated or partially saturated ring fused with a fully saturated ring. Exemplary ring Systems of these aryl groups include indanyl, indenyl, tetrahydronaphthalenyl, and tetrahydrobenzoannulenyl.
Unless otherwise specifically defined, heteroaryl means a monovalent monocyclic aromatic radical of 5 to 10 ring atoms or a polycyclic aromatic radical, containing one or more ring heteroatoms selected from N, O, or S, the remainîng ring atoms being C. Heteroaryl as herein defined also means a bicyclic heteroaromatic group wherein the heteroatom is selected from N, O, or S. The aromatic radical is optionally substituted independently with one or more substituents described herein. Examples include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl, benzopyranyl, thiazolyl, and dérivatives thereof. Furthermore when containing two fused rings the aryl groups herein defined may hâve an unsaturated or partially saturated ring fused with a fully saturated ring. Exemplary ring Systems of these heteroaryl groups include indolinyl, indolinon yl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, and dihydrobenzoxanyl.
Halogen or “halo” refers to fluorine, chlorine, bromine and iodine.
Alkyl refers to a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms. Examples of a CkCô alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.
“Alkoxy” refers to a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms containing a terminal “O” in the chain. Examples of alkoxy groups include without limitation, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups.
“Alkenyl” refers to a straight or branched chain unsaturated hydrocarbon containing 2-12 carbon atoms. The “alkenyl” group contains at least one double bond in the chain. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, iso-butenyl, pentenyl, or hexenyl.
“Alkynyl” refers to a straight or branched chain unsaturated hydrocarbon containing 2-12 carbon atoms. The “alkynyl” group contains at least one triple bond in the chain. Examples of alkenyl groups include ethynyl, propargyl, n-bulynyl, iso-butynyl, pentynyl, or hexynyl.
The tenu “haloalkyl” as used herein refers to an alkyl group, as deiined herein, which is substituted one or more halogen. Examples of haloalkyl groups include, but are not limited to, tri fluorom ethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc.
“Cycloalkyl” means monocyclic or bicyclic saturated carbon rings containing 3-1S carbon atoms. Examples of cycloalkyl groups include, without limitations, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norboranyl, norborenyl, bicyclo[2.2.2]octanyl, bicyclo[ 1.1.1 ]pentyl, or bicyclo[2.2,2]octenyl, “Heterocyclyl” or “heterocycloalkyl” means a monocyclic or polycyclic radical of 3 to 24membered ring containing carbon and heteroatoms taken from containing one or more ring heteroatoms selected from N, O, S, P, or B and wherein there is not delocalized π électrons (aromaticity) shared among the ring carbon or heteroatoms. Heterocyclyl rings include, but are not limited to, oxetanyl, azetadinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyi, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, and homotropanyl. In accordance with the présent invention, heterocyclyl refers to saturated or partially saturated non aromatic rings structures in which there is at least one heteroatoms selected from the group N, O, or S. In some embodiments,
O
S
H the one or more heteroatoms in the heterocyclyl are presented at an oxidated State (e.g., ο
II •S °W°
Jsi.
' , or ^)“Spirocycloalkyl” or “spirocyclyl” means carbogenic bicyclic ring Systems with both rings connected through a single atom. The ring can be different in size and nature, or identical in size and nature. Examples include spiropentane, spriohexane, spiroheptane, spirooctane, spîrononane, or spirodecane. One or both of the rings in a spirocycle can be fused to another carbocychc, heterocyclic, aromatic, or heteroaromatic ring. One or more of the carbon atoms in the spirocycle can be substituted with a heteroatom (e.g., O, N, S, or P). A (C5-C12) spirocycloalkyl is a spirocycle containing between 5 and 12 carbon atoms. One or more of the carbon atoms can be substituted with a heteroatom.
The term “spiroheterocycloalkyl” or “spiroheterocyclyl” is understood ίο mean a spirocycle wherein at least one of the atoms in one of the rings is a heteroatom. In some embodiments, at least one of the atoms in one of the rings is O, N, S, or P.
The term “oxo” as used herein refers to an “=O” group.
The terni solvaté refers to a complex of variable stoichiometry formed by a soluté and solvent. Such solvents for the purpose of the invention may not interfère with the biological activity of the soluté. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvatés wherein water is the solvent molécule are typically refeired to as hydrates. Hydrates include compositions containing stoichîometric amounts of water, as well as compositions containing variable amounts of water.
The term isomer refers to compounds that hâve the same composition and molecular weight but differ in physical and/or Chemical properties. The structural différence may be in constitution (géométrie isomers) or in the ability to rotate the plane of poiarized light (stereoîsomers). With regard to stereoîsomers, the compounds of Formula I may hâve one or more asymmetric atom and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers. The terni stereoisomer may also encompass atropisomers, which anse from hindered rotation about a single bond, e.g., in compounds having a substituted biphenyl moiety.
The disclosure also inciudes pharmaceutical compositions comprising an effective amount of a disclosed compound and a pharmaceutically acceptable carrier. Représentative pharmaceuticaliy acceptable salts înclude, e.g., water-soluble and water-insoluble salts, such as the acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzonate, bicarbonate, bisulfate, bîtartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fiunarate, gluceptate, gluconatc, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, magnésium, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium sait, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (l,l-methene-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate, phosphate/diphosphate, picrate, polygalacturonate, propionate, p-toiuenesulfonate, salicylate, stéarate, subacetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts.
A patient or “subject” is a manimal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-hunian primate, such as a monkey, chimpanzee, baboon or rhésus.
An effective amount when used in connection with a compound is an amount effective for treating or preventing a disease in a subject as described herein.
The tenu canrier, as used in this disclosure, encompasses carriers, excipients, and diluents and means a material, composition or vehicle, such as a liquid or solîd filler, diluent, excipient, solvent or encapsulâting material, involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a subject.
The tenu treating with regard to a subject, refers to improving at least one symptom of the subject’s disorder. Treating inciudes curing, improving, or at least partially ameliorating the disorder.
The tenu disorder is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.
The terni adminîster, administering, or administration as used in this disclosure refers to either directly administering a disclosed compound or pharmaceutically acceptable sait of the disclosed compound or a composition to a subject, or administering a prodrug dérivative or analog of the compound or pharmaceutically acceptable sait of the compound or composition to the subject, which can form an équivalent amount of active compound within the subject's body.
The terrn prodrug, as used in this disclosure, means a compound which is convertible in vivo by metabolic means (e.g., by hydrolysis) to a disclosed compound.
In one embodiment, X, is N or C(RS). In one embodiment, X, is N. In one embodiment, Xj is C(R5). In one embodiment, X2 is N. In one embodiment, X2 is C(R5). In one embodiment, Xj is N. In one embodiment, X3 is C(R$).
In one embodiment, Aj is a bond, —C(R8)(R9)—, -O-, —NR8-, —S—, —S(O)—, oi -SO2-.
In one embodiment, A2 and Y are independently at each occurrence -C(R8)(R9)~, -O- -NR8-, or SO2~.
In one embodiment, Ai is —C(Rs)(Ro)—, -O-, —NR8-, —S-, -S(O)-, or — SO2-. In one embodiment, Ai is a bond. In one embodiment, Ai is -C(R8)(R9)- or -O-. In one embodiment, Ai is -C(R8)(R9)-. In one embodiment, Ai is—O—. In one embodiment, A] is —NR8—. In one embodiment, Aj is —S—. In one embodiment, Aj is -S(O)-. In one embodiment, Ai is -SO2-.
In one embodiment, A2 is —C(R8)(R9)—, — O—, — NR8—, or —SO2—. In one embodiment, A2 is — C(R8)(R9)- or -O-, In one embodiment, A2 is -C(R8)(R9)-- In one embodiment, A2 is-O-. In one embodiment, A2 is -NR8-. in one embodiment, A2 is -S-. In one embodiment, A2 is -S(O)-. In one embodiment, A2 is -SO2-.
In one embodiment, Y is -C(R8)(R9)-, -O-, -NR8-, or -SO2-. In one embodiment, Y is C(R8)(R9)- or -O-. In one embodiment, Y is -C(R8)(R9)-. In one embodiment, Y is-O-. In one embodiment, Y is -NR8- In one embodiment, Y is -S-. In one embodiment, Y is -S(O)-. In one embodiment, Y is -SO2-.
In one embodiment, Ri is H, halogen, -NR8R9, -P(O)(OR8)(OR9), -C(O)R$, -C(O)NR8R9, -CN, CiC6 alkyl, CrC6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C5-C8 cycloalkenyl, C3-C8 spirocycloalkyl, spiroheterocyclyl, heterocyclyl, aryl, or heteroaryl. In one embodiment, Ri is H. In one embodiment, Ri is —NR8R9. In one embodiment, Ri is -P(OR8)(OR9). In one embodiment, Ri is-C(O)R8. In one embodiment, Ri is-C(O)NR8R9. In one embodiment, Ri is -CN. In one embodiment, Ri is CrC6 alkyl. In one embodiment, Rj is CrC6 alkoxy. In one embodiment, Ri is C2-C6 alkenyl. In one embodiment, R( is C2-C6 alkynyl. In one embodiment, Ri is C3-C10 cycloalkyl. In one embodiment, Ri is Cs-Cs cycloalkenyl. In one embodiment, Ri is C3-C8 spirocycloalkyl. In one embodiment, Ri is spiroheterocyclyl. In one embodiment, Ri is heterocyclyl. In one embodiment, R| is aryl. In one embodiment, Ri is heteroaryl.
In one embodiment, R, is CrC& alkyl is optionally substituted with one or more R6. In one embodiment, Ri is CrC6 alkoxy is optionally substituted with one or more R6. In one embodiment, R, is C-r-Ch alkenyl is optionally substituted with one or more R(,. In one embodiment, Ri is C2-C6 alkynyl is optionally substituted with one or more R6. In one embodiment, Ri is Cj-Cio cycloalkyl is 5 optionally substituted with one or more R6. In one embodiment, Ri is C5-C8 cycloalkenyl is optionally substituted with one or more R6. In one embodiment, Ri is C3-C8 spirocycloalkyl is optionally substituted with one or more R6. In one embodiment, R] is spiroheterocyclyl is optionally substituted with one or more R6. In one embodiment, Ri is heterocyclyl is optionally substituted with one or more Ré· In one embodiment, Ri is aryl is optionally substituted with one or more R&10 In one embodiment, R] is heteroaryl is optionally substituted with one or more Rq.
In another embodiment, Ri is ,O
In one embodiment, Ri is 4 ,
In one embodiment, R2 is independently at each occurrence H, halogen, -OH, -NH2, -CN, CrC6 alkyl, C(-C6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl. In one embodiment, R2 is H. In one embodiment, R2 is halogen. In one embodiment, R2 is -OH. In one embodiment, R2 is -NH2. In one embodiment, R2 is -CN. In one embodiment, R2 is CrC6 alkyl. In one embodiment, R2 is Ci-Cs alkoxy. In one embodiment, R2 is C2-Cé alkenyl. In one embodiment, R2 is C2-Cé alkynyl.
In one embodiment, R2 is CrC6 alkyl optionally substituted with one or more R7. In one embodiment, R2 is CrC6 alkoxy optionally substituted with one or more R7. In one embodiment, R2 is C2-C6 alkenyl optionally substituted with one or more R7. In one embodiment, R2 is C2-C6 alkynyl optionally substituted with one or more R7.
In one embodiment, R3 is independently at each occurrence H, halogen, -OH, -NH2, -CN, CpCé alkyl, CrC6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl. In one embodiment, R3 is H. In one embodiment, R3 is halogen. In one embodiment, R3 is -OH. In one embodiment, R3 is -NH2. In one embodiment, R3 is -CN. In one embodiment, Rj is Ci-C6 alkyl. In one embodiment, R3 is CrC6 alkoxy. In one embodiment, R3 is C2-C6 alkenyl. In one embodiment, R3 is C2-C6 alkynyl.
in one embodiment, R3 is CrC6 alkyl optionally substituted with one or more R7. In one embodiment, R3 is CrC6 alkoxy optionally substituted with one or more R7. In one embodiment, R3 is C2-Cé alkenyl optionally substituted with one or more R7. In one embodiment, R3 is C2-Cà alkynyl optionally substituted with one or more R7.
In one embodiment, R4 is independently at each occurrence H, halogen, -OH, -NH2, -CN, Cj-Ce alkyl, CrC6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl. In one embodiment, Ri is H. In one embodiment, R4 is halogen. In one embodiment, R4 is -OH. In one embodiment, R4 is -NH2. In one embodiment, R4 is -CN. In one embodiment, R4 is CrC6 alkyl. In one embodiment, R4 is C]-C6 alkoxy. In one embodiment, R4 is C2-Cè alkenyl. In one embodiment, R4 is C2-Cè alkynyl.
In one embodiment, R4 is CrC6 alkyl optionally substituted with one or more R7. In one embodiment, R4 is CrC6 alkoxy optionally substituted with one or more R7. In one embodiment, R4 is C2-C6 alkenyl optionally substituted with one or more R7. In one embodiment, R4 is C2-C6 alkynyl optionally substituted with one or more R7.
In one embodiment, R4 and R9 can form C3-C10 cycloalkyl, C^-Cs cycloalkenyl, heterocyclyl, atyl, or heteroaryl. In one embodiment, R4 and R9 can form C3-C10 cycloalkyl, Cj-Cg cycloalkenyl, heterocyclyl, aryl, or heteroaryl, wherein the cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more RioIn one embodiment, R4 and R9 can form C3-C10 cycloalkyl. In one embodiment, R4 and R9 can form C5-Cg cycloalkenyl. In one embodiment, R4 and R9 can fonn heterocyclyl. In one embodiment, R4 and R9 can form aryl. In one embodiment, R4 and R9 can form heteroaryl.
In one embodiment, R4 and R9 can form C3-C10 cycloalkyl optionally substituted with one 01 more Rio. In one embodiment, R4 and R9 can form C5-C8 cycloalkenyl optionally substituted with one or more Ri0. In one embodiment, R4 and R9 can form heterocyclyl optionally substituted with one or more Rio. In one embodiment, R4 and Ro can form aryl optionally substituted with one or more Rio· In one embodiment, R4 and R9 can form heteroaryl optionally substituted with one or moie Rio.
In one embodiment, R5 is H, halogen, -CN, —OR8, —NR8R9, —C(O)Rg, —C(O)OR8, —C(O)NRgR9, — NRSC(O)R9, -S(O)Rg, -S(O)2R8, -NR8S(O)2R9, -S(O)2NR8R9, Ci-Q, alkyl, CrC6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R7.
In one embodiment, R5 is H, halogen, —CN, —OR8, -NR8R9, -C(O)Rg, -C(O)OR8, —C(O)NR8R9, — NR8C(O)R9, -S(O)R8, -S(O)2R8, -NR8S(O)2R9i -S(O)2NR8R9, CrC6 alkyl, CrC6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C]o cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl. In one embodiment, R5 is H. In one embodiment, R5 îs halogen. In one embodiment, R 5 is CN. In one embodiment, R5 is - OR8. In one embodiment, R5 is -NR8R9. In one embodiment, R5 is -C(O)R8. In one embodiment, R 5 is —C(O)OR8. In one embodiment, R 5 is —C(O)NR8R9. In one embodiment, R5 is -NR8C(O)R9. In one embodiment, R5 is -S(O)Rs- In one embodiment, Rs is -S(O)2R8 In one embodiment, R5 is -NR8S(O)2R9- hr one embodiment, R5 is -S(O)2NR8R9. In one embodiment, R5 is CrC6 alkyl. In one embodiment, R5 is CrC6 haloalkyl. In one embodiment, R5 îs C2-C6 alkenyl. In one embodiment, R5 is C2-C6 alkynyl. In one embodiment, Rs is C3-C10 cycloalkyl. In one embodiment, Rs is C5-C8 cycloalkenyl. In one embodiment, R5 is heterocyclyl. In one embodiment, R5 is aryl. In one embodiment, R 5 is heteroaryl.
In one embodiment, R5 is C^Cô alkyl, Ci-Cé haloalkyl, C2-Cé alkenyl, or Cz-Cg alkynyl.
In one embodiment, R5 is CrC6 alkyl. In one embodiment, R5 is methyl. In one embodiment, R5 is ethyl. In one embodiment, R5 is propyl. In one embodiment, R5 is butyl. In one embodiment, Rs is pentyl. In one embodiment, R3 is hexyl.
In one embodiment, R5 is CrC6 alkyl optionally substituted with one or more R7. In one embodiment, R5 is methyl optionally substituted with one or more R7. In one embodiment, R5 is ethyl optionally substituted with one or more R7. In one embodiment, Rs is propyl optionally substituted with one or more R7. In one embodiment, R5 is butyl optionally substituted with one oi more R7. In one embodiment, R5 is pentyl optionally substituted with one or more R7. In one embodiment, R5 is hexyl optionally substituted with one or more R7.
In one embodiment, R5 is CrC6 haloalkyl. In one embodiment, R5 is halomethyl. In one embodiment, R5 is haloethyl. In one embodiment, R5 is halopropyl. In one embodiment, R5 is halobutyl. In one embodiment, R5 is halopentyl. In one embodiment, R5 is halohexyl.
In one embodiment, R5 is C2-C6 alkenyl. In one embodiment, R5 is C2-C6 alkynyl.
In one embodiment, R5 is C2-C6 alkenyl optionally substituted with one or more R7- In one embodiment, R5 is C2-C6 alkynyl optionally substituted with one or more R7.
In one embodiment, R 5 is C3-C10 cycioalkyl or Cs-Cg cycloalkenyl.
In one embodiment, R 5 is C3-Cio cycioalkyl or Cs-Cg cycloalkenyl, wherein the cycioalkyl or cycloalkenyl is optionally substituted with one or more R7.
In one embodiment, R5 is C3-Ci0 cycioalkyl. In one embodiment, R5 is monocylic C3-Ci0 cycioalkyl. In one embodiment, R 5 is bicyclic C3-Cjg cycioalkyl. In one embodiment, R5 is polycyclic C3-Cjq cycioalkyl.
In one embodiment, R5 is C3-Ci0 cycioalkyl optionally substituted with one or more R7. In one embodiment, R5 is monocylic C3-C!0 cycioalkyl optionally substituted with one or more R7. In one embodiment, R5 ls bicyclic C3-C10 cycioalkyl optionally substituted with one or more R7. In one embodiment, R5 is polycyclic C3-C10 cycioalkyl optionally substituted with one or more R7.
In one embodiment, R5 is C5-Cg cycloalkenyl. In one embodiment, R5 is heterocyclyl, aryl, or heteroaryl. In one embodiment, R5 is heterocyclyl. In one embodiment, R5 is aryl. In one embodiment, R5 is phenyl.
In one embodiment, R5 is C5-Cs cycloalkenyl optionally substituted with one or more R7. In one embodiment, R5 is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R7. In one embodiment, R5 is heterocyclyl optionally substituted with one or more R7. In one embodiment, R5 is aryl optionally substituted with one or more R7. In one embodiment, R5 is phenyl optionally substituted with one or more R7.
In one embodiment, R5 is heteroaryl. In one embodiment, R5 is pyridine. In one embodiment, R5 is imidazolyl. In one embodiment, R5 is pyrazolyl. In one embodiment, R 5 is pyrimidinyl.
In one embodiment, Rs is heteroaryl optionally substituted with one or more R7. In one embodiment, R5 is pyridine optionally substituted with one or more R7. In one embodiment, R5 is imidazolyl optionally substituted with one or more R7. In one embodiment, R5 is pyrazolyl optionally substituted with one or more R7. In one embodiment, R5 is pyrimidinyl optionally substituted with one or more R7.
In one embodiment, R5 is -CF3. In one embodiment, R5 is -CHF2. In one embodiment, R5 is -CH2F. In one embodiment, R6 is independently at each occurrence oxo, halogen, -CN, OH, -NRSR9, -OR8, -C(O)R8, -C(O)ORb, - C(O)NR8R9, -NR8C(O)R9, -S(O)R8, -S(O)2R8, -NR8S(O)2R9, -S(O)2NR8R9, CrC6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl. In one embodiment, R6 is oxo. In one embodiment, R6 is halogen. In one embodiment, R6 is CN. In one embodiment, R6 is OH. In one embodiment, Re is -NR8R9. In one embodiment, R6 is -OR8. In one embodiment, R6 is -NR8R9. In one embodiment, R6 is -C(O)Rg. In one embodiment, R6 is C(O)OR8. In one embodiment, R6 is -C(O)NR8R9. In one embodiment, R6 is -NR8C(O)R9. In one embodiment, R6 is -S(O)R8. In one embodiment, R6 is -S(O)2Rg In one embodiment, R6 is NR8S(O)?R9. In one embodiment, R9 is —S(O)2NR8R9. In one embodiment, Rô is Cj-C& alkyl. In one embodiment. R6 is Cl-C6 haloalkyl. In one embodiment, R6 is C2-C0 alkenyl. In one embodiment, R6 is C2-C6 alkynyl. In one embodiment, R6 is C3-Cio cycloalkyl. In one embodiment, Rtj is C5-C8 cycloalkenyl. In one embodiment, R9 is heterocyclyl. In one embodiment, Re is aryl. In one embodiment, R^ is heteroaryl.
In one embodiment, R6 is CrC6 alkyl optionally substituted with one or more Rio- In one embodiment, R6 is CrC6 haloalkyl optionally substituted with one or more Rio- In one embodiment, R6 is C2-C0 alkenyl optionally substituted with one or more Rio- In one embodiment, R6 is C2-C6 alkynyl optionally substituted with one or more Rw. In one embodiment, R6 is C3-C(û cycloalkyl optionally substituted with one or more R[0. In one embodiment, R6 is C5-C8 cycloalkenyl optionally substituted with one or more Rio- In one embodiment, R6 is heterocyclyl optionally substituted with one or more R10. In one embodiment, R8 is aryl optionally substituted with one or more Ri0. In one embodiment, R6 is heteroaiyl optionally substituted with one or more RwIn another embodiment, two Rs may combine to form C3-Cio cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl. In another embodiment, two R6 may combine to form C3-Ci0 cycloalkyl. In another embodiment, two R& may combine to form Cs-C8 cycloalkenyl. In another embodiment, two R6 may combine to form a heteroaryl. In another embodiment, two R6 may combine to form a heterocyclyl. In another embodiment, two R& may combine to form an aryl. In another embodiment, two Rô may combine to form C3-C10 cycloalkyl, wherein the cycloalkyl is optionally substituted with one or more Rio. In another embodiment, two R6 may combine to form C5-Cs cycloalkenyl, wherein the cycloalkenyl is optionally substituted with one or more R|0. In another embodiment, two K, may combine to form a heteroaryl, wherein the heteroaryl is optionally substituted with one or more R|0. In another embodiment, two R6 may combine to fonn a heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more Rio. In another embodiment, two R6 may combine to fonn an aryl wherein the aryl is optionally substituted with one or more Rio.
In one embodiment, R7 is independently at each occurrence oxo, halogen, -CN, -ORg, -C(O)R8, C(O)ORH, - C(O)NR8R% -NR8C(O)R9, -S(O)R8, -S(O)2R8j -NR8S(O)2R9, —S(O)2NR8R9, CrC6 alkyl, CrC6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-Cg cycloalkyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, R7 is independently at each occurrence oxo, halogen, or -CN. In one embodiment, R7 is oxo. In one embodiment, R7 is halogen. In one embodiment, R7 is F, Cl, Br, or I. In one embodiment, R7 is F or Cl. In one embodiment, R7 is F. In one embodiment, R7 is Cl. In one embodiment, R7 is -CN.
In one embodiment, R7 is independently at each occurrence -OR8, -C(O)RS, -C(O)OR8, C(O)NR8R9, -NR8C(O)R9, -S(O)R8, -S(O)2R8, -NR8S(O)2R9, or-S(O)2NR8R9. In one embodiment, R7 is -OR8. In one embodiment, R7 is -C(O)R8. In one embodiment, R7 is -C(O)OR8. In one embodiment, R7 is -C(O)NR8R9. In one embodiment, R7 is -NR8C(O)R9. In one embodiment, R7 is -S(O)R8. In one embodiment, R7 is -S(O)2R8. In one embodiment, R7 is -NR8S(O)2R9. In one embodiment, R7 is -S(O)2NR8R9.
In one embodiment, R7 is independently at each occurrence Ci-C6 alkyl, CrC6 haloalkyl, C2-C6 alkenyl, or C2-Cô alkynyl.
In one embodiment, R7 is CrC6 alkyl. In one embodiment, R7 is methyl. In one embodiment, R7 is ethyl. In one embodiment, R7 is propyl. In one embodiment, R7 is butyl. In one embodiment, R7 is pentyl. In one embodiment, R7 is hexyl.
In one embodiment, R7 is Cj-C^ haloalkyl. In one embodiment, R7 is halomethyl. In one embodiment, R7 is haloethyl. In one embodiment, R7 is halopropyl. In one embodiment, R7 is halobutyl. In one embodiment, R7 is halopentyl. In one embodiment, R7 is halohexyl.
In one embodiment, R7 is C2-C6 alkenyl. In one embodiment, R7 is C2-Cô alkynyl.
In one embodiment, R7 is independently at each occurrence C3-C8 cycloalkyl or heterocyclyl. In one embodiment, R7 is C3-Cg cycloalkyl. In one embodiment, R7 is heterocyclyl.
In one embodiment, R7 is independently at each occurrence aryl or heteroaryl. In one embodiment, R7 is aryl. In one embodiment, Ry is heteroaryl.
In one embodiment, Rs is independently at each occurrence H, OH, halogen, CrC6 alkyl, CrC6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Rio.
In one embodiment, R9 is independently at each occurrence H, halogen, CrC6 alkyl, Ci-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Rio.
In one embodiment, R8 and R9 are independently at each occurrence H, CrC6 alkyl, Ci-C6 alkoxy, CrC6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, Rg and R« are independently at each occurrence H.
In one embodiment, Rs and R9 are independently at each occurrence CrC6 alkyl, Ci-C6 alkoxy, C2Cf, alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, R8 and R9 are independently at each occurrence CrC6 alkyl, CrC6 alkoxy, C2C6 alkenyl, C2-C(, alkynyl, C3-Cs cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Rio.
In one embodiment, Rs is independently at each occurrence H, halogen, CrC6 alkyl, Ci-Cs alkoxy, C2-C& alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more RioIn one embodiment, R8 is independently at each occurrence H, Ci-C6 alkyl, Ci-C6 alkoxy, C2-C6 alkenyl, C2-Ce alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, R8 is H.
In one embodiment, R8 is halogen.
In one embodiment, R8 is independently at each occurrence CpCs alkyl, Ci-Q alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, R8 is independently at each occurrence CrCf, alkyl, C]-Cô alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, CrC8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ricin one embodiment, Rg is independently at each occurrence Ci-C6 alkyl, CrC6 alkoxy, C2-C6 alkenyl or CG-Cc alkynyl.
In one embodiment, Rg is independently at each occurrence CrC6 alkyl, Ci-C6 alkoxy, C2-C6 alkenyl or C2-C6 alkynyl, wherein each alkyl, alkoxy, alkenyl or alkynyl is optionally substituted with one or more RioIn one embodiment, R8 is CrC6 alkyl. In one embodiment, R8 is methyl. In one embodiment, Rg is ethyl. In one embodiment, R8 is propyl. In one embodiment, Rg is butyl. In one embodiment, Rg is pentyl. In one embodiment, R8 is hexyl.
In one embodiment, Rg is CrC6 alkyl optionally substituted with one or more Rw. In one embodiment, Rs is methyl optionally substituted with one or more Rw In one embodiment, Rg is ethyl optionally substituted with one or more Rw. In one embodiment, Rg is propyl optionally substituted with one or more Rio. In one embodiment, Rg is butyl optionally substituted with one or more Rio. In one embodiment, Rs is pentyl optionally substituted with one or more Rw· In one embodiment, Rs is hexyl optionally substituted with one or more RioIn one embodiment, R8 is Ci-C& alkoxy. In one embodiment, Rg is methoxy. In one embodiment, Rg is ethoxy. In one embodiment, R8 is propoxy. In one embodiment, Rg is butoxy. In one embodiment, Rs is pentoxy. In one embodiment, Rg is hexoxy.
In one embodiment, Rg is CrC6 alkoxy optionally substituted with one or more RI0- In one embodiment, R8 is methoxy optionally substituted with one or more Rw. In one embodiment, Rg is ethoxy optionally substituted with one or more Rw· In one embodiment, R8 is propoxy optionally substituted with one or more Rw- In one embodiment, Rg is butoxy optionally substituted with one or more Rw- In one embodiment, R8 is pentoxy optionally substituted with one or more Rw In one embodiment, Rg is hexoxy optionally substituted with one or more RwIn one embodiment, Rg is Cs-Cg alkenyl. In one embodiment, R8 is C2-Cé alkynyl.
In one embodiment, Rg is C2-Câ alkenyl optionally substituted with one or more Rw. In one embodiment, Rg is C2-C6 alkynyl optionally substituted with one or more Rl0.
In one embodiment, Rg is independently at each occurrence Cg-Cg cycloalkyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, Rg is independently at each occurrence C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each C3-Cg cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Rw22
In one embodiment, R8 is C3-C8 cycloalkyl. In one embodiment, Rs is heterocyclyl. in one embodiment, Rs is aryl. In one embodiment, R8 is heteroaryl.
In one embodiment, R8 is C3-C8 cycloalkyl optionaliy substituted with one or more Ri0. In one embodiment, Rs is heterocyclyl optionaliy substituted with one or more R[0. In one embodiment, Rs îs aryl optionaliy substituted with one or more Rio. In one embodiment, R8 is heteroaryl optionaliy substituted with one or more Rtû.
In one embodiment, Ry is independently at each occurrence H, halogen, CrQ alkyl, Ci-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionaliy substituted with one or more Rio.
In one embodiment, Ry is independently at each occurrence H, Cj-Cû alkyl, CrC6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, Ry is H,
In one embodiment, Ry is halogen.
In one embodiment, R9 is independently at each occurrence C1-C0 alkyl, Ci-Cg alkoxy, CS-Cg alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, Ry is independently at each occurrence C]-C6 alkyl, CrC6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionaliy substituted with one or more RioIn one embodiment, Ry is independently at each occurrence Cj-Cg alkyl, Cj-C6 alkoxy, C2-C6 alkenyl or C2-Câ alkynyl.
In one embodiment, Ry is independently at each occurrence C,-C6 alkyl, CrC6 alkoxy, C2-C6 alkenyl or C2-Cg alkynyl, wherein each alkyl, alkoxy, alkenyl, or alkynyl is optionaliy substituted with one or more RmIn one embodiment, R? is CpCa alkyl. In one embodiment, Ry is methyl. In one embodiment, Ry is ethyl. In one embodiment, Ry is propyl. In one embodiment, Ry is butyl. In one embodiment, Ry is pentyl. In one embodiment, R9 is hexyl.
In one embodiment, Ry is Cj-C6 alkyl optionaliy substituted with one or more Ri0. In one embodiment, Ry is methyl optionaliy substituted with one or more Rio· In one embodiment, Ry is ethyl optionaliy substituted with one or more R^. In one embodiment, Ry is propyl optionaliy substituted with one or more R10. In one embodiment, R9 is butyl optionaliy substituted with one or more Rio. In one embodiment, Rg is pentyl optionally substituted with one or moie Rio- In one embodiment, R9 is hexyl optionally substituted with one or more Rio·
In one embodiment, Rg is Ci-C6 alkoxy. In one embodiment, R9 is methoxy. In one embodiment, R9 is ethoxy. In one embodiment, R9 is propoxy. In one embodiment, R9 is butoxy. In one embodiment, R9 is pentoxy. In one embodiment, Rg is hexoxy.
In one embodiment, R9 is CrC6 alkoxy optionally substituted with one or more Rio- In one embodiment, R9 is methoxy optionally substituted with one or more Rw. In one embodiment, R9 is ethoxy optionally substituted with one or more Rio- In one embodiment, R9 is propoxy optionally substituted with one or more Riq. In one embodiment, Rg is butoxy optionally substituted with one or more R10. In one embodiment, R9 is pentoxy optionally substituted with one or more R10. In one embodiment, Rg is hexoxy optionally substituted with one or more Rjq.
In one embodiment, Rg is C2-C6 alkenyl. In one embodiment, Rg is C2-C6 alkynyl.
In one embodiment, R9 is C2-C0 alkenyl optionally substituted with one or more Rio. In one embodiment, Rg is C2-C6 alkynyl optionally substituted with one or more Ri0.
In one embodiment, Rg is independently at each occurrence C3-Cg cycloalkyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, R9 is independently at each occurrence C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Rio.
In one embodiment, R9 is C3-C8 cycloalkyl. In one embodiment, R9 is heterocyclyl. In one embodiment, R9 is aryl. In one embodiment, Rg is heteroaryl.
In one embodiment, Rg is CrC8 cycloalkyl optionally substituted with one or more R|0. In one embodiment, R9 is heterocyclyl optionally substituted with one or more Rio· In one embodiment, R9 is aryl optionally substituted with one or more Ri0. In one embodiment, Rg is heteroaryl optionally substituted with one or more Ri0.
In one embodiment, R8 and R9 when taken together fonn a C3-C6 cycloalkyl or heterocycle, wherein the cycloalkyl or heterocycle is optionally substituted with Rio.
In one embodiment, Rg and Rg when taken together form a C3-C6 cycloalkyl, wherein the cycloalkyl is optionally substituted with Rio- In one embodiment, R8 and R9 when taken together form a C3-C6 cycloalkyl. In one embodiment, R8 and R9 when taken together form cyclopropyl, wherein the cyclopropyl is optionally substituted with Riq. In one embodiment, R8 and R9 when taken together form cyclopropyl.
In one embodiment, Rg and R9 when taken together form a heterocycle, wherein the heterocycle is optionally substituted with Rio. In one embodiment, Rs and R9 when taken together form a 4membered heterocycle optionally substituted with Rio. In one embodiment, R8 and R9 when taken together form azetidinyl optionally substituted with Rio- ln one embodiment, Rs and R9 when taken together form oxetanyl optionally substituted with RioIn one embodiment, R|0 is independently at each occurrence oxo, halogen, -CN, -OR, b -C(O)Ri b C(O)ORu, - C(O)NRnRi2, -NRhC(O)Ri2, -S(O)Rn, -S(O)2RU, -NRnS(O)2Ri2, -S(O)2NRnRi2, Ci-C6 alkyl, CrC6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, Rl0 is independently at each occurrence oxo, halogen, -CN, -ORlb -C(O)RU, C(O)ORh, - C(O)NRnR|2, -NRhRi2, -NRhC(O)R,2, -S(O)Ru, -S(O)2Rlb -NRnS(O)2Ri2, S(O)2NRnRi2, CrC6 alkyl, Ci-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, RI0 is independently at each occurrence oxo, halogen, or -CN. In one embodiment, R(0 is oxo. In one embodiment, Rw is halogen. In one embodiment, Rio is F, Ci, Br, or I. In one embodiment, Rm is F or Cl. In one embodiment, Rio is F. In one embodiment, Rio is CL in one embodiment, Rio is -CN.
In one embodiment, Rl0 is independently at each occurrence -OR)b -C(O)Rib -C(O)OR|b C(O)NRhR(2, -NRhC(O)R12, -S(O)Rn, -S(O)2RIb -NRnS(O)2R12, or -S(O)2NRuRi2. In one embodiment, Ræ is -ORn. In one embodiment, Rio is -C(O)Rn- In one embodiment, R10 is C(O)ORii- In one embodiment, Rio is -C(O)NRhR[2. In one embodiment, Rio is -NRnC(O)Ri2. In one embodiment, Rw is -S(O)Rn- In one embodiment, Rio is -S(O)2Rf i- In one embodiment, Rio is NRkS(O)2Ri2. In one embodiment, Rio is -S(O)2NRnRi2.
In one embodiment, R10 is independently at each occurrence CrC6 alkyl, Ci-C6 haloalkyl, C2-C6 alkenyl, or C2-Cû alkynyl.
In one embodiment, Rio is Ci-C6 alkyl. In one embodiment, Rio is methyl. In one embodiment, Rio is ethyl. In one embodiment, Rio is propyl. In one embodiment, R)0 is butyl. In one embodiment, Rio is pentyl. In one embodiment, Rio is hexyl.
In one embodiment, Rjo is Ci-Cg haloalkyl. In one embodiment, Rio is halomethyl. In one embodiment, Rjq is haloethyl. In one embodiment, Rio is halopropyl. In one embodiment, Rjo is halobutyl. In one embodiment, R|0 is halopentyL In one embodiment, Rio is halohexyl.
In one embodiment, Rio is C2-Cf, alkenyl. In one embodiment, Rio is C2-Cô alkynyl.
In one embodiment, Rio is independently at each occurrence C3-C8 cycioalkyl or heterocyclyl. In one embodiment, Rio is C3-Cg cycioalkyl. In one embodiment, Rio is heterocyclyl.
In one embodiment, Rio is independently at each occurrence aryl or heteroaryl. In one embodiment, Rio is aryl. In one embodiment, Rio is heteroaryl.
In one embodiment, Rio is -OH.
In one embodiment, Ru and Rn are independently H, Ci-Cô alkyl, Ci-C6 haloalkyl, C2-Cô alkenyl, C2-C6 alkynyl, C3-C8 cycioalkyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, Ru and Ri2 are independently H.
In one embodiment, Ru and R12 are independently C,-C6 alkyl, Ci-C6 haloalkyl, C2-C6 alkenyl, C2C6 alkynyl, C3-C8 cycioalkyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, Rn is H, CrC6 alkyl, CrC6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycioalkyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, Ru is H.
In one embodiment, Ru is CrC6 alkyl, CrC6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycioalkyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, Ru is Ci-Ce alkyl, Ci-Ce haloalkyl, C2-Ce alkenyl, or C2-Ce alkynyl.
In one embodiment. Ru is C|-Ce alkyl. In one embodiment, Ru is methyl. In one embodiment, Ru is ethyl. In one embodiment, Ru is propyl. In one embodiment, Rn is butyl In one embodiment, Ri ! is pentyl. In one embodiment, Ri । is hexyl.
In one embodiment, Ru is C(-C6 haloalkyl. In one embodiment, Ru is halomethyl. In one embodiment, Ru is haloethyl. In one embodiment, Ru is halopropyl. In one embodiment, Ru is halobutyl. In one embodiment, RH is halopentyl. In one embodiment, Ru is halohexyl.
In one embodiment, Ru is C2-C6 alkenyl. In one embodiment, R| i is C2-C6 alkynyl.
In one embodiment, Ru is C3-C8 cycioalkyl, heterocyclyl, aryl, or heteroaryl. In one embodiment, Ru is C3-Cg cycioalkyl. In one embodiment, Ru is heterocyclyl. In one embodiment, Ru is aryl. In one embodiment, Ru is heteroaryl.
In one embodiment, Ru is H, Ci-Ce alkyl, Ci-Ce haloalkyl, C2-Ce alkenyl, C2-Cô alkynyl, C3-Cg cycioalkyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, R12 is H.
In one embodiment, R[2 is Ci-Ce alkyl, Ci-C& haloalkyl, C2-Cô alkenyl, C2-Cg alkynyl, C3-Cg cycioalkyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, Ri2 is Ci-Cg alkyl, Ci-Ce haloalkyl, C2-Ce alkenyl, or C2-Ce alkynyl.
In one embodiment, R12 is CrC6 alkyl. In one embodiment, R|2 is methyl. In one embodiment, Rl2 is ethyl. In one embodiment, R(2 is propyl. In one embodiment, Ri2 is butyl. In one embodiment, R]2 is pentyl. In one embodiment, R]2 is hexyl.
In one embodiment, Rj2 is C|-C& haloalkyl. In one embodiment, Ri2 is halomethyl. In one embodiment, Ri2 is haloethyl. In one embodiment, Ri2 is halopropyl. In one embodiment, Ri2 is halobutyl. In one embodiment, Ri2 is halopentyl. In one embodiment, Rj2 is halohexyl.
In one embodiment, Rn is C2-Cè alkenyl. In one embodiment, Riz is C2-Cg alkynyl.
In one embodiment, R12 is C3-Cs cycloalkyl, heterocyclyl, aryl, or heteroaryl. In one embodiment, Rl2 is C3-C8 cycloalkyl. In one embodiment, R12 is heterocyclyl. In one embodiment, R12 is aryl. In one embodiment, R, 2 is heteroaryl.
In one embodiment, the compounds of the présent disclosure are represented b y compounds of
Formula II:
or phaimaceutically acceptable salts, prodrugs, solvatés, hydrates, enantiomers, isomers, or tautomers thereof, wherein:
------represents optîonal double bonds which can form an aromatic when présent;
Zi, Z2, Z3, and Z4 are independently C, N, S, O, N(R10), or C(Rio); and
Xb X2, X3, Ai, A2, Y, R2, R3î R4, Rio are described as herein.
In one embodiment, the compounds of the présent disclosure are represented by compounds of
Formula III:
or pharmaceutically acceptable salts, prodrugs, solvatés, hydrates, enantiomers, isomers, 01 tautomers thereof, wherein:
______straight or curved représente optional double bonds that fonn a partially unsaturated ring or an aromatic ring when présent;
Z], Z2, Z3, and Z4 are independently C, N, O, N(Rio), or C(Rio), provided Zi, Z2, Z3, and Z4 are not ail N or N(R[0) when------is présent and aromatic; provided that no three N or
N(Rio) are adjacent; provided that Zi, Z2, Z3, and Z4 are not O when------is présent and aromatic; and
Xh X2, X3, A], A2, Y, R2, Rj, R4, Rio are described as herein.
In one embodiment, the compound is of formula la:
or a pharmaceutically acceptable sait, prodrug, solvaté, hydrate, enantiomer, isomer, or tautomer thereof.
In one embodiment, the compound is of formula Ib:
or a pharmaceutically acceptable sait, prodrug, solvaté, hydrate, enantiomer, isomer, or tautomer thereof, wherein the D ring represents a Cj-C’kj cycloalkyl, Cs-Cg cycloalkenyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, the compound is of formula le:
or a pharmaceutically acceptable sait, prodrug, solvaté, hydrate, enantiomer, isomer, or tautomer thereof, wherein the D ring represents a C3-C10 cycloalkyl, C5-Cg cycloalkenyl, heterocyclyl, aryl, or heteroaryl; and the T ring represents a Cj-Cio cycloalkyl, Cs-Cg cycloalkenyl, C^-Cg spirocycloalkyl, 10 spiroheterocyclyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, the compound is of formula Id:
or a pharmaceuticaliy acceptable sait, prodrug, solvaté, hydrate, enantiomer, isomer, or tautomer thereof, wherein the T ring represents a C3-C10 cycloalkyl, C5-C8 cycloalkenyl, Cj-Cg spirocycloalkyl, spiroheterocyclyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, the compound is of formula le:
or a pharmaceuticaliy acceptable sait, prodrug, solvaté, hydrate, enantiomer, isomer, or tautomer thereof, wherein the T ring represents a C3-C10 cycloalkyl, C5-C8 cycloalkenyl, C3-C8 spirocycloalkyl, spiroheterocyclyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, the compound is of formula If;
or a pharmaceutically acceptable sait, prodrug, solvaté, hydrate, enantiomer, isomer, oi tautomei thereof, wherein the D ring represents a C3-C40 cycloalkyl, C5-C8 cycloalkenyl, heteiocyclyl, aryl, 01 heteroaryl; and the T ring represents a C3-C10 cycloalkyl, Cj-Cg cycloalkenyl, Cj-Cs spirocycloaikyl, 5 spiroheterocyclyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, the compound is of formula Ig:
or a pharmaceutically acceptable sait, prodrug, solvaté, hydrate, enantiomer, isomer, or tautomer thereof.
In one embodiment, the compound is of formula Ih:
or a pharmaceutically acceptable sait, prodrug, solvaté, hydrate, enantiomer, isomer, or tautomer thereof.
In one embodiment, the compound is of formula Ih-a:
or a pharmaceutically acceptable sait, prodrug, solvaté, hydrate, enantiomer, isomer, or tautomer thereof.
In one embodiment, the compound is of formula li:
or a phannaceutîcally acceptable sait, prodrug, solvaté, hydrate, enantiomer, isomer, oi tautomer thereof, wherein the T ring represents a C3-C10 cycloalkyl, C5-C8 cycloalkenyl, C3-C8 spirocycloalkyl, spiroheterocyclyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, the compound is of formula li-a:
or a phannaceutîcally acceptable sait, prodrug, solvaté, hydrate, enantiomer, isomer, or tautomer thereof, wherein the T ring represents a Cj-C^ cycloalkyl, C3-C8 cycloalkenyl, C3-C8 spirocycloalkyl, spiroheterocyclyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, the compound is of formula li or a phannaceutîcally acceptable sait, prodrug, solvaté, hydrate, enantiomer, isomer, or tautomer thereof, wherein the T ring represents a heterocyclyl.
In one embodiment, the compound is of fonnula li-a or a phannaceutîcally acceptable sait, prodrug, solvaté, hydrate, enantiomer, isomer, or tautomer thereof, wherein the T ring represents a heterocyclyl.
In one embodiment, the compound is of formula Ij:
or a phannaceutically acceptable sait, prodrug, solvaté, hydrate, enantiomer, isomer, or tautomer thereof, wherein the T ring represents a C3-C10 cycloalkyl, Cj-Cg cycloalkenyl, C3-C8 spirocycloalkyl, spiroheterocyclyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, the compound is of formula Ij or a phannaceutically acceptable sait, prodrug, solvaté, hydrate, enantiomer, isomer, or tautomer thereof, wherein the T ring represents a heterocyclyl.
In one embodiment, the compound is of formula Ik:
or a pharmaceutically acceptable sait, prodrug, solvaté, hydrate, enantiomer, isomer, or tautomer thereof.
In one embodiment, the compound is of formula Ik-a:
Rs I
r3 (Ik-a) or a pharmaceutically acceptable sait, prodrug, solvaté, hydrate, enantiomer, isomer, or tautomer thereof.
In one embodiment, at least one oi Xi, X2, or X3 is N, Ai is —O—, A2 is —C(Rg)(R9)—, and Y is
C(R8)(R9)-.
In one embodiment, at least one of Xi, X2, or X3 is N, Ai is —C(R8)(R9)-, A2 is -O—, and Y is —
C(R8)(R9)-.
In one embodiment, one of Xi, X2, Xj is C(Rs), Aj is -O-, A2 is -C(R8)(R9)-, and Y is -C(R8)(R9)-In one embodiment, one of Xi, X2, X3 is C(R3), Aj is —C(Rg)(R9)—, A2 is —O—, and Y is —C(R8)(R9) . In one embodiment, at least one of Xi, X2, or Xi is N, Ai is —O—, A2 is — C(Rg)(R9)—, and Y is — C(R8)(R9)-, wherein R4 and R9 can form C3-C1Q cycloalkyl, C3-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, at least one of Xi, X2, or X3 is N, Ai is — C(Rg)(R9)—, A2 is -O-, and Y is — C(R8)(R9)- wherein R4 and R9 can fonn C3-Ci0 cycloalkyl, Q-Cg cycloalkenyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, one of Xh X2, X3 is C(R5), A! is -O-, A2 is -C(R8)(R9)- and Y is -C(R8)(R9)-, wherein R4 and R9 can fonn C3-C10 cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl. In one embodiment, one of Χι, X2, X3 is C(Rj), Ai is — C(Rg)(R9)—, A2 is —O—, and Y is —C(R8)(R9)—, wherein R4 and R9 can fonn C3-C10 cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl. In one embodiment, at least one of Xi, X2, or X3 is N, A] is -O-, A2 is — C(R8)(R9)—, and Y is C(R8)(R9)-, wherein R4 and R9 can fonn heterocyclyl.
In one embodiment, at least one of Xi, X2> or X3 is N, Ai is -C(Rg)(R9)-, A2 is -O-, and Y is C(R8)(R9)-, wherein R4 and R9 can form heterocyclyl.
In one embodiment, one of Xi, X2, X3 is C(R5), Ai is —O—, A2 is — C(R$XR9)—, and Y is — C(R8)(R<>) , wherein R4 and R9 can form heterocyclyl.
In one embodiment, one of Xi, X2, X3 is C(Rs), A| is -C(R8XR9)-, A2 is —O-, and Y is —C(R8XR9)-, wherein R4 and Rq can form heterocyclyl.
in one embodiment, at least one of Xi, X2, or X3 is N, Ai is —S—, A2 is —C(R8XR9)—, and Y is —
C(RSXR9)-.
In one embodiment, at least one of X[, X2, or X3 is N, Aj is —C(R8XR9)~, A2 is —S—, and Y is —
C(R8XR9)-.
In one embodiment, one of Xi, X2, X3 is C(Rj), A] is —S—, A2 is —C(R8)(R9)—, and Y is — C(R8XR9)—. In one embodiment, one of Xi, X2, Xj is C(Rs), Aj is -C(R8XR9)-, A2 is -S—, and Y is —C(R8XR9)In one embodiment, at least one of Xi, X2, or X3 is N, Ai is —S—, A2 is —C(R8XR9)~, and Y is — C(R8XR9)-, wherein R4 and R9 can form C3-C10 cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, at least one of X], X2, or X3 is N, Aj is — C(R8XR9)~, A2 is — S—, and Y is — C(Rg)(R9)-5 wherein R4 and R9 can form C3-C10 cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, one of Χι, X2, X3 is C(Rs), Ai is —S-, A2 is —C(R8)(R9)—, and Y is —C(R8XR9)-, wherein R4 and R9 can form C3-Cw cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl. In one embodiment, one of Xi, X2, X3 is C(Rs), Ai is —C(R8XR9)—, A2 is —S—, and Y is — C(R8XR9)—, wherein R4 and R9 can form C3-C[0 cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl. In one embodiment, at least one of Xi, X2, or X3 is N, Ai is —S—, A2 is —C(R8XR9)—, and Y is — C(R8XR9)-, wherein R4 and R9 can form heterocyclyl.
In one embodiment, at least one of X|, X2, or X3 is N, Ai is — C(R$XR9)-, A2 is —S—, and Y is C(R8XR9)-f wherein Rq and R9 can form heterocyclyl.
In one embodiment, one of Xi, X2, X3 is C(R$), Ai is —S—, A2 is — C(R8XR9)~, and Y is —C(R8XR9)—, wherein R4 and R9 can form heterocyclyl.
In one embodiment, one of Χι, X2, X3 is C(Rj), Ai is —C(RgXRo)-, A2 is -S-, and Y is -C(R8XR9)—, wherein R4 and R9 can form heterocyclyl.
In one embodiment, at least one of Xi, X2, or X3 is N, Ai is - S(O)-, A2 is —C(R8)(R9)—, and Y is —
C(R8XR9)-.
In one embodiment, at least one of Xi, X2, or X3 is N, Ai is —C(R8XR9)—, A2 is — S(O)~, and Y is —
C(R8XR9)36
In one embodiment, one of Xi, X2, X3 is C(Rs), Ai is — S(O)-, A2 is -C(R8)(R9)-, and Y is — C(Rs)(R9)-.
In one embodiment, one of Xb X2, X3 is C(R5), A; is —C(R8)(R9)-, A? is — S (O)-, and Y is — C(R8)(R9)-.
In one embodiment, at least one of Xi, X2, or X3 is N, Ai is — S(O)—, A2 is -C(Rs)(R9)-, and Y is — C(R8)(R9)—, wherein R4 and R9 can form C3-CI0 cycloalkyl, C5-Cg cycloalkenyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, at least one of Xb X2, or X3 is N, Ai is -C(R8)(R9)—, A2 is — S(O)— and Y is — C(R8)(R9)-, wherein R4 and R9 can form C3-C)0 cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, 10 or heteroaryl.
In one embodiment. one of Xi, X2, X3 is ClRs), A] îs - S(O)-, A2 is —C(R8)(R9)—, and Y is C(R8)(R9)-, wherein R4 and R9 can form C3-Ci0 cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, one of X(, X2, X3 is C(R3), Aj is ~C(R8)(R9)-, A2 is - S(O)-, and Y îs 15 C(R8)(R9)-, wherein R4 and R9 can form C3-C[0 cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, al least one of Xi, X2, or X3 îs N, A] is — S(O)-, A2 is —C(R8)(R9)-, and Y is — C(Rs)(R9)-, wherein R4 and R9 can form heterocyclyl.
In one embodiment, at least one of Xb X2, or X3 îs N, Ai is -C(R8)(R9)-, Ai is - S (O)-, and Y is 20 C(R8)(R9)-, wherein R4 and R9 can form heterocyclyl.
In one embodiment, one of Xi, X2, X3 is C(R3), A| is - S(O)-, A2 is -C(R8)(R9)-, and Y is C(R8)(R9)-, wherein R4 and R9 can form heterocyclyl.
In one embodiment, one of Xb X2, X3 is C(R3), Ai is -C(R8)(R9)-> A2 is -S(O)-, and Y îs C(R8)(R9)-, wherein R4 and R9 can form heterocyclyl.
In one embodiment, at least one of Ab A2, and Y îs -C(R8)(R9)-, wherein R8 and R9 are halogen.
In one embodiment, at least one of Ab A2, and Y is -C(R8)(R9)—, wherein R8 and R9 are F.
In one embodiment, at least two of Ai, A2, and Y is -C(R8)(R9)-, wherein R8 and R9 are halogen.
In one embodiment, at least two of Ab A2, and Y is -C(R8)(R9)-, wherein R8 and R9 are F.
In one embodiment, Ab A2, and Y are -C(R8)(R9)“, wherein Rs and R9 are halogen.
In one embodiment, Ai, A2, and Y are -C(R8)(R9)~, wherein R8 and R9 are F.
In one embodiment, Ai is -C(R8)(R9)-, wherein Rg and R9 are halogen.
In one embodiment, Ai is -C(R8)(R9)-, wherein R8 and R9 are F.
In one embodiment, A2 is —C(R8)(R9)-, wherein R8 and R9 are halogen.
In one embodiment, A2 is -C(Rg)(R9)-, wherein Rg and Rg are F.
In one embodiment, Y is -C(R8)(R9)-, wherein Rg and Rg are halogen.
In one embodiment, Y is -C(R8)(R9)-, wherein Rg and R9 are F.
In one embodiment, at least one of Xb X2, or X3 is N, Ai is -O-, A2 is -C(R8)(R9)-, Y is 5 C(R8)(R9)- and R| is H, -NRSR% -P(O)(OR8)(OR9), -C(O)R8, -C(O)NR8R9, -CN, CrC6 alkyl, Cr
C& alkoxy, C2-Cé alkenyl, C2-Cé alkynyl, C3-C10 cycloalkyl, Cs-Cg cycloalkenyl, C3-C8 spirocycloalkyl, spiroheterocyclyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, spirocycloalkyl, spiroheterocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Rg.
In one embodiment, at least one of Xb X2, or Xj is N, A] is -C(R8)(R9)-, A2 is -O-, Y is C(R8)(R9)-, and R| is H, -NR8R9, -P(O)(OR8)(OR9), -C(O)Rr, -C(O)NR8R9, -CN, CrC6 alkyl, Cr C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, Cj-Cw cycloalkyl, C5-C8 cycloalkenyl, C3-Cs spirocycloalkyl, spiroheterocyclyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, spirocycloalkyl, spiroheterocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^.
In one embodiment, one of Xi, X2, X3 is C/Rs), Ai is -O-, A2 is —C(Rg)(R9)-, Y is -C(R8)(R9)-, and R! is H, -NR8R9, -P(O)(OR8)(OR9), -C(O)R8, -C(O)NRsR9, -CN, CrC6 alkyl, CrC6 alkoxy, C2-C9 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C5-Cg cycloalkenyl, C3-C8 spirocycloalkyl, spiroheterocyclyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, 20 cycloalkyl, cycloalkenyl, spirocycloalkyl, spiroheterocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more RéIn one embodiment, one of Xi, X2, X3 is C(Rs), A) is -C(R8)(R9)-, A2 is -O-, Y is -C(R8)(R9)-, and Ri is H, -NRgR9, -P(O)(OR8)(OR9), -C(O)R8, -C(O)NRgR9, -CN, Ci-C6 alkyl, CrC6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C5-Cg cycloalkenyl, Cî-C8 spirocycloalkyl, 25 spiroheterocyclyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, spirocycloalkyl, spiroheterocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ré.
In one embodiment, at least one of Xi, X2, or X3 is N, Ai is -O-, A2 is -C(Rg)(R9)-, Y is C(R8)(R9)-, and Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl 30 îs optionally substituted with one or more RôIn one embodiment, at least one of Xi, X2, or X3 is N, Ai is -C(R8)(R9)-, A2 is -O-, Y is C(R8)(R9)-, and Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R&.
In one embodiment, one of Xi, X2, X3 is C(Rg), Ai is -O-, A2 is -ClRsXRq)-, Y is -C(Rg)(Rs)-, and Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R().
In one embodiment, one of Xi, X2, Xj is C(Rg), Ai is -C(R8)(R9)-, A2 is -O-, Y is -C(RsXRci)-, and Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Rg.
In one embodiment, at least one of Xb X2, or X3 is N, A] is -O-, A2 is -C(R8)(R9)—, Y is C(R8XR9)- and R[ is heterocyclyl optionally substituted with one or more Rg.
In one embodiment, at least one of Xb X2, or X3 is N, Ai is -CfRgXRg)-, A2 is -O-, Y is CtRsXRQ-, and Ri is heterocyclyl optionally substituted with one or more Rg.
In one embodiment, one of Xj, X2, X3 is C(Rs), Ai is -O-, A2 is -C(Rg)(R9)-5 Y is -CIRgXRg)-, and Ri is heterocyclyl optionally substituted with one or more Rg,
In one embodiment, one of Xi, X2, X3 is C(Rs), A) is -QRgXRç)-, A2 is -O-, Y is -C(Rs)(R9)-, and Ri is heterocyclyl optionally substituted with one or more Rg.
In one embodiment, at least one of Xi, X2, or X3 is N, Ai is -O-, A2 is -C(R8XR9)-, Y is C(R8XRÂ-, and Rt is heteroaryl optionally substituted with one or more R6.
In one embodiment, at least one of Xi, X2, or X3 is N, Aj is -C(R8XR9)-, A2 is -O-, Y is C(R8)(R9)-, and Ri is heteroaryl optionally substituted with one or more Rg.
In one embodiment, one of Xi, X2, X3 is C(Rs), Aj is -O-, A2 is -C(R8)(R9)-, Y is -CiRsXRô-, and R] is heteroaryl optionally substituted with one or more Rg.
In one embodiment, one of Xi, X2, X3 is C(Rg), Ai is -C(R8XR9)-, A? is -O-, Y is -C(RgXRg)-, and Ri is heteroaryl optionally substituted with one or more R6.
In one embodiment, at least one of Xi, X2, or X3 is N, Ai is —O-, A2 is -C(R8)(R9)—, Y is — C(R8XR9)-, R| is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Rg, and R2 and R3 are independently at each occurance H, halogen, -OH, -NH2, -CN, CrC6 alkyl, CrCg alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7.
In one embodiment, at least one of Xi, X2, or Xi is N, Ai is -C(R8XR9)-, A2 is -O-, Y is CCRsXRo)-, R] is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Rg, and R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, Ci-Cg alkyl, CrC6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R?
In one embodiment, one of Xj, X2, X3 is CfRs), A| is —O-, A2 is -CiRsXRç)—, Y is -C(R8)(R9)—, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionaliy substituted with one or more Rg, and R2 and R3 are independently at each occurrence H, halogen, OH, -NH2, -CN, Ci-C6 alkyl, C]-C6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionaliy substituted with one or more R7
In one embodiment, one of Xj, X2, X3 is C(R3), A( is -C(R8)(R9)-, A2 is -O-, Y is -C(Rg)(R<))- Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionaliy substituted with one or more Rf„ and R2 and R3 are independently at each occurrence H, halogen, OH, -NH2, -CN, C]-C6 alkyl, CpCg alkoxy, C2-Cg alkenyl, or C2-Cg alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionaliy substituted with one or more R7
In one embodiment, at least one of Xj, X2, or X3 is N, Ai is -O-, A2 is -C(R8)(R9)-, Y is C(Rs)(R9)-, Ri is heterocyclyl optionaliy substituted with one or more Rg, and R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, Cj-Cg alkyl, Ci-Cg alkoxy, C2-Cg alkenyl, or C2-Cg alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionaliy substituted with one or more R7.
In one embodiment, at least one of Xj, X2, or X3 is N, A( is -C(R8XR9)-, A2 is -O-, Y is CfRsXRQ-, Ri is heterocyclyl optionaliy substituted with one or more Rg, and R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, Cj-Cg alkyl, Cj-Cg alkoxy, C2-Cg alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionaliy substituted with one or more R7.
In one embodiment, one of Xj, X2, X3 is C(Rs), Ai is -O-, A2 is -C(R8)(R9)-, Y is -C(R8)(R9)-, Rj is heterocyclyl optionaliy substituted with one or more Rg, and R2 and R3 are independently at each occurrence H, halogen, -OH, —NH2, —CN, Cj-Cg alkyl, Cj-Cg alkoxy, C2-Cg alkenyl, or C2-Cg alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionaliy substituted with one or more R7. In one embodiment, one of Xj, X2, X3 is C(Rg), Ai is -C(R8XR9)-, A2 is -O-, Y is -C(R8XR9)-, Ri is heterocyclyl optionaliy substituted with one or more R<„ and R2 and R3 are independently at each occurrence H, halogen, -OH, —NH2, -CN, Cj-Cg alkyl, C|-Cg alkoxy, C2-Cg alkenyl, or C2-Cg alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionaliy substituted with one or more R7.
In one embodiment, at least one of Xj, X2, or X3 is N, A, is -O—, A2 is -C(R8)(R9)-, Y is C(R8XR9)-, Ri is heteroaryl optionaliy substituted with one or more Rg, and R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, Cj-Cg alkyl, Cj-Cg alkoxy, C2-Cg alkenyl, or C2-Cg alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionaliy substituted with one or more R7.
In one embodiment, at least one of Xi, X2, or Xj is N, Ai is -C(R8)(R9)-, A2 is -O-, Y is C(R8)(R9)-, Ri is heteroaryl optionally substituted with one or more Ré, and R2 and R8 are independently at each occurrence H, halogen, -OH, -NH2, -CN, Ci-Cf, alkyl, C]-Cé alkoxy, C2-Cé alkenyl, or C2-Cé alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7.
In one embodiment, one of Xj, X2, X3 is C(Rs), Ai is -O-, A2 is —C(R8)(R9)-, Y is -C(Rg)(R9)-, Ri is heteroaryl optionally substituted with one or more R&, and R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, C1-C0 alkyl, Ci-Cé alkoxy, C2-Ce alkenyl, or C2-Cé alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7. In one embodiment, one of Xj, X2, X3 is C(Rs), Ai is -C(Rg)(R9)-, A2 is -O-, Y is -C(R8)(R9)-, Ri is heteroaryl optionally substituted with one or more R(), and R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, Cj-Cé alkyl, Ci-Cé alkoxy, C2-Cé alkenyl, or C2-C0 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7.
In one embodiment, ai least one of X2, or X3 is N, Aj is -O-, A2 is -C(R8)(R9)-, Y is C(R8)(R9)-, R| is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ré, and R2 is H.
In one embodiment, at least one of X|, X2, or X3 is N, Ai is -C(R8)(R9)-, A2 is -O-, Y is C(Rg)(R9)-, Rj is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R&, and R2 is H.
In one embodiment, one of Xb X2, X3 is C(R5), Ai is -O-, A2 is -C(R8)(R9)- Y is -C(Rg)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R6, and R2 is H.
In one embodiment, one of Xb X2, X3 is C(Rj), Ai is -C(R8)(Rg)-, A2 is -O-, Y is -C(R8)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ré, and R2 is H.
In one embodiment, at least one of Xi, X2, or X3 is N, Ai is -O-, A2 is -C(R8)(R9)-, Y is C(R8)(R9)-, Rj is heterocyclyl optionally substituted with one or more R&, and R2 is H.
In one embodiment, at least one of Xi, X2, or X3 is N, Ai is -C(R8)(R9)-, A2 is -O-, Y is C(R8)(R9)-, Ri is heterocyclyl optionally substituted with one or more Ré, and R2 is H.
In one embodiment, one of Χι, X2, X3 is CfRs), Aj is -O-, A2 is -C(R8)(R9)-, Y is -C(R8)(R9)-, Ri is heterocyclyl optionally substituted with one or more Ré, and R2 is H.
In one embodiment, one of Xj, X2, Xj is C(Rs), A| is -C(R8)(Rg)-, A2 is -O-, Y is -C(R8)(R9)- Ri is heterocyclyl optionally substituted with one or more Ré, and R2 is H.
In one embodiment, at least one of Xi, X2, or X3 is N, Ai is -O-, A2 is -CCRgXRg)-, Y is C(R8XR9)~, Ri is heteroaryl optionally substituted with one or more R6j and R2 is H.
In one embodiment, at least one of Xj, X2, or X3 is N, At is -QRsXRçi)-, A2 is -O-, Y is C(Rs)(R9)-, Ri is heteroaryl optionally substituted with one or more R6, and R2 is H,
In one embodiment, one of Xb X2, X3 is C(Rs), Ai is -O-, A2 is -CfRsXRç)-, Y is -C(RgXRg)-, Ri is heteroaryl optionally substituted with one or more Rô, and R2 is H,
In one embodiment, one of Xb X2, X3 is C(Rj), Aj is -C(Rg)(R9)-, A2 is -O-, Y is -ClRsXRg)-, Ri is heteroaryl optionally substituted with one or more Râ, and R2 is H.
In one embodiment, at least one of Xi, X2, or X3 is N, A] is -O-, A2 is -C(RsXRq)-, Y is C(R8XR9)-, R, is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R$, and R2 is halogen.
In one embodiment, at least one of Xb X2, or X3 is N, Ai is —C(Rs)(Rg)—, A2 is -O-, Y is C(RsXR9)~, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more RÉ„ and R2 is halogen.
In one embodiment, one of X], X2, X3 is C(R3), Ai is -O-, A2 is -CfRsXRg)-, Y is -QRsXRg)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R6, and R2 is halogen.
In one embodiment, one of Xi, X2, X3 is C(Rs), A| is -CfRsXRç)-, A2 is -O-, Y is -QRsXRç)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Rô, and R2 is halogen.
In one embodiment, at least one of Xi, X2, or X3 is N, Ai is -O-, A2 is -C(RsXRç)-, Y îs CtReXRq)-, Ri is heterocyclyl optionally substituted with one or more R^, and R2 is halogen.
In one embodiment, at least one of Xi, X2, or X3 is N, A| is -C(R8XR9)-, A2 is -O-, Y is C(RsXRç)-, Ri is heterocyclyl optionally substituted with one or more R6, and R2 is halogen.
In one embodiment, one of Xi, X2, X3 is C(R3), Ai is -O~, A2 is -C(RsXRq)-, Y is -C(R8XR9)-, Ri is heterocyclyl optionally substituted with one or more R^, and R2 is halogen.
In one embodiment, one of Xb X2, X3 is C(R3), Ai is -C(R8)(R9)-, A2 is -O-, Y is -CfRgXRgjH R] îs heterocyclyl optionally substituted with one or more R^, and R2 is halogen.
In one embodiment, at least one of Xi, X2, or X3 is N, Aj is -O-, A2 is -Cl'RgXRoH Y is CtRsXRq)-, Ri is heteroaryl optionally substituted with one or more R6, and R2 is halogen.
In one embodiment, at least one of Xi, X2, or X3 is N, Ai is ~C(R8XRq)-, A2 is -O-, Y is C(R8)(R9)-, Ri is heteroaryl optionally substituted with one or more R6, and R2 is halogen.
In one embodiment, one of Xb X2, X3 is C(Rj), Ai is —O—, A2 is —C(R8)(R9)-, Y is -C(R8)(R9)—, R] is heteroaryl optionally substituted with one or more Rfj, and R2 is halogen.
In one embodiment, one of Χι, X2, X3 is C(Rj), A] is -C(R8)(R9)-, A2 is -O-, Y is -C(R8)(R9)-, Ri is heteroaryl optionally substituted with one or more R9, and R2 is halogen.
In one embodiment, at least one of X], X2, or X3 is N, Ai is -O-, A2 is -C(R8)(R<?)-, Y is C(R8)(R9)—, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ré, R2 is H, and R3 is H.
In one embodiment, at least one of Xj, X2, or X3 is N, Ai is -C(R8)(R9)-, A2 is -O-, Y is C(R8)(R9)-, R) is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ré, R2 is H, and R3 is H.
In one embodiment, one of Xj, X2, X3 is C(R3), Ai is -O-, A2 is ~C(R8)(R9)-, Y is —C(R8)(R9)—, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ré, R2 is H, and R3 is H.
In one embodiment, one of Xj, X2, X3 is C(R3), A] is -C(R8)(R9)-, A2 is -O-, Y is -C(R8)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ré, R2 is H, and R3 is H.
In one embodiment, at least one of Xi, X2, or X3 is N, Ai is -O-, A2 is -C(R8)(R9)-, Y is C(R8)(R9)-, R; is heterocyclyl optionally substituted with one or more Ré, R2 is H, and R3 is H.
In one embodiment, at least one of Xi, X2, or X3 is N, Aj is -C(R8)(R9)-, A2 is -O-, Y is C(R8)(R9)-, Ri is heterocyclyl optionally substituted with one or more Ré, R2 is H, and R3 is H.
In one embodiment, one of Xi, X2, X3 is C(R3), Ai is —O—, A2 is —C(R8)(R9)—, Y is —C(R8)(R9)—, Ri is heterocyclyl optionally substituted with one or more R6, R2 is H, and R3 is H.
ïn one embodiment, one of Xj, X2, X3 is C(R3), Ai is —C(R8)(R9)—, A2 is —O—, Y is —C(R8)(R9)-, Rj is heterocyclyl optionally substituted with one or more Ré, R2 is H, and R3 is H.
In one embodiment, at least one of Xi, X2, or X3 is N, Ai is -O-, A2 is -C(R8)(R9)-, Y is C(R8)(R9)-, Ri is heteroaryl optionally substituted with one or more Ré, R2 is H, and R3 is H.
In one embodiment, at least one of Xj, X2, or X3 is N, A| is -C(R8)(R9)-, A2 is -O-, Y is C(Rs)(R9)-, Rj is heteroaryl optionally substituted with one or more Ré, R2 is H, and R3 is H.
In one embodiment, one of Xi, X2, X3 is C(Ré), Ai is -O-, A2 is -C(R8)(R9)-, Y is -C(R8)(R9)-, Ri is heteroaryl optionally substituted with one or more Ré, R2 is H, and R3 is H.
In one embodiment, one of X(, X2, X3 is C(R3), Ai is -C(R8)(R9)- A2 is -O-, Y is -C(R8)(R9)-, Ri is heteroaryl optionally substituted with one or more R&, R2 is H, and R3 is H.
In one embodiment, at least one of X], X2, or X3 is N, A| is -O-, A2 is -C(Rs)(Rq)-, Y is C(Rg)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^, R2 is halogen, and R3 is H.
In one embodiment, at least one of Xi, X2, or X3 is N, A| is -C(Rg)(R9)-, A2 is —O-, Y is — C(Rs)(R9)-, R| is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R&, R2 is halogen, and R3 is H.
In one embodiment, one of Xj, X2, X3 is C(R3), Ai is -O-, A2 is -QRsXR?)-, Y is -CiRgXRy)-, Ri îs heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^, R2 is halogen, and R3 is H.
In one embodiment, one of Xi, X2, X3 is C(Rj), Ai is -C(RgXR9)- A2 is -O-, Y is -C(Rg)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl îs optionally substituted with one or more R^, R2 is halogen, and R3 is H.
In one embodiment, at least one of Xb X2, or X3 is N, Ai is -O-, A2 is -C(Rg)(R9)- Y is CIRsXRo)-, R| is heterocyclyl optionally substituted with one or more Rg, R2 is halogen, and R3 is H.
In one embodiment, at least one of Xi, X2, or X3 is N, Aj is -CiRgXRç)-, A2 is -O-, Y is CXRsXRç)-, Rj is heterocyclyl optionally substituted with one or more Rê, R2 is halogen, and R3 is H.
In one embodiment, one of Xi, X2, X3 is C(R?), Ai îs -O-, A2 is -C(RsXR9)-, Y is -C(RgXR9)-, Ri is heterocyclyl optionally substituted with one or more Rf), R2 is halogen, and R3 is H.
In one embodiment, one of Xj, X2, X3 is C(Rs), Ai is -QRgXRç)-, A2 îs -O-, Y is -C(RsXR9)-, Ri is heterocyclyl optionally substituted with one or more Rj,, R2 is halogen, and R3 is H.
In one embodiment, at least one of Xi, X2, or X3 is N, A[ is -O-, A2 is -C(ReXR9)-, Y is C(R8XR9)-, Ri is heteroaryl optionally substituted with one or more R6, R2 is halogen, and R3 is H.
In one embodiment, at least one of Xj, X2, or X3 îs N, Ai is -CiRsXR?)-, A2 is -O-, Y is CfRsXRy)-, R, is heteroaryl optionally substituted with one or more R&, R2 is halogen, and R3 is H.
In one embodiment, one of Xi, X2, X3 is C(R$), A, is -O-, A2 is -QRsXRg)-, Y is -C(RsXR9)-, Ri is heteroaryl optionally substituted with one or more R6, R2 is halogen, and R3 is H.
In one embodiment, one of Xh X2, X3 is C(R5), Ai is -C(RSXR9)- A2 is -O-, Y is -C(R8)(R9)-, Ri is heteroaryl optionally substituted with one or more R6, R2 is halogen, and R3 is H.
In one embodiment, at least one of Xj, X2, or X3 is N, Ai is -O-, A2 is -CCRsXRo)-, Y is C(RgXR9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Rs, R2 and R3 are independently at each occurrence H, 44 halogen, -OH, -NH2, -CN, Ci-C6 alkyl, CrC6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 is H, halogen, -OH, -NH2, -CN, Cj-C6 alkyl, Cj-Cé alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7.
In one embodiment, at least one of X(, X2, or X3 is N, A| is -C(R8)(Rq)-, A2 is -O-, Y is C(R8)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ré, R2 and Rj are independently at each occurrence H, halogen, -OH, -NH2, -CN, C|-C6 alkyl, Ci-C6 alkoxy, C2-Cé alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 is H, halogen, -OH, -NH2, -CN, CrQ alkyl, Cj-Cé alkoxy, C2-Cé alkenyl, or C2-C& alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7.
In one embodiment, one of Χι, X2, X3 is C(R;), A| is -O-, A2 is -C(R8)(R9)-, Y is -C(R8)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ré, R2 and R3 are independently at each occurrence H, halogen, -OH, NH2, -CN, Cj-Cé alkyl, Ci-Cé alkoxy, C2-C& alkenyl, or C2-Cé alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 is H, halogen, -OH, -NH2, -CN, C|-Cé alkyl, Ci-Cé alkoxy, C2-Cé alkenyl, or C2-Cé alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7.
In one embodiment, one of X(, X2, X3 is C(Rs), A| is -C(RB)(R9)-, A2 is -O-, Y is -C(Rg)(R9)-, R| is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R6, R2 and R3 are independently at each occurrence H, halogen, -OH, NH2, -CN, Ci-Cé alkyl, CrC6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 is H, halogen, -OH, -NH2, -CN, CrC6 alkyl, Ci-C6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7.
In one embodiment, at least one of Xi, X2, or X3 is N, Ai -O-, A2 is -C(R8)(R9)-, Y is -C(Rs)(R9)-, Ri is heterocyclyl optionally substituted with one or more R6, R2 and R3 are independently at each occurrence H, halogen, —OH, —NH2, -CN, Cj-Cé alkyl, Cj-C& alkoxy, C2-Cé alkenyl, or C2-Cé alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 îs H, halogen, -OH, -NH2, -CN, CrC6 alkyl, Ci-C6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7.
In one embodiment, at least one of X|, X2, or X3 is N, Ai is -CfRgXRy)-, A2 is -O-, Y is C(R8)(R9)-, Ri is heterocyclyl optionally substituted with one or more R6, R2 and R3 are 45 independently at each occurrence H, halogen, -OH, -NH2, -CN, Cj-Cô alkyl, C]-C$ alkoxy, C2-C$ alkenyl, or C2-C$ alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 is H, halogen, -OH, -NH2, -CN, Ci-C^ alkyl, Ci-Ce alkoxy, C2-C$ alkenyl, or C2-C$ alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7.
In one embodiment, one of Xi, X2, X3 is C(R3), Ai is -O-, A2 is -C(Rs)(R9)-, Y is -C(R8)(R9)-, Ri is heterocyclyl optionally substituted with one or more R$, R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, C|-C$ alkyl, CrC6 alkoxy, C2-C$ alkenyl, or C2-C$ alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 is H, halogen, -OH, -NH2, -CN, Ci-C6 alkyl, Ci-C6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7.
In one embodiment, one of Xi, X2, X3 is C(R5), Ai is -C(Rs)(R9)-, A2 is -O-, Y is -C(R8)(R9)-, R| is heterocyclyl optionally substituted with one or more Rf„ R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, CrC6 alkyl, Cj-C6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 is H, halogen, -OH, -NH2, -CN, C,-C6 alkyl, C,-C6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7.
In one embodiment, at least one of Xi, X2, or X3 is N, A| is -O-, A2 is -C(R8)(R9)-, Y is C(R8)(R9)-, Ri is heteroaryl optionally substituted with one or more R(„ R2 and R3 are independently at each occurrence H, halogen, -OH, —NH2, -CN, Ci-C$ alkyl, Ci-C$ alkoxy, C2-Cg alkenyl, or C2C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 is H, halogen, -OH, -NH?, -CN, Ci-C6 alkyl, CrC6 alkoxy, C2-C6 alkenyl, or C2-Cà alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7.
In one embodiment, at least one of Xt, X2, or X3 is N, Ai is -C(R8)(R9)-, A2 is -O-, Y is C(R8)(R9)-, R, is heteroaryl optionally substituted with one or more Rût R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, Cj-C$ alkyl, Ci-C$ alkoxy, C2-C$ alkenyl, or C2C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 is H, halogen, -OH, -NH2, -CN, Ci-C6 alkyl, Ci-C6 alkoxy, C2-C6 alkenyl, or C2-Câ alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7.
In one embodiment, one of Xi, X2, X3 is C(R3), Ai is -O-, A2 is -C(R8)(R9)-, Y is -C(R8)(R9)-, Ri is heteroaryl optionally substituted with one or more R$, R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, —CN, Ci-CL alkyl, C]-C$ alkoxy, C2-C$ alkenyl, or C2-C$ alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, 46 and R4 is H, halogen, -OH, -NH2, -CN, CrC6 alkyl, Ci-C6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7.
In one embodiment, one of Xb X2, X3 is C(R$), A, is -C(Rg)(Rg)-, A2 is -O-, Y is -C(R8)(R<))-, Ri is heteroaryl optionally substituted with one or more R(„ R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, Cj-Cô alkyl, Ci-Ce alkoxy, C2-Ce alkenyl, or C2-Ce alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 is H, halogen, -OH, -NH2, -CN, CrC6 alkyl, CrC6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7.
In one embodiment, at least one of Xb X2, or X3 is N, Ai is -O-, A2 is -C(Rg)(R9)-, Y is CiRs/Ry)-, Rj îs heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Rs, R2 is H, R3 is H, and R4 is H, halogen, -OH, -NH2, CN, Ci-Cô alkyl, Ci-C^ alkoxy, C2-Cô alkenyl, or C2-Cg alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7.
In one embodiment, at least one of Xj, X2, or X3 is N, A| is -C(Rg)(R9)-, A2 is -O-, Y is C(Rs)(R9)-, Ri îs heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^, R2 is H, R3 is H, and R4 is H, halogen, -OH, -NH2, CN, Ci-Cô alkyl, C|-C6 alkoxy, C2-C(, alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7,
In one embodiment, one of Xi, X2, X3 is C(Rj), Ai is -O-, A2 is -C(R8)(R9)-, Y is -C(R8)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^, R2 is H, R3 is H, and R4 is H, halogen, —OH, —NH2, —CN, Cj-C^ alkyl, C|-Cô alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7.
In one embodiment, one of Χμ X2, X3 is C(R3), A| is -C(R8)(Rg)-, A2 is -O-, Y is -C(R8)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Rf,, R2 is H, R3 îs H, and R4 is H, halogen, -OH, —NH2, —CN, Ci-C^ alkyl, Cj-C6 alkoxy, C2-C6 alkenyl, or C2-Cô alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl îs optionally substituted with one or more R7.
In one embodiment, at least one of X], X2, or X3 is N, Ai is -O-, A2 is —C(R8)(R9)-, Y is C(R8)(R9)-, Ri is heterocyclyl optionally substituted with one or more R&, R2 îs H, R3 is H, and R4 is H, halogen, -OH, -NH2, -CN, CpCô alkyl, Cj-C6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R?·
In one embodiment, at least one of X], X2, or X3 is N, A] is -CfRsXRç)- A2 is -O-, Y is C(Rg)(R9)-, Rj is heterocyclyl optionally substituted with one or more Rô, R2 is H, Rj is H, and R4 is H, halogen, -OH, -NH2, -CN, C|-C6 alkyl, CrC6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7.
In one embodiment, one of Xi, X2, X3 is C(R3), Ai is —O-, A2 is —C(R8)(R9)-, Y is -C(R8)(R9)-, Ri is heterocyclyl optionally substituted with one or more Rô, R2 is H, Rj is H, and R4 is H, halogen, — OH, -NH2, -CN, Cj-Cô alkyl, Cj-C6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7.
In one embodiment, X is C(R5), Ai îs -C(Rg)(R9)-, A2 is -O-, Y is -C(R8)(R9)-, Ri is heterocyclyl optionally substituted with one or more R^, R2 îs H, R 3 is H, and R4 is H, halogen, -OH, -NH2, CN, Ci-C6 alkyl, Ci-C6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7.
In one embodiment, at least one of X], X2, or Xj is N, Ai is -O-, A2 is -C(RQ(R9)-, Y is C(R8)(R9)-, Ri is heteroaryl optionally substituted with one or more Ré, R2 îs H, R3 is H, and R4 is H, halogen, -OH, -NH2, -CN, Ci-C6 alkyl, CrC6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7In one embodiment, at least one of Xj, X2, or X3 is N, Ai is -C(R8)(R9)- A2 is -O-, Y is C(RS)(R9)-, Ri is heteroaryl optionally substituted with one or more R6, R2 is H, R3 is H, and R4 is H, halogen, -OH, -NH2, -CN, Ci-C6 alkyl, CpCô alkoxy, C2-C6 alkenyl, or C2-Cô alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7.
In one embodiment, one of Xi, X2, X3 is C(Rs), Ai is -O-, A? is -C(R8)(R9)-, Y îs -C(R8)(R9)-, Ri is heteroaryl optionally substituted with one or more R,„ R2 is H, R3 is H, and R4 is H, halogen, OH, -NH2, -CN, Ci-Cô alkyl, CrC6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7.
In one embodiment, one of Xb X2, X3 is C(R3), Aj is -C(R8)(R9)-, A2 is -O-, Y is -C(R8)(R9)-, Ri is heteroaryl optionally substituted with one or more R^, R2 is H, R3 is H, and R4 is H, halogen, OH, -NH2, -CN, CrC6 alkyl, Ci-C6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7.
In one embodiment, at least one of Xj, X2, or X3 is N, A) is -O-, A2 is -C(R8)(R9)-, Y is C(Rs)(R9)-, Rj is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Rf,, R2 is halogen, R3 is H, and R4 is H, halogen, -OH, NH2, -CN, Ci-C6 alkyl, Ci-C6 alkoxy, C2-Cô alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7.
In one embodiment, at least one of Xi, X2, or X3 is N, Ai is -C(R8)(R9)-, A2 is —O-, Y is — C(Rs)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionaliy substituted with one or more Rg, R2 is halogen, R3 is H, and R4 is H, halogen, -OH, NH2, -CN, Ci-Cg alkyl, Cj-C6 alkoxy, C2-Cg alkenyl, or C2-Cs alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionaliy substituted with one or more R7.
In one embodiment, one of Xi, X2, X3 is C(R3), Ai is -O-, A2 is -C(R8)(R9)-, Y is -C(RsXRÿ)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionaliy substituted with one or more Rg, R2 is halogen, R3 is H, and R4 is H, halogen, -OH, —NH2, —CN, Cp C6 alkyl, CpCg alkoxy, C2-Cg alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionaliy substituted with one or more R7.
In one embodiment, one of Xi, X2, X3 is C(Rg), Aj is -C(R8)(R9)-, A2 is -O-, Y is -C(R8XR9)-, R| is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionaliy substituted with one or more Rg, R2 is halogen, R3 is H, and R4 is H, halogen, -OH, -NH2, -CN, Cp Cg alkyl, Cj-Cg alkoxy, C2-Câ alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionaliy substituted with one or more R7.
In one embodiment, at least one of Xi, X2, or X3 is N, Ai is -O-, A2 is —C(R8)(R9)—, Y is — C(R8XR9)-, Ri is heterocyclyl optionaliy substituted with one or more Rg, R2 is halogen, R3 is H, and R4 is H, halogen, -OH, -NH2, -CN, CpCg alkyl, CpCg alkoxy, C2-Cg alkenyl, or C2-Cg alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionaliy substituted with one or more R7.
In one embodiment, at least one of X(, X2, or X3 is N, Ai is -C(R8XR9)-, A2 is -O-, Y is C(R8XR9)-, Ri is heterocyclyl optionaliy substituted with one or more Rg, R2 is halogen, R3 is H, and R4 is H, halogen, -OH, -NH2, -CN, CpCg alkyl, CpCg alkoxy, C2-Cg alkenyl, or C2-Cg alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionaliy substituted with one or more R7.
In one embodiment, one of Xj, X2, X3 is C(Rs), Ai is -O-, A2 is -C(R8)(R9)-, Y is -C(R8XR9)-, Rj is heterocyclyl optionaliy substituted with one or more Rg, R2 is halogen, R3 is H, and R4 is H, halogen, -OH, -NH2, -CN, CpCg alkyl, CpCg alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionaliy substituted with one or more R7.
In one embodiment, one of Xi, X2, X3 is C(Rs), Ai is -C(R8XR9)-, A2 is -O-, Y is -C(R8)(R9)-, Ri is heterocyclyl optionaliy substituted with one or more Rg, R2 is halogen, R3 is H, and R4 is H, halogen, -OH, -NH2, -CN, CpCg alkyl, CpCg alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionaliy substituted with one or more R7.
In one embodiment, at least one of Xi, X2, or X3 is N, Ai is —O-, A2 is -C(Rs)(R9)-, Y is — C(R8)(R9)-, Ri is heteroaryl optionaliy substituted with one or more Rg, R2 is halogen, R3 is H, and 49
R4 is H, halogen, -OH, -NH2, -CN, C(-C6 alkyl, Cj-Cè alkoxy, C2-Ce alkenyl, or CG-Q, alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7.
In one embodiment, at least one of Xb X2, or X3 is N, Ai is -C(R8)(R9)-, A2 is -O-, Y is C(R8)(R9)~, R) is heteroaryl optionally substituted with one or more Rü, R2 is halogen, R3 is H, and R4 is H, halogen, -OH, -NH2, -CN, C,-C6 alkyl, CrC6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7.
In one embodiment, one of Xb X2, X3 is C(Rî), Ai is —O—, A2 is —C(R8)(R9)—, Y is —C(R8)(R9)—, Ri is heteroaryl optionally substituted with one or more Rè, R2 is halogen, R3 is H, and R4 is H, halogen, -OH, -NH2, -CN, C]-C6 alkyl, Ci-Cè alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7.
In one embodiment, one of Xb X2, X3 is C(Rs), Ai is -C(R8)(R9)-, A2 is -O-, Y is -C(R8)(R9)-, R] is heteroaryl optionally substituted with one or more R&, R? is halogen, R3 is H, and R4 is H, halogen, -OH, -NH2, -CN, Cj-C& alkyl, CrC6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R?.
In one embodiment, at least one of Xb X2, or X; is N, Ai is -O-, A2 is -C(R8)(R9)-, Y is C(RB)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R6, R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, CrC6 alkyl, Ci-C6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 is H.
In one embodiment, at least one of Xb X2, or X3 is N, Ai is -C(R8)(R9)-, A2 is -O-, Y is C(Rs)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more 1%, R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, CrC6 alkyl, Ci-C6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 is H.
In one embodiment, one of Xb X2, X3is QR5), Ai is -O-, A2 is -C(R8)(R9)-, Y is -C(R8)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R6, R2 and R3 are independently at each occurrence H, halogen, -OH, NH2, -CN, C^Cô alkyl, CrC6 alkoxy, C2-C6 alkenyl, or C3-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 is H.
In one embodiment, one of Xb X2, X3 is QRs), Ai is -C(R8)(R9)-, A2 is -O-, Y is -C(R8)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R9, R2 and R3 are independently at each occurrence H, halogen, -OH,
NH2, -CN, C1-C6 alkyl, CrC6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 is H.
In one embodiment, at least one of Xi, X2, or X3 is N, Ai is -O-, A2 is -C(Rg)(R9)-, Y is C(R8XR9)-, Ri is heterocyclyl optionally substituted with one or more Ré, R2 and R3 are independently at each occun'ence H, halogen, -OH, -NH2, -CN, Ci-Ce alkyl, Cj-Cé alkoxy, C2-Cé alkenyl, or C2-Cé alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 is H.
In one embodiment, at least one of X[, X2, or X3 is N, A| is -C(R8)(R9)-, A2 is -O-, Y is C(R8XR9)-, Rj is heterocyclyl optionally substituted with one or more Ré, R2 and R3 are independently at each occurrence H, halogen, —OH, —NH2, —CN, Ci-Cé alkyl, Cj-Ce alkoxy, C2-Cé alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 is H.
In one embodiment, one of Xi, X2, Xî is C(Rs), A| is -O-, A2 is -C(R8)(R9)-, Y is -C(RsXRü)-, Ri is heterocyclyl optionally substituted with one or more R6, R? and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, Ci-C& alkyl, Ci-Cé alkoxy, C2-Cé alkenyl, or C2-Cé alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 îs H.
In one embodiment, one of Xi, X2, X3 is C(Rs), Ai is -C(R8XR9)-, A2 is -O-, Y is -C(R8XR9)-, R| îs heterocyclyl optionally substituted with one or more R6, R2 and Rj are independently at each occurrence H, halogen, —OH, —NH2, —CN, C|-C$ alkyl, Cj-Cé alkoxy, C2-Cé alkenyl, or C2-Cé alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 is H.
In one embodiment, at least one of Xj, X2, or X3 is N, Ai is -O-, A2 is -C(RgXR9)-, Y is C(R8XR9)-, Ri îs heteroaryl optionally substituted with one or more R6, R2 and R} are independently at each occurrence H, halogen, —OH, -NH2, -CN, Ci-Cé alkyl, Cj-Cé alkoxy, C2-Cé alkenyl, or C2C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 is H.
In one embodiment, at least one of Xi, X2, or Xj is N, Ai is -C(R8XR9)-, A2 is -O-, Y is C(R8XR9)-, Ri is heteroaryl optionally substituted with one or more R6, R2 and R3 are independently at each occun'ence H, halogen, -OH, —NH2, —CN, Ci-Cé alkyl, Ci-Cé alkoxy, C2-Cé alkenyl, or C2Cé alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 is H.
In one embodiment, one of X], X2, X3 is C(Ré), Aj is —O—, A2 is —C(R8XR9)—, Y is — C(RgXR9)—, Ri is heteroaryl optionally substituted with one or more Rg, R2 and R3 are independently at each occurrence H, halogen, -OH, —NH2, —CN, C]-Cé alkyl, C|-C9 alkoxy, C2-Cé alkenyl, or C2-Cfi alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 is H.
In one embodiment, one of Xi, X2, X3 is C(Rs), Ai is -C(R8XR9)-, A2 is -O-, Y is ~C(R8XR9)-, R) is heteroaryl optionally substituted with one or more Ré, R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, Ci-Cé alkyl, Cj-Cé alkoxy, C2-Cé alkenyl, or C2-Cé alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 is H.
In one embodiment, at least one of Xi, X2, or X3 is N, Ai is -O—, A2 is — C(R8XR9)—, Y is C(R8XR9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Re, R2 is H, R3 is H, and R4 is H.
In one embodiment, at least one of X|, X2, or X3 is N, A| is -C(R8XR9)-> A2 is -O-, Y is C(R8XR9)-, Rj is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ré, R2 is H, R3 is H, and R4 is H.
In one embodiment, one of Xj, X2, X3 is C(Rj), Ai is -O-, A2 is —C(R8XR9)~, Y is -C(R8XR9)-, R] is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ré, R2 is H, R3 is H, and R4 is H.
In one embodiment, one of Xi, X2, X3 is C(Ré), Ai is — CfRgXRé)—, A2 is -O-, Y is -C(RgXR9)—, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ré, R2 is H, R3 is H, and R4 is H.
In one embodiment, at least one of Xj, X2, or X3 is N, A| is -O-, A2 is -C(R8XR9)-, Y is C(RSXR9)-, Ri is heterocyclyl optionally substituted with one or more R6, R2 is H, R3 is H, and R4 is H.
In one embodiment, at least one of Xi, X2, or X3 is N, Ai is -C(R8)(R9)-, A2 is -O-, Y is C(RsXR9)-, R] is heterocyclyl optionally substituted with one or more Ré, R2 is H, R3 is H, and R4 is H.
In one embodiment, one of Xi, X2, X3 is C(Rs), Ai is -O-, A2 is —C(R8XR9)—, Y is —C(R8)(R9)-, Ri is heterocyclyl optionally substituted with one or more Re, R2 is H, R3 is H, and R4 is H.
In one embodiment, one of Xj, X2, X3 is C(Ré), Ai is -C/RgXRç)-, A2 is -O-, Y is — C(R8XR9)-, Ri is heterocyclyl optionally substituted with one or more Ré, R2 is H, R3 is H, and R4 is H.
In one embodiment, at least one of Xb X2, or X3 is N, Ai is -O-, A2 is -C(R8)(R9)-, Y is C(R8)(R9)-, Ri is heteroaryl optionally substituted with one or more Ré, R2 is H, Rj is H, and R4 is H.
In one embodiment, at least one of Xb X2, or X3 is N, A] is -C(Rg)(R9)—, A2 is -O-, Y is C(R8)(R9)~, Ri is heteroaryl optionally substituted with one or more R6, R2 is H, R3 is H, and R4 is H.
In one embodiment, one of Xb X2, X3 is C(R5), Ai is -O-, A2 is -C(R8)(R9)-, Y is -C(R8)(R9)-, Rj is heteroaryl optionally substituted with one or more Ré, R2 is H, R3 is H, and R4 is H.
In one embodiment, one of Xb X2, X3 is C(R.s), Ai is -C(R8)(R9)-, A2 is -O-, Y is -C(Rg)(R9)-, Ri is heteroaryl optionally substituted with one or more Ré, R2 is H, R3 is H, and R4 is H,
In one embodiment, at least one of X], X2, or X3 is N, Aj is -O-, A2 is -C(R8)(R9)—, Y is — C(R8)(R9)- R| is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Re, R2 is halogen, R3 is H, and R4 is H,
In one embodiment, at least one of Xb X2, or X3 is N, A] is -C(R8)(R9)-, A2 is -O-, Y is C(R8)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R&, R2 is halogen, R3 is H, and R4 is H.
In one embodiment, one of Xb X2, X3 is C(Rs), Ai is -O-, A2 is -C(Rg)(R9)-, Y is -C(R8)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ré, R2 is halogen, R3 is H, and R4 is H.
In one embodiment, one of Xb X2, X3 is CfRs), Ai is —C(R8)(R9)-, A2 is -O~, Y is -C(R8)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Re, R2 is halogen, R3 is H, and R4 is H.
In one embodiment, at least one of Xb X2, or X3 is N, Ai is -O-, A2 is -C(R8)(R9)-, Y is C(R8)(R9)-, Ri is heterocyclyl optionally substituted with one or more Ré, R2 is halogen, R3 is H, and R4 is H.
In one embodiment, at least one of Xj, X2, or X3 is N, Ai is —C(R8)(R9)—, A2 is —O-, Y is — C(R8)(R9)-, Ri is heterocyclyl optionally substituted with one or more R6, R2 is halogen, R3 is H, and R4 is H.
In one embodiment, one of Xj, X2, X3 is C(Ré), Ai is -O-, A2 is -C(R8)(R9)-, Y is -C(R8)(R9)~, Ri is heterocyclyl optionally substituted with one or more Ré, R2 is halogen, R3 is H, and R4 is H.
In one embodiment, one of Xb X2, X3 is C(Rs), Ai is -C(R8)(R9)-, A2 is -O-, Y is -C(R8)(R9)-, Rj is heterocyclyl optionally substituted with one or more Ré, R2 is halogen, R3 is H, and R4 is H.
In one embodiment, at least one of Xi, X2, or Xs îs N, Ai is —O-, A2 is — C(R8)(R9) » Y is C(Rg)(R9)-, Ri is heteroaryl optionally substituted with one or more Rô, R2 is halogen, Rj is H, and R4 is H.
In one embodiment, at least one of Xb X2, or X3 is N, Aj is -C(R8)(R9)—, A2 is -O-, Y is C(RK)(R9)-, Ri is heteroaryl optionally substituted with one or more R6, R2 is halogen, Rj is H, and R4 is H.
In one embodiment, X is C(R3), A) is -O-, A2 is -C(R8)(R9)—, Y îs —C(Rs)(R9)~, Ri is heteroaryl optionally substituted with one or more R&, R2 is halogen, R3 is H, and R4 is H.
In one embodiment, X is C(R$), Ai is -C(R8)(R9)—, A2 is -O-, Y is — C(R8)(R9)—, Ri îs heteroaryl optionally substituted with one or more Rf„ R2 is halogen, R3 is H, and R4 is H.
In one embodiment, at least one of Xb X2, or X3 is N, A] is -O-, A2 is —C(R8)(R9)-, Y is C(R8)(R9)-, R| is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Re, R2 and R3 are îndependently at each occurrence H, halogen, -OH, -NH2, -CN, CrC6 alkyl, Ci-C6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 and R9 can form C3-Cio cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, at least one of Xi, X2, or X3 is N, Aj is -C(R8)(R9)-, A2 is -O-, Y is C(R8)(R9)- R1 îs heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R6, R2 and R3 are îndependently at each occurrence H, halogen, -OH, -NH2j -CN, CrC6 alkyl, CrC6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 and R9 can fonn CrCi0 cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, one of Xb X2, X3 is C(Rj), Ai is -O-, A2 is -C(R8)(R9)—, Y is -C(R8)(R9)-, Ri îs heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R6, R2 and R3 are îndependently at each occurrence H, halogen, -OH, NH2, -CN, Cj-C6 alkyl, Ci-C6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 and R9 can fonn C3-C10 cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, one of Xb X2, X3 is C(Rs), Ai is -C(R8)(R9)—, A2 is -O-, Y is -C(R8)(R9)—, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R6, R2 and R3 are îndependently at each occurrence H, halogen, -OH, NH2, -CN, CrC6 alkyl, CrC6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy.
alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 and R9 can form Cj-Cw cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, at least one of Xi, X2, or Xj is N, Ai is -O-, A2 is -C(R8)(R9)-, Y is — C(R8)(R9)- Ri is heterocyclyl optionally substituted with one or more Rg, R2 and R3 are independently at each occurrence H, halogen, —OH, —NH2, -CN, Cj-Cg alkyl, Ci-Cg alkoxy, C2-Cg alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R?, and R4 and Rg can form C3-C10 cycloalkyl, C5-C3 cycloalkenyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, at least one of Xb X2, or X3 is N, Ai is -C(R8)(R9)-, A2 is -O-, Y is C(R8)(R9)- Ri is heterocyclyl optionally substituted with one or more Rg, R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, C[-C6 alkyl, CpCg alkoxy, C2-Cg alkenyl, or C2-Cg alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 and R9 can form C3-Ci0 cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, one of Xi, X2, X3 is C(R3), Ai is -O-, A2 is -C(R8)(R9)-, Y is —C(R8)(R9)-, Ri is heterocyclyl optionally substituted with one or more Rg, R2 and R3 are independently at each occurrence H, halogen, -OH, —NH2, -CN, Ci-Cg alkyl, Ci-Cg alkoxy, C2-Cg alkenyl, or C2-Cg alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 and R9 can form C3-C10 cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, one of Xi, X2, X3 is C(R3), Ai is -C(R8)(R9)-, A2 is -O-, Y is -C(R8)(R9)-, Ri is heterocyclyl optionally substituted with one or more Rg, R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, Ci-Cg alkyl, CpCg alkoxy, C2-Cg alkenyl, or C2-Cg alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 and R9 can form C3-Ci0 cycloalkyl, Cs-Cs cycloalkenyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, at least one of Xb X2, or X3 is N, Ai is -O-, A2 is -C(R8)(R9)-, Y is C(R8)(R9)-, Ri is heteroaryl optionally substituted with one or more Rg, R2 and R3 are independently at each occun'ence H, halogen, -OH, -NH2, -CN, Cj-Cg alkyl, C|-Cg alkoxy, C2-Cg alkenyl, or C2C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 and R9 can form C3-Ci0 cycloalkyl, CrC8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, at least one of Xj, X2, or X3 is N, Ai is -C(R8)(R9)-, A2 is -O-, Y is C(R8)(R9)-, Ri is heteroaryl optionally substituted with one or more Rg, R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, C1-C0 alkyl, CpCg alkoxy, C2-Cg alkenyl, or C2
C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and IG and R 5 can form C3-C1Ü cycioalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl. In one embodiment, one of Xi, X2, X3 is C(R3), Ai is -O-, A2 is -QRsXRç)-, Y is -CtRgXR?)-, Ri îs heteroaryl optionally substituted with one or more Ré, R2 and R3 are independently at each occurrence H, halogen, —OH, —NH2, —CN, Ci-Cé alkyl, Ci-Cé alkoxy, C2-Cé alkenyl, or C2-Cé alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl îs optionally substituted with one or more R7, and IG and R9 can form C3-C10 cycioalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, one of Xb X2, X3 is C(R;), A] is -C(Rg)(R())-, A2 îs -O-, Y is -C(R8)(R9)-, Ri is heteroaryl optionally substituted with one or more R6, R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, C|-C& alkyl, Cj-Cé alkoxy, C2-Cg alkenyl, or C2-Cé alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 and R9 can form C3-Cl0 cycioalkyl, C5-Cg cycloalkenyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, at least one of Xi, X2, or X3 is N, Ai is -O-, A2 is -C(RgXR9)—, Y is — C(R8)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ré, R2 is H, R3 is H, and IG and Rg can form C3-Cio cycioalkyl, C5-Cg cycloalkenyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, at least one of Xb X2, or X3 is N, A| is -CfRgXRg)-, A2 is -O-, Y is C(Rg)(Rg)-, Rj is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R6, R2 is H, R3 is H, and R4 and R9 can form C3-Cio cycioalkyl, C5-Cg cycloalkenyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, one of Xi, X2, X3 is C(R3), Ai is -O-, A2 is -C(R8)(R9)-, Y is -C(R8)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ré, R2 is H, R3 is H, and R4 and R 9 can form C3-Cio cycioalkyl, Cs-Cg cycloalkenyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, one of X|, X2, X3 is C(Rs), Ai is -C(Rg)(R9)-, A2 is -O-, Y îs -C(R8XR9)-, Ri îs heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ré, R2 is H, R3 is H, and 1¾ and R9 can form C3-C1() cycioalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, at least one of Xb X2, or X3 is N, Ai is -O-, A2 is -C(RsXRg)-, Y is C(R8XRg)-, Ri is heterocyclyl optionally substituted with one or more R6, R2 is H, R3 is H, and R4 and R9 can form C3-Ci0 cycioalkyl, C3-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, at least one of Xi, X2, or X3 is N, A| is -C(R8)(R9)-, A? is -O-, Y is C(R8)(R9)-, Ri is heterocyclyl optionally substituted with one or more Rô, R2 is H, R3 is H, and R4 and R9 can fonn C3-Cw cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, one of Χι, X2, X3 is C(Rs), Ai is -O-, A2 is -C(R8)(R9)-, Y is -C(R8)(R9)-, Ri is heterocyclyl optionally substituted with one or more Rg, R? is H, R3 ts H, and R4 and Rg can form C3-Cio cycloalkyl, Cj-Cg cycloalkenyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, one of Xb X2, X3 is C(Rj), A] is -C(R8)(R9)-, A2 is -O-, Y is -C(Rg)(R9)-, Ri is heterocyclyl optionally substituted with one or more R6, R2 is H, R3 is H, and R4 and R9 can form C3-C10 cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, at least one of Xi, X2, or X3 is N, Ai is -O-, A2 is -C(R8)(R9)-, Y is C(R8)(R9)-, Ri is heteroaryl optionally substituted with one or more R^, R2 is H, R3 is H, and R4 and R9 can form C3-Cio cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, at least one of Xi, X2, or X3 is N, Ai is -C(R8)(R9)-, A2 is -O-, Y is C(RS)(R9)-, Ri is heteroaryl optionally substituted with one or more R3, R2 is H, R3 is H, and R4 and R9 can fonn C3-Ci0 cycloalkyl, C3-Cs cycloalkenyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, one of Xb X2, X3 is C(R3), A; is-O-, A2 is -C(Rg)(R9)-, Y is -C(Rg)(R9)-, Ri is heteroaryl optionally substituted with one or more Rg, R2 is H, R3 is H, and R4 and R 9 can fonn C3-Cio cycloalkyl, CYC3 cycloalkenyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment. one of Xj, X2, X3 is C(R3), Ai is -C(R8)(R9)~, A2 is -O-, Y is -C(R8)(R9)-, Ri is heteroaryl optionally substituted with one or more Rô, R2 is H, R3 is H, and R4 and R9 can form C3-C10 cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl
In one embodiment, at least one of Xi, X2, or X3 is N, Ai is -O-, A2 is -C(R8)(R9)-, Y is C(R8)(R9)-, R, is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Rg, R2 is halogen, R3 is H, and R4 and Ry can fonn C3-Cjo cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, at least one of Xi, X2, or X3 is N, Ai is -C(R8)(R9)—, A2 is —O-, Y is C(R8)(R9)-> Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R9, R2 is halogen, R3 is H, and R4 and R9 can fonn C3-Cio cycloalkyl, C3-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, one of Xi, X2, X3 is C(Rs), Ai is -O-, A2 is -C(R8)(R9)~, Y is -C(R8)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ré, R2 is halogen, R3 is H, and R4 and Ry can form C3-Cio cycloalkyl, Cs-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, one of X], X2, X3 is C(Rs), Ai is -C(R8)(Rq)-, A2 is -O-, Y is -C(R8)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R$, R? is halogen, R3 is H, and R4 and R9 can form C3-Cio cycloalkyl, C$-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, at least one of Xi, X2, or X3 is N, A] is -O-, A2 is —C(R8)(R9)-, Y is — C(R8)(R9)-, Ri is heterocyclyl optionally substituted with one or more R6s R2 is halogen, R3 is H, and R4 and R9 can form C3-Ci0 cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, at least one of X|, X2, or X3 is N, Aj is -C(R8)(R9)-, A2 is -O-, Y is — C(R8)(R9)-, Ri is heterocyclyl optionally substituted with one or more R$, R2 is halogen, R3 is H, and R4 and R9 can form C3-C)0 cycloalkyl, C5-Cs cycloalkenyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, one of Xj, X2, X3 is C(Rî), Ai is -O-, A2 is -C(R8)(R9)-, Y is -C(R8)(R9)-, Ri is heterocyclyl optionally substituted with one or more R$, R2 is halogen, R3 is H, and R4 and R9 can form C3-C|0 cycloalkyl, C5-Cs cycloalkenyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, one of Xj, X2, X3 is C(Rs), Ai is -C(R8)(R9)-, A2 is -O-, Y is -C(R8)(R9)-, Ri is heterocyclyl optionally substituted with one or more R$, R2 is halogen, R3 is H, and R4 and R9 can form C3-C]o cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, at least one of Xi, X2, or X3 is N, Ai is -O-, A2 is -C(Rg)(R9)-, Y is C(R8)(R9)-, Ri is heteroaryl optionally substituted with one or more R(„ R2 is halogen, R3 is H, and R4 and R9 can form C3-C10 cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, at least one of Xi, X2, or X3 is N, Ai is -C(R8)(R9)-, A2 is -O-, Y is C(R8)(R9)-, Ri is heteroaryl optionally substituted with one or more R$, R2 is halogen, R3 is H, and R4 and R9 can form C3-CiU cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, one of Xi, X2, X3 is C(R$), Ai is -O-, A2 is -C(R8)(R9)-, Y is -C(R8)(R9)-, Ri is heteroaryl optionally substituted with one or more R6, R2 is halogen, R3 is H, and R4 and R9 can form C3-CI0 cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, one of X), X2, X3 is C(R3), Ai is -C(R8)(R9)-, A2 is -O-, Y is -C(R8)(R9)-, Ri is heteroaryl optionally substituted with one or more R6, R2 is halogen, R3 is H, and R4 and R9 can form C3-Cio cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl.
In one embodiment, at least one of X[, X2, or X3 is N, Ai is -O-, A2 is -C(R8)(R9)~, Y is C(R8)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R$, R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, Ci-C6 alkyl, Cj-C6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 and R9 can form heterocyclyl.
In one embodiment, at least one oi Xi, X2, or Xj is N, Ai is —C(Rg)(R9)—, A2 is —O—, Y is — C(RrXR9)- Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R&, R? and Rj are mdcpendently at each occurrence H, halogen, -OH, -NH2, -CN, CrC6 alkyl, CrC6 alkoxy, C2-C0 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 and Ro can form heterocyclyl.
In one embodiment, one of Χμ X2, X3 is C(Rs), Ai is —O—, A2 is — C(Rg)(R9)—, Y is —C(Rg)(R9)—, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Rft, R2 and R3 are independently at each occurrence H, halogen, -OH, NH2, -CN, CrCb alkyl, CrC6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 and Ry can form heterocyclyl.
In one embodiment, one of X|, X2, X3 is CfRs), Ai îs -C(R8)(R9)-, A2 is -O-, Y is -C(R8XR9)—, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^, R2 and R3 are independently at each occurrence H, halogen, —OH, — NH2, -CN, C|-C(, alkyl, CrC6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 and R9 can form heterocyclyl.
In one embodiment, at least one of Xi, X2, or X3 is N, A] is —O—, A2 is —C(R8XR9)—, Y is — C(RsXR9)-, Ri is heterocyclyl optionally substituted with one or more R6, R2 and Rj are independently at each occurrence H, halogen, -OH, -NH2, -CN, Ci-C& alkyl, Ci-Cè alkoxy, C2-C9 alkenyl, or C2-Cû alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 and R9 can form heterocyclyl.
In one embodiment, at least one of Xi, X2, or Xj is N, A] is —C(RgXR9)—, A2 is -O-, Y is — C(R8XR9)-, Ri îs heterocyclyl optionally substituted with one or more R6) R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, Ci-Cô alkyl, Ci-Ce alkoxy, C2-C6 alkenyl, or C2-Cô alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Xi, X2, Xj is C(Rs), A] is -O-, A2 is -C(R8)(R9)—> Y is -CiReXRç)-, Ri is heterocyclyl optionally substituted with one or more R&, R2 and R3 are independently at each occurrence H, halogen, —OH, —NH2, -CN, Ci-C^ alkyl, Ci-C& alkoxy, C2-Cè alkenyl, or C2-Cô alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 and R 9 can form heterocyclyl.
In one embodiment, one of Xb X2, X3 is C(Rj), A| is -C(R8)(R9)-, A2 is -O-, Y is -C(R8)(R9)-, Ri îs heterocyclyl optionally substituted with one or more Ré, R2 and R3 are independently at each occurrence H, halogen, —OH, —NH2, —CN, C|-Cé alkyl, Ci-Cé alkoxy, C2-Cé alkenyl, or C2-Cé alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 and Ro can form heterocyclyl.
In one embodiment, at least one of Xj, X2, or X3 is N, Ai is —O-, A2 is —C(R8)(R9)-, Y is — C(R8)(R9)-, Ri is heteroaryl optionally substituted with one or more R6, R2 and R3 are independently at each occurrence H, halogen, —OH, — NH2, —CN, Cj-Cé alkyl, Cj-Cé alkoxy, C2-C& alkenyl, or C2C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 and R9 can form heterocyclyl.
In one embodiment, at least one of Xi, X2, or X3 is N, Ai is —C(R8)(R9)-, A2 is —O-, Y is — C(R8)(R9)-, Ri is heteroaryl optionally substituted with one or more R6, R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, Ci-Cé alkyl, Cj-Cé alkoxy, C2-Cé alkenyl, or C2C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Xb X2, X3 is C(Rs), A, is -O-, A2 is -C(R8)(R9)-, Y is -C(R8)(R9)-, Ri is heteroaryl optionally substituted with one or more Ré, R2 and R3 are independently at each occurrence H, halogen, —OH, —NH2, —CN, C|-Cé alkyl, Ci-Cé alkoxy, C2-Cé alkenyl, or C2-Cé alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Xb X2, X3 is C(R3), Ai is —C(R8)(R9)—, A2 is -O-, Y is -C(Rg)(R9)—, Ri îs heteroaryl optionally substituted with one or more Ré, R2 and R3 are independently at each occurrence H, halogen, —OH, —NH2, —CN, Cj-Cé alkyl, Ci-Cé alkoxy, C2-Cé alkenyl, or C2-Cé alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 and R9 can form heterocyclyl.
In one embodiment, at least one of Xb X2, or X3 is N, A| is -O-, A2 is -C(R8)(R9)—, Y is C(R8)(R9)-, R1 is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ré, R2 is H, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, at least one of Xb X2, or X3 îs N, Ai is —C(Rg)(R9)—, A2 is —O-, Y is — C(R8XR9)- Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ré, R2 is H, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Xi, X2, X3 is C(Rj), A( is -O-, A2 is -C(R8)(R9)-, Y is -C(R8)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Rb, R2 is H, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Xj, X2, X3 is C(R$), Aj is -C(Rs)(R9)-, A2 is -O-, Y is -C(R8)(R9)~, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^, R2 is H, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, at least one of X], X2, or X3 is N, A! is -O-, A2 is -C(R8)(R9)-, Y is C(R8)(R9)-, R] is heterocyclyl optionally substituted with one or more Rô, R2 is H, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, at least one of Xj, X2, or X3 is N, Ai is -C(R8)(R9)~, A2 is -O-, Y is — C(R8)(R9)-, R] is heterocyclyl optionally substituted with one or more R6, R2 is H, R3 îs H, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Xi, X2, X3 is C(R?), Ai is -O-, A2 is -C(RsXRy)-, Y is -C(Rg)(R9)-, Ri is heterocyclyl optionally substituted with one or more R&, R2 is H, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Xi, X2, X3 is C(Rj), Ai is -C(Rg)(R9)-, A2 is —O—, Y is -C(R8)(R9)~, Rj is heterocyclyl optionally substituted with one or more Rt„ R2 is H, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, at least one of Xi, X2, or X3 is N, Ai is -O-, A2 is -C(R8)(R9)—, Y is — C(R8)(R9)-, Ri is heteroaryl optionally substituted with one or more Re, R2 is H, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, at least one of Xi, X2, or X3 is N, Ai is —C(R8)(R9)-, A2 is -O-, Y is — C(Rg)(R9)-, Ri is heteroaryl optionally substituted with one or more R^, R2 is H, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, one of X[, X2, X3 îs C(Rs), Ai is —O-, A2 is -C(Rg)(R9)-, Y is -C(R8)(R9)-, Ri îs heteroaryl optionally substituted with one or more Rô, R2 is H, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Xi, X2, X3 is C(Rs), Ai is -C(R8)(R9)-, A2 is -O-, Y is -C(Rg)(R9)-, Ri is heteroaryl optionally substituted with one or more R9, R2 is H, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, at least one of Xb X2, or X3 is N, Ai is -O-, A2 is -C(R8)(R9)-, Y is C(R8)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R&, R2 is halogen, R3 is H, and R; and R9 can iorm heterocyclyl.
In one embodiment, at least one of Xi, X2, or X3 is N, A| is -CÎRsXRq)—, A2 is -O-, Y is — C(Rs)(R9)- Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl îs optionally substituted with one or more R6, R2 is halogen, R3 îs H, and R4 and R9 can fonn heterocyclyl.
In one embodiment, one of Xi, X2, X3 is C(Rj), A; is —O—, A2 is — CtRgXRç)—, Y is — C(R8XR9)—5 Ri îs heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^, R2 is halogen, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Xj, X2, X3 is C(R3), A; is -C(R8)(R9)-, A2 is —O-, Y îs -C(R8XR9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl îs optionally substituted with one or more R(,, R2 îs halogen, R3 is H, and R4 and R9 can lorm heterocyclyl.
In one embodiment, at least one of Xi, X2, or X3 is N, Ai is —O—, A2 is —C(R8XR9)—, Y is — C(R8XRq)-, R| is heterocyclyl optionally substituted with one or more R6, R2 is halogen, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, at least one of Xi, X2, or X3 is N, Aj is —C(R8XR9)—, A2 îs -O-, Y is — C(Rs)(R9)-, Ri is heterocyclyl optionally substituted with one or more R6, R2 is halogen, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Xi, X2, X3 is C(Rs), A] is -O-, A2 îs -C(R8XR9)-, Y is -C(Rg)(Rÿ)-, Ri is heterocyclyl optionally substituted with one or more Rg, R2 is halogen, R3 is H, and R4 and R9 can fonn heterocyclyl.
In one embodiment, one of Xi, X2, X3 is C(Rs), Aj is -C(R8XR9)-, A2 is -O-, Y is -CîRsHRq)-, Ri îs heterocyclyl optionally substituted with one or more R(„ R2 îs halogen, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, at least one of Xi, X2, or X3 is N, Aj is -O-, A2 is -C(R8)(R9)—, Y is — C(R8)(R9)-, R] is heteroaryl optionally substituted with one or more R6, R2 îs halogen, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, at least one of Xi, X2, or X3 is N, Aj is — C(R8XR9)-, A2 is -O-, Y is — C(R8XR9)-, Ri is heteroaryl optionally substituted with one or more R6, R2 is halogen, R3 is H, and R4 and R9 can fonn heterocyclyl.
In one embodiment, one of Xi, X2, X3 is C(R;), Ai is -O-, A2 is -CfRsXRij-, Y is -C(R8)(R9)-, Ri is heteroaryl optionally substituted with one or more Ré, R2 is halogen, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Xj, X2, X3 is C(Rj), At is — C(R8)(R9)—, A2 is -O-, Y is —C(R8)(R9)—, Ri is heteroaryl optionaliy substituted with one or more Rg, R2 is halogen, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Xi, X2, X3 is CtRg), wherein R5 is H, halogen, -CN, —OR8, -NR8R9, C(O)R8, -C(O)OR8, -C(O)NR8R9, -NRgC(O)R9, -S(O)R8j -S(O)2R8, -NR8S(O)2R9, -S(O)2NR8R9, CpCg alkyl, CpCg haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-Cw cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl, A] is -O-, A2 is -C(Rs)(R9)—, Y is -C(Rg)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionaliy substituted with one or more R6, R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, CpCg alkyl, CpCÊ alkoxy, C2-Cg alkenyl, or C2-Cg alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionaliy substituted with one or more R7, and R4 is H.
In one embodiment, one of Xj, X2, X3 is C(Rs), wherein R5 is H, halogen, -CN, —ORg, —NR3R9, — C(O)R8, -C(O)ORs, -C(O)NRsR9, -NR8C(O)R9, -S(O)R8, -S(O)2R8, -NR8S(O)2R9, -S(O)2NRsR9, CpCg alkyl, CrC6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-Cw cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl, Ai is -C(R8)(R9)-, A2 is -O-, Y is -C(R8)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionaliy substituted with one or more Rg, R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, CpCg alkyl, CpCg alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionaliy substituted with one or more R7, and R4 is H.
In one embodiment. one of Xi, X2, X3 is C(Rs), wherein R5 is H, halogen, —CN, -ORg, —NRgRg, — C(O)Rg, -C(O)ORg, -C(O)NR8R9, -NRgC(O)R9, -S(O)R8, -S(O)2Rg, -NR8S(O)2R9, -S(O)2NR8R9, CpCg alkyl, CpC6 haloalkyl, C2-Cg alkenyl, C2-Cg alkynyl, C3-Ci0 cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl, A| is -O-, A2 is -C(R8)(R9)-, Y is -C(R8)(R9)-, R» is heterocyclyl optionaliy substituted with one or more R6, R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, CpCg alkyl, CpCg alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionaliy substituted with one or more R7, and R4 is H.
In one embodiment, one of Xi, X2, X3 is C(R5), wherein R5 is H, halogen, -CN, — OR8, -NR8R9, C(O)R8, -C(O)OR8s -C(O)NR8R9, -NR8C(O)R9, -S(O)Rs, -S(O)2R8, -NR8S(O)2R9, -S(O)2NR8R9, CpCg alkyl, CpC6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-Ci0 cycloalkyl, C5-Cg cycloalkenyl, heterocyclyl, aryl, or heteroaryl, Ai is -C(R8)(R9)-, A2 is -O-, Y is -C(R8)(R9)-, Rj is heterocyclyl optionaliy substituted with one or more Rg, R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, CpCg alkyl, CpCg alkoxy, C2-Cg alkenyl, or C2-Cg alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionaliy substituted with one or more R7, and R4 is H.
In one embodiment, one of Xb X2, X3 is C(Rj), wherein R5 is H, halogen, CN, ORg, NR8R9, C(O)RS, -C(O)OR8, -C(O)NR8R9j -NR8C(O)R9, -S(O)R8, -S(O)2Rs, -NR8S(O)2R9, -S(O)2NR8R9, C(-C6 alkyl, CrC6 haloalkyl, C2-C0 alkenyl, C2-C6 alkynyl, C3-Cl0 cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl. or heteroaryl, Ai is -O-, A2 is -C(R8)(R9)-, Y is -C(R8)(R9)-, Ri is heteroaryl optionally substituted with one or more Ré, R2 and R 3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, CrC6 alkyl, CrC6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 is H.
In one embodiment, one of Xb X2, X3 is C(Rs), wherein R 5 is H, halogen, -CN, —OR8, —NR8R9, — C(O)R8, -C(O)OR8, -C(O)NR8R9, -NR8C(O)R9, -S(O)R8, -S(O)2R8, -NR8S(O)2R9, -S(O)2NR8R9, Cj-Cè alkyl, CrC6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-Ci0 cycloalkyl, C5-Cg cycloalkenyl, heterocyclyl, aryl, or heteroaryl, Aj is -C(R8)(R9)-, A2 is -O-, Y is -C(R8)(R9)-, Ri is heteroaryl optionally substituted with one or more R6, R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, Ci-C6 alkyl, CrC6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 is H.
In one embodiment, one of X], X2, X3 is C(Rs), wherein R5 is H, halogen, —CN, —OR8, —NR8R9, — C(O)RS, -C(O)OR8, -C(O)NR8R9, -NR8C(O)R9, -S(O)Rg, -S(O)2R8î -NR8S(O)2R9, -S(O)2NR8R9, CrC6 alkyl, CrC6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl, Ai is —O-, A2 is -C(R8)(R9)—, Y is —C(R8)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R6, R2 is H, R3 is H, and R4 is H.
In one embodiment. one of Xb X2, X3 is CfRs), wherein R 5 is H, halogen, —CN, -OR8, —NR8R9, — C(O)R8, -C(O)OR8, -C(O)NR8R9j -NR8C(O)R9j -S(O)R8, -S(O)2R8, -NR8S(O)2R9, -S(O)2NR8R9, CrC6 alkyl, CrC6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl, A; is —C(R8)(R9)-, A2 is -O-, Y is -C(R8)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ré, R2 is H, R3 is H, and R4 is H.
In one embodiment, one of Χμ X2, X3 is C(R3), wherein R5 is H, halogen, -CN, -OR8, —NR8R9, — C(O)R8, -C(O)ORg, -C(O)NR8R9, -NR8C(O)R9j -S(O)R8, -S(O)2R8j -NR8S(O)2R9, -S(O)2NR8R9j CrCé alkyl, CrC6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl, Ai is -O-, A2 is -C(R8)(R9)—, Y is — C(R8)(R9)~, Ri is heterocyclyl optionally substituted with one or more Ré, R2 îs H, R3 is H, and R4 is H.
In one embodiment, one of Xb X2, X3 îs C(R5), wherein R5 is H, halogen, -CN, -OR8, -NR8R9, C(O)RS, -C(O)OR8, -C(O)NRsR9, -NR8C(O)R9, -S(O)R8, -S(O)2R8î -NR8S(O)2R9, -S(O)2NR8R9,
C|-C6 alkyl, CrC6 haloalkyl, C2-Câ alkenyl, C2-C6 alkynyl, C3-Cw cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl, Ai is -C(R8)(R9)-, A2 is -O-, Y is -C(R8)(R9)-, Ri is heterocyclyl optionally substituted with one or more R6, R2 is H, R3 is H, and R4 is H.
In one embodiment, one of Xb X2, X3 is C(R3), wherein Rs is H, halogen, -CN, -OR8, -NR8R9, C(O)R8, -C(O)OR8, -C(O)NR8R9, -NR8C(O)R9, -S(O)R8, -S(O)2R8, -NR8S(O)2R9, -S(O)2NR8R9, CrC6 alkyl, CrC6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-Cj0 cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl, Ai is -O-, A2 is -C(R8)(R9)-, Y is —C(Rg)(R9)—, Ri is heteroaryl optionally substituted with one or more R6, R2 is H, R3 is H, and R4 is H.
In one embodiment, one of Xb X2, X3 is C(R5), wherein R5 is H, halogen, -CN, -ORg, -NR8R9, C(O)R8, -C(O)OR8, -C(O)NR8R9, -NR8C(O)R9, -S(O)R8, -S(O)2R8, -NR8S(O)2R9, -S(O)2NR8R9j Crc6 alkyl, CrC6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl, Ai is -C(R8)(R9)-, A2 is —O-, Y is — C(R8)(R9)—, Ri is heteroaryl optionally substituted with one or more R6, R2 is H, R3 is H, and R4 is H.
In one embodiment, one of Xb X2, X3 is C(Rj), wherein Rs is H, halogen, —CN, -OR8, -NR8R9, C(O)R8, -C(O)OR8, -C(O)NR8R9, -NR8C(O)R9, -S(O)R8, -S(O)2R8, -NR8S(O)2R9, -S(O)2NR8R9, CrC6 alkyl, CrC6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-Ci0 cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl, Ai is -O-, A2 is —C(R8)(R9)-, Y is —C(Rg)(R9)—, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R(„ R2 is halogen, R3 is H, and R4 is H.
In one embodiment, one of Xb X2, X3 is C(Rs), wherein R5 is H, halogen, -CN, —OR8, -NR8R9, C(O)R8, -C(O)OR8, -C(O)NR8R9, -NR8C(O)R9s -S(O)R8, -S(O)2R8j -NReS(O)2R9, -S(O)2NR8R9, CrC6 alkyl, Ci-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-Cl0 cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl, Ai is —C(R8)(R9)-, A2 is -O-, Y is —C(R8)(R9)-, R, is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R6, R2 is halogen, R3 is H, and R4 is H.
In one embodiment, one of Xi, X2, X3 is C(Rs), wherein R5 is H, halogen, -CN, —ORg, -NR8R9, C(O)Rs, -C(O)OR8, -C(O)NR8R9j -NR8C(O)R9, -S(O)R8, -S(O)2R8, -NR8S(O)2R9, -S(O)2NR8R9, C1-C6 alkyl, CrC6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-Cl0 cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl, Ai is -O-, A2 is —C(R8)(R9)-, Y is -C(R8)(R9)-, Ri is heterocyclyl optionally substituted with one or more R9, R2 is halogen, R3 is H, and R4 is H.
In one embodiment, one of Xi, X2, X3 is C(Rs), wherein R5 is H, halogen, —CN, -OR8, -NR8R9, — C(O)R8, -C(O)OR8, -C(O)NR8R9, -NR8C(O)R9, -S(O)R8, -S(O)2R8, -NR8S(O)2R9, -S(O)2NR8R9, C|-C6 alkyl, CrC6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-Cw cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl. or heteroaryl, Ai is —C(Rg)(R9)—, A2 is —O—, Y is — C(R8)(R9)~, Ri is heteiocyclyl optionally substituted with one or more R^, R2 is halogen, R3 is H, and R4 is H.
In one embodiment, one of X|, X2, X3 is C(R5), wherein R 5 is H, halogen, -CN, — ORg, -NR8R9, C(O)R8> -C(O)OR8, -C(O)NR8R9, -NR8C(O)R9j -S(O)Rs, -S(O)2R8î -NR8S(O)2R9, -S(O)2NRgR9, CrC6 alkyl, CrC6 haloalkyl, C2-C6 alkenyl, C2-C0 alkynyl, Q-Cw cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl, Aj is -O-, A2 is —C(R8)(R9)-, Y is —C(Rg)(R9)-, Ri is heteroaryl optionally substituted with one or more Rô, R2 is halogen, R3 is H, and R4 is H.
In one embodiment, one of Χμ X2, X3 is C(Rs), wherein R5 is H, halogen, —CN, -ORg, —NR8R9, — C(O)Rg, -C(O)OR8, -C(O)NRSR9, -NR8C(O)R9s -S(O)R8, -S(O)2R8, -NR8S(O)2R9, -S(O)2NR8R9, CrC6 alkyl, CrC6 haloalkyl, C2-Cô alkenyl, C2-C6 alkynyl, C3-Cl0 cycloalkyl, C5-Cg cycloalkenyl, heterocyclyl, aryl, or heteroaryl, Ai is —C(R8)(R9)—, A2 is —O—, Y is —C(R8)(R9)—, Ri is heteioaryl optionally substituted with one or more Rô, R2 is halogen, R3 is H, and R4 is H.
In one embodiment, one of Χμ X2, X3 is C(R$), wherein R5 is H, halogen, —CN, -ORg, —NRgR9, — C(O)R8, -C(O)ORg, -C(O)NR8R9, -NR8C(O)R9, -S(O)R8, -S(O)2R8, -NR8S(O)2R9, -S(O)2NR8R9, C|-C6 alkyl, Ci-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl, Ai is -O-, A2 is —C(R8)(R9)-, Y is -C(R8)(R9)—, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Rf„ R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, Ci-C6 alkyl, Cj-C6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Χι, X2, X3 is C(R5), wherein R5 is H, halogen, -CN, -ORg, -NR8R9, C(O)R8, -C(O)OR8, -C(O)NR8R9, -NR8C(O)R9, -S(O)R8, -S(O)2Rg, -NR8S(O)2R9, -S(O)2NR8R9, CrC6 alkyl, CrC6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl, Ai is -C(R8)(R9)-, A2 is —O-, Y is -C(R8)(R9)—, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R*, R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, Ci-Câ alkyl, CrC6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 and R9 can fonn heterocyclyl.
In one embodiment, one of Xj, X2, X3 is C(Rs), wherein Rj is H, halogen, —CN, —ORg, —NR8R9, — C(O)Rs, -C(O)OR8, -C(O)NR8R9, -NR8C(O)R9, -S(O)R8, -S(O)2R8î -NR8S(O)2R9, -S(O)2NR8R9, CrC6 alkyl, CrC6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C(0 cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl, Ai is -O-, A2 is —C(Rg)(R9)-, Y is -C(R8)(R9)—, Ri is heterocyclyl optionally substituted with one or more R^, R2 and Rj are independently at each occurrence H, halogen, -OH, -NH2, -CN, CrC6 alkyl, CrC6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Xb X2, X3 is C(Rs), wherein R5 is H, halogen, —CN, —ORg, —NRgRy, — C(O)R8, —C(O)OR8, -C(O)NR8R9, -NR8C(O)R9, -S(O)R8, -S(O)2Rg, -NR8S(O)2R9, -S(O)2NR8R9, Cj-Cè alkyl, Ci-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-Ci0 cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl, A] is -C(R8)(R9)-, A2 is -O-, Y is -C(R8)(R9)-, Ri is heterocyclyl optionally substituted with one or more R^, R2 and R3 are independently at each occurrence H, halogen, —OH, —NH2, —CN, Ci-Cé alkyl, Ci-Cg alkoxy, C2-C& alkenyl, or C2-Ce alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Xb X2, X3 is C(Rs), wherein R5 is H, halogen, —CN, -OR8, —NRgR9, — C(O)R8, -C(O)OR8, -C(O)NR8R9, -NR8C(O)R9j -S(O)R8, -S(O)2R8, -NR8S(O)2R9j -S(O)2NR8R9, CrC6 alkyl, CrC6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C[0 cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl, Ai is -O-, A2 is -C(R8)(R9)-, Y is -C(R8)(R9)-, Ri is heteroaryl optionally substituted with one or more R6, R2 and Rj are independently at each occurrence H, halogen, -OH, -NH2, -CN, CrC6 alkyl, Ci-C6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Xb X2, X3 is C(R3), wherein R5 is H, halogen, -CN, —ORg, -NRgR9, — C(O)RS, -C(O)OR8, -C(O)NR8R9, -NR8C(O)R9, -S(O)Rg, -S(O)2R8, -NR8S(O)2R9, -S(O)2NR8R9, CrC6 alkyl, Ci-C6 haloalkyl, C2-C6 alkenyl, C2-Câ alkynyl, C3-C10 cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl, A| is -C(R8)(R9)-, A2 is -O-, Y is -C(Rg)(R9)-, Ri is heteroaryl optionally substituted with one or more R6, R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, CrC6 alkyl, Ci-C6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Xb X2, X3 is C(Rs), wherein R5 is H, halogen, -CN, -ORg, -NR8R9, C(O)R8, -C(O)OR8j -C(O)NR8R9, -NRgC(O)R9, -S(O)R8, -S(O)2R8, -NR8S(O)2R9, -S(O)2NR8R9, Ci-C6 alkyl, CrC6 haloalkyl, C2-C6 alkenyl, C2-Câ alkynyl, C3-Ci0 cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl, Ai is -O-, A2 is -C(R8)(R9)-, Y is -C(R8)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R6, R2 is H, R3 is H, and R4 and R9 can fonn heterocyclyl.
In one embodiment, one of Xi, X2, X3 is C(Rs), wherein R5 is H, halogen, —CN, —OR8, NR8R9, C(O)R8, -C(O)OR8, -C(O)NR8R9, -NR8C(O)R9, -S(O)R8, -S(O)2R8, -NR8S(O)2R9, -S(O)2NR8R9, CrC6 alkyl, Ci-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl, Ai is -C(R8)(R9)-, A2 is -O-, Y is -C(R8)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R6, R2 is H, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Xi, X2, X3 is C(Rj), wherein R5 is H, halogen, -CN, -OR8, -NR8R9, C(O)R8, -C(O)OR8î -C(O)NR8R9, -NR8C(O)R9, -S(O)Rs, -S(O)2R8, -NRsS(O)2R9, -S(O)2NR8R9, C]-C6 alkyl, Ci-C6 haloalkyl, C2-C6 alkenyl, C2-Cé alkynyl, C3-Ci0 cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl, Ai is -O-, A2 is -C(R8)(R9)-, Y is -C(R8XR9)-, Ri is heterocyclyl optionally substituted with one or more Ré, R2 is H, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, one of X], X2, X3 is C(R3), wherein R; is H, halogen, —CN, —OR8, —NRgR9, — C(O)R8, -C(0)OR8, -C(O)NR8R9, -NR8C(O)R9, -S(O)R8, -S(O)2R8, -NRgS(O)2R9, -S(O)2NR8R9, Cj-C6 alkyl, CrC6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-Cl0 cycloalkyl, C5-Cg cycloalkenyl, heterocyclyl, aryl, or heteroaryl, A; is -C(R8XR9)-, A2 is -O-, Y is -C(R8XR9)—, Ri is heterocyclyl optionally substituted with one or more Ré, R2 is H, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Xj, X2, X3 is C(R5), wherein R5 is H, halogen, -CN, -ORg, -NR8R9, C(O)Rg, -C(O)OR8, -C(O)NR8R9, -NRsC(O)R9, -S(O)R8, -S(O)2R8, -NRsS(O)2R9, -S(O)2NR8R9, CrC6 alkyl, CrC6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C[0 cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl, Ai is -O-, A2 is -C(R8)(R9)—, Y is —C(R8XR9)—, Ri is heteroaryl optionally substituted with one or more Ré, R2 is H, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Xb X2, X3 is C(RS), wherein R5 is H, halogen, -CN, -OR8, -NR8R9, C(O)R8, -C(O)ORg, -C(O)NR8R9, -NRsC(O)R9, -S(O)R8, -S(O)2R8, -NR8S(O)2R9, -S(O)2NR8R9j CrC6 alkyl, CrC6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-Ci0 cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl, Ai is -C(Rg)(R9)—, A2 is —O-, Y is — CiRsXRÿ)-, Ri is heteroaryl optionally substituted with one or more R(„ R2 is H, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Xi, X2, X3 is C(Rj), wherein R 5 is H, halogen, -CN, -OR8, -NRgR9, — C(O)Rg, -C(O)OR8, -C(O)NR8R9, -NR8C(O)R9, -S(O)R8, -S(O)2Rg, -NR8S(O)2R9, -S(O)2NR8R9, Ci-Cé alkyl, CrC6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-Cj0 cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl, Aj is —O—, A2 is -C(RgXR9)—, Y is —C(R8XR9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R6, R2 is halogen, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Xb X2, Xj is C(R5), wherein R5 is H, halogen, CN, OR8, NR8R9, C(O)R8, -C(O)ORS, -C(O)NR8R9, -NR8C(O)R9, -S(O)R8, -S(O)2R8, -NR8S(O)2R9, -S(O)2NR8R9, Ci-C6 alkyl, Ci-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl, Ai is -C(R8)(R9)-, A2 îs -O-, Y is -C(R8)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R6, R2 is halogen, R3 is H, and R4 and R9 can fonn heterocyclyl.
In one embodiment, one of Xb X2, X3 is C(R5), wherein R5 is H, halogen, -CN, -ORS, -NR8R9h C(O)R8, -C(O)OR8j -C(O)NR8R9, -NR8C(O)R9, -S(O)R8, -S(O)2R8, -NR8S(O)2R9, -S(O)2NR8R9, CrC6 alkyl, CrC6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl, Ai is -O-, A2 is -C(R8)(R9)-, Y is -C(R8)(R9)-, Ri is heterocyclyl optionally substituted with one or more R^, R2 is halogen, R3 is H, and R4 and R9 can fonn heterocyclyl.
In one embodiment, one of Xb X2, X3 is C(R5), wherein R5 is H, halogen, -CN, -OR8, -NR8R9) C(O)R8, -C(O)OR8, -C(O)NR8R9, -NR8C(O)R9, -S(O)R8j -S(O)2R8j -NR8S(O)2R9, -S(O)2NR8R9, C|-C6 alkyl, Ci-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-Cl0 cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl, Ai is -C(R8)(R9)-, A2 is —O-, Y is -C(R8)(R9)—, Ri is heterocyclyl optionally substituted with one or more R^, R2 is halogen, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Xb X2, X3 îs C(Rs), wherein R5 is H, halogen, -CN, —OR8f -NR8R9, C(O)R8, -C(O)OR8, -C(O)NR8R9, -NR8C(O)R9, -S(O)R8, -S(O)2R8, -NR8S(O)2R9, -S(O)2NRëR9, C|-C6 alkyl, CrC6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-Cio cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl, A, is -O-, A2 is -C(R8)(R9)-, Y is -C(R8)(R9)-, Ri is heteroaryl optionally substituted with one or more R^, R2 is halogen, R3 îs H, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Xb X2, X3 is C(Rî), wherein R5 is H, halogen, -CN, —OR8, -NR8R9, C(O)R8, -C(O)OR8, -C(O)NR8R9, -NR8C(O)R9, -S(O)R8j -S(O)2R8, -NRsS(O)2R9, -S(O)2NR8R9, CrC6 alkyl, CrC6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C|0 cycloalkyl, C5-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl, Ai is -C(R8)(R9)-, A2 îs -O-, Y is -C(R8)(R9)—, Ri is heteroaryl optionally substituted with one or more Rô, R2 is halogen, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Xb X2, X3 is C(R3), wherein Rj is H, Ai is —O—, A2 is —C(R8)(R9)—, Y is -C(R8)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^, R2 and R3 are îndependently at each occurrence H, halogen, -OH, -NH2, -CN, CrC6 alkyl, Cj-Cé alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R?, and R4 is H.
In one embodiment, one of Χμ X2, X3 is C(Rj), wherein R5 is H, Ai is -CfRsXRg)-, A2 is -O-, Y is -C(RsXRç)- Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ré, R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, CrC6 alkyl, Cj-Cé alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl îs optionally substituted with one or more R7, and R4 is H.
In one embodiment, one of Xh X2, X3 is C(R5), wherein R5 is H, Ai is -O-, A2 is -C(R8)(R9)-, Y is -C(R8)(R9)-, Ri is heterocyclyl optionally substituted with one or more R6, R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, Ci-Cé alkyl, Ci-Cé alkoxy, C2-Cé alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 is H.
In one embodiment, one of Xi, X2, X3 is C(Rs), wherein R5 is H, Ai is —C(R8)(R9)—, A2 is -O-, Y is -C(Rs)(R9)- Ri îs heterocyclyl optionally substituted with one or more R6, R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, Ci-Cé alkyl, C[-Cé alkoxy, C2-Cé alkenyl, or C2-Cé alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 is H.
In one embodiment, one of Χμ X2, X3 is C(R3), wherein R 5 is H, A] is -O-, A2 is -CtRsXRy)-, Y is -C(R8)(R9)-, Ri is heteroaryl optionally substituted with one or more Rô, R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, C|-Cé alkyl, Cj-Cé alkoxy, C2-Cé alkenyl, or C2-Cô alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 îs H.
In one embodiment, one of Χμ X2, X3 is C(Rî), wherein R 5 is H, Ai is -C(R8)(Rg)-, A2 is -O-, Y is -C(R8)(Rg)-, Ri is heteroaryl optionally substituted with one or more R6, R2 and R3 are independently at each occurrence H, halogen, —OH, —NH2, —CN, Ci-Cé alkyl, Cj-Cé alkoxy, C2-Cg alkenyl, or C2-Cé alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 is H.
In one embodiment, one of Χμ X2, X3 is C(R3), wherein R3 is H, A| is -O-, A2 is — CiRsXRg)-, Y is -CiReXRç)- Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ré, R2 is H, R3 is H, and R4 is H.
In one embodiment, one of Χμ X2, X3 is C(R3), wherein R 5 is H, A| is -QRgXRg)—, A2 is -O-, Y is -C(RsXR9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ré, R2 is H, R3 is H, and R4 is H.
In one embodiment, one of Xj, X2, X3 is C(R3), wherein R 5 is H, Ai is O , A? is C(R8XR9) , Y is -C(R8XR9)- Ri is heterocyclyl optionally substituted with one or more Rg, R2 is H, R3 is H, and R4 is H.
In one embodiment, one of Xi, X2, Xj is C(R5), wherein R5 is H, Ai is -C(R8)(R9)-, A2 is -O-, Y is -C(R8XR9)-, Ri is heterocyclyl optionally substituted with one or more Rg, R2 is H, R3 is H, and R4 isH.
In one embodiment, one of Xj, X2, X3 is CfRg), wherein R5 is H, A] is —O-, A2 is —C(R8XR9)-, Y is -C(R8XR9)-, Ri is heteroaryl optionally substituted with one or more Rg, R2 is H, R3 is H, and R4 is H.
In one embodiment, one of Xi, X2, X3 is C(R5), wherein R5 H, Aj is -C(R8XR9)-, A2 is -O-, Y is C(R8XR9)-, R1 is heteroaryl optionally substituted with one or more R6, R2 is H, R3 is H, and R4 is H.
In one embodiment, one of Xi, X2, X3 is C(Rs), wherein R 5 is H, Aj is -O-, A2 is -C(R8XR9)-, Y is -C(RsXR9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Rg, R2 is halogen, R3 is H, and R4 is H.
In one embodiment, one of Xj, X2, X3 is C(Rg), wherein Rg is H, Aj is — C(R8XR9)—, A2 is -O-, Y is -C(R8)(R9)- Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Rg, R2 is halogen, R3 is H, and R4 is H.
In one embodiment, one of Xj, X2, X3 is C(Rg), wherein R5 is H, Aj is -O-, A2 is — C(R8XR9)-, Y is -C(RsXR9)-, Ri is heterocyclyl optionally substituted with one or more Rg, R2 is halogen, R3 is H, and R4 is H.
In one embodiment, one of Xj, X2, Xj is C(R5), wherein R5 is H, A| is -C(R8)(R9)-, A2 is -O-, Y is -C(R8XR9)-, Rj is heterocyclyl optionally substituted with one or more R6, R2 is halogen, R3 is H, and R4 is H.
In one embodiment, one of Xi, X2, X3 is C(Rg), wherein R5 is H, Aj is —O—, A2 is —C(R8XR9)—, Y is -C(R8XR9)-5 Ri is heteroaryl optionally substituted with one or more Rg, R2 is halogen, R3 is H, and R4 îs H.
In one embodiment, one of Xi, X2, X3 is C(Rs), wherein R5 is H, Aj is —C(R8XR9)-, A2 is -O-, Y is -C(R8XR9)-, Rj is heteroaryl optionally substituted with one or more R6, R2 îs halogen, R3 is H, and R4 is H.
In one embodiment, one of Xj, X2, X3 is C(Rg), wherein R5 is H, Aj is -O—, A2 is ~C(R8XR9)—, Y is -C(R8XR9)-, R1 is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Rg, R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, CrC6 alkyl, CrC6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 and R9 can fonn heterocyclyl.
In one embodiment, one of Χι, X2, X3 is C(R3), wherein R 5 is H, A] is —C(R8)(R9)—, A2 is —O—, Y is -C(RS)(R9)- R1 is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R$, R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, CrC6 alkyl, CrC6 alkoxy, C2-C6 alkenyl, or C2-Cfi alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 and R9 can fonn heterocyclyl.
In one embodiment, one of Xi, X2, X3 is C(Rj), wherein R5 is H, Ai is —O-, A2 is —C(R8)(R9)~ Y is -C(Rg)(R9)-, R( îs heterocyclyl optionally substituted with one or more R6, R2 and R3 are independently at each occunence H, halogen, —OH, —NH2, —CN, C|-C'é alkyl, Cj-C^ alkoxy, C2-Cé alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Xi, X2, X3 is C(R3), wherein R5 is H, A| is -C(R8)(R9)-, A2 is -O—, Y is -C(Rs)(R9)-, Ri is heterocyclyl optionally substituted with one or more R6, R2 and R3 are independently at each occurrence H, halogen, -OH, —NH2, -CN, C]-C9 alkyl, Ci-Cô alkoxy, C2-Cé alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Xj, X2, X3 is C(R3), wherein R 5 is H, Ai is -O-, A2 is -C(R8)(R9)-, Y is —C(R8)(R9)-, Ri is heteroaryl optionally substituted with one or more Ré, R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, Cj-C& alkyl, Ci-Ce alkoxy, C2-Cé alkenyl, or C2-C6 alkynyl, wherein the alkyi, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Xi, X2, X3 is C(R3), wherein R 5 is H, Ai is —C(Rs)(R9)-, A2 is -O-, Y is -C(Rs)(R9)-, Ri is heteroaryl optionally substituted with one or more Rb, R2 and R3 are independently at each occurrence H, halogen, -OH, —NH2, —CN, C1-C5 alkyl, Ci-C6 alkoxy, C2-C9 alkenyl, or C2-C(, alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 and R9 can fonn heterocyclyl.
In one embodiment, one of Xi, X2, X3 is C(Rs), wherein R5 is H, A| is -O-, A2 is -C(R8)(R9)-, Y is -C(R8)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R9, R2 is H, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Xh X2, X3 is C(R5), wherein R5 is H, Aj is -C(R8)(R9)-, A2 is -O-, Y is -C(R8)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Rô, R2 is H, Rj is H, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Χι, X2, X3 is C(R5), wherein Rs îs H, Ai is -O-, A2 is -C(R8)(R9)-, Y is
-C(R8)(R9)- Ri is heterocyclyl optionally substituted with one or more R6, R2 is H, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Xi, X2, X3 is C(R5), wherein R5 is H, Ai is -C(R8)(R9)- A2 is -O-, Y is -C(R8)(R9)-, R1 is heterocyclyl optionally substituted with one or more R6, R2 is H, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Xi, X2, X3 is CIRs), wherein R5 is H, Ai is —O-, A2 is —C(R8)(R9)-, Y is -C(R8)(R9)-, Ri is heteroaryl optionally substituted with one or more R&, R2 is H, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Xi, X2, X3 is CfRs), wherein R 5 H, Ai is -C(R8)(R9)-, A2 is -O-, Y is — C(R8)(R<))-, R| is heteroaryl optionally substituted with one or more R6, R2 is H, R3 is H, and R4 and 15 R9 can form heterocyclyl.
In one embodiment, one of Xi, X2, Xj is C(R5), wherein R5 is H, Ai is -O-, A2 is -C(R8)(R9)-, Y is -C(R8)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R9, R2 is halogen, Rj is H, and R4 and R9 can form heterocyclyl,
In one embodiment, one of Xj, X2, X3 is CfRs), wherein R 5 is H, Ai is -C(R8)(R9)—, A2 is -O-, Y is -C(R8)(R9)-5 Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ri,, R2 is halogen, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Χι, X2, X3 is C(Rj), wherein R5 is H, A] is -O-, A2 is -C(R8)(R9)-, Y is 25 -C(R8)(R9)-, Ri is heterocyclyl optionally substituted with one or more R6, R2 is halogen, R 3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Χι, X2, X3 is QR5), wherein R5 is H, Ai is -C(R8)(R9)-, A2 is -O-, Y is -C(R8)(R9)-, Ri is heterocyclyl optionally substituted with one or more R6, R2 is halogen, Rj is H, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Χι, X2, X3 is C(R5), wherein R5 is H, A] is —O—, A2 is —C(R8)(R9)—, Y is -C(R8)(R9)-, Ri is heteroaryl optionally substituted with one or more R^, R2 is halogen, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, one of X(, X2, X3 is C(R5), wherein R5 is H, A, îs -C(R8)(R9)- A2 is -O-, Y is -C(R8)(R9)- Ri is heteroaryl optionally substituted with one or more R6, R2 is halogen, R3 is H, and R4 and Rq can form heterocyclyl.
In one embodiment, one of Xj, X2, X3 is C(R5), wherein Rj is Ci-Cs alkyl, Aj is —O—, A2 îs — C(R8)(R9)-, v is -C(R8)(R9)-, R] is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Rô, R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, C(-C6 alkyl, Ci-C6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 is H.
In one embodiment, one of Xj, X2, X3 is C(R3), wherein R5 is C]-Cô alkyl, Ai is —C(R8)(R9)—, A2 is -O-, Y is -C(RS)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Rs, R2 and R3 are independently at each occurrence H, halogen, —OH, —NH2, —CN, Cj-C^ alkyl, Ci-Cè alkoxy, C2-C$ alkenyl, 01 C2-C& alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 is H.
In one embodiment, one of Xj, X2, X3 is C(Rs), wherein R5 is Cj-C^ alkyl, Ai is —O—, A2 is — C(R8)(R9)-, y is -C(R8)(R9)-, R| is heterocyclyl optionally substituted with one or more R6, R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, Ci-Ce alkyl, Ci-C^ alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 îs H.
In one embodiment, one of Xi, X2, X3 is C(Rs), wherein R5 is C1-C0 alkyl, A] is —C(R8)(R9)—, A2 is -O-, Y is -C(R8)(R9)- Ri is heterocyclyl optionally substituted with one or more Râ, R2 and R3 are independently at each occurrence H, halogen, —OH, —NH2, —CN, Cj-C^ alkyl, Cj-Cû alkoxy, C2-Cg alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 is H.
In one embodiment, one of Xi, X2, X3 is C(Rj), wherein R5 is Ci-C& alkyl. Ai is —O-, A2 is — C(R8)(R9)-, y is -C(Rg)(R9)-, Ri is heteroaryl optionally substituted with one or more R^, R2 and Rj are independently at each occurrence H, halogen, -OH, -NH2, -CN, Ci-C& alkyl, Ci-Cê alkoxy, C2C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 is H.
In one embodiment, one of Xj, X2, X3 is C(R3), wherein R5 is Ci-C^ alkyl, A, is —C(R8)(R9)—, A2 is -O-, Y is -C(R8)(R9)-, Ri is heteroaryl optionally substituted with one or more Rô, R2 and R3 are independently at each occurrence H, halogen, —OH, —NH2, —CN, Cj-Cô alkyl, Ci-C9 alkoxy, C2-Cô alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 is H.
In one embodiment, one of Xb X2, X3 îs C(R>), wherein R 3 is Ci-Cé alkyl, A| is -O-, A2 is C(R8)(R9)- y is -C(R8)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more RÊ, R? is H, Rj is H, and R4 is H.
In one embodiment, one of Xi, X2, X3 is C(R5), wherein R5 is CrC6 alkyl, Aj is -C(R8)(R9)- A2 is _q_ y is -C(R8)(R9)-, R] is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R6, R2 is H, R3 is H, and R4 is H.
In one embodiment, one of Xi, X2, X3 is C(Ré), wherein R5 is Ci-CL alkyl, Ai is -O-, A2 is — C(R8)(R9)-, Y is -C(R8)(R9)-, R1 is heterocyclyl optionally substituted with one or more R6, R2 is H, R3 is H, and R4 is H.
In one embodiment, one of Xb X2, X3 is C(Rj), wherein R5 is C|-Cg alkyl, Ai is —C(R8)(R9) , A2 is -O-, Y is -C(R8)(R9)-, Ri is heterocyclyl optionally substituted with one or more R6, R2 is H, R3 is
H, and R4 is H.
In one embodiment, one of Xb X2, X3 is C(Rj), wherein R5 is Cj-Ce alkyl. Ai is —O—, A2 is — C(R8XR9)- Y is -C(R8)(R9)- Ri is heteroaryl optionally substituted with one or more R6, R2 is H, R3 is H, and R4 is H.
In one embodiment, one of Xj, X2, X3 is CfRs), wherein R5 is C|-Cé alkyl. A] îs —C(R8)(R9)—, A2 is -O-, Y is -C(R8)(R9)-, Ri is heteroaryl optionally substituted with one or more Ré, R2 is H, R3 is H, and R4 is H.
In one embodiment, one of Xi, X2, X3 is C(Rs), wherein R 5 îs C1-C0 alkyl, Ai is -O-, A2 is C(R8)(R9)-, Y is -C(R8)(R9)- Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ré, R2 is halogen, R3 is H, and R4 is H.
In one embodiment, one of Xi, X2, X3 is C(R3), wherein R5 is C1-C& alkyl. Ai is — C(R8)(R9)—, A2 is -O-, Y is -C(Rk)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ré, R2 is halogen, R3 îs H, and R4 is H.
In one embodiment, one of Xi, X2, X3 is C(Rj), wherein R5 is C]-Cé alkyl, Ai is — O—, A2 is — C(R8)(R9)-, y is -C(Rs)(R9)~, R1 is heterocyclyl optionally substituted with one or more Rf„ R2 is halogen, R3 is H, and R4 is H.
In one embodiment, one of Xj, X2, X3 is C(Rs), wherein R 3 is Ci-Cé alkyl, Ai is —C(Rs)(R9)~, A2 is -O-, Y îs -C(R8)(R9)-, Ri is heterocyclyl optionally substituted with one or more R6, R2 is halogen, R3 is H, and R4 is H.
In one embodiment, one of X|, X2, X3 is C(Rg), wherein R 5 is Cj-Cg alkyl, Ai is O-, A2 is C(R8)(R9)-, Y is -C(R8)(R9)-, Ri is heteroaryl optionally substituted with one or more Rg, Ri is halogen, R3 is H, and R4 is H.
In one embodiment, one of Xi, X2, X3 is C(R$), wherein Rg is Cj-Cg alkyl, Ai is — C(R8)(R9) , A2 is Y is -C(R8)(R9)-, Ri is heteroaryl optionally substituted with one or more R6, R2 is halogen,
R3 is H, and R4 is H.
In one embodiment, one of Χι, X2, X3 is C(Rs), wherein R 5 is C[-C$ alkyl, Aj is —O—, A2 is C(R8)(R9)- Y is -C(R8)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R$, R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, C(-Cg alkyl, Ci-C$ alkoxy, C2-C$ alkenyl, or C2-Cg alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 and R9 can fonn heterocyclyl.
In one embodiment, one of Xi, X2, X3 is C(Rg), wherein Rg is Cj-Cg alkyl, Ai is —C(R8)(R9)—, A2 is -O-, Y is -C(R8)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R6, R2 and R3 are independently at each occurrence H, halogen, —OH, —NH2, -CN, Cj-Cg alkyl, Ci-Cg alkoxy, C2-C$ alkenyl, 01 C2-Cg alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 and R9 ean form heterocyclyl.
In one embodiment, one of Xj, X2, Xj is C(Rg), wherein R5 is Ci-C$ alkyl, Ai is -O-, A2 is — C(R8)(Rq)-, Y is -C(R8)(R9)-, R| is heterocyclyl optionally substituted with one or more R6, R2 and Rj are independently at each occurrence H, halogen, -OH, -NH2, -CN, Ci-Cg alkyl, Cj-C6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 and R9 can fonn heterocyclyl.
In one embodiment, one of X|, X2, X3 is C(Rg), wherein Rg is Ci-Cg alkyl, Ai is —C(R8)(R9)—, A2 is -O-, Y is -C(R8)(R9)-5 Ri is heterocyclyl optionally substituted with one or more Rg, R2 and R3 are independently at each occurrence H, halogen, -OH, —NH2, -CN, Ci-Cg alkyl, Ci-Cg alkoxy, C2-Cg alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 and R9 can fonn heterocyclyl.
In one embodiment, one of Xi, X2, X3 is C(Rg), wherein R5 is C]-Cg alkyl, Ai is -O-, A2 is — C(R8)(R9)-, Y is -C(Rs)(R9)- Ri is heteroaryl optionally substituted with one or more Rg, R2 and R3 are independently at each occun'ence H, halogen, -OH, -NH2, -CN, Ci-C$ alkyl, C]-Cg alkoxy, C2C6 alkenyl, or C2-Cg alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 and R9 can form heterocyclyl.
In one embodiment, one of X], X2, X3 is C(Rj), wherein R5 is CpCg alkyl, Ai is C(Rs)(R9)—, A2 is -O-, Y is -C(R8)(R9)- Ri is heteroaryl optionaliy substituted with one or more R6, R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, CpCg alkyl, CpCg alkoxy, C2-Cg alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionaliy substituted with one or more R7, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Xi, X2, X3 is C(R3), wherein R5 is CpCg alkyl, A] is —O—, A2 is — C(Rg)(R9)-, Y is -C(R8)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionaliy substituted with one or more Rg, R2 is H, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Xb X2, X3 is C(R5), wherein R5 is CpCg alkyl, Ai is -C(R8)(R9)-, A2 is -O-, Y is -C(R8)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionaliy substituted with one or more Rg, R2 is H, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Xi, X2, X3 is C(Rg), wherein R5 is CpCg alkyl, Aj is -O-, A2 is C(R8)(R9)- y is -C(R8)(R9)-, Ri is heterocyclyl optionaliy substituted with one or more Rg, R2 is H, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, one of X|, X2, X3 is C(Rs), wherein R5 is CpCg alkyl, Ai is — C(R8)(R9)—, A2 is -O-, Y is -C(R8)(R9)- Ri is heterocyclyl optionaliy substituted with one or more Rg, R2 is H, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Xi, X2, X3 is C(R5), wherein R5 is CpCg alkyl, A] is -O-, A2 is — C(R8)(R9)-, Y is -C(Rs)(R9)- Ri is heteroaryl optionaliy substituted with one or more Rg, R2 is H, R3 is H, and R4 and R9 can fonn heterocyclyl.
In one embodiment, one of X), X2, X3 is C(R3), wherein R 5 is CpCg alkyl, A] is —C(R8)(R9)-, A2 is -O-, Y is -C(Rg)(R9)-, Ri is heteroaryl optionaliy substituted with one or more Rg, R2 is H, R3 is H, and R4 and R9 can fonn heterocyclyl.
In one embodiment, one of Xi, X2, X3 is C(R3), wherein R5 is CpCg alkyl, A] is -O-, A2 is — C(RS)(R9)-, Y is -C(Rg)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionaliy substituted with one or more Rg, R2 is halogen, R3 is H, and R4 and R9 can fonn heterocyclyl.
In one embodiment, one of Xi, X2, X3 is C(R3), wherein R5 is CpCg alkyl, Ai is -C(R8)(R9)-, A2 is -O-, Y is -C(Rg)(R9)-, Rj is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionaliy substituted with one or more Rg, R2 is halogen, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Xb X2, Xj is C(R5), wherein R5 is CrC6 alkyl, Ai is -O-, A2 is C(R8)(R9H y is -C(Rs)(R9)-, Ri is heterocyclyl optionally substituted with one or more R6, R2 is halogen, Rj is H, and R4 and Ry can fonn heterocyclyl.
in one embodiment, one of Xj, X2, X3 is C(R3), wherein R5 is Ci-Cû alkyl, Ai îs —C(Rs)(R9)—, A2 is -O-, Y is -C(R8)(R9)-, Ri is heterocyclyl optionally substituted with one or more R(„ R2 is halogen, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, one of X|, X2, X3 is C(Rs), wherein R5 is Ci-Cè alkyl. Ai is -O-, A2 is C(R8)(R9)-, y is -C(R8)(R9)- Ri is heteroaryl optionally substituted with one or more R6, R2 is halogen, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Xi, X2, X3 is C(R5), wherein R 5 is CrC6 alkyl, Ai is -C(R8)(R9)-, A2 is -O-, Y is -C(Rg)(R9)-, Ri is heteroaryl optionally substituted with one or more R6, R2 is halogen, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, at least one ot Xi, X2, or X3 is N, Ai is —O—, A2 îs — C(R8)(R9)—, Y is — C(R8)(R9)-, R| is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^, wherein R$ is independently at each occurrence oxo, halogen, -CN, -OR8, -C(O)R8, -C(O)ORS, - C(O)NR8R9, -NR8C(O)R9: -S(O)R8, -S(O)2R8, NRsS(O)2R9, -S(O)2NR8R9, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more Rio, R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, C|-Cé alkyl, C|-Ce, alkoxy, C2-Cé alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 is H.
In one embodiment, at least one of Xi, X2, or X3 is N, Ai is -C(R8)(R9)-, A2 is —O-, Y is — C(R8)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R6, wherein R6 is independently at each occurrence oxo, halogen, -CN, -ORS, -C(O)R8, -C(O)ORg, - C(O)NR8R9, -NRiiC(O)R9, -S(O)R8, -S(O)2R8, NR8S(O)2R9, -S(O)2NR8R9, Ci-C6 alkyl, C2-C6 alkenyl, C2-Cft alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more R10, R2 and R3 are independently at each occurrence H, halogen, —OH, -NH2, -CN, Ci-C^ alkyl, Ci-Cg alkoxy, C2-Cô alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 is H.
In one embodiment, one of Xb X2, Xj is C(R3), Ai is —O—, A2 is C(R8)(R9) , Y is C(R8)(R9) , Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R6, wherein Rô is independently at each occurrence oxo, halogen, -CN, -ORs, -C(O)R8, -C(O)OR8, - C(O)NR8R9, -NRsC(O)R9, -S(O)R8, -S(O)2R8, -NR8S(O)2R9, S(O)2NR8R9, CrC6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more Rio, R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, CrC6 alkyl, CrC6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 is H.
In one embodiment, one of Xb X2, X3 is C(Rî), Ai is —C(R8)(R9)-, A2 is -O-, Y is -C(R8)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R9, wherein Ré is independently at each occurience oxo, halogen, -CN, -ORs, -C(O)RS, -C(O)OR8, - C(O)NR8R9, -NR8C(O)R9, -S(O)R8j -S(O)2R8, -NR8S(O)2R9, S(O)2NR8R9, C|-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more Rio, R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2s -CN, CrC6 alkyl, CrC6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 is H.
in one embodiment, at least one of Xb X2, or X3 is N, Ai is —O—, A2 is —C(R8)(R9)—, Y is — C(R8)(R9)-, R| is heterocyclyl optionally substituted with one or more Ré, wherein R6 is independently at each occurrence oxo, halogen, -CN, -OR8, -C(O)R8, -C(O)OR8, - C(O)NR8R9, NR8C(O)R9, -S(O)R8, -S(O)2Rs, -NR8S(O)2R9, -S(O)2NR8R9î CrC6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more R[0, R2 and R3 arc independently at each occurrence H, halogen, -OH, -NH2, -CN, CrC6 alkyl, CtC6 alkoxy, C2-Cé alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 is H.
In one embodiment, at least one of Xi, X2, or X3 is N, Ai is -C(R8)(R9)—, A2 is -O-, Y is C(R8)(R9)-, Ri is heterocyclyl optionally substituted with one or more R6, wherein R6 is independently at each occurrence oxo, halogen, -CN, -OR8, -C(O)R8, -C(O)OR8, - C(O)NR8R9, NR8C(O)R9, -S(O)R8, -S(O)2R8, -NR8S(O)2R9, -S(O)2NR8R9, CrC6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more
R10, R2 and R3 are indcpendenily at each occurrence H, halogen, -OH, -NH2, -CN, CrC6 alkyl. CiC6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 is H.
In one embodiment, one of X], X2, X3 is QRs), Ai is -O—, A2 is —C(R8)(R9)-, Y is -C(R8)(R9) , Ri is heterocyclyl optionally substituted with one or more R6, wherein R6 is independently at each occurrence oxo, halogen, -CN, -OR8, -C(O)R8, -C(O)OR8, - C(O)NRgR9, -NR8C(O)R9, -S(O)R8, S(O)2R8, -NR8S(O)2R9, -S(O)2NR8R9, CrC6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-Cg cycioalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycioalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more Rw, R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, Ci-Cé alkyl, Cj-Cé alkoxy, C2-C& alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 is H,
In one embodiment, one of Χμ X2, X3 is C(R5), A! is -C(R8)(R9)-, A2 is -O-, Y is -C(R8)(R9)- Ri is heterocyclyl optionally substituted with one or more Rf„ wherein R* is independently at each occurrence oxo, halogen, -CN, -OR8, —C(O)R8, -C(O)OR8, — C(O)NR8R9, —NR8C(O)R9, -S(O)R8, S(O)2R8, -NR8S(O)2R9î -S(O)2NR8R9, CrC6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycioalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycioalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more Rio, R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, Ci-C& alkyl, Cj-Cô alkoxy, C2-Cé alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and IG is H.
In one embodiment, at least one of Χμ X2, or X3 is N, Ai is —O—, A2 is —C(R8)(R9)—, Y is — C(R8)(R9)-, Ri is heteroaryl optionally substituted with one or more R6, wherein R6 is independently at each occurrence oxo, halogen, -CN, -ORg, -C(O)Rg, —C(O)ORg, — C(O)NR8R9, —NRsC(O)R9, S(O)R8, -S(O)2Rs, -NR8S(O)2R9, -S(O)2NR8R9, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycioalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycioalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more Rio, R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, Cj-Cé alkyl, CrC6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and IG is H.
In one embodiment, at least one of Χμ X2, or X3 is N, Aj îs —C(Rg)(R9)-, A2 is -O-, Y is — C(R8)(R9)-, Ri is heteroaryl optionally substituted with one or more R6, wherein Rf, is independently at each occurrence oxo, halogen, -CN, -ORg, -C(O)Rg, —C(O)ORg, — C(O)NR8R9, —NR8C(O)R9, 80
S(O)R8, -S(O)2R8, -NR8S(O)2R9, -S(O)2NR8R9, CrC6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more Rio, R? and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, CrC(j alkyl, Ci-C6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 is H.
In one embodiment, one of Xi, X2, X3 is C(R5), Ai is -O-, A2 is -C(R8)(R9)-, Y is -C(R8)(R9)- Ri is heteroaryl optionally substituted with one or more R6, wherein R6 is independently at each occurrence oxo, halogen, -CN, -OR8, -C(O)R8, -C(O)OR8, - C(O)NR8R9, -NRgCfOjRç, -S(O)R8, S(O)2R8, -NR8S(O)2R9, -S(O)2NR8R9, CrC6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more Rio, R2 and R3 are independently at each occun’ence H, halogen, -OH, —NH2, -CN, C[-Cé alkyl, CfCé alkoxy, C2-Cé alkenyl, or C2-Co alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 is H.
In one embodiment, one of Xb X2, X3 is C(R3), Ai is -C(R8)(R9)-, A2 is —O-, Y is —C(R8)(R9)-, Ri is heteroaryl optionally substituted with one or more Ré, wherein Ré is independently at each occun’ence oxo, halogen, -CN, -OR8, — C(O)R8, —C(O)OR8, — C(O)NR8R9, -NR8C(O)R9, -S(O)R8, S(O)2Rs, -NR8S(O)2R9, -S(O)2NR8R9, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more Rio, R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, Ci-Ce alkyl, Cj-Cé alkoxy, C2-Cé alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 is H.
In one embodiment, at least one of Xj, X2, or X3 is N, Ai is -O—, A2 is -C(R8)(R9)—, Y is C(R8)(R9)-, R1 is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl îs optionally substituted with one or more R6, wherein R6 is independently at each occun’ence oxo, halogen, -CN, -OR8, -C(O)R8, -C(O)OR8, - C(O)NR8R9, -NR8C(O)R9, -S(O)R8, -S(O)2R8, NR8S(O)2R9, -S(O)2NR8R9, CrC6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more Rio, Ri is H, R3 is H, and R4 is H.
In one embodiment, at least one of Xi, X2, or Xj is N, Ai is C(R8)(R9) , A2 is O , Y is C(R8)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R&, wherein Rû is independently at each occurrence oxo, halogen, -CN, -OR8, -C(O)R8, -C(O)ORg, - C(O)NR8R9, -NR8C(O)R9, -S(O)R8, -S(O)2R8, NR8S(O)2R9, -S(O)2NR8R9, CrC6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more Rio, R2 is H, R3 is H, and R4 is H.
In one embodiment, one of Xi, X2, Xj îs C(Rs), Ai is —O—, A2 is — C(Rs)(R9)—» Y is —C(R8)(R9)—, Ri îs heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^, wherein Rg is independently at each occurrence oxo, halogen, -CN, -OR8, -C(O)R8, -C(O)OR8, - C(O)NR8R9, -NR8C(O)R9, -S(O)R8, -S(O)2R8, -NR8S(O)2R9, S(O)2NR8R9, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, 01 heteioaiyl can be optionally substituted with one or more Rio, R2 is H, R3 is H, and R4 is H.
In one embodiment, one of X|, X2, X3 is C(R3), Ai is —C(R8)(R9)—, A2 is —O—, Y is —C(R8)(R9)—, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R6, wherein R6 is independently at each occurrence oxo, halogen, -CN, -OR8, -C(O)R8, -C(O)OR8, - C(O)NR8R9, -NR8C(O)R9, -S(O)R8, -S(O)2R8s -NR8S(O)2R9, S(O)2NR8R9, C]-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more Rio, R2 îs H, R3 is H, and R4 is H.
In one embodiment, at least one of Xj, X2, or X3 is N, Ai is —O—, A2 is —C(R8)(R9)—, Y is — C(R8)(R9)-, R] is heterocyclyl optionally substituted with one or more R^, wherein R6 is independently at each occurrence oxo, halogen, -CN, ~OR8, -C(O)R8, -C(O)OR8, - C(O)NR8R9, NRSC(O)R9, -S(O)R8, -S(O)2R8j -NR8S(O)2R9, -S(O)2NRsR9, CrC6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3~C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more Rio, R2 is H, R3 is H, and R4 is IL
In one embodiment, at least one of Xi, X2, or X3 is N, Ai is -C(R8)(R9)—, A2 is —O-, Y is C(R8)(R9)-, Ri is heterocyclyl optionally substituted with one or more R^, wherein R9 is independently at each occurrence oxo, halogen, -CN, -OR8, -C(O)R8, -C(O)OR8, - C(O)NR8R9, NR8C(O)R9, -S(O)R8, -S(O)2R8, -NR8S(O)2R9î -S(O)2NR8R9, CrC6 alkyl, C2-C6 alkenyl, C2-C6 82 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more R10, R2 is H, R3 is H, and R4 is H,
In one embodiment, one of X|, X2, X3 is C(Rs), Ai is -O-, A2 is -C(R8)(R9)-, Y is —C(R8)(R9)-, Ri is heterocyclyl optionally substituted with one or more Re, wherein Ré is independently at each occurrence oxo, halogen, -CN, -OR8, -C(O)R8, -C(O)OR8, - C(O)NR8R9, —NR8C(O)R9, -S(O)R8, S(O)2R8, -NR8S(O)2R9, -S(O)2NR8R9, CrC6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl. or heteroaryl can be optionally substituted with one or more Rio, R2 is H, R3 is H, and R4 is H.
In one embodiment, one of Xi, X2, X3 is C(R3), Ai is -C(R8)(R9)—, A2 is —O-, Y is -C(R8)(R9)-, Ri is heterocyclyl optionally substituted with one or more Ré, wherein Ré is independently at each occurrence oxo, halogen, -CN, —OR8, —C(O)R8, —C(O)OR8, — C(O)NR8R9, —NR8C(O)R9, -S(O)R8, S(O)2R8, -NR8S(O)2R9, -S(O)2NR8R9, Cj-Cé alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl. or heteroaryl can be optionally substituted with one or more Rio, R2 is H, R3 is H, and R4 is H.
In one embodiment, at least one of Xi, X2, or X3 is N, A| is -O-, A? is -C(R8)(R9)-, Y is C(R8)(R9)-, Rj is heteroaryl optionally substituted with one or more R6, wherein R6 is independently at each occurrence oxo, halogen, -CN, —OR8, —C(O)R8, —C(O)OR8, — C(O)NR8R9, -NR8C(O)R9, S(O)R8s -S(O)2Rf, -NRsS(O)2R9, -S(O)2NR8R9, Cj-Cé alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more Rio, R2 is H, R3 is H, and R4 is H.
In one embodiment, at least one of X], X2, or X3 is N, A[ is -C(R8)(R9)—, A2 is -O-, Y is C(R8)(R9)-, R1 is heteroaryl optionally substituted with one or more R6, wherein Ré is independently at each occurrence oxo, halogen, -CN, -OR8, -C(O)R8, -C(O)OR8, - C(O)NR8R9, -NR8C(O)R9, S(O)R8, -S(O)2Rs, -NR8S(O)2R9, -S(O)2NR8R9, Ci-Cé alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more Rio, R2 is H, R3 is H, and R4 is H.
In one embodiment, one of Xi, X2, X3 is C(Rs), Aj is -O-, A2 is -C(R8)(R9)-, Y is -C(R8)(R9)-, Ri is heteroaryl optionally substituted with one or more R9, wherein Ré is independently at each occurrence oxo, halogen, -CN, -OR8, -C(O)R8, -C(O)OR8, - C(O)NR8R9f NR8C(O)R9, -S(O)R8, S(O)2R8, -NR8S(O)2R9, -S(O)2NR8R% C|-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more Rio, R2 is H, R3 is H, and R4 is H.
In one embodiment, one of Xb X2, Xî is CfRs), Ai is —C(R8)(R9)—, A2 is —O—, Y is —C(R8)(R9)—, Ri is heteroaryl optionally substituted with one or more R6, wherein R6 is independently at each occurrence oxo, halogen, -CN, — OR8, -C(O)R8, —C(O)OR8, — C(O)NR8R9, -NR8C(O)R9, -S(O)R8, S(O)2R8, -NR8S(O)2R9, -S(O)2NR8R9, CrC6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-Cs cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more Rio, R2 is H, R3 is H, and R4 is H.
In one embodiment, at least one of Xb X2, or X3 is N, Ai is —O—, A2 is —C(R8)(R9)—, Y is — C(R8)(R9)-, Rj is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Rs, wherein 1% is independently at each occurrence oxo, halogen, -CN, -OR8, -C(O)R8, -C(O)OR8, - C(O)NR8R9, -NR8C(O)R9, -S(O)R8, -S(O)2R8, NR8S(O)2R9, -S(O)2NR8R9, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more Ræ, R2 is halogen, R3 is H, and R4 is H.
In one embodiment, at least one of Xb X2, or X3 is N, Ai is -C(R8)(R9)~, A2 is -O-, Y is C(R8)(R9)-, R| is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Rs, wherein Rs is independently at each occurrence oxo, halogen, -CN, —OR8, —C(O)R8, —C(O)OR8, — C(O)NR8R9, —NR8C(O)R9, -S(O)R8, -S(O)2R8, — NR8S(O)2R9, -S(O)2NR8R9, CrC6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more Rio, R2 is halogen, R3 îs H, and R4 is H.
In one embodiment, one of Xb X2, X3 is C(Rs), Ai is -O-, A2 is —C(R8)(R9)-, Y is -C(R8)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R6, wherein R6 is independently at each occurrence oxo, halogen, -CN, -OR8, -C(O)R8, -C(O)OR8, - C(O)NR8R9, -NR8C(O)R9, -S(O)R8, -S(O)2R8, -NR8S(O)2R9, S(O)2NR8R9, CrC6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more Rio, R2 is halogen, R3 is H, and R4 is H.
In one embodiment, one of Xb X2, Xj is C(R5), Aj is -C(Rg)(R9)-, A2 is -O-, Y is -C(R8)(R9)- Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R6, wherein R6 is independently at each occurrence oxo, halogen, -CN, -ORs, -C(O)R8, -C(O)OR8, - C(O)NR8R9, -NRsC(O)R9, -S(O)Rg, -S(O)2Rg, -NR8S(O)2R9, S(O)2NR8R9, CrC6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, CrC8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more Rio, R2 is halogen, R3 is H, and R4 is H.
In one embodiment, at least one of Xb X2, or X3 is N, Ai is -O-, A2 is -C(R8)(R9)—, Y is C(Rg)(R9)-, R1 is heterocyclyl optionally substituted with one or more R(t, wherein R6 is independently at each occurrence oxo, halogen, -CN, -ORg, -C(O)R8, -C(O)ORg, - C(O)NR8R9, NR8C(O)R9, -S(O)R8, -S(O)2R8, -NR8S(O)2R9, -S(O)2NR8R9î CrU alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more Rio, R2 is halogen, R3 is H, and R4 is H.
In one embodiment, at least one of Xb X2, or X3 is N, A] is -C(R8)(R9)-, A2 is -O—, Y is C(R8)(R9)-, Ri is heterocyclyl optionally substituted with one or more R6, wherein R6 is independently at each occurrence oxo, halogen, -CN, —ORg, —C(O)Rg, —C(O)OR8, — C(O)NRgR9, — NR8C(O)R9, -S(O)R8, -S(O)2R8, -NR8S(O)2R9, -S(O)2NR8R9, CrC6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-Cg cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more Rio, R2 is halogen, R3 is H, and R4 is H.
In one embodiment, one of Xb X2, X3 is C(R$), Ai is —O—, A2 is —C(R8)(R9)—, Y is —C(Rg)(R9)—, Ri is heterocyclyl optionally substituted with one or more Rô, wherein R^ is independently at each occurrence oxo, halogen, -CN, -ORg, —C(O)Rg, —C(O)OR8, — C(O)NR8R9, -NR8C(O)R9, -S(O)R8, S(O)2R8, -NR8S(O)2R9, -S(O)2NR8R9, CrC6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more Rio, R2 is halogen, R3 is H, and R4 is H.
In one embodiment, one of Xb X2, X3 is C(Rs), Ai is —C(Rg)(R9)—, A2 is —O-, Y is ~C(Rg)(R9)-, Ri is heterocyclyl optionally substituted with one or more R6, wherein Ro is independently at each occurrence oxo, halogen, -CN, —OR8, —C(O)Rg, —C(O)OR8, — C(O)NR8R9, —NR8C(O)R9, -S(O)R8, 85
S(O)2R8, -NRsS(O)2R% -S(O)2NRsR9, CrC6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more Rio, R 2 is halogen, R3 is H, and R4 is H.
In one embodiment, at least one of X), X2, or Xj is N, A] is -O-, A2 is -C(R8XR9)-, Y is — C(RsXR9)-, Ri is heteroaryl optionally substituted with one or more 1%, wherein R(, is independently at each occurrence oxo, halogen, -CN, —ORg, —C(O)Rg, —C(O)ORg, — C(O)NR8R9, —NRgC(O)R9, S(O)R8s -S(O)2R8, -NR8S(O)2R9, -S(O)2NR8R9, crc6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more Rio, R2 is halogen, Ri is H, and R4 is H.
In one embodiment, at least one of Xi, X2, or X3 is N, Ai is —C(R8XR9)—, A2 is —O—, Y is C(R8)(R9)-, R| is heteroaryl optionally substituted with one or more R6, wherein R6 is independently at each occurrence oxo, halogen, -CN, -ORg, -C(O)R8, —C(O)OR8, — C(O)NR8R9, —NR8C(O)R9, S(O)Rg, -S(O)2R8, -NR8S(O)2R9, -S(O)2NR8R9, CrC6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more Rio, R2 is halogen, R3 is H, and R4 is H.
In one embodiment, one of X|, X2, X3 is C(Rs), A| is —O—, A2 is —C(R8XR9)—, Y is —C(R8)(R9)—, Ri is heteroaryl optionally substituted with one or more R/,, wherein R& is independently at each occurrence oxo, halogen, -CN, —OR8, —C(O)R8, —C(O)OR8, - C(O)NR8R9, -NR8C(O)R9, -S(O)R8, S(O)2R8, -NR8S(O)2R9, -S(O)2NR8R9, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-Cg cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more R(0, R2 is halogen, R3 is H, and R4 is H.
In one embodiment, one of Xj, X2, X3 is C(Rs), A| is — C(R8XR9)—, À2 is -O-, Y is -C(R8XR9)-, Ri is heteroaryl optionally substituted with one or more R<„ wherein R6 is independently at each occurrence oxo, halogen, -CN, —OR8, —C(O)Rg, —C(O)ORg, — C(O)NR8R9, —NR8C(O)R9, -S(O)Rg, S(O)2R8, -NR8S(O)2R9j -S(O)2NR8R9, CrC6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more Rio, R2 is halogen, R3 is H, and R4 is H.
In one embodiment, at least one of Xi, X2, or X3 is N, A] is -O-, A2 is —C(Rg)(R9) , Y is C(R8)(R9)- Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R6, wherein Rô is independently at each occurrence oxo, halogen, -CN, —OR8, —C(O)R8, —C(O)OR8, — C(O)NRgR9, —NR8C(O)R9, -S(O)Rg, -S(O)2R8, — NR8S(O)2R9, -S(O)2NR8R9, CrC6 alkyl, C2-Câ alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more R|0, R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, C|-Cê alkyl, Ci-Ce alkoxy, C2-C& alkenyl, or C2-C0 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 and R9 can form heterocyclyl.
In one embodiment, at least one of Xj, X2, or X3 is N, Ai is -C(Rg)(R9)-, A2 is -O-, Y is C(R8)(R9)-, R1 is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Rû, wherein R„ is independently at each occurrence oxo, halogen, -CN, -OR8, -C(O)RS, -C(O)OR8, - C(O)NR8R9, -NR8C(O)R9, -S(O)R8, -S(O)2R8, NR8S(O)2R9, -S(O)2NR8R9, C]-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl. or heteroaryl can be optionally substituted with one or more Rio, R2 and R3 aie independently at each occurrence H, halogen, —OH, -NH2, -CN, Ci-Cô alkyl, Cj-Ce alkoxy, C2-C9 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Xi, X2, X3 is C(Rj), Aj is -O-, A2 is -C(R8)(R9)-, Y is -C(R8)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R6, wherein Rf, îs independently at each occurrence oxo, halogen, -CN, -OR8, -C(O)R8, -C(O)OR8, - C(O)NR8R9, -NR8C(O)R9, -S(O)R8î -S(O)2R8, -NRsS(O)2R9, S(O)2NR8R9, CrC6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more Rio, R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, Ci-C6 alkyl, C]-C(i alkoxy, C2-C6 alkenyl, or C2-Cô alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Xi, X2, X3 is C(R3), Ai îs -C(Rg)(R9)-, A2 is -O-, Y is -C(R8)(R9)~, Ri is heterocyclyl. aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R&, wherein R(s is independently at each occurrence oxo, halogen, -CN,
-OR8, -C(O)R8, -C(O)OR8, - C(O)NR8R9, -NR8C(O)R9, -S(O)R8, -S(O)2R8, -NR8S(O)2R9, S(O)2NR8R9, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more Rw, R2 and R3 are independently at each occurrence 5 H, halogen, -OH, -NH2, -CN, CrC6 alkyl, CrC6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 and R9 can fonn heterocyclyl.
In one embodiment, at least one of Xj, X2, or X3 is N, Ai is -O-, A2 is —C(R8)(R9)-, Y is — C(R8)(R9)-, R1 is heterocyclyl optionally substituted with one or more R6, wherein R6 is 10 independently at each occurrence oxo, halogen, -CN, -OR8, -C(O)R8, -C(O)OR8, - C(O)NR8R9, NR8C(O)R9, -S(O)R8, -S(O)2R8, -NR8S(O)2R9, -S(O)2NR8R9, CrC6 alkyl, C2-C6 alkenyl, C2-Cg alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more Rw, R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, CrC6 alkyl, Ct15 C6 alkoxy, C2-Cf, alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 and R9 can fonn heterocyclyl.
In one embodiment, at least one of Xi, X2, or X3 is N, A| is -C(R8)(R9)—, A2 is —O—, Y is C(R8)(R9)-, Ri is heterocyclyl optionally substituted with one or more R6, wherein R6 is independently at each occurrence oxo, halogen, -CN, -OR8, -C(O)R8, -C(O)OR8, - C(O)NR8R9, 20 NR8C(O)R9, -S(O)Rg, -S(O)2R8, -NR8S(O)2R9, -S(O)2NR8R9, CrC6 alkyl, C2-C0 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more Rw, R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, C|-C6 alkyl, Cr C6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl îs 25 optionally substituted with one or more R7, and R4 and R9 can form heterocyclyl.
In one embodiment, one of X;, X2, X3 is C(R3), Ai is -O-, A2 is —C(R8)(R9)-, Y is —C(R8)(R9)-, Ri îs heterocyclyl optionally substituted with one or more R6, wherein R6 is independently ai each occurrence oxo, halogen, -CN, -OR8, -C(O)R8, -C(O)OR8, - C(O)NR8R9, -NR8C(O)R9, -S(O)R8, S(O)2R8, -NRsSÎOXRo, -S(O)2NR8R9, CrC6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 30 heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more Rw, R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, Cj-Cg alkyl, Ci-Cg alkoxy, C2-Cg alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7) and R4 and Rg can fonn heterocyclyl.
In one embodiment, one of Xb X2, X3 is C(R3), Ai is -C(R8)(R9)-, A2 is -O-, Y is -C(Rg)(R9)—, Ri is heterocyclyl optionally substituted with one or more Rg, wherein Rg is îndependently at each occurrence oxo, halogen, -CN, -OR8, -C(O)Rg, -C(O)ORg, — C(O)NR8R9, —NR8C(O)R9, -S(O)Rg, S(O)2Rs, -NR8S(O)2R9, -S(O)2NR8R9, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more Rio, R2 and R3 are îndependently at each occurrence H, halogen, -OH, -NH2, -CN, Cj-Cô alkyl, Ci-Cé alkoxy, C2-Co alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 and R9 can form heterocyclyl.
In one embodiment, at least one of Xi, X2, or X3 is N, Ai is -O-, A2 is —C(Rg)(R9)-, Y is C(R8)(R9)-, Ri Îs heteroaryl optionally substituted with one or more R6, wherein Rô is îndependently at each occurrence oxo, halogen, -CN, —ORg, —C(O)Rg, -C(O)OR8, — C(O)NR8R9, -NR8C(O)R9f S(O)Rg, -S(O)2Rg, -NRgS(O)2R9, -S(O)2NR8R9, CrC6 alkyl, C2-Câ alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more R|0, R2 and R3 are îndependently at each occurrence H, halogen, -OH, -NH2, -CN, Cj-C6 alkyl, Ci-C6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7f and R4 and R9 can fonn heterocyclyl.
In one embodiment, at least one of Xb X2, or X3 is N, A, is — C(R8)(R9)—, A2 is —O—, Y is — C(Rg)(R9)-, Ri is heteroaryl optionally substituted with one or more R(„ wherein R6 îs îndependently at each occurrence oxo, halogen, -CN, —ORg, —C(O)Rg, —C(O)OR8, — C(O)NR8R9, —NR8C(O)R9, S(O)R8, -S(O)2Rs, -NR8S(O)2R9, -S(O)2NR8R9, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more Rio, R? and R3 are îndependently at each occurrence H, halogen, -OH, -NH2, -CN, Ci-Ce alkyl, Ci-Cg alkoxy, C2-C6 alkenyl, or C2-Cô alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Xb X2, X3 is C(R3), Ai is —O-, A2 is -C(Rg)(Rg)-, Y is -C(R8)(R9)-, Ri is heteroaryl optionally substituted with one or more Re, wherein R9 is îndependently at each occurrence oxo, halogen, -CN, -ORg, -C(O)Rg, —C(O)OR8, — C(O)NRgR9, -NR8C(O)R9, -S(O)Rg, S(O)2R8, -NR8S(O)2R9, -S(O)2NR8R9, C]-C6 alkyl, C2-C6 alkenyl, C2-C0 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionaliy substituted with one or more Rio, R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, CpCg alkyl, CpCg alkoxy, C2-Cg alkenyl, or C2-Cg alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionaliy substituted with one or more R7, and R4 and Ro can fonn heterocyclyl.
In one embodiment, one of Xi, X2, X3 is C(R3), Ai is -C(R8)(R9)-, A2 is -O—, Y is —C(R8)(R9)—, Ri is heteroaryl optionaliy substituted with one or more Rg, wherein Rg is independently at each occuiTence oxo, halogen, -CN, -ORg, -C(O)R8, -C(O)OR8, - C(O)NR8R9, -NR8C(O)R9, -S(O)R8, S(O)2Rg, -NR8S(O)2R9, -S(O)2NRgR9, CrC6 alkyl, C2-C6 alkenyl, C2-Cg alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionaliy substituted with one or more R10, R2 and R3 are independently at each occuiTence H, halogen, -OH, -NH2, -CN, CpCg alkyl, CpCg alkoxy, C2-Cg alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionaliy substituted with one or more R7, and R4 and R9 can fonn heterocyclyl.
In one embodiment, at least one of Xi, X2, or X3 is N, Ai is —O—, A2 is —C(R8)(R9)—, Y is — C(R8)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionaliy substituted with one or more Rg, wherein Rg is independently at each occunence oxo, halogen, -CN, —OR8, —C(O)R8, — C(O)OR8, — C(O)NR8R9, —NRgC(O)R9, -S(O)R8, -S(O)2R8, — NR8S(O)2R9, -S(O)2NR8R9, CpC6 alkyl, C2-Cg alkenyl, C2-C6 alkynyl, C3-Cg cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionaliy substituted with one or more Rio, R2 is H, R3 is H, and R4 and R9 can fonn heterocyclyl.
In one embodiment, at least one of Xj, X2, or X3 is N, Ai is —C(R8)(R9)—, A2 is —O—, Y is — C(R8)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionaliy substituted with one or more Rg, wherein Rg is independently at each occurrence oxo, halogen, -CN, -OR8, -C(O)R8, -C(O)ORg, - C(O)NRgR9, -NR8C(O)R9, -S(O)Rg, -S(O)2R8, NR8S(O)2R9, -S(O)2NR8R9, CrC6 alkyl, C2-Cg alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionaliy substituted with one or more Rio, R2 is H, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Xi, X2, X3 is C(Rj), At is -O-, A2 is -C(Rg)(R9)-, Y is -C(R8)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionaliy substituted with one or more Rg, wherein Rg is independently at each occuiTence oxo, halogen, -CN,
-ORg, -C(O)R8, -C(O)OR8, - C(O)NR8R9, -NR8C(O)R9, -S(O)R8, -S(O)2R8, -NRsS(O)2R9, S(O)2NR8R9, Cj-Cg alkyl, C2-Cg alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more Rio, R2 is H, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Xi, X2, X3 is C(R5), Ai is —C(R8)(R9)—, A2 is —O—, Y is — C(R8)(R9)—, Rj îs heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Rg, wherein R6 is independently at each occurrence oxo, halogen, -CN, -OR8, -C(O)R8s -C(O)OR8, - C(O)NR8R9, -NR8C(O)R9j -S(O)R8, -S(O)2R8, -NR8S(O)2R% S(O)2NR8R9, CrC6 alkyl, C2-Cg alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more Rl0, R2 is H, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, at least one of Xi, X2, or X3 is N, Ai is —O—, A2 is —C(R8)(R9)—, Y is C(R8)(R9)-5 Ri is heterocyclyl optionally substituted with one or more Rg, wherein Rg is independently at each occurrence oxo, halogen, -CN, -OR8, -C(O)R8, -C(O)OR8, - C(O)NR8R9, NR8C(O)R9, -S(O)R8, -S(O)2R8, -NR8S(O)2R9, -S(O)2NRsR9, Ci-Cg alkyl, C2-C6 alkenyl, C2-Cg alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more Rio, R2 is H, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, at least one of Xi, X2, or X3 is N, Ai is -C(R8)(R9)-, A2 is -O-, Y is C(Rr)(R9)- R| is heterocyclyl optionally substituted with one or more Rg, wherein Rfi is independently at each occurrence oxo, halogen, -CN, -OR8, -C(O)R8, -C(O)OR8, - C(O)NR8R9, NR8C(O)R9, -S(O)R8, -S(O)2R8s -NR8S(O)2R9, -S(O)2NR8R9, Ci-Cg alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more Rio, R2 is H, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Xi, X2, X3 is C(Rg), Ai is -O-, A2 is -C(R8)(R9)-, Y is -C(R8)(R9)-, Ri is heterocyclyl optionally substituted with one or more Rg, wherein Rg is independently at each occurrence oxo, halogen, -CN, -OR8, -C(O)R8, -C(O)OR8, - C(O)NR8R9, -NR8C(O)R9, -S(O)R8, S(O)2R8, -NR8S(O)2R9, -S(O)2NRsR9, Ci-Cg alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more Rio, R? is H, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Xb X2, X3 is C(R3), A] is -C(R8)(R9)-, A2 is -O-, Y is -C(R8)(R9)-, Ri is heterocyclyl optionally substituted with one or more Ré, wherein Ré is independently at each occurrence oxo, halogen, -CN, — OR8, —C(O)R8, —C(O)OR8, — C(O)NR8R9, —NR8C(O)R9, -S(O)R8, S(O)2R8, -NRsS(O)2R9, -S(O)2NR8R9, Ci-C6 alkyl, C2-C6 alkenyl, C2-C0 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more R10, R2 is H, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, at least one of Xj, X2, or X3 is N, A| is —O—, A2 is —C(R8)(R9)—, Y is — C(R8)(R9)-, Ri is heteroaryl optionally substituted with one or more R^, wherein R6 is independently at each occurrence oxo, halogen, -CN, -OR8, -C(O)Rg, -C(O)OR8, — C(O)NR8R9, -NR8C(O)R9, S(O)R8, -S(O)2Rs, -NRsS(O)2R9, -S(O)2NR8R9, Cj-Cé alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more R10, R2 is H, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, at least one of Xb X2, or X3 is N, Ai is -C(R8)(R9)—, A2 is -O-, Y is C(R8)(R9)-, Ri is heteroaryl optionally substituted with one or more R6, wherein R6 is independently at each occurrence oxo, halogen, -CN, -ORs, -C(O)R8, -C(O)OR8, — C(O)NR8R9, -NR8C(O)R9, S(O)Rg, -S(O)2R8, -NR8S(O)2R9s -S(O)2NR8R9, CrC6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more R^, R2 is H, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Xb X2, X3 is C(Ré), Ai is -O-, A2 is —C(R8)(R9)—, Y is -C(R8)(R9)—, Ri is heteroaryl optionally substituted with one or more R(„ wherein Ré is independently at each occurrence oxo, halogen, -CN, -ORs. -C(O)R8, -C(O)OR8, - C(O)NR8R9, -NR8C(O)R9, -S(O)R8, S(O)2R8, -NRsS(O)2R9, -S(O)2NR8R9, Ci-Cô alkyl, C2-Cé alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl. or heteroaryl can be optionally substituted with one or more Rio, R2 is H, R3 is H, and R4 and R9 can fonn heterocyclyl.
In one embodiment, one of Xb X2, X3 is C(Rs), Ai is —C(R8)(R9)-, A2 is -O-, Y is -C(R8)(R9)—, Ri is heteroaryl optionally substituted with one or more R6, wherein R6 îs independently at each occurrence oxo, halogen, -CN, -OR8, -C(O)R8, ~C(O)OR8, - C(O)NR8R9, -NR8C(O)R9, -S(O)R8, 92
S(O)2R8, -NR8S(O)2R9, -S(O)2NR8R9, C,-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more Rio, R2 is H, R3 is H, and R4 and Ro can fonn heterocyclyl.
In one embodiment, at least one oi Xi, X2, or X3 is N, Ai is —O—, A2 is — C(R8)(R9)—, Y is — C(R8)(R9)-, R1 is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R(„ wherein R(, is independently at each occurrence oxo, halogen, -CN, —OR8, —C(O)R8, —C(O)OR8, — C(O)NR8R9, —NR8C(O)R9, -S(O)R8, -S(O)2R8, — NR8S(O)2R9, -S(O)2NR8Rq, CrC6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more Rio, R2 is halogen, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, at least one of Xi, X2, or X3 is N, A] is —C(R8)(R9)-, A2 is -O-, Y is — C(R8)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R6, wherein R6 is independently at each occurrence oxo, halogen, -CN, —OR8, -C(O)R8, -C(O)OR8, — C(O)NR8R9, —NR8C(O)R9, -S(O)R8, -S(O)2R8, — NRsS(O)2R9, -S(O)2NR8R9, CrC6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more Rio, R2 is halogen, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Xi, X2, X3 is C(Rg), Aj is -O-, A2 îs -C(R8)(R9)-, Y is -C(R8)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R6, wherein R6 is independently at each occurrence oxo, halogen, -CN, -OR8, -C(O)R8, -C(O)OR8, - C(O)NRsR9, -NR8C(O)R9, -S(O)R8, -S(O)2R8, -NR8S(O)2R9, S(O)2NR8R9, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more Rio, R2 is halogen, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Xj, X2, X3 is C(Rs), Ai is -C(R8)(R9)-, A2 is -O-, Y is -C(R8)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R9, wherein R6 is independently at each occurrence oxo, halogen, -CN, -OR8, -C(O)R8j -C(O)OR8, - C(O)NR8R9, -NR8C(O)R9, -S(O)R8, -S(O)2R8, -NR8S(O)2R9î S(O)2NR8R9, CrC6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more Rio, R2 is halogen, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, at least one of Xb X2, or X3 is N, Ai is —O—, A2 is —C(R8)(R9)—, Y is C(R8)(R9)-, Ri is heterocyclyl optionally substituted with one or more R6, wherein R6 is independently at each occurrence oxo, halogen, -CN, -OR8, -C(O)R8, -C(O)OR8, - C(O)NR8R9, NR8C(O)R9, -S(O)R8, -S(O)2R8, -NR8S(O)2R9, -S(O)2NR8R9, CrC6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more R10, R2 is halogen, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, at least one of Xb X2, or X3 is N, A] is —C(R8)(R9)—, A2 is —O—, Y is — C(R8)(R9)-, Ri is heterocyclyl optionally substituted with one or more Ré, wherein Ré is independently at each occurrence oxo, halogen, -CN, -OR8, -C(O)R8, -C(O)OR8, - C(O)NR8R9, NR8C(O)R9, -S(O)R8, -S(O)2R8, -NR8S(O)2R9, -S(O)2NR8R9, Ci-Cé alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more Rio, R2 is halogen, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Xb X2, X3 is C(Ré), Ai is —O—, A2 is —C(R8)(R9)—, Y is —C(R8)(R9)—, Rj is heterocyclyl optionally substituted with one or more Ré, wherein Ré is independently at each occurrence oxo, halogen, -CN, —ORg, —C(O)R8, —C(O)OR8, — C(O)NR8R9, —NR8C(O)R9, -S(O)R8, S(O)2R8, -NR8S(O)2R9, -S(O)2NR8R9, Ci-Cé alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more Rw, R2 is halogen, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Xb X2, X3 is C(Ré), A( is -C(R8)(R9)-, A2 is —O-, Y is -C(R8)(R9)-, Ri is heterocyclyl optionally substituted with one or more Ré, wherein Ré is independently at each occurrence oxo, halogen, -CN, —OR8, —C(O)R8, -C(O)OR8, — C(O)NR8R9, -NR8C(O)R9, -S(O)R8, S(O)2R8, -NR8S(O)2R9, -S(O)2NR8R9, CrC6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more Rio, R2 is halogen, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, at least one of Xb X2, or X3 is N, Aj is —O-, A2 is -C(R8)(R9)-, Y is — C(R8)(R9)- RI is heteroaryl optionally substituted with one or more R(„ wherein R6 is independently at each occurrence oxo, halogen, -CN, — ORs, —C(O)R8, —C(O)OR8, C(O)NR8R9, NR8C(O)R9,
S(O)R8, -S(O)2R8, -NR8S(O)2R9, -S(O)2NR8R9, CrC6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more Ri0, R2 is halogen, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, at least one of Xi, X2, or X3 is N, Ai is -C(R8)(R9)-, A2 is -O-, Y is — C(R8)(R9)-, Ri is heteroaryl optionally substituted with one or more R6, wherein Ré is independently at each occurrence oxo, halogen, -CN, —ORg, —C(O)R8, —C(O)OR8, — C(O)NR8R9, —NR8C(O)R9, S(O)R8, -S(O)2Rg, -NR8S(O)2R9, -S(O)2NR8R9, CrCé alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more Rio, R2 is halogen, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Xb X2, X3 is C(Rj), Ai is -O-, A2 îs -C(R8)(R9)—, Y is -C(R8)(R9)—, Ri is heteroaryl optionally substituted with one or more Ré, wherein Ré is independently at each occurrence oxo, halogen, -CN, -OR8, —C(O)R8, — C(O)OR8, - C(O)NR8R9, —NR8C(O)R9, -S(O)R8, S(O)2R8, -NR8S(O)2R9, -S(O)2NR8R9, CrC6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more Rio, R2 is halogen, R3 is H, and R4 and R9 can fonn heterocyclyl.
In one embodiment, one of Xb X2, X3 is C(Rj), Ai is -C(R8)(R9)-, A2 is -O-, Y is -C(R8)(R9)-, Ri is heteroaryl optionally substituted with one or more R&, wherein R6 is independently at each occurrence oxo, halogen, -CN, -OR8, -C(O)R8, —C(O)OR8, - C(O)NR8R9, -NR8C(O)R9, -S(O)Rg, S(O)2R8, -NR8S(O)2R9, -S(O)2NRsR9, CrC6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted with one or more Rio, R2 is halogen, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, at least one of Xb X2, or X3 is N, Aj is —O—, A2 is — C(R8)(R9)—, Y is — C(R8)(R9)—, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R6, wherein R6 is independently at each occurrence CpCé alkyl optionally substituted with one or more Ri0, R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, CrC6 alkyl, CrC6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 is H.
In one embodiment, at least one of Xb X2, or X3 is N, Aj is -C(R8XR9) , *s 1S
C(Rs)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ré, wherein Ré is independently at each occurrence CrCô alkyl optionally substituted with one or more Rio, R; and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, CrC6 alkyl, CrC6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl îs optionally substituted with one or more R7, and R4 is H.
In one embodiment, one of Xb X2, X3 is C(R3), Ai is -O-, A2 is -C(R8)(Rg)—, Y is -C(Rs)(Rg)—, Rj is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R6, wherein RÉ is independently at each occurrence CrC6 alkyl optionally substituted with one or more Rio, R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, CrC6 alkyl, CrC6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 is H.
In one embodiment, one of Xb X2, X3 is C(R3), Ai is —C(R8XR9)—, A2 is —O—, Y is —C(R8)(R9)—, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ré, wherein Ré is independently at each occunence Ci-Cé alkyl optionally substituted with one or more Rio, R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, CrC6 alkyl, C,-C6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 is H.
In one embodiment, at least one of Xb X2, or X3 is N, Ai is -O-, A2 is —C(RsXRg)-, Y is C(R8)(R9)-, R| is heterocyclyl optionally substituted with one or more R6, wherein R() is independently at each occurrence CrC6 alkyl optionally substituted with one or more R]0, R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, Cj-Cé alkyl, Ci-Cé alkoxy, C2C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 is H.
In one embodiment, at least one of Xb X2, or X3 is N, Ai is -C(R8XR9)-, A2 is —O-, Y is — C(R8XR9)-, Ri is heterocyclyl optionally substituted with one or more R6, wherein Rb is independently at each occurrence CrC6 alkyl optionally substituted with one or more R10, R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, Ci-Cé alkyl, Ci-Cé alkoxy, C2C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 is H.
In one embodiment, one of Xb X2, X3 is C(R$), Aj is —O—, A2 is —C(R8XR9)—, Y îs —C(RsXR9)—, Ri is heterocyclyl optionally substituted with one or more R6, wherein R6 is independently at each occurrence Ci-C6 alkyl optionally substituted with one or more Rio, R2 and R3 are independently at each occurrence H, halogen, —OH, —NH2, —CN, Ci-C^ alkyl, Ci-Cg alkoxy, C2-Cé alkenyl, or C2-Cé alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 is H.
In one embodiment, one of Χι, X2, X3 is QRs), Ai is -C(R8)(R9)-, A2 is -O-, Y is -C(R8)(R9)-, Ri is heterocyclyl optionally substituted with one or more R^, wherein R6 is independently at each occurrence Cj-C6 alkyl optionally substituted with one or more Rio, R2 and R3 are independently at each occurrence H, halogen, —OH, —NH2, —CN, Cj-Cg alkyl, Cj-Cg alkoxy, C2-Cé alkenyl, 01 C2-Cg alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 is H.
In one embodiment, at least one of Xi, X2, or X3 is N, A] is -O-, A2 is -C(R8)(R9)-, Y is — C(R8)(R9)- R1 is heteroaryl optionally substituted with one or more R^, wherein R6 is independently at each occurrence CrC6 alkyl optionally substituted with one or more R|0, R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, Cj-Cé alkyl, Cj-Cs alkoxy, C2-Cé alkenyl, or C2-C0 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 is H.
In one embodiment, at least one of Xi, X2, or X3 is N, Ai is — C(R8)(R9)-, A2 is —O—, Y is — C(R8)(R9)-, Ri is heteroaryl optionally substituted with one or more R6, wherein R6 is independently at each occurrence CrC6 alkyl optionally substituted with one or more Rt0, R2 and R3 are independently at each occurrence H, halogen, -OH, —NH2, -CN, Ci-C^ alkyl, Ci-Cé alkoxy, C2-C& alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 is H.
In one embodiment, one of Χι, X2, X3 is C(Rs), Ai is -O-, A2 is -C(Rs)(Rg)-, Y is —C(R8)(R9)-, Ri is heteroaryl optionally substituted with one or more R^, wherein Ré is independently at each occurrence C]-C6 alkyl optionally substituted with one or more Rio, R2 and R3 are independently at each occurrence H, halogen, —OH, —NH2, —CN, Ci-Cé alkyl, Ci-C^ alkoxy, C2-C$ alkenyl, or C2-Cé alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 is H.
In one embodiment, one of Xi, X2, X3 is C(R3), Ai is -C(R8)(R9)-, A2 is -O-, Y is -C(R8)(R9)-, Ri is heteroaryl optionally substituted with one or more R^, wherein Rg is independently at each occurrence Ci-Cû alkyl optionally substituted with one or more Rio, R2 and R3 are independently at each occurrence H, halogen, —OH, —NH2, -CN, C]-C(s alkyl, Ci-Cg alkoxy, C2-Cb alkenyl, or C2-Cs alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 is H.
In one embodiment, at least one of Xi, X2, or X3 is N, A] is -O-, A2 îs -C(R8XR9) , Y is C(RgXR9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R9, wherein R9 is independently at each occurrence C|-C6 alkyl optionally substituted with one or more Rio, R2 îs H, Rj is H, and R4 is H.
In one embodiment, at least one of Xi, X2, or X3 is N, Af is -C(RgXR9)-, A2 is -O-, Y is — C(R8XR9)-, Rj is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R6, wherein R6 is independently at each occurrence CrC6 alkyl optionally substituted with one or more Rio, R2 is H, R3 is H, and R4 is H.
In one embodiment, one of X|, X2, X3 is C(R3), At is —O—, A2 is —C(RgXR9)—, Y is —C(RgXR9)—, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ro, wherein Rf, is independently at each occurrence Ci-Cg alkyl optionally substituted with one or more Rio, R2 is H, R3 is H, and R4 is H.
In one embodiment, one of Χι, X2, X3 is C(Rj), Ai is -C(R8XR9}-, A2 is -O-, Y is -CfRgXRg)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R6, wherein R6 is independently at each occurrence Ci-C6 alkyl optionally substituted with one or more Rio, R2 is H, R3 is H, and R4 is H.
In one embodiment, at least one of Xi, X2, or X3 is N, Aj is -O-, A2 is -C(R8XR9)—, Y is — C(R8XR9)-, R1 is heterocyclyl optionally substituted with one or more R6, wherein R6 is independently at each occurrence Cj-Cô alkyl optionally substituted with one or more Rio, R2 is H, R3 îs H, and R4 is H.
In one embodiment, at least one of Xi, X2, or X3 is N, Ai is -C(RsXR9)-, A2 is —O-, Y is C(R8)(R9)- R| is heterocyclyl optionally substituted with one or more R6, wherein R6 is independently at each occurrence Ci-C6 alkyl optionally substituted with one or more Rio, R2 is H, R3 is H, and R4 is H.
In one embodiment, one of Χι, X2, X3 is C(Rs), Ai is —O-, A2 is -C(RgXR9)-, Y is -C(Rg)(R9)-, Ri is heterocyclyl optionally substituted with one or more R&, wherein R(, is independently at each occurrence C(-C6 alkyl optionally substituted with one or more Rio, R2 is H, R3 is H, and R4 is H.
In one embodiment, one of Χι, X2, X3 is C(R5), Ai is -C(R8XR9)-, A2 is -O-, Y is -C(Rg)(R9)-, Ri is heterocyclyl optionally substituted with one or more R6, wherein R6 is independently at each occurrence Cj-C6 alkyl optionally substituted with one or more Rio, R2 is H, R3 is H, and R4 is H.
In one embodiment, at least one of Xi, X2, or X3 is N, A| is O-, A2 is -C(R8)(R9)-, Y is C(RgXR9)-, Ri is heteroaryl optionally substituted with one or more R6, wherein R6 is independently at each occuiTence CpC6 alkyl optionaliy substituted with one or more Rio, R2 is H, R3 is H, and R4 isH.
In one embodiment, at least one of Xj, X2, or X3 is N, A| is -C(R8)(R9)-, A2 is -O-, Y is C(R8)(R9)-, Ri is heteroaryl optionaliy substituted with one or more Rg, wherein Rg is independently at each occuiTence CpCg alkyl optionaliy substituted with one or more Rio, R2 is H, R3 is H, and R4 isH.
In one embodiment, one of Xi, X2, X3 is C(Rg), Ai is —O—, A2 is —C(R8)(R9)—, Y is ~C(Rg)(R9)—, Ri is heteroaryl optionaliy substituted with one or more R6, wherein R6 is independently at each occurrence CpCg alkyl optionaliy substituted with one or more Rio, R2 is H, R3 is H, and R4 is H.
In one embodiment, one of X,, X2, X3 is C(R$), A] is —C(R8)(R9)-, A2 is -O—, Y is — C(R8)(R9)-, Ri is heteroaryl optionaliy substituted with one or more Rg, wherein R6 is independently at each occunence CpCg alkyl optionaliy substituted with one or more Rio, R2 is H, R3 is H, and R4 is H.
In one embodiment, at least one of Xi, X2, or X3 is N, A| is -O—, A2 is —C(Rg)(R9)—, Y is C(R8)(R9)- Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionaliy substituted with one or more Rg, wherein Rg is independently at each occurrence CpCg alkyl optionaliy substituted with one or more Rio, R2 is halogen, R3 is H, and R4 is H.
In one embodiment, at least one of X|, X2, or X3 is N, Aj is — C(Rs)(R9)—, A2 is —O—, Y is — C(R8)(R9)-, R1 is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionaliy substituted with one or more Rg, wherein Rg is independently at each occunence CpCg alkyl optionaliy substituted with one or more Rio, R2 is halogen, R3 is H, and R4 is H.
In one embodiment, one of Xi, X2, X3 is C(R3), Ai is -O-, A2 is — C(R8)(R9)-, Y is -C(R8)(R9)—, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionaliy substituted with one or more Rg, wherein Rg is independently at each occurrence CpCg alkyl optionaliy substituted with one or more Rio, R? is halogen, R3 is H, and R4 is H.
In one embodiment, one of Xi, X2, X3 is C(R3), Ai is — C(Rs)(R9)—, A2 is -O-, Y is —C(R8)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionaliy substituted with one or more Rg, wherein Rg is independently at each occuiTence CpCg alkyl optionaliy substituted with one or more Rio, R2 is halogen, R3 is H, and R4 is H.
In one embodiment, at least one of Xi, X2, or X3 is N, A| is —O—, A2 is —C(Rg)(R9)-, Y is — C(R8)(R9)-, R] is heterocyclyl optionaliy substituted with one or more R6, wherein Rg is independently at each occurrence CpCg alkyl optionaliy substituted with one or more Rio, R2 is halogen, R3 is H, and R4 is H.
In one embodiment, at least one of Xi, X2, or X3 is N, Ai is -C(R8)(R9)-, A2 is -O-, Y is C(Rs)(R9)- Ri is heterocyclyl optionally substituted with one or more R9, wherein Rô is independently at each occurrence Cj-Cô alkyl optionally substituted with one or more Rio, R2 is halogen, R3 is H, and R4 is H,
In one embodiment, one of Xi, X2, X3 is C(Rs), Ai is -O-, A2 is -C(R8)(R9)-, Y is -C(R8)(R9)-, Ri is heterocyclyl optionally substituted with one or more Ro, wherein R^ îs independently at each occurrence CrC6 alkyl optionally substituted with one or more Rj0, R2 is halogen, R3 is H, and R4 is
H.
In one embodiment, one of Xi, X2, X3 is C(R3), Ai is —C(R8)(R9)—, A2 is —O—, Y is —C(R8)(R9)—, Ri is heterocyclyl optionally substituted with one or more R9, wherein Rg is independently at each occurrence CrC6 alkyl optionally substituted with one or more Rio, R2 is halogen, R3 îs H, and R4 is
H.
In one embodiment, at least one of Xi, X2, or X3 is N, A] is -O-, A2 is -C(R8)(R9)-, Y is — C(Rs)(R9)-, Ri is heteroaryl optionally substituted with one or more R6, wherein RÈ is independently at each occurrence C1-C& alkyl optionally substituted with one or more Rio, R2 is halogen, R3 is II, and R4 is H.
In one embodiment, at least one of Xj, X2, or X3 is N, Ai is -C(R8)(R9)—, A2 is —O-, Y is — C(R8)(R9)-, R| is heteroaryl optionally substituted with one or more R6, wherein R6 is independently at each occurrence CrCô alkyl optionally substituted with one or more Rio, R2 is halogen, R3 is H, and R4 is H.
In one embodiment, one of Xi, X2, X3 is C(R3), Aj is -O-, A2 îs -C(R8)(R9)-, Y îs —C(R8)(R9)-, Ri is heteroaryl optionally substituted with one or more Rô, wherein Rô is independently at each occurrence CrC6 alkyl optionally substituted with one or more Rio, R2 is halogen, R3 is H, and R4 is
H.
In one embodiment, one of Xi, X2, X3 is C(R$), Ai is — C(R8)(R9)—, A2 is —O—, Y is —C(R8)(R9)—, Ri is heteroaryl optionally substituted with one or more R6, wherein R6 is independently at each occurrence Ci-C6 alkyl optionally substituted with one or more Rjo, R2 is halogen, R3 is H, and R4 is
H.
In one embodiment, at least one of Xi, X2, or X3 is N, Ai is —O—, A2 is —C(R8)(R9)—, Y is — C(R8)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R6, wherein R6 is independently at each occurrence CrC& alkyl optionally substituted with one or more Rl0, R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, CrC6 alkyl, CrC6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the
100 alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 and R9 can form heterocyclyl.
In one embodiment, at least one of Xj, X2, or Xj is N, Ai is -C(R8)(R9)-, A2 is -O-, Y is C(Rs)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R6, wherein R6 is independently at each occurrence Ci-C6 alkyl optionally substituted with one or more Rw, R2 and R3 are independently at each occunence H, halogen, -OH, -NH2, -CN, CrC6 alkyl, CrC6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Xb X2, X3 is CfRj), Ai is -O-, A2 is -C(R8)(R9)-, Y is —C(R8)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Rs, wherein Rs is independently at each occurrence CpCs alkyl optionally substituted with one or more Rio, R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, Ci-C6 alkyl, Cj-C6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Xb X2, X3 is C(R3), Ai is -C(Rs)(R9)~, A2 is -O-, Y is —ClRgHRy)—, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Rs, wherein Rs is independently at each occurrence Ci-Cs alkyl optionally substituted with one or more Rio, R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, CrC6 alkyl, Ci-C6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 and R9 can form heterocyclyl.
In one embodiment, at least one of Xb X2, or X3 is N, Ai is —O—, A2 is —C(R8)(R9)—, Y is — C(R8)(R9)-, Ri is heterocyclyl optionally substituted with one or more Rs, wherein R6 is independently at each occurrence CrC6 alkyl optionally substituted with one or more Rio, R2 and R3 are independently at each occurrence H, halogen, -OH, -NH2, -CN, Ci-Cs alkyl, Cj-Cs alkoxy, C2C6 alkenyl, or C2-Cs alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 and R9 can fonn heterocyclyl.
In one embodiment, at least one of Xb X2, or X3 is N, Ai is -C(R8)(R9)-, A2 is -O-, Y is C(R8)(R9)-, Ri is heterocyclyl optionally substituted with one or more R6, wherein R6 is independently at each occurrence Ci-C6 alkyl optionally substituted with one or more Rio, R2 and R3 are independently at each occurrence H, halogen, —OH, —NH2, —CN, Ci-Cs alkyl, Ci-Cs alkoxy, C2
101
C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 and Rç can form heterocyclyl.
In one embodiment, one of Xb X2, X3 is C(R5), Ai is —O—, A2 is —C(RsXRg)—, Y is —ClRsXRg)—, Ri is heterocyclyl optionally substituted with one or more R5, wherein Rg îs îndependently at each occurrence Cj-C6 alkyl optionally substituted with one or more Rio, R2 and Rj are îndependently at each occurrence H, halogen, -OH, -NH2, -CN, Ci-Cô alkyl, Ci-C& alkoxy, C2-C& alkenyl, 01 C2-Cé alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Xb X2, X3 is C(Rs), Ai is -C(R8)(R9)-, A2 îs —O-, Y is -C(R8)(R9)—, Ri is heterocyclyl optionally substituted with one or more Ro, wherein R^ is îndependently ai each occurrence CrC6 alkyl optionally substituted with one or more Rio, R2 and R3 are îndependently at each occurrence H, halogen, —OH, —NH2, —CN, Ci-C^ alkyl, Ci-C^ alkoxy, C2-C6 alkenyl, 01 C2-Cé alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 and R9 can fonn heterocyclyl.
In one embodiment, at least one of Xb X2, or X3 is N, Ai is —O—, A2 is —C(RgXRg)—, Y is — C(R8)(R9)-, R1 is heteroaryl optionally substituted with one or more R6, wherein R6 is îndependently at each occun'ence Ci-C6 alkyl optionally substituted with one or more Rio, R2 and R3 are îndependently at each occurrence H, halogen, -OH, -NH2, -CN, CpCg alkyl, Cj-Cg alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 and Rg can form heterocyclyl.
In one embodiment, at least one of Xb X2, or X3 is N, Ai is — C(RsXRg)—, A2 îs -O-, Y is — C(R8)(R9)-, Ri is heteroaryl optionally substituted with one or more R6, wherein R6 is îndependently at each occurrence CrC6 alkyl optionally substituted with one or more Rio, R2 and R3 are îndependently at each occurrence H, halogen, -OH, -NH2, -CN, Cj-C^ alkyl, Ci-C8 alkoxy, C2-Cé alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Xb X2, X3 îs C(Rj), Ai is -O-, A2 is —ClRsXRg)-, Y is —C(R8XR9)-> Ri is heteroaryl optionally substituted with one or more R(„ wherein Rg is îndependently at each occurrence CrC6 alkyl optionally substituted with one or more Rio, R2 and R3 are îndependently at each occurrence H, halogen, -OH, —NH2, -CN, Ci-C^ alkyl, Ci-Cg alkoxy, C2-Cé alkenyl, or C2-C& alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7) and R4 and R9 can form heterocyclyl.
102
In one embodiment, one of Xi, X2, Xî is C(Ré), A| is -C(R8)(R9)-, A2 is -O-, Y is C(R8)(R9) , Ri is heteroaryl optionally substituted with one or more R&, wherein Ré is independently at each occurrence CrC6 alkyl optionally substituted with one or more Rio, R2 and R3 are independently at each occurrence Tl, halogen, —OH, —NH2, —CN, Ci-C^ alkyl, Ci-Cé alkoxy, C2-Ce alkenyl, or C2-Cé alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one or more R7, and R4 and Rq can form heterocyclyl.
In one embodiment, at least one of Xi, X2, or X3 is N, Ai is —O—, A2 is —C(Rg)(R9)—, Y is — C(Rg)(R5)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R6, wherein R6 is independently at each occurrence CrC6 alkyl optionally substituted with one or more Rio, R2 is H, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, at least one of Xj, X2, or X3 is N, Ai is —C(Rg)(R9)-, A2 is -O-, Y is — C(R8)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ré, wherein Ré is independently at each occurrence Cj-Cg alkyl optionally substituted with one or more Rio, R2 is H, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Xi, X2, X3 is C(Rj), Ai is -O-, A2 is —C(R8)(Ry)—, Y is -C(R8)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ré, wherein Ro is independently at each occurrence Ci-Cé alkyl optionally substituted with one or more Rio, R2 is H, R 3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Xi, X2, X3 is C(Rs), Ai is —C(Rs)(R9)-, A2 is —O-, Y is -C(Rg)(R9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R6, wherein R6 is independently at each occurrence CrC6 alkyl optionally substituted with one or more Rio, R2 is H, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, at least one of Xi, X2, or X3 is N, A] is -O-, A2 is -C(R8)(R9)—, Y is — C(R8)(R9)-, Ri is heterocyclyl optionally substituted with one or more R6, wherein R6 is independently at each occurrence Cj-C6 alkyl optionally substituted with one or more Rio, R2 is H, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, at least one of X|, X2, or X3 is N, Ai is -C(R$)(R9)-, A2 is -O-, Y is — C(R8)(R9)~, Ri is heterocyclyl optionally substituted with one or more Ré, wherein Ré is independently at each occurrence Ci-C6 alkyl optionally substituted with one or more Rio, R? is H, R3 is H, and R4 and R9 can form heterocyclyl.
103
In one embodiment, one of Xb X2, X3 is C(Rs), Ai is -O-, A2 is —C(R8XR9)— Y is -CCRsXRç)—) Ri is heterocyclyl optionally substituted with one or more Rû, wherein Ro is independently at each occurrence Ct-C6 alkyl optionally substituted with one or more Rio, R2 is H, Rj is H, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Xb X2, X3 is C(R3), A; is — C(R8XR9)—, A2 is —O—, Y is —C(R8XR9)—, Ri is heterocyclyl optionally substituted with one or more Rg, wherein Ro is independently at each occurrence Ci-C6 alkyl optionally substituted with one or more Rio, R2 is H, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, at least one of Xb X2, or X3 is N, Ai is —O—, A2 is — C(RgXR9)—, Y is — C(RsXR0- Ri is heteroaryl optionally substituted with one or more R6, wherein R6 is independently at each occurrence CpCg alkyl optionally substituted with one or more Rio, R2 is H, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, at least one of Xi, X2, or X3 is N, Ai is — C(R8XR9)—, A2 is —O—, Y is — C(RsXRy)-, Ri is heteroaryl optionally substituted with one or more R6, wherein R6 is independently at each occurrence Ci-Cô alkyl optionally substituted with one or more Rio, R2 is H, R3 is H, and R4 and Ry can form heterocyclyl.
In one embodiment, one of Xb X2, X3 is CiRj), Aj is -O-, A2 is -C(R8XR9)-, Y is -QRsXRg)-, Ri is heteroaryl optionally substituted with one or more R6, wherein R6 is independently at each occurrence Ci-C6 alkyl optionally substituted with one or more Rio, R2 is H, R3 is H, and R4 and Ry can form heterocyclyl.
In one embodiment, one of Xi, X2, X3 is C(Rs), Ai is — C(R8XR9)-, A2 is -O-, Y is —C(RsXRy)-, Ri îs heteroaryl optionally substituted with one or more R6, wherein R6 is independently at each occurrence Ct-C6 alkyl optionally substituted with one or more Rio, R2 is H, R3 îs H, and R4 and R9 can form heterocyclyl.
In one embodiment, at least one of Xj, X2, or X3 is N, Aj is -O-, A2 is —C(R8XR9)-, Y is — C(Rs)(Ry)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R5, wherein R6 is independently at each occurrence C|-C6 alkyl optionally substituted with one or more Rio, R2 is halogen, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, at least one of Xb X2, or X3 is N, Ai is —C(R8XR9)—, A2 is -O-, Y is — C(RsXR9)-, Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R6, wherein R6 is independently at each occurrence CrC6
104 alkyl optionally substituted with one or more Rw, R2 is halogen, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Xi, X2, X3 is C(Rj), Aj is -O-, A2 is -C(Rg)(Rq)-, Y is -C(R$)(R9)-, R, is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Rg, wherein Rg is independently at each occurrence CpCg alkyl optionally substituted with one or more Rio, R2 is halogen, R3 is H, and R4 and R9 can fonn heterocyclyl.
In one embodiment, one of Xj, X2, X3 is C(R3), A| is -C(Rg)(R9)-, A2 is -O-, Y is -C(Rg)(R9)— Ri is heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Rg, wherein Rg is independently at each occurrence C|-Cg alkyl optionally substituted with one or more Rio, R2 is halogen, Rj is H, and R4 and R9 can form heterocyclyl.
In one embodiment, at least one of Xi, X2, or X3 is N, A| is —O—, A2 is — C(Rg)(R9)—, Y is — C(R8)(R9)-, Ri is heterocyclyl optionally substituted with one or more Rg, wherein R6 is independently at each occurrence Cj-Cg alkyl optionally substituted with one or more R10, R2 is halogen, R3 is H, and R4 and R9 can fonn heterocyclyl.
In one embodiment, at least one ot Xi, X2, or X3 is N, Ai is —C(R8)(R9)—, A2 is —O—, Y is — C(R8)(R9)- Ri is heterocyclyl optionally substituted with one or more R6, wherein R6 is independently at each occurrence C]-Cg alkyl optionally substituted with one or more Rw, R2 is halogen, R3 is H, and R4 and R9 can fonn heterocyclyl.
In one embodiment, one of Xi, X2, X3 is C(Rg), A] is -O-, A2 is -C(Rg)(R9)-, Y is —C(R8)(R9)—, Ri is heterocyclyl optionally substituted with one or more Rg, wherein Rg is independently at each occurrence Cj-Cg alkyl optionally substituted with one or more Rio, R2 is halogen, R3 is H, and R4 and R9 can fonn heterocyclyl.
In one embodiment, one of Xi, X2, X3 is C(Rs), Ai is -C(R8)(R9)-, A2 is -O-, Y is -C(R8)(R9)—, Ri is heterocyclyl optionally substituted with one or more Rg, wherein Rg is independently at each occurrence Ci-Cg alkyl optionally substituted with one or more Rio, R2 is halogen, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, at least one of Xj, X2, or X3 is N, Ai is -O-, A2 is -C(Rg)(R9)~, Y îs — C(R8)(R9)-, Ri is heteroaryl optionally substituted with one or more Rg, wherein Rg is independently at each occurrence CrC6 alkyl optionally substituted with one or more Rio, R2 is halogen, R3 is H, and R4 and R9 can form heterocyclyl.
105
In one embodiment, at least one of Xi, X2, or Xj is N, Aj is -C(Rg)(R9)—, A2 is -O-, Y is — C(Rg)(R9)-, Ri is heteroaryl optionally substituted with one or more Ré, wherein Ré is independently at each occurrence C|-Cé alkyl optionally substituted with one or more Rio, R2 is halogen, R 3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Xb X2, X3 is C(R.5), Aj is -O-, A2 is -C(R8XR9)—, Y is -C(R8XR9)~, Ri is heteroaryl optionally substituted with one or more R6, wherein Ré is independently at each occurrence Ci-C6 alkyl optionally substituted with one or more Rio, R2 is halogen, R3 is H, and R4 and R9 can form heterocyclyl.
In one embodiment, one of Xb X2, Xj îs C(Rs), A] is -C(R8XR9)—, A2 is -O-, Y is —C(R8XR9)—, Ri is heteroaryl optionally substituted with one or more R&, wherein Ré is independently at each occurrence Ci-C6 alkyl optionally substituted with one or more Rio, Rz is halogen, Rj is H, and R4 and R9 can form heterocyclyl.
In one embodiment, suitable compounds of the disclore are and phannaceutically acceptable salts, prodrugs, solvatés, hydrates, enantiomers, isomers, and tautomers thereof are described in Table 1.
Table 1
Compound No. Compound Name
1 (15R)-10-(2-methyl-3-pyiidyl)-13,17-dioxa-3,5,7,8-tetrazapentacyclo 113.6.1.04,12.05,9.018,22] docosa-H^MI 121,6.8,10,18,20-heptaene
3 (S)-l-(4-(7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4’,3':l,6]pyrido[3,2blbenzofuiO[4,3-fg][l,4]oxazonin-4-yl)piperidin-l-yl)ethan-l-one__
4 l-(4-(12-fluoro-7,8,13,14-tetrahydro-[l,2,4]triazolo[4’,3':l,6]pyrido[3,2- b]benzolfiri,41oxazonin-4-yl)piperidin-l-yl)ethan-l-one__
5 12-fluoro-4 -(2 -methylpyri din-3 -yl)-7,8,13,14-tetrahydro- Il,2,41triazolo[4’,3':l,6]pyrido[3,2-b]benzo[f][l,4]oxazonine___________
6 12-fluoro-4-(2-methylpyri din-3 -yl)-6,8,13,14-tetrahydro- [l,2,4]triazolo[4',3':I,6]pyrido[3,2-c]benzo[g][l ,5]oxazonine _________
7 ( S )-4-( ( 1 - methy 1 -1 H-p y razo 1 -4 -y 1) me thy 1) - 7 a, 8,13.14 - tetrahy dro - 7 H - 11,2,4]triazolo[4',3': 1,6]pyrido[3,2-b]benzofïiro[4,3-fg] [ 1,4]oxazonine ___
8 (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetraliydro-7H- ri,2,41triazolo[4',3’:l,61pyrido[3,2-blbenzofuro[4,3-fg][l,4]oxazonine__
9 (S)-l-(4-(12-fluoro-7a,8)13,14-tetrahydro-7H-[l,2,4]triazolo[4,,3':l,6]pyrido[3,2blbenzofurord^-fglilXIoxazotMn-d-ylipiperidin-l-yljethan-l-one___
10 (S)-12-fluoro-4-((l-methyl-lH-pyrazol-4-yI)inethyl)-7a,8,13,14-tetrahydro-7Hil^.dltriazoloïd’.S'YôlpyridoD^dflbeiizofurofdjS-fgin.dloxazonine
11 (S)-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4’,3':l,6]pyrido[3,2blbenzofuror4,3-fg]|T,4]oxazonine _
12 (S)-12-fluoro-4-(oxetan-3-yl)-7a,8,13,14-tetrahydro-7H- [ 1,2,4]triazolo[4,,3’:l16]pyrido[3,2-b]benzofuro[4,3-fg][l!4]oxazonine
106
13 (S)-4-(2,4-dimethyIpyrimidin-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7Hri7 4liriA7olof4'V:1.61pvridor3.2-b]benzofuro[43-tg][L4]oxazonme
14 4-(2,4-diniethylpyrimidin-5-yl)-12-fluoro-7,8,13,14-tetrahydro- f 1,2,4]triazolo[4(3’: 1,61pyrido [3,2-b]benzo [f] [ 1,4] oxazonine____
15 (S)-12-fluoro-4-(4-methyl-lH-imidazol-l-yl)-7a,8,13,14-tetrahydro-7H______[ 1 7 4]tri a 70I n [4' A 1: 6]pyridol3.2-blbenzofurol4,3 -fg! [ 1,4] oxazonine
16 methyl (S)-4-( 12-fluoro-7a,8,13,14-tetrahydro-7H- [l,2,4]triazolo[4(3’:l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonin-4- vDpîperidine-1 -carboxylate __
17 (S)-12-fluoro-4-(J -methyl-lH-pyrazol-5-yl)-7a,8,13,14-tetrahydro-7HL1,2,41triazolo[4(3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][l ,4]oxazonine
18 (S) -4 -( 1,3-di methyl-1 H-pyrazol-5 -yl)-12-fluoro-7a, 8,13,14-tetrahydro-7H- 11.2.41103701014(3’: l,61pyrido[3,2-b]benzofuro[4,3-fg][l ^oxazonine
19 (S)-12-fluoro-4-(4-metliylpyomidm-5-yl)-7a,8,13,14-tetrahydiO-7H11,2,411nazokd4’,3': 1 61pvridor3.2-b1benzofarol4Î3-fg][l!4]oxazonme
20 (S)-12-fluoro-4-(2-methylpyrimidin-5-yl)-7a,8,13,14-tetrahydro-7H- Π 2 41^3701014.3^ I.61nvridor3.2-b1benzofuro[4,3-fg][l ,4]oxazonine
21 (S)-12-fl uoro-4-(pyri din-2-yl)-7a,8,13,14-tetrahydro-7H- 11 ? 41tri a 7010 [4'T 3 1.6]pvridol3.2-blbenzofurol4.3 -fa] 11,41 oxazonine
22 (S)-4-(l,3-dimethyl-lH-pyrazol-4-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H- H 7 41103701014^3^1 6lDvridor3.2-b1benzofurol413-fg][l,4]oxazonine
23 (3)-4-(3-( difhioromethyl)-1 -methyl- J H-pyrazol -4-y l ) -12-fluoro-7 a,8,l3,l4tetrahydro-7H-[l,2,4]triazolo[4(3(l,6]pyrido[3,2-b]benzofuro[4,3- fg][l,4]oxazonine ________
24 (S)-4-((S)-l2-fluoro-7a ,8,13,14-tetrahydro-7H- [l,2,4]triazolo[4(3':l,6]pyrido[3,2-b]benzofüro[4,3-fg][l,4]oxazonin-4-yl)-l- methylpiperidin-2-one ________
25 (R)-4-((S)-12-fluoro-7a,8,13,14-tetrahydro-7H- [l,2,4]triazolo[4(3':I,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonin-4-yl)-l- methylpiperidin-2-one ________
26 (S)-4 -ethyl -12-fluoro-7a, 8,13,14-tetrahydro-7H - fl ,2,41 tri azolof 4(3': 1,6]pyrido[3,2-b]benzofuro[4,3-fg][l ,4] oxazonine_______
27 (S)-12-fluoro-4-(lH-pyrazoI-l-yl)-7a,8,13,14-tetrahydro-7H- 11 2 4ltria7olor4';3':l.61pvndol3.2-blbenzofurol4,3-fgl[l,4]oxazonine
28 (S)-4-(l,5-dimethyl-lH-pyrazol-4-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H11. 2.41triazolo 14(3’: 1.6]pvridol3,2-b1benzofuro[4,3-fg] [1,4] oxazonine
29 (S)-4-(2,3-dimethylpyridin-4-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H- fl ,2,41toazolo[4(3( 1,6]pyrido[3,2-b]benzofuro[4,3-fg][l ,4]oxazonine
30 (S) -12-fluoro-4-(2-methoxypyrimidin-5 -yl) -7a,8,13,14-tetrahydro-7 H- 11,2.41103701014(3': L61pvridol3.2-blbenzofiiro[4,3-fg][l,4loxazonine
31 (S)-12-fluoro-4-(6 -methoxypyridin-3 -yl )-7a,8,13,14-tetrahydro-7H11,2,41 triazolo [4(3 1,61 pyrido [ 3,2-b]benzofuro[4,3 -fg] [ 1,4] oxazonine
32 (S)-4-(6-ethyl-4-methylpyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H- [ 1,2,41triazolo[4(3':l,6]pyrido[3Î2-b]benzofuro[4,3-fg][l,4]oxazonine______
107
33 (S)-4-('2-(difluoroinethyl)pyridîn-3-yl)-12“fluoro-7a,8,13,14-tetrafo Γ1 9 4ltriazalor4'-3':l.6lnvrido[3.2-b1benzoftiro[4,3-fg][l,4]oxazonine
34 (S)-4-(2,6-dimethylpyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7Hn.2:41triazolor4'.3’:l.61pvndo[3,2-b]benzofuro[4,3-fg][l,4]oxazonÎne
35 (S)-2-(5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4’,3’:l,6]pyrido[3,2- b]benzofuror4,3-fg][lt4]üxazonin-4-yl)pyndin-2-yl)propan-2-ol__
36 (S)-12-fluoro-4-(4-(methylsulfonyl)phenyl)-7a,8,13,14-tetrahydro-7H[ 1 .2.41triazolo[4, Î3 ': 1,6]pyrido[3,2-b]benzofuro[4,3-fg] [1,4] oxazonine
37 ( S ) -12-fl uoro-N,N-dimethyl -7a,8,13,14-tetrahydro-7H- [LZ.dJtriazoloK^M.ôJpyridoP^-blbenzofuro^-fgXMloxazonine^carboxamide
38 (S)-12-fluoro-N-methyl-N-(2,2,2-trifluoroethyl)-7a,8,13,14-tetraliydro-7H[l,2,4]triazolo[4;3’:l,6]pyrido[3,2-b]benzofiiro[4,3-fg][l,4]oxazonine-4- carboxamide _____
39 (S)-12-fluoro-4-(l-methyl-lI-I-pyrazol-3-yl)-7a,8,13,14-tetrahydro-7HrL2.41triazolor4'.3':l.61pyridol3,2-blbenzofuro[4,3-fg][l;4]oxazonine
40 (S) -12 -fluoro-4-(5 -fluoTo-2-methylpyridin-3 -yl)-7a,8,13,14-tetrahydro-7Hri.2.41Înazolor4\3':1.61pvrido[37-blbenzofuro[4,3-fg][l,4]oxazonme
41 (S)-12-iluoro-4-(3-fluoropyridin-2-yl)-7a,8,13,14-teÎraliydro-7H- [l,2,41triazolo[4',3':l,6]pyndo[3,2-b]benzofuro[4,3-fg][l,4]oxazonine______
42 (S)-12-nuoro-4-(5-fluoropyridin-2-yl)-7a,8,13,14-tetrahydro-7H- Γ1.2.41triazolo 14',3 1.élpyridoB ,2-b]benzofuro[4,3-fg] [1,4] oxazonine
43 (S)-12-fluoiO-4-(3-fluoiO-5-methylpyridin-2-yl)-7a,8,13,14-tetraliydro-7H[l,2,41triazolo[4’, 3': J ,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine______
44 (S)-4-(3,5 -difluoropyridin-2-y] ) -12-fluoro-7a,8,13,14-tetrahydro-7H- [1,2,41triazolo[4',3': 1,6]pyrido[3,2-b]benzofuiO[4,3-fg][l,4]oxazonine
45 (S)-12-fluoro-4-(5-fluoro-3-methylpyridin-2-yl)-7a,8,13,I4-tetrahydro-7H- [l,2,4]triazolo[4’,3': 1.61pvrido[ 3.2-blbenzofuro[ 4,3-fg][l ,4] oxazonine
46 (S)-12-fl uoro-4-(5 -methy lpyrazin-2 -yl)-7a, 8,13,14-tetrahydro-7H- ri.2,41triazolo[4'.3,:l,6]pxTido[3.2-b]benzofutO[4,3-±g][},4]oxazonm^_^ ---------------1--------
47 (S)-12-fluoro-4-(3-methylpyrazin-2-yl)-7a,8,13,14-tetrahydro-7H- Π -2-41 triazolor4'.3': 1.61pvrido 13.2-b1benzofaro[4,3 -fg] [ 1,4]oxazonine
48 (S)-4-(12-fluoro-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4',3':I,6]pyrido[3,2b]benzofuro[4,3-fg][l,4]oxazonin-4-yl)benzonitrile
49 (SlA-fU-fluoro^aA.UJd-tetraliydro^H-tl^Ajtriazolo^'Q’iLôjpyridoCS^blbenzofuro[4,3-fg][l,4]oxazonin-4-yl)-3-methylbenzonitrile__________
50 (S)-12-fluoro-4-(2-methoxypyridin-4-yl)-7a,8,13,14-tetrabydro-7HΓ1.2.41 triazoior4'.3': 1.61pyrîdo [3,2-blbenzofurof 4,3-fg] [ 1,4] oxazonine
51 (S)-3-(12-flLioro-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4’,3':l,6]pyrido[3,2- blbenzofuro[4,3-fg][l ,4]oxazonin-4-yl)-2-methyl pyridine 1 -oxide________
52 (S)-4-(3,5 -dimethylpyrazin-2-yl)-12-fluoro-7a,8,13,14-tetrahydro-7Hf1.2.41triazolor4'.3':l.6lpvrido[3,2-b1benzofuro[4,3-fg][l!4]oxazonine
53 (S)-12-fluoro-4-(3-methylpyridazin-4-yl)-7a,8,13,14-tetrahydro-7H- [ 1,2,4] tnazoio^'.S1:1,6]pyrÎdo[3,2-b]beiizofuro[4,3-fg][l XJoxazonine
108
54 (S)-12-fluoro-4-(4-methylpyridazin-3-yl)-7a,8,13,14-tetrahydro-7H- [l^dltriazoloH'Q'YôlpyridoCS^-blbenzofurotd^-fgJLlAjoxazonÎne ____
55 (S)-12-fluoro-4-(6-methylpyridin-2-yl)-7a,8,13,14-tetrahydro-7H- ri.2.41triazolor4',3,:l,61pyrido[3,2-blbenzofuro[4,3-fg][l,4]oxazonine
56 (S)-12-fluoro-4-(2-methylpyrimidm-4-yl)-7a,8,13,14-tetrahydro-7H[1.2,41Lriazolo[4',3':l,61pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
57 (S)-12-fluoro-4-(2-methoxy-4-methylpyrimidin-5-yl)-7a,8,13,14-tetrahydro-7Hfl ,2.41triazolor4’,3’: 1,6]pyrido[3,2-blbenzoftiro[4,3-fg] [ 1,4]oxazonine
58 (S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4',3':l,6]pyrido[3,2b]benzoturo[4,3-fg][l,4]oxazonin-4-yl)-N,N,4-tnmethylpynmidine-2carboxamide
59 (S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4’,3':l,6]pyrido[3,2- blbenzofuro[4,3-fg] Γ1,41oxazonin-4-yl) -N,N-di methylpicolinamide
60 (S)-4-(l,3-dimethyl-!H-l,2,4-triazol-5-yl)-12-fluoro-7a,8,13,!4-tetrahydro-7Hri.2.41triazolor4',3':l;61pYridor3,2-b]benzofiiro[4,3-fg][l;4]oxazonine
61 (S)-l 2-fluoro-4-(5-methyl-l ,3,4-oxadiazol-2-yl)-7a,8,13,14-tetrahydro-7Hri,2,41triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazomne
62 (S)-4-(3,5-dimethylisoxazol-4-yl)-12-nuoro-7a,8,13,14-tetrahydro-7H- [l,2,4]triazolor4,,3':l,61pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
63 (S)-12-fkioro-4-(l-(2-methoxyethyl)-3,5-dimethyl-lH-pyrazol-4-yl)-7a,8,13,14tetrahydro^H-fUZ/lJtriazolo^'Q'ffôlpyridoQjl-bJbenzofuiO^Qfg][ 1,41oxazonine
64 (S )-l 2-fluoro-N-methyl-N-(tetrahydro-2H-pyran-4-yl)-7a, 8,13,14-tetrahydro7H-[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-4carboxamide __
65 (S)-12-fluoro-4-(5-methylpyrimidin-2-yl)-7a,8,13,14-tetrahydro-7Hri,2,41triazolo[4',3’:l,61pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
66 (S)-12-fluoro-4-(6-methylpyrîdazin-3-yl)-7a,8,13,14-tetrahydro-7H[l,2,41triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
67 (S)-4-(4,6-dimethylpyridazin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H[l^AltriazoloIT^'rf^lpyridotS^-blbenzofurofT^-fglflAloxazonine
68 (S)-4-(4-(difluoromethyl)-2-methylpyrimidin-5-yl)-12-fluoro-7a,8,13,14tetrahydro^Hdl^Xjtriazolo^’Q'rlXlpyridofS^-bjbenzofurofAQfg] [ 1,4]oxazonine
69 (S)-4-(2-(difluoromethyl)-4-methy]pyrimidin-5-yl)-12-fluoro-7a,8,13,14letrahydro^H-fhZXjtriazolo^'Q'il.ôIpyridotS^-blbenzofuiO^Qfg][l ,4]oxazonine
70 (S)-444-(difluoromethy])pyrimidin-5-yl)-12'fluoro-7a,8,13,14-tetrahydro-7HΓ1,2,41 tri azolof 4',3 ' : 1,61pyrido[3,2-b]benzofuro [4,3 -fg] [ 1,4] oxazonine
71 ( S )-4 - ( 1,4-dimethyl-l H-pyrazol-5 -yl) -12 -fluoro-7a,8,13,14-tetrahydro-7Hri,2,4]triazo!o[4',3':l,61pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
72 (8)-4-(1 -ethyl -1 H-pyrazol-5 -yl)-12-fl uoro-7a ,8,13,14-tetrahydro-7Hri,2,41triazolo[4',3':l,6]pyrido[3,2-b]benzofLiiO[4,3-fg][l,4]oxazonine
109
73 (S)-12-fluoro-4-(l-(2,2,2-trifluoroethyl)-lH-pyrazoI-5-yl)-7a,8,13,14-tetrahydro- 7H-nt2.41lriazolor4,.3':l.61pvridor3,2-blbenzofüroÎ4,3-fg][lt4]oxazoiiine
74 (S) -1 -(5-(12-fluoro-7a,8,l 3,14-tetrahydro-7H-[ 1,2,4]triazolo[4',3’: 1,6]pyrido[3,2b]bpnzofuro (4:3-fg] [ 1 ;4]oxazonin-4-vD-1H -pyrazol -1 -yl)-2-methylpropan-2 -ol
75 ( S) -12 -fluoro-4-( 1 -isopropyl-1 H-pyrazol -5 -yl)-7a,8,13,14-tetrahydro-7HnT2,4ltriazolor4,.3':l.6lpvridor3,2-b1benzofurof4l3-fg][l,4]oxazonine
76 (S)-4-(2-(dinuoromethoxy)pyrimidin-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7Hri.2.41triazolol4,,3':l,61pyrido[3,2-b]benzofiiro[4,3-fg][L4]oxazonine__
77 (S)-12-fluoro-4-(2-methoxypyridin-3-yl)-7a,8,13,14-tetrahydro-7HΓ17 2 7 41 tri azoloH'.S 1.61 p vrido 13.2-b1benzofurol4,3 -fg] [ 1,4]oxazonîtie
78 (S)-4-(2-(difluoromethoxy)pyridin-3-yl)-12-fIuoro-7a,8,13,14-tetrahydro-7H- 11.2.41triazolol4',3': 1,61pyrido[3,2-b]benzofuro[4,3-fg][l ,4]oxazonine
79 (S )-12-fluoro-4-(3 -methyl -1 H-pyrazol-1 -yl)-7a, 8,13,14-tetrahydro-7Hri:241triazolor4,.3,:l.61pvrido[3.2-b]benzofuro[4,3-fg][ll4]oxazonine
80 ( S ) -12-fluoro-4-(4-melhyl -1 H-pyrazol -1 -yl)-7a,8,13,14-tetraliydro-7H- Π ^AltriazoloHO':] .61pvrÎdo[3.2-b]benzofuro(4,3-fg][l,4]oxazonine
81 (S)-1 -(3-( 12-fluoro-7a,8, ] 3, l4-tetrahydro-7H-[ 1,2,4] triazolo[4',3’: 1,6]pyrido[3,2blbenzofuro[4,3-fg]ri,4]oxazomn-4-yl)pyridin-2-yl)-2-methyIpropan-2-oI
82 (S)-4-(3-(12-fluoro-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4,,3,:l,6]pyrido[3,2- b1henzûfuror4.3-fgiri.41oxazonin-4-vl)pyridin-2-yl)-2-methylbutan-2-ol
83 ( S )-12-fluoro-4-(2-(trifluoromethoxy)pyridin-3 -yl)-7a, 8,13,14-tetrahydro-7H (1,2,4] triazolo[4’, 3 ' : l,6]pyrido[3,2-b]benzofuro[4,3-fg] [1,4] oxazonine_______
84 (S)-4-(6-(difluoromethyl)-2-methylpyridin-3-yl)-12-fluoro-7 a,8,13,14tetrahydro^H-tLZAÎtriazolotT^ILôjpyridotS^-bjbenzofuroEl^- fg][l,4]oxazonine _____
85 (S)-4-(2-(difluoromethyl)-6-methylpyridin-3-yl)-12-fluoro-7a,8,13,14tetrahydro-7H-[ 1,2,4]triazolo[4',3': 1,6]pyrido [3,2-b]benzofriro[4,3 fg][ 1,4]oxazonine
86 (S)-4-(4,6-dimethylpyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H- H,241triazolo[4',3’:l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine______
87 (S)-12-fluoiO-4-(3-fluoro-2-methylpyridin-4-yl)-7a,8,13,14-tetrahydro-7H- (1,2,4] tri azolopr, 3 1,6]pyrido[3,2-b] benzofuro[4,3 -fg] [ 1,4] oxazonine ____
88 (S)-4-(4-(difluoromethyl)-6-methylpyridin-3-yl)-12-fluoro-7a,8,13,14- tetrahydro-7 H-[ 1,2,4]triazolo[4',3’: 1,6]pyri do[3,2-b] benzofuro[4,3 - fgH 1 ,4]oxazonine ___
89 (S )-12-fluoro-4-(5 -fiuoro-2-methylpyridin-4 -yl)-7a,8,13,14-tetrahydro-7H- 11,2,4]triazolo[4',3': 1,6]pyrido[3,2-b]benzofuro[4,3-fg] [1,4] oxazonine_______
90 (S)-4-(6-(difluoromethyl)-4-methylpyridin-3-yl)-12-fluoro-7a,8,13,14tetrahydro-7H-[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3fg][l,41oxazonîne ___
91 (S)-12-tluoro-4-(pyri midin-5-yl )-7a,8,13,14-tetrahydro-7 Hn,2,41triazolol4',3': l,61pyridor3,2-b]benzofiiro[4,3-fg][l,4]oxazonine _
92 (S)-12-fluoro-4-(3-methylisoxazol-4-yl)-7a,8,13,14-tetrahydro-7H- [ 1,2,4]ίπ3ζο1ο[4',3 1,6]pyrido[3,2-b] benzofuro[4,3 -fg] [ 1,4]oxazonine_______
110
93 (S)-12-fluoro-4-(thiazol-5-yl)-7a,8,13,14-tetrahydro-7H- Γ1,2,4]triazolo[4’,3': 1,6]pyrido[3,2-b]benzofuro[4,3-fg] [ 1,4]oxazonine_______
94 (S)-l 2-fluoro-4-(6-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7Hri.2.41triazolor4',3':l,61pyrido['3,2-b]benzofuro[4,3-fg][ll4]oxazotiine
95 (S)-12-fluoro-4-(3-methylpyridin-2-yl)-7a,8,13,14-tetrahydro-7H- ri,2,41triazolor4',3,:l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazomne__
96 (S)-4-(2 -ethylpyri din-3 -yl)-12-fluoro-7a,8,13,14-tetrahydro-7Hri.2.41triazolor4',3': 1,61pyrido[3,2-b]benzofuro[4,3-fg][l ,4] oxazonine
97 (S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4’,3’:l,6]pyrido[3,2- blbenzofuro[4,3-fg]ri,4]oxazonin-4-yl)-l-methylpyridin-2(lH)-one ______
98 (S)-12-fl uoro-4-(6-methoxypyridin-2-yl)-7a,8,13,14-tetrahydro-7 H- Γ1,2,41 triazoJorALS': 1,6]pyrido[3,2-b]benzofuro[4,3-fg][l ,4]oxazonme ____
99 (S)-12-fluoro-4-(i,3,5-trimethyl-lH-pyrazol-4-yl)-7a,8,13,14-tetrahydro-7H- Γ1,2,4] triazolo[4',3': 1,6]pyrido[3,2-b]benzofiiro[4,3-fg] [ 1,4]oxazonine
100 (S)-4-(3-ethyl-1 -methyl-1 H-pyrazol-4-y!)-l 2-fluoro-7a, 8,13,14-tetrahydro-7H- Γ1,2,4]triazolo[4',3': 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4] oxazonine_______
101 ( S )-4-(5 -chl oropyridin-2-yl)-12 -fluoro-7a,8,13,14-tetrahydro-7Hri.2.41triazolor4',3':l,6]pyridoi3,2-b]benzofuro[4,3-fg][l,4]oxazonine
102 (S)-4-(4-cyclopropylp yrimidin-5 -yl)-12-fluoro-7 a, 8,13,14-tetrahydro-7I4Γ 1.2,4] tri azolo[4’,3 1,6]pyrido[3,2-b]benzofuro[4,3-fg] [ 1,4] oxazonine
103 ( S)-5-(l 2-fl uoro-7a,8,13,14-tetrahydro-7H-[ 1,2,41^7010^, 3’: l,6]pyrido[3,2blbenzoiuror4,3-fgiri,4]oxazonin-4-yl)-N,N-diniethylpyridin-2-amine
104 (S)-12-fluoro-4-(6-methoxy-4-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H[1,2,41triazolo [4',3 1,6]pyrido[3,2-b] benzofuro[4,3-fg] [1,4] oxazonine
105 (S) -12 -fluoro-4-(2 -methoxy-6-methylpyrî din-3-yl)-7a, 8,13,14-tetrahydro-7H[l,2J4]triazolo[4',3':l,6]pyiido[3,2-b]benzofuro[4,3-fg][I,4]oxazomne__
106 (S)-12-fluoiO-4-(6-methoxy-2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H[ 1,2,4]triazolof4',3’: 1,6]pyrido[3,2-b]benzofuro[4,3-fg][l ,4] oxazonine
107 (S)-12-fluoro-4-(2-methoxy-4-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7Hri,2,4]triazolor4',3':l,6]pyridor3,2-b]benzofuiO[4,3-fg][l,4]oxazonine
108 (S}-5-(12-fluoro-7a,8 J3 ^-tetrahydro-THdl^.dltriazolo^'J’d.ôJpyridop^blbenzofuror4,3-fgiri,4]oxazonin-4-yl)-N,N-dimethylpyrimidin-2-amine
109 (S)-4-(2-ethoxypyrimidin-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7Hri,2,4]triazolor4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
110 (S)-12-fluoro-4 -(5 -fluoro-6-methoxypyridin-3 -yl) -7a,8,13,14-tetrahydro-7H11,2,4]triazoloî4’,3 1,6] pyrido(3,2-b] benzofuro[4,3-fg] [ 1,4] oxazonine
111 (S)-12-fluoro-4-(5-fluoro-2-methoxypyridin-3-yl)-7a,8,13,14-tetrahydro-7Hn,2,41triazolor4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
112 ( S)-12-fluoro-4-(6 -(trifluoromethyl)pyr îdin-3-yl)-7a,8,13,14-tetrahydro-7HΓ1,2,4]triazolor4’,3 1,6]pyrido[3,2-b]benzofuro [4,3 -fg] [ 1,4] oxazonine
113 (S)-12-flüoro-4-(5-(trifluoromethyl)pyridin-2-yl)-7a,8,13,14-tetrahydro-7HΓ l ,2,4]triazolo [4',3 1,6]pyrido[3,2-b]benzofuro[4,3-fg] [ 1,4]oxazonine
114 (S)-12-fluoro-4-(2-(trifluoromethyl)pyrimidin-5-yl)-7a,8,13,14-tetrahydro-7H- [1,2,4]triazolo[4',3': 1,6]pyrido[3,2-b]benzofuro [4,3 -fg] [ 1,4]oxazonîne______
111
115 (S)-12-fluoro-4-(l-methyl-3-(trifluoromethyl)-lH-pyrazol-5-yl)-7a,8,13,14telrahydro-7H-[ 1,2,4] triazolo[4',3' : 1,6 ] py ri do[3,2-b] benzofuro[4,3 fg][l,4]oxazonine
116 (S)-12-fluoro-4-(6-morpholinopyri din-3 -yl)-7a,8,13,14-tetrahydro-7HΓ1,2,4]triazolor4\3': 1,6]pyridoÎ3,2-b]benzofuro[4,3-fg][l ,4]oxazonine
117 (S)-12-fluoro-4-(6-(4-methylpiperazin-l-yl)pyndîn-3-yl)-7a,8,13,14-tetrahydro7H41,2,41triazolo[4’,3':l,61pyrîdo[3,2-b]benzofuro[4,3-fg][l,4]oxazonîne
118 (S)-12-fluoro-4-(2-(4-niethylpiperazin-l-yl)pyrimidin-5-yl)-7a,8,13,14tetrahydro-7H-[l,2,4]triazolo[4',3’;l,6]pyrido[3,2-b]benzofuro[4,3fg] [ 1,4] oxazon i ne
119 (S)-12-fluoro-4-(2-(trifluoromethyl)pyridin-3-yl)-7a,8,13J14-tetrahydro-7HΓ1,2,4] triazolo[4',3 1,6]pyrido[3,2-b] benzofuro[4,3 -fg] [1,4] oxazonine
120 (S)-12-fluoro-4-(5-fluoro-6-methyIpyridin-2-yl)-7a,8,13,14-tetrahydro-7H[ 1,2,4] triazolo[4',3 ' : 1,6]pyrido[3,2-b]benzofuro[4,3-fg] [ 1,4]oxazonine
121 (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-ietrahydro-7H- [ 1,2,4] triazolonAS'ilAlpyridoU^-blbenzofuro [4,3-fg][ 1,4] oxazonine
122 (S)-l 2-fluoro-4-( 1 -(2,2,2-trifluoroethyl)-1 H-pyrazol-3-yl)-7a,8,13,14-tetrahydro71-l-[l,2,41triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
123 (S)-12-fluoro-4-(6-methylpyridazin-4-yl)-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
124 (S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4',3':l,6]pyrido[3,2b]benzofuro[4,3-fg][l ,4]oxazonm-4-yl)-l -methyl-1 H-pyrazol-3-amine
125 (S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4,,3':l,6]pyrido[3,2b]benzofuiO[4,3-fg][l,4]oxazonin-4-yl)-N,l-dimethyl-lH-pyrazol-3-amine
126 (S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4',3';l,6]pyrido[3,2b] benzo furo[4,3-fg][l,4] oxazonin-4-yl)-N,N, 1-trimethyl-l H-pyrazol-3-amine
127 (S)-(5-(12-fluoro-7a,8,13,l4-tetrahydro-7H-[l,2,4]triazolo[4',3':l,6]pyrido[3,2b]benzofuro[4,3-fg][l,4]oxazonin-4-yl)-l-methyl-1 H-pyrazol-3-yl)methanamme
128 (S)-l-(5-(12-iluoro-7a,8,13,14-tetraliydro-7H-[l,2,4]triazolo[4',3':l,6]pyrido[3,2b]benzofuiO[4,3-fg][l,4]oxazonin-4-yl)-l -methyl-1 H-pyrazol-3-yl)-Nmethylmethanamine
129 (S)-l-(5-(12-ïïuoro-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4',3':l,6]pyrîdo[3,2b]benzofuro[4,3-fg][l ,4] oxazonin-4-yl)-l-metliyl-1 H-pyrazol-3-yl)-N,Ndimethylmethananiine
130 (S)-4-(3-(difluoromethyl)-l-methyl-lH-pyrazol-5-yl)-12-tluoro-7a,8,13,14tetrahydro-7H-[I,2,4]triazolo[4’,3':l,6]pyrido[3,2-b]benzofuro[4,3fg][l,4]oxazonine
131 (S)-2-(5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4',3':lJ6]pyrido[3,2b]benzofuro[4,3-fg] [ 1,4]oxazonin -4-yl )-1 -methyl-1 H-pyrazol-3 -yl )ethan-1 -ol
132 (S)-2-(5-(12-tluoro-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4',3':l,6]pyrido[3,2bjbenzofuro [4,3 -fg] [ l ,4]oxazonin-4 -yl)-1 -methyl-1 H-pyrazol -3 -yl)-N,Ndimethylethan-1-amine
133 (S)-4-(l,2-dimetliyl-IH-imidazol-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H- [ 1,2,4] triazolo [4',3 ' : 1,6]pyrido[3,2-b]benzofuro [4,3 -fg] [ 1,4] oxazonine
112
134 (S)-4-(l,4-dimethyI-lH-imÎdazol-5-yl)-l2-fluoro-7a,8,13,14-tetrahydro-7Hri,2,41triazolor4,,3':l,61pyrido[3J2-b]benzofuro[413-fg][l,4]oxazonine
135 (S)-4-(l,4-dimeÎhyl-lH-imidazol-2-yl)-12-fluoro-7a,8,13,14-tetiahydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
136 (S)-4-(l,5-dimethyl-lH-imîdazol-2-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
137 (S)-12-flLioro-4-(l-methyl-lH-imidazol-2-yl)-7a,8,13,14-tetrahydro-7H[l,2J4]lriazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
138 (S)-12-fluoro-4-(l-methyl-lH-imidazol-4-yl)-7aJ8,13,14-tetrahydro-7H[l,2,4]triazolof4’,3(l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonme
139 ( S)-4-( 1,5-di methyl -1 H-imi dazol-4-yl)-12-fluoro-7a ,8,13,14 -tetrahydro-7HILZAltriazololA^'iLôlpyridoIS^-bJbenzofLiroIX^-fgKlAloxazonine
140 (S)-4-(l,2-dimethyl-lH-imidazol-4-yl)-12-fiuoro-7a,8,13,14-tetrahydro-7HILZAltnazoloR^UXlpyridoIX^-blbenzofïirol/lG-fgJll/ljoxazonine
141 (S)-4-(5-(difluoroinethyl)-6-methyipyridm-2-yl)-12-nuoro-7a,8,13,14tetrahydro-7H-[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3fg][l,4]oxazonine
142 ( S)-12-fluoro-4-( 1H -pyrazol-5 -y l)-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3,:l,6]pyrido[3,2-b]benzofuro[4J3-fg][l,4]oxazonine
143 (S)-l-(3-(12-fluoro-7a,8,13,14-tetrahydro-7H-[l,2î4]tnazolo[4'J3':l,6]pyrido[3,2b]benzofuro[4,3-fg][l,4]oxazomn-4-yl)-lH-pyrazol-l-yl)-2-methylpropan-2-ol
144 (S)-4-(3-(difluoromethyl)-6-methylpyridin-2-yl)-12-fiuoro-7a,8,13,14telrahydro-7H-[l,2,4]triazolo[4',3':l,6]pyrido[3>2-b]benzofuro[4,3fg] [ 1,4]oxazonine
145 (S)-4-(3-ethyl-l-methyl-lH-l,2,4-triazol-5-yl)-12-fluoro-7a,8,13,14-tetrahydro7H-ri,2,41triazolof4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
146 (S)-4-(3-ethyl-l-methyl-lH-pyrazol-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H[1 J2,4]triazolo[4',3,:l)6]pyrido[3,2-b]benzofLiro[4,3-fg][l,4]oxazonine
147 ( S)-12-fhioro-4-( 1,2,4-trimethyl-1 H-imîdazoI-5 -yl)-7a, 8,13,14-tetrahydro-7H[1,2,4]triazolo[4',3': 1,6]pyrido[3,2-b]benzofuro[4,3-fg][l ,4]oxazonine
148 (S)-12-fluoro-4-(l,4,5-trimethyl-lH-îmidazol-2-yl)-7a,8,13,14-tetrahydro-7Hfl, 2,4]triazolo[4,,3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonme
149 (S)-12-fluoro-4-(4-methylpyridin-2-yl)-7a,8,13,14-tetrahydro-7[-[[1,2,41triazolor4',3': l,61pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
150 (S)-12-fluoro-4-(5-methylpyridîn-2-yl)-7a,8,13î144etrahydro-7H[1,2,4] tri azolo[4(3(l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
151 (S)-4-(3 -chloropyridi n-2 -yl)-12 -fluoro-7a,8,13,14-tetrahydro-7H[ 1,2,41triazolo[4',3 ’ : 1,6] pyrîdo[3,2-b]benzofuiO[4,3 -fg] [1,4] oxazonine
152 (S)-4-(5-chloro-2-methylpyridin-3-yl)-12-fluoro-7a,8J13,14-tet.rahydro-7H’ [l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
153 (S)-4-(5-ch]oro-6-meihy]pyndin-3-yl)-12-fluoro-7as8,13,14-tetrahydro-7H[l,2,4]tnazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazomne
154 ( S ) -12-fluoro-4-(5 -fluoro-6-methylpyridin-3 -y 1 ) - 7 a, 8,13,14-tetrahydro-7H[ 1,2,4]triazolo[4',3': 1,6]pyrido[3,2-b]benzofuiO[4,3-fgKl ,4] oxazonine
113
155 ( S)-12-fluoro-4-(2-methylpyridin-4-yl)-7a,8,13,14-tetrahydro-7H- Γ1,2,41 tri azolo [4',3 ' : 1,6]pyridof 3,2-b] benzofuro[4,3 -fg] [ 1,4] oxazonine _____
156 (S)-4-(2,5-dimethylpyridin-4-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H- 11,2,4]triazolof4',3’:1,6]pyrido[3,2-b]benzofuro[4,3-fg] [1,4]oxazonine
157 (S)-4-(3-chloro-2-methylpyridin-4-yl)-12-fluoro-7a,8,I3,]4-tetrahydro-7Hri,2,41triazoloÎ4',3': 1,6]pyrido[3,2-b]benzofuro[4,3-fg][l ,4] oxazonine
158 (S)-4-(3-chloro-5 -fluoropyridin-2-yl) - J 2- fluoro-7a,8,13,14-tetrahydro-7Hfl,2,4]triazolof4’,3,:l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine _____
159 (S)-12-fiuoro-4-(3-methoxypyridin-2-yl)-7a,8,13,14-tetrahydro-7H- ri.2.41Îriazolor4,,3':l,61pyridof3,2-b]benzofuro[4,3-fg][l,4]oxazonme __
160 (S)-12-fluoro-4-(pyrimidin-4-yl)-7a,8,13,14-tetrahydro-7H- [l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine______
161 (S)-12-fluoro-4-(6-methylpyrimidin-4-yl)-7a,8,13,14-tetrahydro-7HΓ1,2,4] triazolo[4',3 ' : 1,61 pyrido [3,2-b]benzofuro[4,3-fg] [ 1,4]oxazonine
162 (S)-12-fluoro-4-(5-methylpyrimidin-4-yl)-7a,8,13,14-tetrahydro-7HΓ1,2,4]triazolof4',3': 1,6]pyrido[3,2-b]benzofuro[4,3-fg][l ,41oxazonine
163 (S)-4-(5-ch]oropyrimidin-4-yl)-12-fluoro-7a,8,13,14-tetrahydro-7HΠ -2-41ΐπ&ζο1οΓ4'·3’: 1.61pvridor3.24fibenzofurof4,3-ffi1il,4]oxazonine
164 (S)-12-fluoro-4-(5-fluoropyrimidin-4-yl)-7a,8,13,14-tetrahydro-7Hri,2,41triazolor4’,3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
165 ( S) -4-bromo-12-fluoro-7 a, 8,13,14-tetrahydro-7H- Γ1,2,41 tri azo 1 ο Γ4 ', 3 ’ : 1,6]pyrido[3,2-b]benzofuro [4,3 -fg] [ 1,4]oxazonine ___
166 (S)-4-(5-chloro-3-methylpyridin-2-yl)-12-fluoro-7a,8,13,14-tetrahydro-7Hfl, 2,4] tri azolo!4', 3': 1,6] pyridof3,2-b]benzofuro[4,3-fg][ 1,4] oxazonine
167 ( S )-4-( 3 - (d i fl uorometlioxy)-1 -methyl-1 H-pyrazoI-5 -y 1 ) -12-fluoro-7 a ,8,13,14tetrahydro-7H-[l,2,4]triazolo[4',3’:l,6]pyrîdo[3,2-b]benzofuro[4,3fg][ 1,4]oxazonine
168 (S)-12-fliioro-4-(3-fluoro-l-methyl-lH-pyrazol-5-yl)-7a,8,13,14-tetrahydro-7H- [ 1,2,4]triazoiof4',3’: 1,6]pyrido[3,2-b]benzofuro[4,3-fg] [ 1,4]oxazonine
169 (SJ^-fS-i^-fluoro^a.SjlSjM-tetrahydro^H-fl^jAltriazolo^’^'ibôjpyridoIS^- b]benzofuro[4,3-fg][l }4]oxazonm-4-yl)-l-methyl-lH-pyrazol-3-yl)-2methylpropanenitrile ___
170 (S)-5-(12-fiuoro-7a,8,î3,14-tetrahydro-7H-[l,2,4]triazolo[4’,3’:i,6]pyrido[3,2b]benzofuror4,3-fgKl,4]oxazonin-4-yl)-l-methyl-lH-pyrazole-4-carbonitrile
171 (5)-4-(5,6-0ί1ιγ4Γθ-4Η-ργπ·ο1ο[1,2-6]ργΓ3ζο1-3-γ1)-12-ΑηοΓθ-73,8,13,14tetrahydro-7H-[l,2,4]triazolo[4’,3’:l,6]pyrido[3,2-b]benzofuro[4,3fg] [ 1,4] oxazonine
172 (S)-5-fluoro-12-(l-methyMH-pyrazol-5-yl)-6,7,15,15a-tetrahydro4Hbenzofuro[4,3-fg]imidazo[r,2':l,6]pyrido[3,2-b][l,4]oxazonine-10-carbonitrile
174 (S)-5 -fluoro-12-( 1 -methyl-1 H-pyrazol-5 -yl)-6,7,15,15 a-tetrahydro-1Hbenzofuro[4,3-fg] imidazo[ Γ,2 1,6]pyrido[3,2 -b] [ 1,4]oxazonine-10-carboxylic acid
175 (S)-5-fluoro-12-(l-methyl-lH-pyrazol-5-yl)-6,7,15,15a-tetrahydro-lHbenzofuro[4,3-fg] imidazo[ 1 ’,2’: 1,6 ] p yrido [ 3,2-b ] [ 1,4]oxazonine-10-carboxamide
114
176 (S)-5-fluoro-12-(2-methylpyridin-3-yl)-6,7,15,15a-tetrahydro-lH-benzofuro[4,3__j^imidazof 1L2': 1 ,6]pyrido[3.2-bVl .41oxazonine-l0-carboxamide___
177 (S)-5-fluoro-12-(2-methylpyridin-3-yl)-6,7,15,15a-tetrahydro-lH-benzofuro[4,3- fg1imidazorr.2':l.6]pYridof3,2-b][l,4]oxazonnie-l0-carboxylic acid
178 ( S)-4-(2-cyclopropylpyrimi din-5 -yl)-12-fluoro-7a,8,13,14-tetrahydro-7HΠ 7 4]maznlo[4, ;3':1;61pyridor3.2-b1benzofuror413-fg][l,4]oxazonine
179 (S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H~[l,2,4]triazolo[4',3':l,6]pyrido[3,2blbenzofuro[4,3-fg][l,4]oxazomn-4-yl)-2-methylpyridin-^^___
181 methyl 4-(12-fluoro-6,8,13,14-tetrahydro-[l,2,4]triazolo[4,,3’:l,6]pyrido[3,2- clbenzol g] [ 1,51oxazonin-4-yl)piperidine-1 -carboxylate___
182 4-(2,4-dimethylpyrimidin-5-yl)-12-fluoro-6,8,13,14-tetrahydrori,2,4]triazoloÎ4',3': 1,6]pyrido[3,2-c]benzo[g][l ,5]oxazonine____________
183 12-fluoro-4-((l-methyl-lH-pyrazol-4-yl)rnethyl)-6,8,13,14-tetrahydrof 1,2,4]triazolo|4',3': 1,6]pvrido[3,2-c1benzo[g][] ,5]oxazonine_____
184 (S)-4-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H- 11,2,4]triazolof4',3': 1.61pvridol3.2-blbenzofuroi4,3-fgj [ 1,4] oxazonine
185 (R)-12-fluoro-4-(2-methylpyndin-3 -yl)-7 a,8,13,14-tetrahydro-7Hί 1,2,4]triazolo[4',3': 1,6]pyrido[3.2-blbenzofurol4,3-fgl[l,4]oxazonine
186 (S)-5-fluoro-12-(2-methylpyridin-3-yl)-6,7,15,15a-tetrahydro-lH-benzofuro[4,3- fglimidazorr.2': l.ôlpyrido [3,2-blI 1,41 oxazonine-10-carbonitrile__
187 (S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[l,2,4]triazoio[4,,3':l,6]pyrido[3,2- blbenzofuro[4.3-fgin.41oxazonin-4-yl)-6-methylpyridin-2-ol___
188 (S)-12-fluoro-4-(oxazol-5-yl)-7a,8,13,14-tetrahydro-7H[1 7 4]triazolo[4,,3,:l,6]pyrido[3.2-b1benzofurol4,3-fgiri,41oxazonine
189 (S)-12-fluoro-4-(4-methyloxazol-5-yl)-7a,8,13,14-tetrahydro-7H- Jl,2,41triazolo[4’,3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine______
190 (S)-4-(2-cyclopropyl-4-methylpyrimidiii-5-yl)-12-fluoro-7a,8,13,14-tetrahydro7Η-Γ1 7.41rriazolor4'.3’: I.6lpvridol3.2-blbenzof:uror4,3-fg1[l,4]oxazomne
191 (S)-3-(5-(12-fluoiO-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4’,3':l,6]pyrido[3,2b]benzofuro[4,3 -fg] [ 1,4]oxazonin -4-yl)-6-methylpyridin-2-y 1) -Nmethylpropanamide _____
192 (S)-3-(12-fluoro-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4',3':l,6]pyrido[3,2- blbenzofuro[4,3-fglfl,4]oxazonin-4-yl)-2-methylpyridin-4-ol__
193 (S)-l-(4-(12-fluoro-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4’,3':l,6]pyrido[3,2- b]benzofuro[4,3 -fg] [ 1,4]oxazonin-4-yl)-3,6 -dihydropyridin-1 (2H)-yl)ethan-1 - one ____________
194 (Sj-S-ClZ-fluoro^a^JJjM-tetrahydiOVH-fl^Altriazolofd'^^LôlpyridotS^b] benzofuro[4,3-fg] [ 1.4]oxazonin-4-yl)-6-methylpyridin-3-ol___________
195 (S)-(3-(12-fluoro-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4’,3':l,6]pyrido[3,2- blbenzofuroÎ4,3 -fg] [ 1,4]oxazonin-4-yl)pyridin-2 -yl)methanol
196 (S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4',3,:l,6]pyrido[3,2blbenzofuro[4,3-fg][l,4]oxazonîn-4-yl)-l-methyl-lH-pyrazol-4-ol _______
197 (S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[l,2,4]tTiazolo[4',3':l,6]pyrido[3,2- blbenzofuro [4,3-fg] [ 1,4]oxazonin-4-yl)-1 -methyl-1 H-pyrazol-3-o 1________
115
198
I-(4-( 12-fluoro-6,8,13,14-tetrahydro-[ 1,2,4]triazolo[4’,3': l,6]pyrido[3,2c]benzo[g][l ,5]oxazonin-4-yl)piperidin-l-yl)ethan-l-one
In another embodiment of the invention, the compounds of Formula I are enantiomers. In some embodiments the compounds are (S)-enantiomer. In other embodiments the compounds may also be (R)-enantiomer. In yet other embodiments, the compounds of Formula I may be (+) or (-) enantiomers.
In another embodiment of the invention, the compounds of Formula I contain isotopes of atoms forming the structure of Formula I. Isotopes herein means, each of two or more forms of the same element (e.g., H and D; l2C and lîC) that contain equal numbers of protons but different numbers of neutrons in theîr nuclei, and hence differ in relative atomic mass.
It should be understood that ail isomeric forms are included wîthin the présent invention, including mixtures thereof. If the compound contaîns a double bond, the substituent may be in the E or Z configuration. If the compound contaîns a disubstituted cycloalkyl, the cycloalkyl substituent may hâve a cis or trans configuration. Ail tautomeric forms are also intended to be included.
Methods of Using the Disclosed Compounds
Another aspect of the invention relates to a method of a disease or disorder associated with modulation of embryonic ectoderm development (EED) and/or Polycomb Répressive Complex 2 (PRC2). The method involves administering to a patient in need thereof an effective amount of the composition or compound of Formula I.
Another aspect of the invention relates to a method of a disease or disorder associated with modulation of embryonic ectoderm development (EED). The method involves administering to a patient in need thereof an effective amount of the composition or compound of Formula I.
Another aspect of the invention is directed to a method treating a disease or disorder associated with modulation of Polycomb Répressive Complex 2 (PRC2). The method involves administering to a patient in need thereof an effective amount of the composition or compound of Formula I.
Another aspect of the invention is directed to a method treating a disease or disorder associated with modulation of Polycomb Répressive Complex 2 (PRC2). The method involves administering to a patient in need thereof an effective amount of the composition or compound of Formula 1.
In one embodiment, the disease or disorder is a blood disorder.
In one embodiment, the blood disorder is Acute lymphoblastic leukemia (ALL), Acute myeloid leukemia (AML) (e.g., acute promyelocytic leukemia, APL), Amyloidosis, Anémia, Aplastic
116 anémia, Bone marrow failure syndromes, Chrome lymphocytic leukemia (CLL), Chronic myeloid leukemia (CML), Deep vein throinbosis (DVT), Diamond-Blackfan anémia, Dyskeratosîs congenita (DKC), Eosinophilie disorder, Essential thrombocythemia, Fanconi anémia, Gaucher disease, Hemochromatosis, Hemolytic anémia, Hemophilia, Hereditary spherocytosis, Hodgkin’s lymphoma, Idiopathic thrombocytopénie purpura (ITP), Inherited bone marrow failure syndromes, Irondeficiency anémia, Langerhans cell histiocytosis, Large granular lymphocytic (LGL) leukemia, Leukemia, Leukopenia, Mastocytosis, Monoclonal gammopathy, Multiple myeloma, Myelodysplastîc syndromes (MDS), Myelofib rosis, Myeloproliferative neoplasms (MPN), NonHodgkin’s lymphoma, Paroxysmal nocturnal hemoglobinuria (PNH), Pernicious anémia (B 12 deficiency), Polycythemia vera, Porphyria, Post-transplant lymphoproliférative disorder (PTLD), Pulmonary embolism (PE), Shwachman-Diamond syndrome (SDS), sickle cell disease (SCD), Thalassemia, Thrombocytopenia, Thrombotic thrombocytopénie purpura (TTP), Venons thromboembolism, Von Willebrand disease, or Waldenstrom’s macroglobulinemia (lymphoplasmacytic lymphoma).
In one embodiment, the blood disorder is sickle cell disease.
In one embodiment, the blood disorder is thalassemia (e.g., β-thalassemia).
In one embodiment, the disease or disorder is cancer. In one embodiment, the disease or disorder is selected from diffused large B cell lymphoma, follîcular lymphoma, other lymphomas, leukemia, multiple myeloma, mesothelioma, gastric cancer, malignant rhabdoid tumor, hepatocellular carcinoma, prostate cancer, breast carcinoma, bile duct and gallbladder cancers, bladder carcinoma, brain tumors including neuroblastoma, schwannoma, glioma, glioblastoma and astrocytoma, cervical cancer, colon cancer, melanoma, endométrial cancer, esophageal cancer, head and neck cancer, lung cancer, nasopharyngeal carcinoma, ovarian cancer, pancreatic cancer, rénal cell carcinoma, rectal cancer, thyroîd cancers, parathyroîd tumors, uterine tumors, and soft tissue sarcomas.
The présent invention further provides a method of treating sickle cell disease (SCD) or β-thalassemia. The method comprises administering to a patient in need thereof an effective amount of the compound of Formula I. In one embodiment, the administration resuits in modulation of EED regulated expression of a fêtai orthologue (e.g., fêtai hemoglobin (e.g., HbF or α2γ2)) in the blood of the patient. In one embodiment, the modulation resuits in compensation for the function of one or more mutations affecting the β-globin genes in adult hemoglobin A (α2β2).
In one embodiment, the disease or disorder is a disease or disorder capable of being treated by réactivation of a developmentally regulated fêtai ortholog in another disease or another tissue.
117
The présent invention further provides a method of treating sickle cell disease (SCD) or β-thalassemia. The method comprises administering to a patient in need thereof an effective amount of the composition or compound of Fonnula I. In one embodiment, the administration résulta in modulation of EED regulated expression of a fêtai orthologue (e.g-, fêtai hemoglobin (e.g., HbF or α2γ2)) in the blood of the patient. In one embodiment, the modulation results în compensation for the function of one or more mutations affecting the β-globin genes in adult hemoglobin A (α2β2). The présent invention further provides methods of treating thoracic aortic aneurysm, coronary heart disease, stenotic disease, pulmonary artery hypertension (PAH), liver fibrosis, allergie inflammation, retînitis pigmentosa, septic shock, herpes simplex virus, human cytomégalovirus, a-thalassemia, familial atrial fibrillation, common variable immunodeficiency, aneurysm-osteoarthritis syndrome, and acquired immunodeficiency syndrome. The method comprises administering to a patient in need thereof an effective amount of the compound of Fonnula I.
In one embodiment, the method of the présent disclosure further comprises administering to a patient in need thereof an effective amount of at least one addition al therapeutic agent. In one embodiment, at least one therapeutic agent is selected from anti-cancer agents, immunomodulators, anti-allergie agents, anti-emetics, pain relievers, cytoprotective agents, or combinations thereof. In one embodiment, al least one therapeutic agent is hydroxyurea, L-glutamine, gene thérapies (e.g., CRISPR and AAV or other viral HBG delivery), PDE9 inhibitors, RBC anti-adhension thérapies (e.g., P-selectin), or other compounds targeting transcriptional régulation. In one embodiment, at least one therapeutic agent is an EZH2 inhibitor. In one embodiment, at least one therapeutic agent is N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-5-(elhyI(tetrahydro-2H-pyran-4yl)amino)-4-methyl-4,-(morphoÎinonietlîyl)-[l,r-biphenyl]-3-carboxamide (tazemetostat), (2R)-7chloro-2-[4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-lH-pyridm-3-yl)methyl]-2,4dimethyl-l,3-benzodioxole-5-carboxamide (valemetostat, DS-3201b), N-[(4-methoxy-6-methyl-2oxo- lH-pyridin-3-yl)methyl]-2-methyl-l-[(lR)-l-[ 1-(2,2,2-trifluoroethyl)piperidin-4yI]ethyl]indole-3-carboxamide (CPI-1205), (S)-l-(sec-butyI)-N-((4,6-dimethyl-2-oxo-I,2dihydropyridin-3-yl)methyl)-3-methyl-6-(6-(piperazin-l-yI)pyridin-3-yl)-lH-indole-4-carboxamide (GSK2816126), or (R)-5,8-dichloro-7-(methoxy(oxetan-3-yl)methyl)-2-((4-methoxy-6-methyl-2oxo-l,2-dihydropyridin-3-yl)methyl)-3,4-dîhydiOisoquinolin-l(2H)-one (PF-06821497), or SHR2554, or a combination thereof. In one embodiment, at least one therapeutic agent is hydroxyurea. In one embodiment, at least one therapeutic agent is 2-hydroxy-6-((2-(l-isopropyllH-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde (voxelotor, GBT-440), P-Selectin antibodîes, or L-Glutamine, or a combination thereof. In one embodiment, the at least one therapeutic agent is
118 selected from anti-adhesion agents. In one embodiment, the at least one therapeutic agent is crizanlizumab (SEG101), (2S)-2-[(2R,3R,4S,5S,6R)-3-benzoyloxy-2-[(lR,2R,3S,5R.)-3-[(2,4-dioxolH-pynmidine-6-carbonyl)animo]-5-[2-[[2-[2-[2-oxo-2-[(3,6,8-trisulfonaphthalen-lyl)ainino]ethoxy]ethoxy]acetyl]amino]ethylcarbamoyl]-2-[(2S,3S,4R,5S,6S)-3,4,5-trihydroxy-6methyloxan-2-yl]oxycyclohexyl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3cyclohexylpropanoic acid (rivipansel, GMI-1070), sevuparin, 6-[(3S,4S)-4-methyl-l-(pyrimidin-2ylmethyl)pynOlidin-3-yl]-l-(oxan-4-yl)-5H-pyrazolo[3,4-d]pyrimidin-4-one (PF-04447943), inclacumab (LC1004-002), or 3-[3-[4-(l-aminocyclobutyl)phenyl]-5-phenylimidazo[4,5-b]pyridin2-yl]pyridin-2-amine (miransertib, ARQ 092), or combinations thereof. In one embodiment, the at least one therapeutic agent îs selected from other anti-sickling agents. In one embodiment, at least one therapeutic agent is 2-hydroxy-6-((2-( 1-isopropyl-l H-pyrazo 1-5-yl)pyridin-3yl)methoxy)benzaldehyde (voxelotor, GBT-440) or 6-[(3S,4S)-4-Methyl-l-(2-pyrimidinylmethyl)3-pynolidinyl]-3-(tetrahydro-2H-pyran-4-yl)imidazo[l,5-a]pyrazin-8(7H)-one (IMR-687), or combinations thereof. In one embodiment, at ieast one therapeutic agent is selected from détoxification agents. In one embodiment, at least one therapeutic agent is LJPC-401. In one embodiment, at least one therapeutic agent is selected from anti-inflammatory agents, antithrombiotic agents, or combinations thereof. In one embodiment, the at least one therapeutic agent is (lS,2S,3R,5S)-3-[7-{[(lR,2S)-2-(3,4-difluorophenyl)cyclopropyi]amino}-5(propylthio)-3H[ 1 )2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol (Brilinta, tricagrelor), (2R)-3,3,3-trifluoro-2-[[[5-fluoro-2-[l-[(2-fluorophenyl)methyl]-5-(l,2-oxazol-3yl)pyrazol-3-yl]pyrimidin-4-yl]amino]methyl]-2-hydiOxypiOpanamide (olinciguat), orNKTT120, or combinations thereof. In one embodiment, at least one therapeutic agent is sanguinate. In one embodiment, at least one therapeutic agent causes disruption of PRC2. In one embodiment, at least one therapeutic agent is AZD9291.
Another aspect of the invention is directed to a method of inducing fêtai hemoglobin (hemoglobin γ (ΗΒγ), or HbF) expression in erythroid cells. The method involves administering to a patient in need thereof an effective amount of the composition or compound of Formula I.
In one embodiment, the composition or compound of Formula I induces upregulation of mRNA levels (e.g., HBG1 or FIBG2, with sequences shown herein) or upregulation of fêtai hemoglobin protein (ΗΒγ) that results in an élévation in HbF protein.
119
In one embodiment, the method further involvs administering to a patient in need thereof one or more additional therapeutic agents that upregulate HbF and/or reduce or alleviate one or more symptoms of SCD and/or β—thalassemia (e.g., vaso-occlusion and anémia).
Hemoglobin Subunit Gamma-1 (HBGl) Sequence (SEQ ID NO: 1):
MGHFTEEDKATITSLWGKVNVEDAGGETLGRLLVVYPWTQRFFDSFGNLSSASAIMGNPK VKAHGKKVLTSLGDA1KHLDDLKGTFAQLSELHCDKLHVDPENFKLLGNVLVTVLAIHFG KEFTPEVQASWQKMVTAVASALSSRYH
Hemoglobin Subunit Gamma-2 (HBG2) sequence (SEQ ID NO: 2):
MGHFTEEDKATITSLWGKVNVEDAGGETLGRLLVVYPWTQRFFDSFGNLSSASAIMGNPK VKAHGKKVLTSLGDAIKHLDDLKGTFAQLSELHCDKLHVDPENFKLLGNVLVTVLAIHFG KEFTPEVQASWQKMVTGVASALSSRYH
Hemoglobin Subunit Alpha-1 (HBA1) amino acid sequence (SEQ ID NO: 3):
MVLSPADKTNVKAAWGKVGAHAGEYGAEALERMFLSFPTTKTYFPHFDLSHGSAQVKGH gkkvadaltnavahvddmpnalsalsdlhahklrvdpvnfkllshcllvtlaahlpaef TPAVHASLDKFLASVSTVLTSKYR
Hemoglobin Subunit Alpha-2 (HBA2) amino acid sequence (SEQ ID NO: 4) MVLSPADKTNVKAAWGKVGAHAGEYGAEALERMFLSFPTTKTYFPHFDLSHGSAQVKGH GKKVADALTNAVAHVDDMPNALSALSDLHAHKLRVDPVNFKLLSHCLLVTLAAHLPAEF TPAVHASLDKFLASVSTVLTSKYR
Another aspect of the invention is directed to use of a compound of Formula I for treating a disease or disorder associated with the modulation of embryonic ectoderm development (EED) and/or Polycomb Répressive Complex 2 (PRC2).
Another aspect ofthe invention is directed to use of a compound of Formula I for treating a disease or disorder associated with the modulation of embryonic ectoderm development (EED).
Another aspect ofthe invention îs directed to use ofa compound of Formula I for treating a disease or disorder associated with the modulation of Polycomb Répressive Complex 2 (PRC2).
Another aspect ofthe invention is directed to a compound of Formula I for use in the manufacture of a médicament for treating a disorder or disease associated with embryonic ectoderm development (EED) and/or Polycomb Répressive Complex 2 (PRC2).
Another aspect ofthe invention is directed to a compound of Formula I for use in the manufacture of a médicament for treating a disorder or disease associated with embryonic ectoderm development (EED).
120
Another aspect of the invention is directed to a compound of Formula I for use in the manufacture of a médicament for treating a disorder or disease associated with Polycomb Répressive Complex 2 (PRC2).
The disclosed compounds of the invention can be administered in effective amounts to treat or prevent a disorder and/or prevent the development thereof in subjects.
Administration of the disclosed compounds can be accomplished via any mode of administration for therapeutic agents. These modes include systemic or local administration such as oral, nasal, parentéral, transdermal, subcutaneous, vaginal, buccal, rectal or topical administration modes. Dependîng on the intended mode of administration, the disclosed compositions can be in solid, semi-solid or liquid dosage fonn, such as, for example, injectables, tablets, suppositories, pills, timerelease capsules, élixirs, tinctures, émulsions, syrups, powders, liquids, suspensions, or the like, sometimcs in unit dosages and consistent with conventîonal pharmaceutical practices. Likewise, they can also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous or intramuscular fonn, and ail using forms well known to those skilled in the phannaceutical ails. Another aspect of the invention is directed to phannaceutical compositions comprising a compound of Formula I and a phannaceuticaily acceptable carrier. The phannaceutical acceptable carrier may further include an excipient, diluent, or surfactant.
In one embodiment, the phannaceutical composition further comprises at least one additional therapeutic agent. In one embodiment, the at least one therapeutic agent is selected from other anticancer agents, îminunomodulators, anti-allergie agents, anti-emetics, pain relievers, cytoprotectîve agents, and combinations thereof. In one embodiment, the at least one therapeutic agent is selected from hydroxyurea, L-glutamine, gene thérapies (e.g., CRIS PR and AAV or other viral HBG delîvery), PDE9 inhibitors, RBC antî-adhension thérapies (e.g., P-selectin), and other compounds targeting transcriptional régulation.
Illustrative phannaceutical compositions are tablets and gelatin capsules comprising a Compound of the Invention and a phannaceuticaily acceptable carrier, such as a) a diluent, e.g., purified water, triglycéride oils, such as hydrogenated or partially hydrogenated vegetable oil, or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oils, such as EPA or DHA, or their esters or triglycérides or mixtures thereof, omega-3 fatty acids or dérivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and/or glycine; b) a lubricant, e.g., silica, talcum, stearic acid, its magnésium or calcium sait, sodium oleate, sodium stéarate, magnésium stéarate, sodium benzoate, sodium acetate, sodium chloride and/or polyethylene glycol; for tablets also; c) a binder, e.g., magnésium aluminum silicate, starch paste, gelatin, tragacanth.
121 methylcellulose, sodium carboxymethylcellulose, magnésium carbonate, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, waxes and/or polyvinylpyrrolidone, if desired; d) a désintégrant, e.g., starches, agar, methyl cellulose, bentonite, xanthan gum, algiic acid or its sodium sait, or effervescent mixtures; e) absorbent, colorant, flavorant and sweetener; f) an emulsifier or dispersing agent, such as Tween 80, Labrasol, HPMC, DOS S, caproyl 909, labrafac, labrafd, peceol, transcutol, capmul MCM, capmul PG-12, captex 355, gelucire, vitamin E TGPS or other acceptable emulsifier; and/or g) an agent that enhances absorption of the compound such as cyclodextrin, hydroxypropyLcyclodextrin, PEG400, PEG200.
Liquid, particularly injectable, compositions can, for example, be prepared by dissolution, dispersion, etc. For example, the disclosed compound is dissolved in or mixed with a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, éthanol, and the like, to thereby form an injectable isotonie solution or suspension. Proteins such as albumin, chylomicron particles, or sérum proteins can be used to solubîlize the disclosed compounds.
The disclosed compounds can be also formulated as a suppository that can be prepared from fatty émulsions or suspensions; using polyalkylene glycols such as propylene glycol, as the carrier. The disclosed compounds can also be administered in the form of liposome delîvery Systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, containing cholestérol, stearylamine or phosphatidylcholines. In some embodiments, a film of lipid components is hydrated with an aqueous solution of drug to a form lipid layer encapsulating the drug, as described in U.S. Pat. No. 5,262,564.
Disclosed compounds can also be delivered by the use of monoclonal antibodies as individual carriers to which the disclosed compounds are coupled. The disclosed compounds can also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspanamidephenol, or polyethyleneoxidepoiylysine substituted with palmitoyl residues. Furthermore, the Disclosed compounds can be coupled to a class of biodégradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels. In one
122 embodiment, disclosed compounds are not covalently bound to a polymer, e.g., a polycarboxylîc acid polymer, or a polyacrylate.
Parental injectable administration is generally used for subcutaneous, intramuscular or intravenous injections and infusions. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions or solid forms suitable for dîssolving in liquid prior to injection.
Compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the présent pharmaceutical compositions can contain from about 0.1% to about 99%, from about 5% to about 90%, or from about 1% to about 20% of the disclosed compound by weight or volume.
The dosage regimen utilizing the disclosed compound is selected in accordance with a variety of factors including type, species, âge, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the rénal or hepatic function of the patient; and the particular disclosed compound employed. A physician or veterinarîan of ordinary skill in the art can readily détermine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress ofthe condition.
Effective dosage amounts of the disclosed compounds, when used for the indicated effects, range from about 0.1 mg to about 5000 mg of the disclosed compound as needed to treat the condition. Compositions for in vivo or in vitro use can contain about 0.1, 0.5, 5, 20, 50, 75, 100, 150, 250, 500, 750, 1000, 1250, 2500, 3500, or 5000 mg of the disclosed compound, or, in a range of from one amount to another amount in the list of doses. In one embodiment, the compositions are in the form of a tablet that can be scored.
Method of Synthesizing the Compounds
The compounds of the présent invention may be made by a variety of methods, including standard chemistry. Suitable synthetic routes are depicted in the Schemes given below.
The compounds of Formula I may be prepared by methods known in the ail of organic synthesis as set forth in part by the following synthetic schemes. In the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles or chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, Third édition, Wiley, New York 1999). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled
123 in the art. The sélection processes, as well as the réaction conditions and order of their execution, shall be consistent with the préparation of compounds of Formula 1.
Those skilled in the art will recognize if a stereocenter exists in the compounds of Formula I. Accordîngly, the présent invention includes both possible stereoisomers (unless specified in the synthesis) and includes not only racemîc compounds but the individu al enantiomers and/or diastereomers as well. When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an întermediate, or a starting material may be affected by any suitable method known in the art. See, for exampie, Stereochemistry of Organîc Compounds by E. L. Eliel, S, H. Wilen, and L. N. Mander (Wiley-lnterscîence, 1994).
The compounds described herein may be made from commercially available starting materials or synthesized using known organic, inorganic, and/or enzymatic processes.
Préparation of compounds
The compounds ofthe présent invention can be prepared in a number of ways well known to those skilled in the art of organic synthesis. By way of example, compounds of the présent invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. General methods include but are not limited to those methods described below. Moreover, the suitable starting material readily available and known by one of skilled in the art can be selected to arrive at spécifie compounds of the présent disclosure. Compounds of the présent invention Formula I can be synthesized by following the steps outlined in Schemes 1-4, wherein Rb R2, and R3 are deftned in Formula L Starting materials are either commercially available or made by known procedures in the reported literature or as îllustrated.
124
Scheme 1
The general way of preparing a common intermediate 1g is outlined in Scheme 1, wherein R2 and R3 are defined in Formula 1. Deprotonatîon of la followed by a reaction with a formylation agent, such 5 as DMF, yields intermediate 1b whieh can be treated with boron tribromide to deprotect the phénolic moiety to afford le. Protection of the alhedyde results in intermediate Id which can be reacted with commercially available epoxide le to afford If. Treatment with a strong base, such as π-butyl lithium, yields the common intermediate 1g that can be converted în a number of ways to the final compounds.
Scheme 2
125
2a
BûCjO
acid
2k
The general way of preparing target compound 21 is outlined in Scheme 2, wherein Rt, R2 and Ri are defined in Formula 1. 5-Bromo-6-chloro-2-nitropyridin-3-ol (Example 2) is reacted with the alcohol Ig under Mitsunobu conditions. Nitro group réduction followed by the aldéhyde 5 deprotection step afforts intermediate 2d which can be converted into an alcohol and subsequently into a leaving group such as chloride 2f. The cyclization step can be conducted, for example, with césium carbonate and tetrabutyl ammonium iodide. Boc protection affords intennediate 2h which 126 then can be reacted with hydrazine hydrate to afford intermediate 2i. The triazole ring formation can be accomplished, for example, by means of triethyl orthoformate, thus affording a common intermediate 2j. The Boc group can be removed in acidic conditions followed by coupling steps with a variety of reagents to resuit in final products 21. Altematively, the coupling step can be performed 5 on the Boc-protected intermediate 2j with a subséquent Boc-deprotection step.
Scheme 3
NIS
3b
NaH, PMB-CI
Another general way of preparing cyclization precursor 2e îs outlined in Scheme 3, wherein R2 and R3 are defined in Formula 1. lodide 3b is obtained from 5-bromo-6-chIoropyridin-2-amîne by means 10 of jV-iodosuccinimide and the amino group is protected by alkylation with, for example, pmethoxybenzyl chloride. The resultîng intermediate 3c can be coupled with the alcohol of 1g under copper-mediated conditions, for example. The dioxolane moiety is cleaved under acidic conditions, for example with aqueous HCl, and the resulting aldéhyde is converted into alcohol 3f with a reducing agent, such as sodium borohydride. Full deprotection of the aminogroup with a strong acid, 15 such as TFA, resuits in intermediate 2e, which can then be converted into the final products as described in Scheme 2.
Scheme 4
127
Another general way of preparing the common intermediate 2k is outlined in Scheme 4, wherein R2 and Ri are defined in Formula 1. Nosyl protection of the amîno group in intermediate 2c with a subséquent aldéhyde deprotection affords compound 4b, which can be reduced to provide alcohol 5 4c. The cyclization can be accomplished under Mitsunobu conditions to resuit in intermediate 4d.
Removal of the nosyl protecting group with PhSH affords common intermediate 2k which can then be converted into the final products as described in Scheme 2.
Examples
The disclosure is further illustrated by the foliowing examples and synthesis schemes, which are not to be construed as limiting this disclosure in scope or spirit to the spécifie procedures herein described. It is to be understood that the examples are provided to illustrate certain embodiments and that no limitation to the scope of the disclosure is intended thereby. It is to be further understood that resort may be had to various other embodiments, modifications, and équivalents thereof which may suggest themselves to those skilled in the ait without departing from the spirit of the présent disclosure and/or scope of the appended daims.
Abbrevïations used in the following examples and elsewhere herein are:
128
23 °C room température;
Ac2O acetic anhydride
ACN acetonitrile
AcOH or HOAc acetic acid
5 aq aqueous
Boc2O dî-tert-butyl dicarbonate
B OP ammonium 4-(3-(pyridin-3-ylmethyl)ureido)benzenesulfinate
(Bpin)2 bis(pinacolato)diboron;
CDC13 deuterated chloroform
10 CDjOD deuterated methanol
Comins’ reagent N-bis(trifluoromethanesulfonimide);
δ Chemical shift
DBDMH l,3-dibromo-5,5-dimethylhydantoin
DCM dichloromethane or methylene chloride
15 DCE 1,2-dîchloroethane
DEAD diethyl azodicarboxylate
DI AD diisopropyl azodicarboxylate
DIBAL-H diisobutylaluminum hydride
DIEA MV-diisopropyl ethyl amine
20 DMA XTV-dimethylacetamide
DME dimethoxyethane
DMF MV-dimethylformamide
DMP Dess-Martîn Periodinane
DMSO dimethylsuifoxide
25 DMSO-<4 deuterated dimethylsuifoxide
DPPA diphenyl phosphoryl azide
dppf 1,1 '-Bis(diphenylphosphino)fenOcene
EDCI A-(3-dimethylaminopropyl)-V’-ethylcarbodiimide hydrochloride
EDTA ethyl en ediaminetetraacetic acid
30 ee enantiomeric excess
eq. or equiv. équivalent
Et20 diethyl ether
EtOAc ethyl acetate
129
EtOH éthanol
FA formate
Fe iron
h or hr ’hnmr hour(s) proton nuclear magnetic résonance
HATU 2<3H-[ 1,2,3]triazolo[4,5-b]pyridin-3-yl)-l, I,3,3-tetramethylisouroniuni hexafluorophosphate
HFIP hexafluoroisopropanol
HOBT lH-benzo[d][l,2f3]triazol-l-ol hydrate
HPLC high performance liquid chromatography
Hz hertz
IPA isopropyl alcohol
KOAc potassium acetate
LAH lithium alumînum hydride
LCMS liquid chromatography/mass spectrometry
LC-MS liquid chromatography/mass spectrometry
LiHMDS lithium bis(trimethylsilyl)ainide
m minute(s)
(M+l) mass + 1
m-CPBA w-chloroperbenzoîc acid
MBTE methyl Zeri-butyl ether
MeOH methanol
MeMgBr MPLC methyl magnésium bromide medium-pressure liquied chromatography
MS mass spectrometry
NaHMDS sodium bis(trimethylsilyl)amide
NCS N-chlorosuccinimide
NMP N-methylpyrrolidone
NMR nuclear magnetic résonance
Ns nosyl (4-nitrobenzenesulfonyl)
Pd(dppf)Cl2 Palladium tetrakis [ 1,1 '-Bis(diphenylphosphino)ferrocene]dichloropalladium(ll) Tetrakis(triphenylphosphine)palladium(0)
PMB para-methoxybenzyl
130
1r rétention time
sat. saturated
SFC supercritical fluid chromatography
TBAI tetrabutylammonium iodide
TBDMS-C1 tert-butyl dimethylsilyl chloride
TB ME tert-butyl methyl ether
TEA tri methy lamine
TFA trifluoroacetic acid
TF AA trifluoroacetic anhydride
HFIP hexafluoroisopropanol
THF tetrahydrofuran
TLC thin layer chromatography
OTf trifluoromethanesulfonate
Xantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene
General Methods
Ail températures are in degrees Celsius (°C) and are uncorrected. Reagent grade Chemicals and anhydrous solvent were purchased from commercial sources and unless otherwise mentioned, were used without further purification. Silica gel chromatography was performed on Teledyne Isco instruments using pre-packaged disposable SÎO2 stationary phase columns with eluent flow rate range of 15 to 200 mL/min, UV détection (254 and 280 nm). Reverse phase préparative HPLC was carried out using Cl 8 columns, UV détection (214 and 254 nm) eluting with gradients of MeCN in water (0.03% (NH4)2CO3/ 0.375% NH4OH) or MeCN in water (0.1% HCOOH). The analytical HPLC chromatograms were performed using an Agilent 1100 sériés instrument with DAD detector (190 nm to 300 nm). The mass spectra were recorded with a Waters Micromass ZQ detector at 130 °C. The mass spectrometer was equipped with an electrospray ion source (ESI) operated in a positive ion mode and was set to scan between m/z ! 50-750 with a scan time of 0.3 s. Unless otherwise specified, products and intermedi aies were analyzed by HPLC/MS on a Gemini-NX (5 μΜ, 2.0 x 30 mm) using a high pH buffer gradient of 5% to 100% of MeCN in water (0.03% (NH4)2CO3/ 0.375% NH4OH) over 2.5 min at 1.8 mL/min for a 3.5 min run (B05) and EVO Cl8 (5 μΜ, 3.0 x 50 mm) using a low pH buffer gradient of 5% to 100% of MeCN in water (0.1% HCOOH) over 2.5 min at 2.2 mL/min for a 3.5 min run (A05). Unless otherwise specified, prep131
HPLC purification was performed using the following eluents: MeCN/10 mM aqueous NH4HCO3 for the “neutral conditions” method, MeCN/0.04% aqueous HCl for the “HCl conditions” method, and MeCN/0.2% aqueous HCOOH for the “FA conditions” method, The ’H NMR Chemical shifts are referenced to solvent peaks, which in lH NMR appear at 7.26 ppm for CDCI3, 2.50 for DMSOd6, and 3,31 ppm for CD3OD.
Example 1: 5-bromo-6-chloropyridin-3-ol
Br
Cl
OH
A mixture of NaNO2 (31.9 g, 4620 mmol, 1.20 eq) in water (80.0 mL) was added to an ice-cooled solution of 5-bromo-6-chloropyridin-3-amine (80.0 g, 386 mmol, 1.00 eq) in H2SO4 (567 g, 2.89 mol, 308 mL, 50% purity, 7.50 eq) at 0°C, and then the mixture was stirred at 25°C for 30 mins. The mixture was added to AcOH (400 mL) at 100°C. The mixture was stirred at 100°C for 12 h. LCMS showed the reaction was complété. The mixture was concentrated under reduced pressure. The mixture was added to ice-water (2000 mL) and adjusted the pH to 6-7 using sat. aq. Na2CO3. The mixture was extracted with EtOAc (5000 mL). The organic layer was washed with brine (2000 mL), dned overNa2CO3, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 1/0 to 4/1, Petroleum ether/Ethyl acetate = 2/1, Rf= 0.56). 5-bromo-6-chloropyridin-3-ol (52.0 g, crude) was obtained as a yellow solid. *H NMR CDClj 400 MHz, δ = ppm 7.95 (d, 7= 2.6 Hz, 1H), 7.45 (d,7=2.6 Hz, 1H).
Example 2: 5-bromo-6-chloro-2-nitropyridin-3-ol
Br
Cl·. J·.
XX
Y OH
NO2
The reaction was set up in two separate batches. A mixture of 5-bromo-6-chloropyridin-3-ol (46.0 g, 220 mmol, 1.00 eq) in H2SO4 (138 mL, 98% purity) was stirred at 0°C for 75 min. H2SO4 (42.3 g, 423 mmol, 23.0 mL, 98% purity, 1.92 eq) and fuming HNO3 (19.3 g, 294 mmol, 13.8 mL, 96% purity, 1.33 eq) was added to the reaction mixture at 0°C. The mixture was stirred at 0°C for 2 h. After stirring for 2 h, the mixture was stirred at 20°C for 12 h. LCMS showed that a small amount
132 of 5-bromo-6-chloiOpyridin-3-ol remained and the desîred mass was detected. The two reaction mixtures were combined and added to ice-water (3000 mL) and stirred at 20°C for 1 hr. The mixture was filtered and the filter cake was dried under reduced pressure to give 5-bromo-6-chloro2-nitropyridîn-3-ol (83.0 g, crude) as a yellow solid. lH NMR DMSO-</6 400 MHz, δ = ppm 7.97 (s, 1H).
Example 3: 2-bromo-6-fluoro-3-methoxybenzaIdehyde
The reaction was set up in 3 separate batches. To a solution of 2-bromo-4-lluoro-l-methoxybeiizene (170 g, 829 mmol, 1.00 eq) in THF (2500 mL) was added LDA (2 M, 456 mL, 1.10 eq) at -78°C under nitrogen. The mixture was stirred at -78°C for 1 hr, then DMF (121 g, 1.66 mol, 128 mL, 2.00 eq) was added under -65°C. The reaction mixture was stirred at -65°C for 1 hr. TLC (Petroleum ether:Ethyl acetate = 3:1, Rf = 0,6) detected one major new spot with larger polarity. Each batch was quenched by addition of water (700 mL) and then the organic solvent was evaporated. The three batches of the remaining aqueous phase were combined and extracted with EtOAc (1000 mL * 3). The combined organic layers were washed with brine (1000 mL) and dried over Na2SO4, filtered and concentrâted under reduced pressure. The residue was triturated with MTBE (1000 mL) and filtered to afford 2-bromo-6-fluoro-3-methoxybenzaldehyde (600 g, crude) as a yellow solid. ’H NMR CDClj 400 MHz, δ = ppm 10.39 (s, 1H), 7.19 - 7.03 (m, 2H), 3.93 (s, 3H).
Example 4: 2-bromo-6-fluoro-3-hydroxybenzaldehyde
The reaction was set up in 3 separate batches. To a solution of 2~bromo-6-fluoro-3methoxybenzaldehyde ( 165 g, 708 mmol, 1.00 eq) in DCM (2000 mL) was added BBr3 (408 g, 1.63 mol, 157 mL, 2.30 eq) dropwise over 0.5 hr whiie keeping inner température between 0-10°C under N2. The mixture was stirred at 25°C for 2 h under N2. TLC (Petroleum ether:Ethyl acetate = 3:1, Rf = 0.25) detected one major new spot with higher polarity. The reaction mixture was quenched with water (2500 mL) and extracted with EtOAc (1000 mL * 3). The organic layers from the three batches were combined, washed with brine (800 mL), dried over Na2SO4, filtered and then concentrâted under reduced pressure. The residue was washed with PE/EtOAc (1/1, 600 mL) and
133 fïltered, the fil ter cake was dried in vacuum to afford 2-bromo-6-lluoro-3-hydroxybenzaldehyde (408 g, 1.86 mol, 87% yietd) as a yellow solid. 'H NMR CDCIj 400 MHz, δ = ppm 10.32 (s, 1H), 7.28 - 7.22 (m, 1H), 7.15 - 7.05 (m, 1H), 5.90 (s, 1H).
Example 5: 2-bronio-3-(l,3-dioxolan-2-yl)-4-fluorophenoI
F cr
HC) Br
To a solution of 2-bromo-6-fluoro-3-hydroxybenzaldehyde (136 g, 621 mmol, 1.00 eq), ethylene glycol (193 g, 3.10 mol, 173 mL, 5.00 eq) in toluenetoluene(2000 mL) was added TsOH (10.7 g, 62.1 mmol, 0.100 eq) at 25°C. The mixture was stirred at 130°C for 8 h under N2. Three parallel reactions were set up. LC-MS showed no 2-bromo-6-fluoro-3-hydroxybenzaldehyde was remained. Several new peaks were shown on LC-MS and the desired mass was detected. Each batch of the reaction mixture was cooied to room température and concentrated to the third of the initial volume. The residual solution was then diluted with the saturated NaHCO3 solution (1000 mL) and extracted with EtOAc (300 mL * 3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, fïltered and concentrated to provide the title compound as a solid. The three batches were combined and the residue was triturated with MTBE (100 mL) and fïltered, the filter cake was 2-bromo-3-( 1,3-dioxolan-2-yl)-4-fluorophenoï. 2-bronio-3-( 1,3-dîoxolan-2-yl)-4-fluorophenol (355 g, 1.35 mol, 72% yîeld) was obtained as a white solid. *H NMR CDCfj 400 MHz, δ = ppm 7.08 6.92 (m, 2H), 6.28 (s, 1H), 5.67 (s, 1H), 4.33 - 4.20 (m, 2H), 4.14 - 4.01 (m, 2H).
Example 6: (R)-2-(2-bromo-6-fluoro-3-(oxiran-2-ylinethoxy)phenyl)-l,3-dioxolane
To a mixture of NaH (18.2 g, 456 mmol, 60% purity, 1.2 eq) in DMF (700 mL) was added dropwise 2-bromo-3-(l,3-dioxolan-2-yl)-4-fluorophenol (100 g, 380 mmol, 1.00 eq) in DMF (500 mL) at 0°C. The mixture was allowed to warm up to 25°C and stirred for 0.5 hr. Then (R)-oxîran-2-ylmethyl 3nitrobenzenesulfonate (98.6 g, 380 mmol, 1.00 eq) in DMF (500 mL) was added dropwise at 0°C and the mixture was stirred at 25°C for 12 h. HPLC showed that some 2-bromo-3-(l,3-dioxolan-2yl)-4-fluorophenol remained. Addîtional (R)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (19.7 g, 76.0 mmol, 0.2 eq) in DMF (100 mL) was added dropwise at 25°C and the mixture was stirred at
134
25°C for 4 h. HPLC showed no 2-bromo-3-(l,3-dioxolan-2-yl)-4-fluorophenol remained. The mixture was quenched by the addition of water (2500 mL), filtered, and the filter cake was dried under reduced pressure. Then mother liquor was extracted with EtOAc (1000 mL * 3). The combined organic layers were washed with brine (1000 mL), dried over Na2SO4, filtered, and concentrated to a solid. The solid and the filter cake were combined and triturated with MTBE (100 mL) and filtered to afford (R)-2-(2-bromo-6-fluoro-3-(oxiran-2-ylmethoxy)phenyl)-l,3-dioxolane (105 g, 329 mmol, 86% yield) as a white solid. 'HNMR CDC134OO MHz, δ = ppm 7.06 - 6.99 (m, 1H), 6.99 - 6.94 (m, 1H), 6.42 (d,7 = 1.0 Hz, 1H), 4.34-4.21 (m, 3H),4.13 - 3.98 (m, 3H), 3.40 (tdd, 7= 5.3, 4.1, 2.8 Hz, 1 H), 2.99 - 2.90 (m, 1H), 2.85 (dd,7=4.9, 2.7 Hz, 1H).
Example 7: (S)-(4-(l,3-dioxolan-2-yl)-5-fluoro-2,3-dihydrobenzofuran-3-yl)methanol
To a mixture of (R)-2-(2-bromo-6-fluoro-3-(oxiran-2-ylmethoxy)phenyl)-l,3-dioxolane (113 g, 352 mmol, 1.00 eq) in THF (1200 mL) was added dropwise n-BuLi (2.5 M, 169 mL, 1.20 eq) at -78°C. The mixture was stirred at -78°C for 2 h under N2. TLC (Petroleum ether : Ethyl acetate = 2:1, Rf = 0.24) detected one major new spot with higher polarîty. LC-MS showed no (R)-2-(2-bromo-6fluoiO-3-(oxiran-2-ylmethoxy)phenyI)-l,3-dioxoiane remained. The reaction mixture was quenched by the addition of water (500 mL) at 0°C and extracted with EtOAc (100 mL * 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain (S)-(4-(l,3-dioxolan-2-yl)-5-fluoro-2,3-dihydrobenzofuran-3yl)methanol (85 g. crude) as a yellow oil. ’l-I NMR DMSO-7ê 400 MHz, δ = ppm 7.05 - 6.91 (m, 1H), 6.79 (dd, 7= 8.7, 3.9 Hz, 1 H), 5.91 (s, 1H),4.95 (t,7=5.3 Hz, 1H), 4.62 (dd,7=8.8, 1.8 Hz, 1H), 4.42 (t, 7 = 8.7 Hz, 1H), 4.15 - 4.07 (m, 2H), 3.99 - 3.90 (m, 2H), 3.70 - 3.58 (m, 2H), 3.25 3.15 (m, 1H).
Example 8: (R)-3-((4-(l,3-dioxolan-2-yl)-5-fluoro-2,3-dihydrobenzofuran-3-yl)methoxy)-5bromo-6-chloro-2-nitropyndine
135
The reaction was set up in to parallel batches. To a solution of (S)-(4-(l,3-dioxolan-2-yl)-5-fluoro2,3-dihydrobenzofuran-3-yl)methanol (45.0 g, 187 mmol, 1.00 eq) and 5-bromo-6-chloro-2nitropyridin-3-ol (41.8 g, 165 mmol, 0.88 eq) in toluenetoluene (1800 mL) was added PPh3 (73.7 g, 281 mmol, 1.50 eq). Then DIAD (45.5 g, 225 mmol, 43.7 mL, 1.20 eq) was added to the mixture at 20°C. The mixture was stirred at 20°C for 12 h. LCMS indicated that the reaction was complété. The two batches were combined. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 1/0 to 0/1; Petroleum ether/Ethyl acetate = 2/1, Rf= 0.72). (R)-3-((4-(l,3-dioxolan-2-yl)-5-nuoro~2,3dihydrobenzofuran-3-yl)methoxy)-5-bromo-6-chloro-2-nitropyiÎdine (300 g, crude) was obtained as yellow oil. 'HNMRCDClj 400 MHz, δ = ppm 7.80 (s, 1H), 6.94 (dd, J- 10.3,8.8 Hz, 1H), 6.81 (dd, 8.7, 4.0 Hz, 1H), 6.05 (s, 1H), 4.75 - 4.70 (m, 1H), 4.54 - 4.46 (m, 2H), 4.20 - 4.15 (m, 2H), 4.11-3.99 (m, 4H).
Example 9: (R)-3-((4-(l,3-dioxolan-2-yl)-5-fluoro-2,3-dihydrobenzofuran-3-yl)methoxy)-5bromo-6-chloropyridin-2-amine
To a solution of (R)-3-((4-(l,3-dioxolan-2-yl)-5-fluoro-2,3-dihydrobenzofuran-3-yI)methoxy)-5bromo-6-chloiO-2-nitropyrîdine (150 g, 315 mmol, 1.00 eq) in AcOH (1250 mL) was added Fe (176 g, 3.15 mol, 10.0 eq) at 20°C. The mixture was stirred at 35°C for 2 h. LCMS showed that the reaction was complété. The mixture was fïltered and the filtrate was concentrated under reduced pressure to give (R)-3-((4-(l,3-dioxolan-2-yl)-5-fluoro-2,3-dihydrobenzofuran-3-yl)methoxy)-5bromo-6-chloropyridin-2-amine (90.0 g, crude) as a black oil.
Example 10: (R)-3-(((2-amino-5-bromo-6-chloropyridin-3-yl)oxy)methyl)-5-fluoro-2,3dihydrobenzofuraii-4-carbaldehydc
136
To a solution of (R)-3-((4-(l,3-dioxolan-2-yl)-5-fluoiO-2,3-dihydrobenzofLiran-3-yl)niethoxy)-5bromo-6-chloropyridin-2-amine (90.0 g, 202 mmol, 1.00 eq) in THF (1000 mL) was added HCl (1.5 M, 240 mL, 1.78 eq) at 20°C. The mixture was stirred at 20°C for 10 h. The mixture was concentrated under reduced pressure. EtOAc ( 1000 mL) was added to the residue and the mixture 5 was stirred at 20°C for 10 rnins. The mixture was filtered and the solid was washed with EtOAc (300 mL) and dried under reduced pressure. EtOAc (1000 mL) was added to the residue and the pH was adjusted to 8-9 with sat. aq. NaHCO3. The organic layer was separated, washed with brine (300 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give (R)-3-(((2-amino-5-bromo-6-chIoropyridin-3-yl)oxy)methyI)-5-fluoro-2,3-dihydiObenzofuran10 4-carbaldehyde (40.0 g, crude) as an off-white solid. lH NMR DMSO-^6 400 MHz, S = ppm 10.26 (s, 1H), 7.45 - 7.34 (m, 1H), 7.27-7.16 (m, 2H), 4.74 (br d, 8.2 Hz, 1H), 4.61 - 4.50 (m, 1H), 4.23 (brs, 1H), 4.16 (br dd, J= 9.5, 3.5 Hz, 1H), 3.89 - 3.80 (m, 1H).
Example 11: (R)-(3-(((2-amino-5-bromo-6-chloropyndin-3-yl)oxy)methyl)-5-fluoro-2,3dihydrobenzofuran-4-yl)methanol
Cl
To a solution of (R)-3-(((2-aniino-5-bromo-6-chloropyridin-3-yl)oxy)methyl)-5-fluoiO-2,3dihydrobenzofuran-4-carbaldehyde (29.0 g, 72.2 mmol, 1.00 eq) in THF (300 mL) and MeOH (60 mL) was added NaBH4 (4.10 g, 108 mmol, 1.50 eq) at 25°C. The mixture was stirred at 25°C for 1 hr. LCMS showed the reaction was complété. The residue was poured into water (400 mL) and stirred for 5 mins. The aqueous phase was extracted with EtOAc (200 mL * 2), dried with Na2SO4, filtered and concentrated in vacuum. (R)-(3-(((2-amino-5-broino-6-chloropyridin-3-yl)oxy)methyl)5-iluoro-2,3-dihydiObenzofuran-4-yl)methanol (32.0 g, crude) was obtained as a yellow solid. ’H NMR DMSO-^ 400 MHz, δ = ppm 7.42 (s, III), 7.02 (dd, J= 10.2, 8.7 Hz, 1H), 6.78 (dd, J= S.6, 3.9 Hz, 1H), 6.47 (br s, 2H), 5.39 (t,J= 5.4 Hz, 1H), 4.75 - 4.67 (m, 2H), 4.63 - 4.56 (m, 2H), 4.40 (dd, J= 9.4, 4.2 Hz, 1H), 4.22 - 4.09 (m, 1H), 4.03 - 3.95 (m, 1H).
Example 12: (R)-5-bromo-6-cliloro-3-((4-(chloromcthyl)-5-fhioro-2,3-dihydrobenzofuran-3yl)methoxy)pyrîdin-2-amine
137
Cl
To a solution of (R)-(3-(((2-amino-5-bromo-6-chloropyridÎn-3-yi)oxy)methyl)-5-fluoro-2,3dihydrobenzofuran-4-yi)methanol (30.0 g, 74.3 mmol, 1.00 eq) in THF (310 mL) was added SOC12 (13.3 g, 111 mmol, 8.09 mL, 1.5 eq) at 20°C. The mixture was stirred at 20°C for 1 hr. LCMS showed the reaction was complété. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 1/0 to 0/1, Petroleum ether/Ethyl acetate = 2/1, Rf= 0.56). (R)-5-bromo-6-chloro-3-((4-(chloroniethyl)-5fluoiO-2,3-dihydiObenzofuran-3-yl)methoxy)pyridin-2-amine (30.0 g, crude) was obtained as a yellow solid. ‘H NMR DMSO-t/6 400 MHz, δ = ppm 7.48-7.53 (br. m, 2H), 7.32 (s, 1H), 7.06 (t, J = 9.6 Hz, 1H), 6.82-6.85 (m, 1H), 4.82-4.84 (m, 2H), 4.62-4.64 (m, 2H), 4.28-4.31 (m, 1H), 3.98-4.07 (m, 2H).
Example 13: (R)-10-bromo-9-chloro-5-fluoro-6,7,13,13a-tetrahydro-lH-benzofuro[4,3fg|pyrido[3,2-b][l,4|oxazonine
The reaction was set up in four parallel batches. To a solution of (R)-5-bromo-6-chloro-3-((4(chloromethyl)-5-nuoro-2,3-dihydrobenzofuran-3-yl)methoxy)pyridin-2-amine (7.50 g, 17.8 mmol, ] .00 eq) in CH3CN (1600 mL) was added Cs2CO3 (21.3 g, 65.4 mmol, 3.67 eq) and TBAI (1.21 g, 3.27 mmol, 0.18 eq) at 20°C. The mixture was stirred at 65°C for 3.5 h. The four batches were combined and water (1000 mL) was added to the reaction mixture. The mixture was concentrated under reduced pressure to remove CH3CN and the aqueous phase was extracted with EtOAc (500 mL * 3). The combined organic layers were washed with brine (500 mL), dried overNa2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 1/0 to 2/1, Petroleum ether/Ethyl acetate = 2/1, R| = 0.76). (R)-10-bromo-9-chloro-5-fluoro-6,7,13,I3a-tetrahydro-IH-benzofuro[4,3fg]pyrido[3,2-b][l,4]oxazonine (12.0 g, 20.3 mmol, 47% yield) was obtained as a whîte solid. !H NMR CDCh 400 MHz, δ = ppm 7.25 (s, IH), 6.88 - 6.80 (m, IH), 6.62 (dd, J= 8.7, 3.9 Hz, 1H),
138
5.36 (brt,7=7.8 Hz, 1H), 4.79 (dd,7= 14.9, 9.2 Hz, 1H), 4.65 - 4.55 (m, 2H), 4.49 (dd,7= 14.8,
6.8 Hz, 1 H), 4.21 (dd, 7= 9.5, 2.9 Hz, 1 H), 3.92 - 3.82 (m, 1H), 3.80 - 3.71 (m, 1H).
Example 14: tert-butyl (R)-10-bromo-9-chloro-5-fluoro-13,13a-dihydro-lII-benzofuro[4,3fg]pyrido[3,2-b][l,4]oxazonine-7(6H)-carboxylate
To a solution of (R)-10-biOmo-9-chloro-5-fluoro-6,7,13,13a-tetrahydiO-lH-benzofuro[4,3fg]pyrido[3,2-b][l,4]oxazonine (5.80 g, 15.0 mmol, 1.00 eq) in THF (90 mL) was added DMAP (441 mg, 3.61 mmol, 0.24 eq), TE A (4.57 g, 45.1 mmol, 6.28 mL, 3.00 eq) and Boc2O (19.70 g, 90.25 mmol, 20.73 mL, 6 eq) at 25°C. The mixture was stirred at 50°C for 12 h. The reaction mixture was quenched by addition of water (50 mL) and extracted with EtOAc (30 mL * 3). The combined organic layers were washed with sat. NaCl (30 mL), dried over Na2SO4, fdtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 1/0 to 0/1, Petroleum ether/Ethyl acetate = 2:1, Rf = 0.65). tertbutyl (R)-10-bromo-9-chloro-5-fluoro-13,13a-dihydro-lH-benzofuro[4,3-fg]pyrido[3,2b][l,4]oxazonine-7(6H)-carboxylate (6.60 g, 13.6 mmol, 90% yield) was obtained as a white solid. ‘H NMR CDC13 400 MHz, Ô = ppm 7.60 (s, 1H), 6.83 (t, 7= 9.4 Hz, 1H), 6.65 (dd, 7= 8.6, 3.7 Hz, 1H), 5.00-4.87 (m, 2H), 4.46 - 4.38 (m, 1 H), 4.31 (br dd, 7 = 11.0, 5.1 Hz, 1H), 4.18-4.14 (m, 1H), 4.12-4.08 (m, 1H), 3.94-3.81 (m, 1H), 1.36 (s, 9H).
Example 15: tert-butyl (R)-10-bromo-5-fluoro-9-hydrazineyl-13,13a-dîhydro-lHbenzofuro[4,3-fg]pyrido|3,2-b][l,4]oxazonine-7(6H)-carboxy]ate
The reaction was set up in four parallei batches. To a solution of tert-butyl (R)-10-bromo-9-chloro5-fluoro-13,13a-dihydro-lH-benzofuro[4,3-fg]pyrido[3,2-b][l,4]oxazonîne-7(6H)-carboxylate (1.60 g,3.29 mmol, 1.00 eq) in n-BuOH (60 mL) was added hydrazine hydrate(4.21 g, 82.4 mmol, 4.08 mL, 98% purity, 25 eq) at 25°C. The mixture was stirred at 100°C for 12 h. The four batches were combined and the resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 1/0 to 0/1, Petroleum
139 etherEthyl acetate =1:1, Rf= 0.1). tert-butyl (R)-10-bromo-5-fluoro-9-hydrazineyl-13,l3adihydro-IH-benzofuro[4,3-fg]pyrido[3,2-b][l,4]oxazonine-7(6H)-carboxylate (4.20 g, 8.73 mmol, 66% yield) was obtained as a white solid. tert-butyl (R)-10-bronio-9-chloro-5-fluoro-13,I3adihydiO-lH-benzofuro[4,3-fg]pyndo[3,2-b][l,4]oxazonine-7(6H)-carboxylate (0.7 g, crude) was recovered as a yellow oil. ’H NMR CDC13 400 MHz, δ = ppm 7.47 (s, IH), 6.88 - 6.82 (m, 1H), 6.65 (dd, 7=8.7, 3.8 Hz, IH), 6.06 (s, IH), 5.11 (brd,7= 15.7 Hz, 1H), 4.77 (brd,7 = 15.8 Hz, 1H), 4.39 (t, 7= 8.9 Hz, 1H), 4.18 - 4.12 (m, 1 H), 4.10 - 4.05 (m, 2H), 3.96 - 3.87 (m, 2H), 1.33 (s, 9H). Example 16: tert-butyl (S)-4-bromo-12-fluoro-7a,13-dihydro-7H[l,2,4]triazolo[4’,3*:l,6]pyrido[3,2-blbenzofuroI4,3-fg|[l,4]oxazonme-14(8H)-carboxylate
To a solution of tert-butyl (R)-10-bromo-5-fluoro-9-hydrazineyL13,l 3a-dihydiO-HI-benzofuro[4,3fg]pyrido[3,2-b][l,4]oxazonme-7(6H)-carboxylate (4.20 g, 8.73 mmol, 1.00 eq) in CH(OEt)3 (40.1 g, 271 mmol, 45.0 mL, 31 eq) was added TFA (49.8 mg, 436 umol, 32.3 uL, 0.05 eq) at 25°C. The mixture was stirred at 100°C for 3 h The reaction mixture was concentrated under reduced pressure. The resîdue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 1/0 to 0/1, Petroleum ether/Ethyl acetate = 1/2, Rf = 0.28). tert-butyl (S)-4-bromo-12-fluoro-7a,13dihydro-7H-[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)carboxylate (4.20 g, 8.55 mmol, 97% yield) was obtained as a yellow solid. lH NMR CDC13 400 MHz, δ = ppm 8.70 (br s, 1H), 7.30 - 7.27 (m, IH), 6.70 - 6.55 (m, 2H), 5.31 (br s, 1H), 4.78 - 4.54 (m, 2H), 4.53 - 4.45 (m, IH), 4.27 (d, J= 9.8 Hz, IH), 4.03 - 3.83 (m, 2H), 1.34 (br s, 9H).
Example 17: (S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H[l,2,4]triazolol4,,3':l,6]pyrido[3,2-b]benzoiuro[4,3-fg][l,4]oxazonine
To tert-butyl (S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[ l,2,4]triazolo[4',3':l,6]pyrido[3,2b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (2.50 g, 5.09 mmol, 1.00 eq) was added HFIP (25 mL) at 25°C. The mixture was stirred at 100°C for 12 h The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2,
140
Petroleum ether/Ethyl acetate = 1/0 to 0/1, Petroleum ethenEthyl acetate = 0:1, Rf = 0.10). (S)-4bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-[ 1,2,4]triazolo[4',3’: 1,6]pyrido[3,2-b]benzofuro[4,3fg][l,4]oxazonine (1.60 g, 4.09 mmol, 80% yield) was obtained as a white solid. *H NMR DMSO400 MHz, δ = ppm 9.46 (s, lH),7.68(s, 1H), 7.50 (br t, J= 6.4 Hz, 1H), 6.97 - 6.89 (m, 1H), 6.67 (dd, J = 8.6, 3.9 Hz, 1H), 4.88 - 4.69 (m, 2H), 4.57 - 4.38 (m, 2H), 4.19 (dd, 9.5, 3.5 Hz, 1H), 4.01 - 3.94 (m, 1H), 3.89 - 3.78 (m, 1H).
Example 18: (S)-2-(5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo|4',3':l,6]pyrido[3,2b]benzofuro|4,3-fg][l,4]oxazonin-4-yl)pyridin-2-yl)propan-2-ol
Step 1: tert-butyl (S)-4-(6-acetylpyridin-3-yl)-i2-fluoro-7a,13-dihydro-7H[l,2,4]triazolo[4',3':l, 6]pyrido[3,2-b] benzofuroj4,3-fg][1,4] oxazonine-14(8H)-carboxylate
To a solution of tert-butyl (S)-4-bromo-12-fluoro-7a,13-dihydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (100 mg, 204 uniol, 1.00 eq) in dioxane (5 mL) and water (0.5 mL) was added 1-(5-(4,4,5,5-tetranrethyll,3,2-dioxaborolan-2-yl)pyridin-2-yl)ethan-l-one (65.4 mg, 265 umoi, 1.3 eq), NaHCOj (85.5 mg, 1.02 mmol, 39.6 uL, 5.00 eq) and Pd(dppf)Cl2 (14.9 mg, 20.4 umol, 0.100 eq) at 20°C under nitrogen atmosphère, the mixture was stirred at 80°C for 12 h. The reaction was concentrated under the reduced pressure. The residue was purified by prep-TLC (SiO2, Petroleum ether/Ethyl acetate = 0/1). Tert-butyl (S)-4-(6-acetylpyridin-3-yl)-12-fluoiO-7a,13-diliydro-7H[1,2,4)^2010(4)3^ l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (80.0 mg, 151 umol, 73% yield) was obtained as a yellow oiL
Step 2: (8)-2-(5-( 12-fluoro-7a,8,13,14-tetrahydro- 7H-[l,2,4]triazolo[4',3 *: 1,6]pyrido[3,2b] benzofwo[4,3-fg][I,4]oxazomn-4-yl)pyridin-2-yl)propan-2-ol formate sait
141
To a solution of tert-butyl (S)-4-(6-acetylpyridin-3-yl)-12-fluoro-7a,13-dihydro-7H[ l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][ l,4]oxazonine-I4(8H)-carboxylate (70.0 mg, 132 umol, 1.00 eq) in toluene (4 mL) was added trimethylalumane (2 M, 217 uL, 3.3 eq) at 20°C, the mixture was stirred at 50°C for 12 h. LC-MS showed tert-butyl (S)-4-(6-acetylpyridin-3yl)- I2-fluoro-7a, 13-dihydro-7H-[ l,2;4]triazoio[4',3,: 1,6]pyrido[3,2-b]benzofuro[4,3fg][I,4]oxazonine-14(8H)-carboxylate was consumed completely and the desired mass was detected. Water (3 mL) was added to the mixture, the mixture was the mixture was extracted with ethyl acetate (5 mL * 3), the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by /?rep-HPLC (column: N a no-micro Kromasil C18 100*30 mm 5 um; mobile phase: [water (0.225% FA)-ACN]; B%: 10% - 45%, 12 min). (S)-2(5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[L2,4]triazoio[4',3,:lf6]pyrido[3,2-b]benzofuro[4,3fg][ l,4]oxazonin-4-yl)pyridin-2-yl)piOpan-2-ol (25.0 mg, 50.6 umol, 38% yield, 99.9% purity, formate sait) was obtained as a yellow solid. 'H NMR DMSO-<4 400 MHz, δ = ppm 9.44 (s, 1H), 9.19 (s, 1H), 8.49 (dd, J = 8.5, 1.9 Hz, IH), 7.76 - 7.65 (m, 2H), 7.58 (br t, J= 5.8 Hz, 1H), 6.94 (br t, 9.6 Hz, 1H), 6.67 (dd, J = 8.5, 3.6 Hz, 1H), 5.25 (s, 1H), 4.97 - 4.71 (m, 2H), 4.60 - 4.43 (m, 2H), 4.30 - 4.14 (m, 1H), 4.09 - 3.85 (m, 2H), 1.46 (s, 6H). LCMS (ESI+): m/z 448.2 (M+H) Example 19: General Procedure D. Préparation of (S)-12-fluoro-4-(4-(methyIsulfonyl)phenyl)7a,8,13,14-tetrahydro-7H-[l,2,4]tt-iazolo[4',3':l,6]pyrido[3,2-b|benzofuro|4,3fgl|l,4]oxazonine
To a solution of (S)-4-bromo~12-fluoro-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine (55.0 mg, 141 umol, 1.00 eq) and 4,4,5,5-tetramethyl-2-(4-(methylsulfonyl)phenyl)-1,3,2-dioxaborolane (51.6 mg, 183 umol, 1.3 eq) in dioxane (1 mL) and water (0.1 mL) were added Pd(dppf)Cl2 (10.3 mg, 14.1 umol, 0.100 eq) and NaHCOj (59.1 mg, 703 umol, 27.3 uL, 5.00 eq) at 20°C. The mixture was degassed and purged with nîtrogen 3 times, then stirred at 80°C for 3 h under nitrogen atmosphère. Reaction progress was monitored by LC-MS. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by prep-HPLC (neutral condition). (S)-12-fluoro-4-(4-(methylsulfonyl)phenyl)-7a,8,13,14-tetrahydro-7H142
[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4] oxazonine (12.7 mg, 26.3 umol, 18% yield, 96.7% purity) was obtained as a yellow solid. 'H NMR DMSO-rié 400 MHz, δ = ppm 9.48 (s, 1H), 8.52 (d,7= 8.6 Hz, 2H), 7.97 (d, J = 8.6 Hz, 2H), 7.89 (s, iH), 7.77 (br s, 1H), 6.99 - 6.92 (m, 1H), 6.69 (dd, 7 = 8.6, 3.7 Hz, 1H), 4.97 - 4.86 (m, 1H), 4.86 - 4.76 (m, 1H), 4.54 (br t, J= 9.2 Hz, 5 2H), 4.21 (dd, 7= 9.6, 3.2 Hz, 1H), 4.11 - 4.01 (m, 114), 3.97 (br d,7 = 10.8 Hz, 1H), 3.25 (s, 3H).
LCMS (ES1+): m/z 467.1 (M+H).
Compounds 22 and 30 were prepared according to General Procedure D using the suitable starting materials, precursors, intennediates, and reagents.
Cmpd No. Compound Name Structure Spectral Data
22 (S)-4-(l,3-dimethyl- 1H- pyrazol-4-yl)-12fluoro- 7a, 8,13,14tetrahydro-7H-[ 1,2,4] triazolo[4',3':l,6] pyrido[3,2b]benzofuro[4,3fg][l,4] oxazonine T| /v x /=^ r — 'H NMR CDCh 400 MHz, δ = ppm 8.74 (s, 1H), 8.48 (s, 1H), 7.17 (s, 1H), 6.89 - 6.79 (m, 1H), 6.64 (dd, 7=8.7, 4.1 Hz, 1H), 5.04 (br dd, ./=14.8, 7.7 Hz, 1H), 4.80 (br dd, 7=14.6,6.0 Hz, 1H),4.654.58 (m, 2H), 4.47 (br s, 1H), 4.26 (dd, 7=9.8, 2.5 Hz, 1H), 3.89 (s, 3H), 3.88 - 3.81 (m, 1H), 2.49 (s, 3H). LCMS (ESI+): m/z 407.1 (M+H).
30 (S)-12-fluoro-4-(2methoxy p y rimi d i n - 5 yl)-7a,8,l 3,14tetrahydro-7H[l,2,4]triazolo[4',3':l,6] pyrido[3,2b]benzofuro[4,3fg][l,4] oxazonine O Me w HN^b F. / t Oj lH NMR DMSO-76 400MHz, δ = ppm 9.47 (s, 1H), 9.38 (s, 2H), 7.85 (s, 1H), 7.67 - 7.62 (m, 1H), 6.96 (t, 7= 9.6 Hz, 1 H), 6.69 (dd, J= 8.4, 3.6 Hz, 1H), 4.94 -4.87 (m, 1 H), 4.81 (br s, 1H),4.58 4.50 (m, 2H), 4.22 (br d, 7= 9.2 Hz, 1H), 4.04 (br s, 1H), 3.98 (s, 3H), 3.97 - 3.91 (ni, 1H). LCMS (ESI+): m/z 421.2 (M+H).
Example 20: (S)-4-(2-niethylpyridÎn-3-yl)-7a,8,13,14-tetrahydro-7H 11,2,4] tri azolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg|[l,4]oxazonine
Step 1: 5-bromo-6-chloro-2-nitro-pyridin-3~ol
Br
NO2
5-Bromo-6-chloro-pyridin-3-ol (5.00 g, 24.0 mmol) was added portion-wise to concentrated H2SO4 15 ( 15.0 mL) at 0 °C. After 75 min, a mixture of conc. H2SO4 (98%) and fuming nitric acid (4.00 mL,
2.50/1.50 (v/v)) was added over 5 min with a dropping funnel under vigorous stirring. After stîrring
143 for 2 h at 0 °C, the mixture was warmed to room température for 16 h. The mixture was slowly poured into 300 g of ice-water (2/1), and the mixture was stirred for 1 h. The mixture was filtered through a Buchner funnel, and the filter cake was washed with water (3 xl50 mL). The solid was dissolved in EtOAc (50 mL), and the organic phase was washed with brine (15 mL). The organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure to afford 5-bromo-6chloro-2-nitro-pyridin-3-ol as a solid (3.98 g, 65%). 'H NMR DMSO 500 MHz, S 8.02 (s, 1 H).
Step 2: 2-bromo-3-(J,3-dîoxolan-2-yl) phénol
p-Toluenesulfonic acid (857 mg, 4.98 mmol) was added to a solution of 2-bromo-3-hydroxybenzaldehyde (10.0 g, 49.8 mmol) and ethylene glycol (13.9 mL, 249 mmol) in toluene (225 mL). The mixture was stirred for 5 h at reflux. The mixture was cooled to room température and concentrated to a ihîrd of the initial volume. The residual solution was diluted with a saturated NaHCO3 solution (150 mL), and the aqueous phase was extracted with EtOAc (3 x 75 mL). The combined organic layers were washed with brine (150 mL), dried (MgSO4), filtered, and concentrated to provide 2-bromo-3-(l,3-dioxolan-2-yl) phénol as an oil (8.53 g, 70 %). *H NMR CDClj 500 MHz, ô 7.29-7.23 (m, IH), 7.20-7.16 (m, IH), 7.06 (dd, J = 8.0, 1.7 Hz, IH), 6.08 (s, IH), 5.88 (s, IH), 4.22-4.13 (m, 2H), 4.13-4.06 (m, 2H).
Step 3: 2~[2-bromo-3-[[(2R)-oxiran-2-yl] methoxy] phenyl]-!,3-dioxolane
CsF (10.6 g, 69.6 mmol) was added to a solution of 2-bromo-3-(l,3-dioxolan-2-yl) phénol (8.53 g, 34.8 mmol) in dry DMF (160 mL). The mixture was stirred for 1 hour at room température. [(2R)Oxiran-2-yl] methyl 3-nitrobenzenesulfonate (9.02 g, 34.8 mmol) was added, and the mixture was stirred for 18 h. Water (250 mL) was added, and the aqueous phase was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with water (2 x 300 mL) and brine (250 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silîca gel chromatography (120 g cartridge) eluting with EtOAc in hexanes (30-80 %) to provide 2
144
[2-bromo-3-[[(2R)-oxiran-2-yl] methoxy] phenyl]-l,3-dioxolane as an oïl (6.11 g, 58 %). *H NMR CDC134ÛO MHz, δ 7.28 (t, J = 7.7 Hz, 1 H), 7.24 (dd, J = 7.8, 1.9 Hz, IH), 6.94 (dd, J = 7.7, 1.9 Hz, lH),6.16(s, 1 H), 4.29 (dd, J = 11.2, 3.1 Hz, IH), 4.15 - 4.12 (m, IH), 4.11 - 4.04 (m, 4H), 3.43 3.35 (m, IH), 2.91 (dd, J = 5.0, 4.2 Hz, IH), 2.86 (dd, J = 5.0, 2.6 Hz, IH).
Step 4: [(35)-4-(1,3-dïoxolan-2-yl)-2,3-dihydrobenzofuYan-3-yl] methanol
n-BuLi (8.93 mL, 22.3 mmol, 2.50 M in hexanes) was added drop wise to a solution of 2-[2-bromo3-[[(2R)-oxiran-2-yl] methoxy] phenyl]-l,3-dioxolane (6.11 g, 20.3 mmol) in THF (100 mL) at -78 °C. The mixture was warmed to room température over 3 h. A saturated NH4C1 solution (100 mL) was added. The aqueous phase was extracted with EtOAc (3 x 100 mL), and the combined organic layers were washed with brine (100 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (120 g cartridge) eluting with EtOAc in hexanes (0-100 %) to provide [(3S)-4-(l,3-dioxolan-2-yl)-2,3-dihydrobenzofuran-3yl] methanol as a solid (1.93 g, 43 %). 'H NMR CDC13 400 MHz, δ 7.19 (t, J = 7.8 Hz, IH), 7.05 (dd, J = 7.7, 0.9 Hz, IH), 6.84 (dd, J = 8.0, 0.9 Hz, IH), 5.87 (s, IH), 4.62 - 4.49 (m, 2H), 4.24 4.11 (m, 2H), 4.10-4.01 (m, 2H), 3.85 - 3.68 (m, 3H), 2.33 (t, J = 6.1 Hz, IH). m/z (ES+) [M+H]+: 223.0; HPLC tR (B05) = 1.39 min.
Step 5: 3-bromo-2-chloro-5-[[(3R)-4-(l ,3-dioxolan-2-yl)-2,3-dihydrobenzo[uran-3-yl] methoxy]-6mtro-pyridine
DIAD (1.92 mL, 9.77 mmol) was added drop wise to a solution of 5-bromo-6-chloro-2-nitropyrîdin-3-ol (2.19 g, 8.64 mmol), [(3S)-4-(l,3-dioxolan-2-yl)-2,3-dihydrobenzofuran-3-yl] methanol (1.81 g, 8.14 mmol), and PPh3 (3.20 g, 12.2 mmol) in toluene (60.0 mL) at room température. The mixture was stirred at room température for 20 h and concentrated under reduced pressure. The
145 residue was purified by silica gel chromatography (120 g cartridge) eluting with EtOAc in hexanes (0-60%) to afford the title compound, which was further purified by reverse phase column chromatography (C-18, 80 g cartridge) eluting with water (0.5% formic acid added)/ACN to provide 3-bromo-2-chloiO-5-[[(3R)-4-(l,3-dioxolan-2-yl)-2,3-dihydiObenzofuran-3-yl] methoxy]-6-nitropyridine as a solid (3.38 g, 91 %), lH NMR CDC13 500 MHz, δ 7.85 (s, 1H), 7.23 (t, J = 7.9 Hz, 1H), 7.06-7.02 (m, 1 H), 6.87 (d, J = 8.0 Hz, 1H), 5.85 (s, 1 H), 4.71 (dd, J = 9.4, 1.8 Hz, 1H),4.554.48 (m, 2H), 4.19-4.12 (m, 2H), 4.12 - 4.06 (m, 2H), 4.06 - 3.96 (m, 2H). m/z (ES+) [M+H]+: 458.86; HPLC tR (B05) = 2.11min.
Step 6: 5-bromo-6-chloro-3-[[(3R)-4-(l, 3-dioxolan-2-yl)-2,3-dihydrobenzofuran-3-yl] methoxy] pyridi n-2-amine
Fe (3.74 g, 67.0 mmol) was added in portions to a suspension of3-bromo-2-chloro-5-[[(3R)-4-(l,3dioxolan-2-yl)-2,3-dihydrobenzofuran-3-yl] methoxy]-6-nitro-pyridine (3.07 g, 6.70 mmol) in HOAc (60.0 mL) at room température. The mixture was stirred at room température for 2 h. The mixture was filtered through a pad of Celite. The Celite was washed with EtOAc (3x50 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (40.0 g cartridge) eluting with EtOAc in hexanes (0-70%) to afford 5-bromo-6chloro-3-[[(3R)-4-(l,3-dioxolan-2-yl)-2,3-dihydrobenzofuran-3-yl] methoxy] pyridin-2-amine as a solid (2.39 g, 84%), *H NMR CDCI3 500 MHz, δ 7.23 (t, J = 7.9 Hz, 1H), 7.14 (s, 114), 7.05 (d, J = 7.7 Hz, 1H), 6.87 (dd, J = 8.0, 0.7 Hz, 1H), 5.88 (s, 1H), 4.81 (s, 2H), 4.66 (dd, J = 9.2, 1.8 Hz, 1H), 4,58 _ 4.49 (m, 1H), 4.34 - 4.23 (m, 1H), 4.19 - 4.12 (m, 2H), 4.11 - 4.04 (m, 2H), 4.04 - 3.97 (m, 2H); m/z (ES+) [M+H]+ : 429.16; HPLC tR (B05) = 2.02 min.
Step 7: N-[5-bromo-6-chloro-3-[[(3R)-4-(l,3-dioxolan-2-yl)-2,3-dihydrobenzofuran-3-yl] methoxy]2-pyridyl]-2-nitro-benzenesulfonamide
146
2-Nitrobenzenesulfonyl chloride (3.71 g, 16.7 mmol) was added to a stirred solution of 5-bromo-6chloro-3-[[(3R)-4-(l,3-dioxolan-2-yl)-2,3-dihydrobenzofuran-3-yl] methoxy] pyridin-2-amine (1.59 g, 3.72 mmol) in pyridine (50.0 mL) at room température. The mixture was heated to 60 °C for 24 h. The mixture was concentrated, and water (30 mL) was added to the residue. The mixture was filtered through a Buchner funnei, and the solid was washed with water (100 mL). The solid was diluted in sat. NaHCO3 (30 mL) and EtOAc (30 mL). The aqueous phase was extracted with EtOAc (3x50 mL). The combined organic layers were washed with brine (30 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography ( 120 g cartridge) eluting with EtOAc in hexanes (0-60%) to afford the mono-Ns protected product as a solid (657 mg, 29%). m/z (ES+) [M+H]': 613.93, HP LC tR (A05) = 2.10 min (see step 8) and the bis-Ns protected product as a solid (1.04 g, 35 %), ’l-I NMR CDCfi 500 MHz, δ 8.64 (dd, J = 7.9, 1.5 Hz, IH), 8.62 - 8.58 (m, IH), 7.89 - 7.80 (m, 4H), 7.73 (s, IH), 7.72 - 7.65 (m, 2H), 7.19 (t, J = 7.9 Hz, IH), 6.98 (d, J = 7.4 Hz, IH), 6.81 (d, J = 7.7 Hz, IH), 5.74 (s, IH), 4.31 (dd, J = 9.2, 2.7 Hz, 1 H), 4.19 (dd, J = 9.4,2.2 Hz, IH), 4.17-4.09 (m, 3H), 4.08 - 4.02 (m, 2H), 3.73 (dd, J = 11.0, 9.2 Hz, IH), 3.57 - 3.48 (m, IH); m/z (ES+) [M+Hf :798.64, HPLC tR (A05) = 2.18 min.
Step 8: N-[5-bromo-6-chloro-3-[[(3R)-4-(I,3-dioxolan-2-yl)-2,3-dihydfobenzofuran-3-yl] methoxy]2-pyridyl]-2-nitro-benzenesidfonamiâe
147
PhSH (27,9 pL, 0,263 mmol) and Cs2CO3 (85,7 mg, 0.263 mmol) were added to a solution of3bromo-2-chloro-5-[[(3R)-4-(l,3-dioxoian-2-yl)-2,3-dihydrobenzofuran-3-yl] methoxy]-6-nitro pyridine (210 mg, 0.263 mmol) in MeCN (15.0 mL) at room température. The mixture was stirred at room température for 3 h. The mixture was diluted with sat. aq. NaHCO3 (10 mL) and EtOAc (30 mL). The aqueous phase was extracted with EtOAc (3x30 mL), The combined organic layers were washed with brine (25 mL), dried over MgSO4, fdtered, and concentraied. The residue was purified by silica gel chromatography (12 g, cartridge) elutîng with EtOAc in hexanes (0-70 %) to afford N[5-bromo-6-chloro-3-[[(3R)-4-(l,3-dioxolan-2-yl)-2f3-dihydrobenzofuran-3-yl] methoxy]-2pyridyl]-2-nitro-benzenesulfonamide as a solid (125 mg, 78 %). lH NMR CDC13 500 MHz, δ 8.59 (dd, J = 7.8, 1.1 Hz, 1H), 8.39 (s, 1H), 7,81-7.73 (m, 3H), 7.33 (s, 1H), 7,24 (t, J = 8.0 Hz, 1H), 7.06 (d, J = 7.5 Hz, 1H), 6,89 (d, J = 7.9 Hz, JH), 5.97 (s, 1H), 4.63-4.55 (m, 2H), 4.30 (dd, J = 8.7, 5.1 Hz, 1 H), 4.18 - 4.10 (m, 4H), 4.08-4.05 (m, 1H), 4.00 (t, J = 8.7 Hz, 1H); m/z (ES+) [M+H]’ : 613,56, HPLC tR (B05) = 1.78 min.
Step 9: N-[5-bromo-6-chloro-3-[[(3R)-4-formyl-2,3-dihydrohenzofuran-3-yl] methoxy]-2-pyridyl]2-nitro-benzenesulfonamide
Aqueous HCl (10.5 mL, 10,5 mmol, 1.00 M) was added to a solution ofN-[5-bromo-6-chloro-3[[(3R)-4-(l,3-dioxolan-2-yl)-2,3-dihydrobenzofuran-3-yl] methoxy]-2-pyridyl]-2-nitrobenzenesulfonamide (1.28 g, 2.09 mmol) in THF (25.0 mL) at room température. The mixture was stirred at room température for 18 h. A saturated NaHCO3 solution (8 mL) was added, and the aqueous phase was extracted with EtOAc (3 x 25 mL). The combined organic extracts were washed with brine (15 mL), dried over MgSO4, fdtered, and concentrated to afford N-[5-bromo-6-chloro-3[[(3R)-4-formyl-2,3-dihydrobenzofuran-3-yl] methoxy]-2-pyridyl]-2-nitro-benzenesulfonamide as a solid ( 1.18 g, 99%), which was used as such in next step wîthout purification, m/z (ES+) [Μ+ΗΠ 569.91, HPLC tR (A05) = 2.16 min.
Step 10: N-[5-bromo-6-chloro-3-[[(3R)-4-(hydroxymethyl)-2,3-dihydrobenzofiiran-3-yl] methoxy]2-pyridyl]-2-nitro-henzenestdfonamide
148
NaBH4(0.118 g, 3.13 mmol) was added in portions to a mixture of 3-[(2-amino-5-bromo-6-chloro3-pyridyl) oxymethyl]-2,3-dihydrobenzofuran-4-carbaldehyde (1.19 g, 2.08 mmol) in THF (15.0 mL) and MeOH (3.00 mL) at room température. The mixture was stirred at room température for 2 h. The mixture was diluted with sat. NH4C1 (8.00 mL), water (10.0 mL), and EtOAc (30.0 mL). The aqueous phase was extracted with EtOAc (4 x 25.0 mL). The combined organic layers were washed with brine (30 mL), dried (MgSO4), fïltered, and concentrated. The residue was purified by silica gel chromatography (40 g, cartridge) with EtOAc in Hexanes (0-60 %) to afford N-[5-bromo-6-chloro3-[[(3R)-4-(hydroxymethyI)-2,3-dihydrobenzofuran-3-yl] methoxy]-2-pyridyl]-2-nitrobenzenesulfonamide as a solid (877 mg, 74 %). 'H NMR CDC13 500 MHz, 8 8.60 (d, J = 7.8 Hz, IH), 7.77 (d, J = 7.6 Hz, 1 H), 7.73 (s, 2H), 7.30 (s, IH), 7.22 (t, J = 7.8 Hz, IH), 6.90 (d, J = 7.6 Hz, IH), 6.84 (d, J = 7.9 Hz, IH), 4.82 (dd, J = 27.5, 12.3 Hz, 2H), 4.60 (dd, J = 9.4, 7.5 Hz, IH), 4.56 4.48 (m, IH), 4.23 (t, .1 = 7.1 Hz, IH), 4.09-3.99 (m, 2H); m/z(ES+) [M+H]+: 571.59, HPLC tR (B05) = 1.71 min.
Step 11 : (R)-l0-bromo-9-chloro-7f(2-nitrophenyl)sulfonyl)-6,7,13,13a-tetrahydro-lHbenzofuro[4,3-fg]pyrido[3,2~b] [1,4] oxazonine
A solution of DIAD (0.398 mL, 2.02 mmol) in toluene (40.0 mL) was added drop wîse over 1 h to a stirred solution of N-[5-bromo-6-chIoro-3-[[4-(hydroxymethyl)-2,3-dihydrobenzofiiran-3-yl] methoxy]-2-pyridyl]-2-nitro-benzenesulfonamîde (770 mg, 1.35 mmol) and PPh3 (637 mg, 2.43 mmol) in toluene (300 mL) at room température. The mixture was stirred at room température for 15 h and concentrated under reduced pressure. The residue was purified by silica gel chromatography
149 (80 g, cartridge) with EtOAc in hexanes (0-50 %) to provide (R)-10-bromo-9-chloro-7-((2nitrophenyl)sulfonyl)-6,7,13,13a-tetrahydiO-lH-benzofuro[4,3-fg]pyrido[3,2-b][l,4]oxazonineas a solid (600 mg, 81 %). lH NMR CDC13 500 MHz, δ 8.42-8.35 (m, IH), 7.79-7.73 (m, 3H), 7.42 (s, ÎH), 7.04 (t, J = 7.9 Hz, 1 H), 6.86 (d, J = 7.8 Hz, 1 H), 6.68 (d, J = 7.8 Hz, 1 H), 5.28 (d, J = 13.3 Hz, IH), 5.08 (d, J = 13.3 Hz, IH), 4.69 (dd, J = 10.6, 5.5 Hz, IH), 4.50 (dd, J = 9.6, 8.2 Hz, IH), 4.23 (dd, J = 9.7, 2.0 Hz, IH), 4.07-3.98 (m, IH), 3.90 (t, J= 11.1 Hz, IH); lîC NMR CDC13125MHz, 159.71, 149.69, 148.38, 141.65, 141.11, 134.71, 134.60, 133.89, 133.76, 132.27, 131.64, 130.04, 127.65, 123.87, 122.62, 117.39, 109.80, 78.11, 72.09, 50.99, 40.87; m/z (ES+) [M+H]+: 553.44, HPLC tR (B05) = 2.42 min.
Step 12: (R)-10-hromo-9-chloro-6,7,13,13a-tetrahydro-lH-benzofuro[4,3-fg]pyrido[3,2b] [ 1,4] oxazonine
PhSH (0.0187 mL, 0.176 mmol) and Cs2CO3 (0.115 g, 0.353 mmol) were added to a solution of provide (R)-10-bromo-9-chloiO-7-((2-nitrophenyl)sulfonyl)-6,7,13,13a-tetrahydro-l Hbenzofiiro[4,3-fg]pyrido[3,2-b][ 1,4]oxazonine (65.0 mg, 0.118 mmol) in MeCN (1.00 mL) at room température. The mixture was stirred at room température for 3 h. The mixture was diluted with sat. NaHCOj (10 mL) and EtOAc (10 mL). Water (10 mL) was added. The aqueous phase was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (15 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silîca gel chromatography (12 g, cartridge) eluting with EtOAc in hexanes (0-70%) to afford (R)-10-bromo-9chloro-6,7,13,13a-tetrahydro-lH-benzofuro[4,3-fg]pyrido[3,2-b][ 1,4]oxazonine as a solid (43.0 mg, 99%). ’H NMR CDCh 500 MHz, δ 7.29 (s, IH), 7.14 (t, J = 7.8 Hz, IH), 6.76 (d, J = 7.6 Hz, IH), 6.71 (d, J = 8.0 Hz, IH), 5.35 (t, J = 7.8 Hz, IH),4.70 (dd, J = 15.1, 8.5 Hz, 1 H), 4.54 (t, J = 9.2 Hz, 2H), 4.46 (dd, J = 9.5, 3.9 Hz, IH), 4.17 (dd, J = 9.6, 3.2 Hz, IH), 3.95 (ddd, J = 12.5, 8.4, 3.7 Hz, IH), 3.90 - 3.79 (m, IH). m/z (ES+) [M+H]+:368.97; HPLC tR (B05) = 2.73 min.
Step 13:
150
Boc anhydride (4.05 mL, 17.6 mmol) was added to a solution of (R)-10-bromo-9-chloro-6,7,13,13atetrahydro-lH-benzofuro[4,3-fg]pyrido[3,2-b][l,4]oxazonine (1.08 g, 2.94 mmol), TEA (1.23 mL, 8.82 mmol), and DMAP (90.0 mg, 0.735 mmol) in THF (50.0 mL). The mixture was stirred at 50 C for 8 h. Water (40 mL) was added, and the aqueous phase was extracted with EtOAc (3 x 75 mL). The combinée! organic layers were washed with brine (30 mL), dried over MgSO4, filtered, and concentrated under reduc ed pressure. The residue was purified b y sîlica gel chromatography (40 g cartridge) eluting with EtOAc in hexanes (30-80 %) to provide tert-butyl (R)-10-bromo-9-chloro13,13a-dihydro-lH-benzofuro[4,3-fg]pyrido[3,2-b][l,4]oxazonine-7(6H)-carboxylate as a solid (1.37 g, 99%). ‘H NMR CDCl3400 MHz, δ 7.52 (s, 1H), 7.06 (t, J = 7.8 Hz, 1H), 6.78 (d, J = 7.6 Hz, 1H), 6.68 (d, J = 7.8 Hz, 1H), 4.92 (d, J = 14.6 Hz, 1H), 4.74 (d, J = 14.5 Hz, 1H), 4.42-4.33 (m, 2H), 4.15 (dd, J = 9.5, 2.0 Hz, IH), 4.01 (t, J = 11.3 Hz, 1H), 3.81-3.72 (m, 1H), 1.35 (s, 9H). m/z (ES+) [M-Boc] : 367.6; HPLC îr (B05) = 2.87 min.
Step 14: tert-butyl (R)-10-bromo-9-hydrazineyl-13,13a-dihydro-lH-benzofuro[4,3-fg]pyrido[3,2b] [1,4] oxazonine-7(6H)-carboxylate
Hydrazine monohydrate (0.519 mL, 10.7 mmol) was added to a solution of tert-butyl (R)-10-bromo9-chloro-13,13a-dihydro- IH-benzofuro[4,3-fg]pyrîdo[3,2-b][ l ,4]oxazonine-7(6H)-carboxylate (0.200 g, 0.428 mmol) in EtOH (10.0 mL). The mixture was heated to 100 °C for 72 h. After cooling to room température, the mixture was concentrated under reduced pressure, and the residue was purified by silîca gel chromatography (24 g cartridge) with MeOH in DCM (0-10%) to afford tertbutyl (R)-10-bromo-9-hydrazineyl-13,13a-dihydro-lH-benzofuro[4,3-fg]pyrido[3,2b][ 1,4] oxazonine-7(6H)-carboxyIate as a solid (178 mg, 90%). m/z (ES+) [M]+: 463.77, HPLC îr (B05) = 2.59 min.
Step 15: tert-butyl (S)-4-bromo- 7a, 13-dihydro-7H-[1,2,4]triazolo[4 , 3 6]pyrido[3,2b]benzofuro[4,3-fg] [1,4] oxazonine-14(8H)-carboxylate
151
A mixture of tert-butyl (R)-10-bromo-9-hydrazineyl-13,13a-dihydiO-lH-benzofuro[4,3fg]pyrido[3,2-b][l,4]oxazonine-7(6H)-carboxylate (330 mg, 0.712 mmol), triethyl orthoformate (21.3 mL, 128 mmol), and TFA (2.70 uL, 0.0356 mmol) was heated to 100 °C for I h. After cooling to room température, the mixture was concentrated, and the residue was purified by silica gel chromatography (24 g) with MeOH in DCM (0-10%) to afford tert-butyl (S)-4-bromo-7a,13dihydiO-7H-[l,2,4Jtriazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)carboxylate as a solid (315 mg, 93%). m/z (ES+) [M]T 473.74; HPLC tR (B05) = 2.51 min.
Step 16: (S)-4-bromo-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4!,3':l,6]pyrido[3,2b] benzofuro]4,3-fg] [ 1,4] oxazonine
A solution of tert-butyl tert-butyl (S)-4-bromo-7a,13-dihydro-7H[ l,2,4]triazolo[4',3': l,6]pyrido[3,2-b]benzofuiO[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (0.110 g, 0.232 mmol) in HFIP (5.00 mL) was heated to 100 °C in an oil bath for 3 h. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography ( 12 g) with MeOH in DCM (0-20%) to afford (S)-4-bromo-7a,8,13,14-tetrahydro-7H[ EZjdjtriazolofd'jS'iLôjpyridofS^-bjbenzofurofdjS-fgjfl^joxazonine as a solid (44,0 mg, 51%). ’H NMR CD3OD 400 MHz, δ 9.24 (s, J = 15.5 Hz, 1H),7.61 (s, 1H), 7.07 (t, J = 7.8 Hz, 1H), 6.81 (d, J = 7.5 Hz, 1H), 6.61 (d, J = 7.9 Hz, 1H), 4.48 (t, J = 9.4 Hz, 1H), 4.42 (dd, J = 10.4, 4.4 Hz, 1H), 4.16 (dd. J = 9.6, 3.6 Hz, 1H), 4.01 - 3.91 (m, J = 13.1, 8.4, 4.0 Hz, 1H), 3.86- 3.77 (m, IH), 2.24 (t, J = 7.4 Hz, 1H), 1.33 - 1.27 (m, 1H). m/z (ES+) [M]+: 373.80; HPLC tR (B05) = 2.35 min.
Step 17: (S)-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[ 1,2,4] triazolo[4!,3' : 1,6]pyrido[3,2b]henzofuro[4,3-fg] [1,4] oxazonine
152
Dioxane (3.00 mL) and water (0.600 mL) were sequentially added to a mixture of (S)-4-bromo7 a, 8,13,14-tetrahydro-7H-[ 1,2,4]triazolo[4',3': 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4]oxazonîne (44.0 mg, 0.118 mmol), 2-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaboiOlan-2-yl)pyridine (31.0 mg, 0.141 mmol), Pd(dppf)Cl2 (8.63 mg, 0.0118 mmol), andNaHCO3 (49.5 mg, 0.589 mmol) underN2. The mixture was heated to 90 °C for 2 h. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (12 g cartridge) eluting with MeOH in DCM (0-30%) and further purified by HPLC (BEH 30x100mm ACN/AmForm 31-51%) to afford (S)-4(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4',3': l,6]pyrido[3,2b]benzofuiO[4,3-fg][l,4]oxazonine as a solid (30.0 mg, 66%). N MR DMSO 400 MHz, δ 9.38 (s, 1H), 8.47 (dd, J = 4.8, 1.7 Hz, 1H), 7.76 (dd, J = 7.7, 1.7 Hz, 1H), 7.52 (t, J = 6.5 Hz, 1H), 7.31 (s, 1 H), 7.29 (dd, J = 7.7, 4.9 Hz, 1H), 7.13 (t, J = 7.8 Hz, 1H), 6.91 (d, J = 7.5 Hz, 1H), 6.68 (d, J = 7.8 Hz, 1H), 4.87 - 4.74 (m, 2H), 4.51 (t, J = 9.5 Hz, 1H), 4.47 - 4.39 (m, 1H), 4.16 (dd, J = 9.6, 3.8 Hz, 1H), 4.07 -3.96 (m, 1H), 3.83 (t, J = 11.4 Hz, 1H), 2.36 (s, 3H). m/z (ES+) [M+H]+: 386.91; HPLC tR (B05) = 2.30 min.
Example 21: (S)-l-(4-(7a,8,13,14-tetrahydro-7H-[l,2,4]trÎazo]o[4',3':l,6]pyrido[3,2b]benzofuro[4,3-fg][l,4]oxazonin-4-yl)piperidin-l-yl)ethan-l-one
Step 1: (S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4>,3’: 1,6]pyrido[3,2b] benzofuro]4,3-fg] [ 1,4] oxazonine (S)-4-bromo-l 2-fluoro-7a,8,13,14-tetrahydro-7H-[ l,2,4]triazolo[4',3’: 1,6]pyrido[3,2b]benzofuro[4,3-fg][I,4]oxazonine was synthesized according to Example 20, step 15. Step 2: tert-butyl (S)-4-(l-acetyl-l,2,3,6-tetrahydropyridin-4-yl)-7a,13-dihydro-7H[1,2,4] triazolo[4',3' : 1,6]pyrido[3,2-b] benzofuro]4,3-fg][1,4] oxazonine-14(8H)-carboxylate
153
Dioxane (2.00 mL), water (0.400 mL), and NaHCO3 (Ü.634 mmol, 53.2 mg) were added to a mixture of tert-butyl (S)-4-(Lacetyl-l ,2,3,6-tetrahydropyridin-4-yl)-7a,13-dihydro-7H[1,2,4]triazolo[4,,3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][i,4]oxazonine-l4(8H)-carboxylate (0.127 mmol, 60.0 mg), 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-l5 yl]ethanone (0.133 mmol, 33.3 mg), and Pd(dppf)Cl2 (0.0127 mmol, 9.28 mg) under N2. The mixture was heated to 100 °C for 2 h. After cooling to room température, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (12 g cartridge) eluting with MeOH in DCM (0-30 %) to tert-butyl (S)-4-(l-acetyl-l,2,3,6tetrahydropyridin-4-yl)-7a, 13-dihydro-7H-[ 1,2,4]triazolo[4’,3': l,6]pyrido[3,2-b]benzofuiO[4,310 fg][l,4]oxazonine-14(8H)-carboxylate as a solid (63.0 mg, 96%). m/z (ES+) [M+H]C 518.8; HPLC îr (B05) = 2.42 min.
Step 3: tert-butyl (S)-4-(I-acetylpiperidin-4-yl)-7a,13-dihydro-7H[1,2,4] triazolo[4’,3 ':1,6]pyrido[3,2-b]benzo/ùro[4,3-fg] [ 1,4] oxazonine-14(8H)-carboxylate
MeOH (10.00 mL) was added to a mixture of tert-butyl (S)-4-(l-acetyl-l,2,3,6-tetrahydropyridin-4yl)-7a, 13-dihydro-7H-[ 1,2,4]triazolo[4',3': 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4]oxazonine14(8H)-carboxylate(0.122 mmol, 63.0 mg) and Pd/C (10.0 %, , 24.3 pmol, 25.9 mg) at room température. The reaction vessel was evacuated and purged with H2. The solution was stirred at rt for 12 h. The mixture was filtered over Celîte, and the Celite pad was washed with DCM (3X15 mL). The filtrate was concentrated under reduced pressure. The residue was used as such in the next step without further purification (63 mg, quant.), m/z (ES+) [M+H]+: 520.97. HPLC îr (B05) = 2.36 min.
Step 4: (S)-l-(4-(7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4',3!: 1,6]pyrido[3,2-b]benzofuro[4,3fg] [1,4]oxazomn-4-yl)piperidm-l-yl)ethan-l-one
154
A solution of tert-butyl (S)-4-(l-acetylpiperidin-4-yl)-7a,13-dihydro-7H[ l,2,4]triazolo[4',3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (0.121 mmol, 63.0 mg) in HFIP (2.00 mL) was heated to 100°C for 3 h. The mixture was concentrated under reduced pressure, and the residue was purified by HPLC (BEH 30x 100mm ACN/AmBicarb, 27-47%) to afford (S)-l-(4-(7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4',3':l,6]pyiido[3,2b]benzofuro[4,3-fg][l,4]oxazonin~4-yl)piperidin-l-yl)ethan-l-oneas a solid (32.0 mg, 63 %). 'H NMR DMSO 500 MHz, δ 9.29 (s, 1H), 7.18 (t, J = 6.7 Hz, 1H), 7.08 (t, J = 7.8 Hz, 1H), 7.06 (s, 1H), 6.86 (d, J = 7.6 Hz, 1H), 6.64 (d, J = 7.8 Hz, 1H), 4.75 (dd, J = 14.7, 6.4 Hz, 1H), 4.69-4.59 (m, 1H), 4.57-4.50 (m, l H), 4.48 (t, J = 9.4 Hz, 1H), 4.45 - 4.38 (m, 1H), 4.16 (dd, J = 9.6, 3.5 Hz, 1H), 4.00- 3.87 (m, 2H), 3.74 (td, J = 11.7, 3.7 Hz, 1H), 3.25 - 3.10 (m, 2H), 2.66-2.56 (m, 1H), 2.02 (d, J = 3.8 Hz, 3H), 1.97- 1.82 (m, 2H), 1.82 - 1.67 (m, IH), 1.67 -1.53 (m, lH).m/z(ES+) [M+H] 4 420.8; HPLC tR (B05) = 2.22 min.
Example 22: 12-fluoro-4-(2-mcthylpyridin-3-yl)-7,8,13,14-tetraliydro[l,2,4]triazolol4’,3,:l,6jpyrido[3,2-b]beiizo[f|[l,4]oxazomne hydrochloride hydrochloride
Step 1: methyl 2-bromo-6-fluoro-benzoate
2-Bromo-6-fluorobenzoic acid (12.5 g, 57.1 mmol) was dissolved in a mixture of MeOH (60.0 mL) and concentrated sulfuric acid (60.0 mL). The solution was heated to 80 °C for 12 h. The mixture was slowly added to solution of aq. sodium carbonate solution (20%, 500 mL) at 0 °C. The aqueous phase was extracted with DCM (3 x 175 mL), and the combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure to provide methyl 2-bromo-6-fluoro-benzoate as an oil (7.06 g, 53%). 'H NMR CDCfi 500 MHz, δ 7.40 (dt, J = 8.1, 0.8 Hz, 1H), 7.27 (dd, J = 14.1, 8.3 Hz, 1H), 7.09 (td, J = 8.6, LO Hz, 1H), 3.97 (s, 3H).
Step 2: methyl 2~allyl-6-fluoro-benzoate
155
Dioxane (50.0 mL) and water (12.5 mL) were sequentially added to a mixture of methyl 2-bromo-6fluoro-benzoate (5.00 g, 21.5 mmol), K2CO3 (9.00 g, 65.1 mmol), and Pd(dppf)Cl2 (1.50 g, 2.05 mmol) under nitrogen. 2-Allyl-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (6.04 mL, 32.2 mmol) was added, and the mixture was heated to 90 °C for 24 h. The mixture was diluted with DCM (150 mL), filtered (Celite), and the filtrated was concentrated under reduced pressure. The residue was purified by silîca gel chromatography (40 g, cartridge) with a gradient of EtOAc in hexanes (0-100%) to afford methyl 2-allyl-6-fluoro-benzoate as an oîl (2.12 g, 51%). !H NMR CDC13 500 MHz, δ 7.40 — 7.32 (ni, 1H), 7.06 (d, J = 7.7 Hz, 1H), 7.00 (t, J = 8.9 Hz, 1H), 5.93 (ddt, J = 16.8, 10.1, 6.6 Hz, 1H), 5.08 (tq, J = 17.2, 1.6 Hz, 2H), 3.94 (s, 3H), 3.51 (d, J = 6.6 Hz, 2H).
Step 3: (2-AUyl-6-fluoro-phenyl) methanol
DIBAL-H (30.0 mL, 30.0 mmol) was added to a solution of methyl 2-alIyl-6-fluoro-benzoate (2.10 g, 10.8 mmol) in THF (40.0 mL) at 0 °C. The mixture was stirred at room température for 14 h. Water (1.60 mL) was added drop wise at 0 °C, followed by NaOH (1.60 mL, 1.00 M) and additional water (1.60 mL). The mixture was stirred at room température for 1 h and filtered through Celite, washing with Et2O ( 150 mL). The filtrate was concentrated under reduced pressure, and the residue was used as such without further purification (1.79 g, > 99%). ‘H NMR CDC13 500 MHz, δ 7.23 (td, J = 8.0, 5.9 Hz, 1H), 7.00 (d, J = 7.6 Hz, 1H), 6.96 (t, J = 9.0 Hz, 1H), 6.02 (ddt, J = 16.3, 10.1, 6.2 Hz, 1H), 5.10 (dq, J = 10.1, 1.6 Hz, 1H), 5.01 (dq, J = 17.1, 1.7 Hz, 1H), 4.76 (dd, J = 6.3, 1.8 Hz, 2H), 3.55 (dt, J = 6.2, L5 Hz, 2H).
Step 4: (2-Allyl-6-jluoro-phenyl) methoxy-triisopropyl-silane
156
TIPS-C1 (3.52 mL, 16.4 mmol) was added to a solution of (2-allyl-6-fluoro-phenyl) methanol (2.10 g, 12.6 mmol), imîdazole (2.58 g, 37.9 mmol), and DMAP (30.0 mg, 0.246 mmol) in DCM (36.0 mL) at rt under nitrogen. The mixture was stirred at rt for 18. The solution was diluted with water (125 mL), and the aqueous phase was extracted with Et2O (125 mL) and hexanes (2x50.0 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (40 g, cartridge) with a gradient of EtOAc in hexanes (0-100%) to afford (2-Allyl-6-fluoro-phenyl) methoxy-triisopropyl-silane as an oil (3.97 g, 97%). ‘H NMR CDC13 400 MHz, δ 7.19 - 7.13 (m, 1H), 6.96 (d, J = 7.6 Hz, 1H), 6.87 (t, J = 9.0 Hz, 1H), 5.97 (ddt, J = 16.6, 10.1, 6.4 Hz, 1H), 5.01 (tq, J = 17.0, 1.7 Hz, 2H), 4.81 (d, J = 2.0 Hz, 2H), 3.57 (dt, J = 6.4, L4 Hz, 2Hj, 1.20- 1.07 (m, 3H), 1.06- 1.00 (m, 18H).
Step 5: 2-[3-Fluoro-2-(triisopropylsilyloxymethyl) phenyl] acetaldehyde
Ο
NaIO4 (10.5 g, 49.2 mmol) was added to a stirred solution of OsO4 (4.00 %, 0.500 mL, 0.0787 mmol) and (2-allyL6-lluoro-phenyl) methoxy-triisopropyl-silane (3.97 g, 12.3 mmol) in a mixture of 1,4-dioxane (50.0 mL) and water (16.0 mL) under N2. The mixture was stirred at rt for 12 h. Sat. aq. Na2SO3 (100 mL) was added, and the aqueous phase was extracted with EtOAc (3 x 100 mL). The combined organic phases were washed with sat. aq. NaHCO3 (100 mL), dried over MgSO4, fïltered, and concentrated under reduced pressure. The residue was used as such without further purification. 'HNMR CDC13 500 MHz, δ 9.74 (t, J = 1.9 Hz, 1H), 7.30-7.20 (m, 1H), 7.03-6.96 (m, 2H), 4.84 (d, J = 1.9 Hz, 2H), 3.90 (d, J = 1.9 Hz, 2H), 1.17- LH (m, 3H), 1.05 (s, 18H).
Step 6: 2fi3-Fluoro-2-(triisopropylsilyloxymethyl) phenyl] éthanol
Η
NaBH4 (700 mg, 18.5 mmol) was added to a solution of 2-[3-fluoro-2-(triisopropylsilyloxymethyl) phenyl] acetaldehyde (3.98 g, 12.3 mmol) in THF (60.0 mL) and MeOH (20.0 mL) at 0 °C. The
157 mixture was warmed to room température and stirred for 1 h. The mixture was diluted with sat. NH4CI (10 niL), water (100 mL), and EtOAc (200 mL). The mixture was stirred at room température for 30min. The aqueous phase was extracted with EtOAc (2x200 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (24 g, cartridge) with a gradient of EtOAc in hexanes (0-40%) to afford 2-[3-Fluoro-2-(triisopropylsilyloxymethyl) phenyl] éthanol as an oil (2.44 g, 61% over 2 steps). 'H NMR CDC13 500 MHz, δ 7.30 - 7.24 (m, 1H), 7.08 (d, J = 7.6 Hz, 1H), 6.96 (ddd, J = 9.5, 8.3, 1.1 Hz, 1H), 4.89 (d, .1 = 2.1 Hz, 2H), 3.92 (t, J = 6.2 Hz, 2H), 3.06 (t, J = 6.2 Hz, 2H), 1.27-1.18 (m, 3H), 1.12 (dd, J = 7.1, 1.9 Hz, 18H).
Step 7: [2-[2-[(5-Bromo-6-chloro-2-nitro-3-pyridyl) oxy] ethyl] -3-fluoro-phenyl] methoxytri isopropyl-silane
D1AD (1.00 mL, 5.08 mmol) was added drop wise to a solution of 2-[3-fluoro-2(triisopropylsilyloxymethyl) phenyl] éthanol (1.20 g, 3.68 mmol), 5-bromo-6-chforo-2-nitro-pyridin3-ol (1.02 g, 4.04 mmol), and triphenylphosphine (1.45 g, 5.51 mmol) in toluene (39.0 mL) at room température. The mixture was stirred at room température for 48 h. The mixture was concentrated under reduced pressure, and the residue was purified twice by silica gel chromatography with a gradient of MeOH in DCM (0-5%, 80 g, cartridge) and a gradient of ether in hexanes (0-10%, 40 g, cartridge) to afford [2-[2-[(5-Bromo-6-chloro-2-nitro-3-pyridyl) oxy] ethyl]-3-fluoro-phenyl] methoxy-triisopropyl-silaiie as an oil (480 mg, 23%). *H NMR CDC13 500 MHz, δ 7.64 (s, 1 H), 7.25 -7.19 (m, 1H), 7.06 (d, J = 7.4 Hz, 1H), 6.96 (t, J = 9.0 Hz, 1H), 4.88 (d, J = 2.0 Hz, 2H), 4.42 (t, J = 6.6 Hz, 2H), 3.31 (t, J = 6.6 Hz, 2H), 1.20- 1.12 (m, 3H), 1.09- 1.04 (m, 18H).
Step 8: 5-Bromo-6-chloro-3-[2-[2-fluoro-6-(triisopropylsilyloxymethyl) phenyl] ethoxy] pyridin-2amine
158
Fe (1.00 g, 17.9 mmol) was added to a solution of [2-[2-[(5-bromo-6-chloro-2-nitro-3-pyridyl) oxy] ethyl]-3-fluoro-phenyl] methoxy-triisopropyl-silane (1.09 g, 1.94 mmol) in HOAc (18.0 mL) at 0 °C. The mixture was slowly warmed to room température and stirred for 2 h. The mixture was fïltered through a pad of Celite. The Celite was washed with EtOAc (3X100 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (12 g, cartridge) with a gradient of EtOAc in Hexanes (0-100%) to afford 5-Bromo-6-chloro-3-[2-[2fluoiO-6-(triisopropylsilyloxymethyl) phenyl] ethoxy] pyridin-2-amine as an oil (978 mg, 95%). ’H NMR CDClj 500 MHz, S 7.26 - 7.20 (m, IH), 7.04 (d, J = 7.2 Hz, IH), 7.02 (s, IH), 6.96 (ddd, J = 9.5, 8.3, 1.0 Hz, LH), 4.88 (d, J = 2.0 Hz, 2H), 4.72 (s, 2H), 4.25 (t, .1 = 7.0 Hz, 2H), 3.30 (t, J = 7.0 Hz, 2H), 1.19- LU (m, 3H), 1.09-0.97 (m, 18H). m/z (ES+) [M-OTIPS]+: 359.05; HPLC tR (A05) = 3.07 min.
Step 9: [2-[2-[(2ximino-5-bromo-6-chloro-3-pyridyl) oxy] ethyl]-3-fiuoro-phenyl] methanol
TB AF (1.04 mL, 1.04 mmol) was added to a stirred solution of 5-bromo-6-chloro-3-[2-[2-fluoro-6(triisopropylsilyloxymethyl) phenyl] ethoxy] pyridin-2-amine (0.158 g, 0.297 mmol) in THF (2.00 mL) at room température. The mixture was stirred at room température for 2 h and concentrated under reduced pressure. The residue was purified by silica gel chromatography (12 g, cartridge) with MeOH in DCM (0-20%) to afford (2-[2-[(2-amino-5-bromo-6-chloro-3-pyridyl) oxy] ethyl]-3fluoro-phenyl] methanol (0.105 mg, 94%) as a solid. 'H NMR CDjOD 400 MHz, δ 7.31 - 7.24 (m, IH), 7.23 (s, IH), 7.17 (d, J = 7.1 Hz, IH), 6.99 (ddd, J = 9.6, 8.2, 1.1 Hz, IH), 4.76 (d, J = 2.0 Hz, 2H), 4.27 (t, J = 6.7 Hz, 2H), 3.30 - 3.26 (m, 2H). m/z (ES+) [M+H]h: 377.0; HPLC tR (A05) = 2.46 min.
Step 10: 5-Bromo-6-chloro-3-[2~[2-(chloromethyl)~6-fluoro-phenyl] ethoxy]pyridin-2-amine; hydrochloride
159
SOCi2 (0.250 mL, 3.43 mmol) was added to a stirred solution of [2-[2-[(2-amino-5-bromo-6-chloro3-pyridyl) oxy] ethyl]-3-fluoro-phenyl] methanol (0.670 g, 1.78 mmol) in THF (15.0 mL) at room température. The mixture was stirred at room température for 4 h. The mixture was concentrated under reduced pressure, and the residue was used as such in the next step without further purification (636 mg, 83%). !H NMR CD3OD 400 MHz, δ 7.34 - 7.28 (m, 2H), 7.18 (d, J = 7.6 Hz, 1H), 7.01 (ddd, J = 9.5, 8.4, 1.0 Hz, 1H), 4.79 (d, J = 1.6 Hz, 1H), 4.31 (t, J = 6.8 Hz, 1H), 3.29 3.27 (m, 2H). m/z (ES+) [M+H]: 395.09; HPLC tR (A05) = 2.66 min.
Step 11: 3-Bromo-2-chloro-l l-Jluoro-6,7,12,13-tetrahydropyrldo[2,3-c] [5,2] benzoxazonine
CS2CO3 (1.59 g, 0.153 mmol) and TBAI (0.636 g, 1.72 mmol) were added to a solution of5-bromo6-chloro-3-[2-[2-(chloromethyl)-6-fluoro-phenyl] ethoxy] pyrîdin-2-amine (636 mg, 1.61 mmol) in DMF (400 mL) at room température under nitrogen. The mixture was heated to 70 °C for 5 h. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (12 g, cartridge) with MeOH in DCM (0-20%) to afford 3-bromo-2-chloro-l 1fluoro-6,7,12,13-tetrahydropyrido[2,3-c] [5,2] benzoxazonine as a solid (307 mg, 53%). ’H NMR CDC13 500 MHz, Ô 7.59 (s, 1H), 7.19 (td, J = 8.0, 5.9 Hz, 1H), 7.10 - 6.95 (m, 3H), 4.58 (s, 2H), 4.33 (s, 2H), 3.01 (s, 2H). m/z (ES+) [M+H]+: 359.0; HPLC tR (B05) = 2.61 min.
Step 12: Tert-butyl 3~bromo-2-chloro-l l-fluoro-7,12-dihydro-6H-pyrido[2,3-c] [5,2] benzoxazonine-13-carboxylate
160
Boc2O (3.85 mL, 16.8 mmol) was added to a mixture of tert-butyl 3-bromo-2-chloro-l l-fluoro-7,12dihydro-6H-pyrido[2,3-c][5,2]benzoxazonine-l 3-carboxylate (300 mg, 0.839 mmol), Et3N (2.92 mL, 21.0 mol), and DMAP (0.0102 g, 0.0839 mmol) in THF (20.0 mL), and the mixture was stirred at room température for 12 h. DMAP (200 mg, 1.64 mmol) was added, and the mixture was stirred for 72 h. The mixture was concentrât ed under reduced pressure, and the residue was purified b y silica gel chromatography (40 g, cartridge) with EtOAc and hexane (0-100%) to afford tert-butyl 3bromo-2-chloro-1 l-fluoro-7,12-dihydro-6H-pyrido[2,3-c] [5,2] benzoxazomne-13-carboxylate as a solid (293 mg, 76 %). 'H NMR CDC13 500 MHz, δ 7.49 (s, 1H), 7.13 (td, J = 7.9, 5.6 Hz, 1H), 6.91 - 6.78 (m, 2H), 4.99 (s, 2H), 4.37 (s, 2H), 2.92 (s, 2H), 1.40 (s, 9H). m/z (ES+) [M-tBu]+: 403.02; HPLC tR (A05) = 2.70 min.
Step 13: Tert-butyl 3-bromo-ll-fluoro~2-hydrazino-7J2-dihydro-6Hpyrido[2,3-c] [5,2] benzoxazonine-13-carboxylate
H Br
Hydrazine monohydrate (0.776 mL, 0.0160 mmol) was added to a solution of tert-butyl 3-bromo-2chloro-1 l-fluoro-7,12-dihydiO-6H--pyrido [2,3-c] [5,2] benzoxazonine-13-carboxylate (293 mg, 0.64 mmol) in EtOH (15.0 mL). The mixture was stirred at 105 °C for 36 h. The mixture was concentrât ed under reduced pressure, and the residue was purified by silica gel chromatography (24 g, cartridge) with MeOH in DCM (0-15%) to afford tert-butyl 3-bromo-I l-fluoro-2-hydrazino-7,12dihydro-6H pyrido[2,3-c] [5,2] benzoxazonine-13-carboxylate as a solid (232 mg, 80 %). m/z (ES+) [M+2H-'Bu]1: 399.02; HPLC tR (A05) = 2.39 min.
161
Step 14: tert-butyl 4-bromo-l 2-fiuoro-8,13-dihydro-[l ,2,4] triazolo[4',3’: 1,6]pyrido[3,2b] benzo[fj[1,4] oxazonine-14 (7 H)-carboxylate
TFA (1.90 pL, 0.0256 mmol) was added to a solution of tert-butyl 3-bromo-l l-fluoro-2-hydrazino7,12-dihydro-6H-pyrido[2,3-c] [5,2] benzoxazonine-13-carboxylate (232 mg, 0.512 mmol) in triethyl orthofoimate (15.0 mL, 90.2 mmol). The mixture was heated to 100 °C for I h. The mixture was concentrated under reduced pressure, and the residue was puriiîed by silica gel chromatography (24 g, cartridge) with MeOH in DCM (0-30%) to afford tert-butyl 4-bromo-12-fluoro-8,13-dihydro[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzo[f][l,4]oxazonme-I4(7H)-carboxyIateas a solid (218 mg, 92%). 'H NMR (500 MHz, CDC13) S 8.72 (s, 1H), 7.27 (s, 1H), 7.10 (dd, J = 13.9, 7.8 Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H), 6.68 (t, J = 8.7 Hz, 1H), 4.91 (d, J= 11.6 Hz, 1H),4.72 (dt, J = 11.8, 3.2 Hz, 1 H), 4.08 (t,J= 11.6 Hz, 1 H), 3.47 (t, J = 13.2 Hz, 1 H), 2.75 (d, J = 14.7 Hz, 1H), 1.69 (s, 1H), 1.46 - 1.30 (m, 9H). 111+ (ES+) [M-fBu+2H]+: 409.01; HPLC tR (A05) = 2.37 min.
Step 15: tert-butyl 12-fluoro-4-(2-methylpyridin-3-yl)-8,13-dihydro[1,2,4] triazolo[4 3 6]pyrido[3,2-b]benzo[j] [1,4] oxazonine-14(7H)-carboxylate
Dioxane (1.70 mL) and water (0.300 mL) were sequentially added to a mixture of tert-butyl 4bronio-12-fluoro-8,13-dihydro-[I,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzo[f][l,4]oxazonine14(7H)-carboxylate (50.0 mg, 0.108 mmol), 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl) pyridine (28.4 mg, 0.130 mmol), Pd(dppf)C12 (13.0 mg, 0.0178 mmol), andNaHCOs (50.0 mg, 0.595 mmol) under N2. The mixture was heated to 90 °C for 3 h. The mixture was diluted with
162
DCM (10 mL) and filtered though Celite. The filtrate was conccntrated under reduced pressure, and the residue was purified by siiica gel chromatography (12 g, cartridge) eluting with MeOH in DCM (0-30 %) to afford tert-butyl 12-Îluoro-4-(2-methylpyridin-3-yl)-8,13-dihydro[ l,2,4]triazolo[4',3': l,6]pyrido[3,2-b]benzo[f][l,4]oxazonine-14(7H)-carboxylateas a solid (51.3 mg, > 99%). m/z (ES+) [M-'Bu+2H]4:420.14, HPLC tR (A05) = 2.29 min.
Step 16: 12filiioro-4-(2-methylpyridin-3-yl)-7,8,13,14-tetmhydro[ 1,2,4]triazolo[4',3': 1,6]pyrido[3,2-b]benzo[f][ 1,4]oxazonine hydrochloride
A solution of tert-butyl tert-butyl 12-fluoro-4-(2-methylpyridin-3-yl)-8,13-dihydiO[ I,2,4]triazoJo[4',3’: 1,6]pyrido[3,2-b]benzo[f][ l,4]oxazonine-14(7H)-carboxylate (25.8 mg, 0.0543 mmol) în HFIP (2.50 mL) was heated at 100 °C in an oil bath for 6 h. The mixture was concentrated under reduced pressure, and the residue was purified by préparative HPLC (Gemini C18 30x100mm AmBicarb/ACN 30-50%) to afford the free form of 12-fiuoro-4-(2-methylpyridin-3-yl)-7,8,13,14tetrahydro-[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzo[f][l,4]oxazonine hydrochloride as a solid (16.2 mg, 80%). ’H NMR (500 MHz, MeOD) δ 9.31 (s, IH), 8.44 (dd, J = 5.0, 1.7 Hz, IH), 7.73 (dd, J = 7.7, 1.7 Hz, 1H), 7.33 (dd, J = 7.9, 4.8 Hz, 1H), 7.29 (s, 1H), 7.17 (td, J = 7.9, 5.9 Hz, 1H), 7.00 (d, J = 7.7 Hz, 1H), 6.95 - 6.90 (m, 1H), 5.01 (s, 2H), 4.41 (s, 2H), 3.13 (s, 2H), 2.32 (s, 3H). m/z (ES+)[M+H]+: 376.1, HPLC tR (B05)= 1.21 min.
HCl (0.0535 mmol, 13.4 pL, 4.0 M in 1, 4-dîoxane) was added drop wise to a solution of 12-fluoro4-(2-methylpyridin-3-yl )-7,8,13,14-te trahydro-[l, 2,4] triazoio[4',3': 1,6] pyrido[3,2b]benzo[fj[l,4]oxazonine (16.2 mg, 0.0432 mmol) in DCM/MeOH (3.00 mL/0.300 mL). The mixture was stirred at room température for 1 h. The mixture was concentrated under reduced pressure to afford I2-fluoro-4-(2-methylpyridin-3-yl)-7,8,13,14-tetrahydro[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzo[f][l,4]oxazonine hydrochloride as a solid (23.3 mg, 74%). 'H NMR MeOD 500 MHz, δ 9.34 (s, 1H), 8.53 (dd, J = 5.0, 1.2 Hz, IH), 7.96 (dd, J = 7.8, 1.2 Hz, IH), 7.51 (dd, J = 7.7, 5.3 Hz, IH), 7.39 (s, IH), 7.18 (td, J - 7.9, 5.9 Hz, IH), 7.01 (d, J = 7.7 Hz, IH), 6.98 -6.90 (m, IH), 5.03 (s, 2H), 4.42 (s, 2H), 3.14 (s, 2H), 2.40 (s, 3H). ES+ [M+H]+: 376.1, HPLC tR (B05) = 1.21 min.
163
Example 23: l-(4-(J2-fluoro-7,8,13,14-tetrahydro-[l,2,4]triazolo(4',3’:l,6]pyrido|3,2b]benzo[f][l,4|oxazonin-4-yl)piperidin-l-yl)ethan-l-one bismesylate
Step i: tert-butyl 4-(l-acetyl-l,2,3,6-tetrahydropyridin-4-yl)-12-fluoro-8,13-dihydro[l,2A]triazolo[4',3':l,6]pyrido[3,2-b]benzo[f] [ 1,4] oxazomne-14(7H)-carboxylate
O
1, 4-Dîoxane (1.80 mL) and water (0.350 mL) were sequentially added to a mixture of tert-butyl 4biOmo-12-fluoro-8,] 3-dihydro-[ l,2,4]triazolo[4’,3’: l,6]pyrido[3,2-b]benzo[f][l,4]oxazonine~ 14(7H)-carboxylate (from Example 22; 50.0 mg, 0.108 mmol), l-[4-(4,4,5,5-tetramethyl-l,3,2dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-l-yl] ethanone (28.4 mg, 0.113 mmol), Pd(dppf)Cl2 (11.8 mg, 0.0162 mmol), and NaHCO3 (30.0 mg, 0.357 mmol) under N2. The mixture was stirred at °C for 2.5 h. The mixture was fdtered though a short silica pad, washing with DCM (3x5 mL).
The fdtrate was concentrated under reduced pressure, and the residue was purified by silica gel chroniatography (12.0 g cartridge) eluting with MeOH in DCM (0-30 %) to provide tert-butyl 4-(lacetyl-1,2,3,6-tetrahydropyridin-4-yl)- 12-fluoro-8,13-dihydro-[ 1,2,4]triazolo[4',3': 1,6]pyrido[3,215 b]benzo[f][l,4]oxazonine-14(7H)-carboxylateas a solid (66.1 mg, 97%, 80% purîty). m/z (ES+) [MtBu +2Hf: 552.2; HPLC tR (B05) = 2.28 min.
Step 2: tert-butyl 4-(l-acetylpiperidin-4-yl)-l 2-fluoro-8,l 3-dihydro[ 1,2,4]triazolo[4 3 !:1,6]pyrido[3,2-b] benzo[f] [ 1,4] oxazonine-14(7H)-carboxylate
164
A solution of tert-butyl 4-(l-acetyl-l,2,3,6-tetrahydiOpyridin-4-yl)-12-fluoro-8J 3-dihydro[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzo[f][l,4]oxazonine-14(7H)-carboxylate (54.8 mg, 0.108 mmol) in MeOH (2.00 mL) was added to a flask charged with Pd/C (100 mg, 0.094 mmol) under nitrogen atmosphère at room température. The flask was evacuated and purged with H2 3 times. The mixture was stirred at 23 °C for 62 h and filtered through Celite, washing with MeOH (3 x 10.0 mL). The filtrated was concentrated under reduced pressure to provide tert-butyl 4-(lacetylpiperidin-4-yl)-12-fluoro-8,I3-dihydro-[ l,2,4]triazolo[4',3': l,6]pyrido[3,2b]benzo[fj[l,4]oxazonine-14(7H)-carboxylate as a solid (25.8 mg, 47%), which was used as such in the next step without further purification, m/z (ES+) [M+H]1: 510.3; HPLC îr (A05) = 2.26 min. Step 3: l-(4-(12-fluoro-7,8,13,14-tetrahydro-[l,2,4]triazolo[4',3': l,6]pyrido[3,2b]benzo[]][1,4] oxazonin-4-yl)pipendin-l -yl)ethan-l -one
A solution of tert-butyl 4-(l-acetylpiperidin-4-yl)-12-fluoro-8,13-dihydro15 [l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzo[f][l,4]oxazonine-14(7H)-carboxylate (25.8 mg, 0.0506 mmol) in HFIP (2.50 mL) was heated at 100 °C for 3 h. The mixture was concentrated under reduced pressure, and the residue was purified by préparative HPLC (BEH Cl8 30x150mm AmBicarb/ACN 25-45%) to 1 -(4-( 12-fluoro~7,8,13,14-tetrahydro165
[ l,2,4]triazolo[4',3': L6]pyrido[3,2-b]benzo[f][l,4]oxazonin-4-yl)piperidin-l-yl)ethan-l-one as a solid (11.1 mg, 53%). 'HNMRMeOD 500 MHz, δ 9.23 (s, IH), 7.13 (td, J = 8.0, 5.9 Hz, IH), 7.10 (s, IH), 6.96 (d, J = 7.2 Hz, IH), 6.87 (ddd, J = 9.9, 8.2, 0.9 Hz, IH), 4.91 (s, 2H), 4.67 (ddt, J = 13.2, 4.4, 2.2 Hz, IH), 4.42 - 4.29 (m, 2H), 4.02 (ddt, J = 13.5, 4.1, 1.9 Hz, IH), 3.30 - 3.22 (m, 2H), 3.08 (s, 2H), 2.75 (td, J = 13.0, 2.7 Hz, IH), 2.13 (s, 3H), 2.05 - 1.98 (m, IH), 1.97-1.91 (m, IH), 1.75 - 1.57 (m, 2H). m/z (ES+) [M+H]+:410.2; HPLC tR (B05) =1.12 min.
Step 5: 1 -(4-(12-fluoro-7,8,13,]4-tetrcihydro-[l,2,4]triazolo[4’,3':I,6]pyrido[3,2b]benzo[f] [1,4] oxazomn-4-yl)piperidin-l-yl)ethan-l-one bismesylate
MsOH (3.52 pL, 0.0542 mmol) was added to a solution of l-(4-(12-fluoro-7,8,13,14-tetrahydro[l,2,4]triazolo[4',3': 1,6]pyrido[3,2-b]benzo[f][l,4]oxazonin-4-yl)piperidin-l-yl)elhan-l-one (11.1 mg, 0.0271 mmol) in MeCN (1.50 mL) and water (0.500 mL) at rt. The mixture was stirred for 14 h and concentrated under reduced pressure to provide the title compound as a solid (13.5 mg, 83%). 'HNMRMeOD 500 MHz, δ 9.42 (s, IH), 7.77 (s, 1 H), 7.19 (td,7=7.9, 5.9 Hz, IH), 7.01 (d, J= 7.6 Hz, IH), 6.97-6.92 (m, IH), 5.04 (s, 2H), 4.71 (ddt, 7= 8.1,4.2, 2.1 Hz, 1 H), 4.45 (s, 2H),4.12 -4.04 (m, IH), 3.25 (td,7= 13.4, 2.8 Hz, IH), 3.19-3.05 (m, 3H), 2.76 - 2.71 (m, IH), 2.71 (s, 6H), 2.14 (s, 3H), 1.97- 1.86 (m, 2H), 1.76 (ddd, 7= 25.1, 12.6, 4.0 Hz, IH), 1.63 (qd,7= 12.4,4.0 Hz, lH).m/z(ES+) [M+H]^ 410.2; HPLC tR (B05) = 1.13 min.
Example 24: 12-fluoro-4-(2-methylpyridin-3-yl)-6,8,13,14-tetrahydroIl,2,4)triazolo[4’,3*:l,61pyrido[3,2-c]benzo[g][l,5]oxazonine hydrochloride sait
Step 1: 5-bromo-6-chloro-3-iodo-pyridin-2-amine
166
Acetic acid (100 mL) was added to a mixture of 5-biOmo-6-chloro-pyridin-2-amine (10.4 g, 50.0 mmol) and W-iodosuccinimide (12.4 g, 55.0 mmol). TFA (1.00 mL) was added, and the mixture was stirred at 23 °C for 3 h. The mixture was poured into crushed ice, and the aq. phase was diluted to pH 10 with ammonium hydroxide (150 mL). The solid was fïltered, washed with water and hexane, and dried under high vacuum to provide 5-bromo-6-chloro-3-iodo-pyridin-2-amine as a solid (16.4 g, 98%). hNMRCDCMOOMI-Iz, δ 7.99 (d,7=0.8 Hz, IH), 5.06 (br, 2H). m/z (ES+), [M+H]T 332.9. HPLC (A05) tR = 2.46 min.
Step 2: 5-bi-oino-6--chlorü-3-vinybpyi'idin-2-amine
DME (60.0 mL) and water (20.0 mL) were added to a mixture of 5-biOmo-6-chloro-3-iodo-pyridin2-amine (6.67 g, 20.0 mmol), potassium vinyltrifluoroborate (2.68 g, 20.0 mmol), K2CO3 (2.76 g, 20.0 mmol), and Pd(dppf)C12~DCM (1.63 g, 2.00 mmol). The mixture was heated to 85 °C for 18 h. After cooling down to 23 °C, EtOAc (100 mL) was added, and the mixture was fïltered through Celite. The filtrate was washed with brine (100 mL), and the organic phase was dried (MgSO4), fïltered, and concentrated under reduced pressure. The product was purified by silica gel chromatography (80 g cartridge) elutîng with hexanes and EtOAc (0-20%), followed by trituration from hexanes (50.0 mL) to provide 5-bromo-6-chloro-3-vinyl-pyridîn-2-amine as a solid (2.51 g; 54%). ‘H NMR CDC13 500 MHz, δ 7.68 (s, IH), 6.52 (ddd,7= 17.3, 11.1, 0.6 Hz, IH), 5.70 (dd,7 = 17.4, 0.8 Hz, IH), 5.48 (dd,7= 11.1, 0.8 Hz, IH), 4.70 (br, 2H). m/z (ES+), [M+H]+: 232.9. HPLC (A05) tR = 2.38 mm.
Step 3: 5-bromo~6-chloro-N,N-bis[(4-methoxyphenyl)methyl]-3-vinyl-pyridin-2-amine Br Cl
N(PM8)2 5-bromo-6-chloro-3-vmyl-pyridin-2-amine (0.500 g, 2.14 mmol) was dissolved in DMF (10.0 mL), and the mixture was cooled to 0 °C. 60 wt.% NaH in minerai oil (0.343 g, 8.57 mmol) was added portion-wise, and rhe mixture was stirred at 0 °C for 10 min. 4-Methoxybenzyl chloride (0.639 mL, 4.71 mmol) was added, and the mixture was stirred at 0 °C for 1 h. Water (10.0 mL) was added drop-wise, and the mixture was stirred at 0 °C for 5 min. The aqueous phase was extracted with
167
EtOAc (3 x 20.0 mL). The combined organic phases were washed with brine (20.0 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. The product was purified by silica gel chromatography (40 g cartridge) eluting with hexanes and EtOAc (0-10%) to provide 5-bromo-6chloro-N,N-bis[(4-methoxyphenyl)methyl]-3-vinyl-pyridin-2-amine as an oil (0.859 g; 85%). lH NMR CDCl3400 MHz, δ 7.78 (s, 1 H), 7.16 - 7.08 (m, 4H), 6.87-6.81 (m, 4H), 6.77 (dd, J = 17.5, 10.9 Hz, 1H), 5.64 (dd, J = 17.5, 0.8 Hz, 1H), 5.35 - 5.28 (m, 1H), 4.35 (s, 4H), 3.80 (s, 6H). m/z (ES+), [M+H]+: 473.1. HPLC (A05) tR = 2.98 min.
Step 4: 2-[bis[(4-methoxyphenyl)methyl]amino]-5-bromo-6-chloro-pyridine-3-carbaldehyde
1,4-Dioxane (21.0 111L) and water (7.00 mL) were added to 5-bromo-6-chloro-M,Wbis[(4methoxyphenyl)methyl]-3-vinyl-pyridin-2-amine (0.845 g, 1.78 mmol). After cooling down to 0 °C, 2,6-lutidine (0.415 mL, 3.57 mmol), 4 wt.% OsO4 in water (0.568 mL, 0.0892 mmol) and NaIO4 (0.763 g, 3.57 mmol) were added. The mixture was warmed to 23 °C and stirred for 18 h. Water (20.0 mL) was added, and the aqueous phase was extracted with EtOAc (3 x 25.0 mL). The combined organic phases were washed with brine (25.0 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. The product was purified by silica gel chromatography (40 g cartridge) eluting with hexanes and EtOAc (0-15%) to provide 2-[bis[(4methoxyphenyl)methyl]amino]-5-bromo-6-chloro-pyi'idine-3-carbaldehyde as an oil (0.675 g; 80%). 'H NMR CDC13 500 MHz, δ 9.80 (s, 1H), 8.09 (s, 1H), 7.13 - 7.06 (m, 4H), 6.89-6.79 (m, 4H), 4.62 (s, 4H), 3.80 (s, 6H). m/z (ES+), [M+H]+: 475.1. HPLC (A05) tR = 2.84 min.
Step 5: [2-[bis[(4~methoxyphenyl)methylJamino] -5-bromo-6-chloro-3-pyridyl] methanol
Br Cl
OH
N(PMB)2
2-[Bis[(4-methoxyphenyi)methyl] amino]-5-bromo-6-chloro-pyridi ne-3-carbaldehyde (0,670 g, 1,41 mmol) was dissolved in a mixture of THF (8.00 mL) and MeOH (2.00 mL). NaBH4 (6.51 mg, 0.172 mmol) was added portion-wise, and the mixture was stirred at 23 °C for 30 min. Sat. NH4C1 (20.0 mL) was added drop-wise, and the aqueous phase was extracted with EtOAc (3 x 25.0 mL). The combined organic phases were washed with brine (25.0 mL), dried (MgSO4), filtered and
168 concentrated under reduced pressure. The product was purified by silica gel chromatography (25 g cartridge) eluting with hexanes and EtOAc (0-40%) to provide [2-[bis[(4methoxyphenyl)methyl]amino]-5-bromo-6-chloro-3-pyridyl] as an oil (0.558 g; 83%). 'H NMR CDC13 500 MHz, δ 7.80 (s, 1 H), 7.18 - 7.11 (m, 4H), 6.85 - 6.79 (m, 4H), 4.57 (d, J = 5.4 Hz, 2H), 4.26 (s, 4H), 3.79 (s, 6H), 2.50 (t, J= 5.6 Hz, 1H). m/z (ES+), [M+Hp 477.3. HPLC (A05) tR = 2.72 min.
Step 6: methyl 2-(bromomethyl)-6-fluoro-benzoate
Benzoyl peroxide (75.0 %, 1.15 g, 3.57 mmol) was added to a solution of methyl 2-fluoro-6-methylbenzoate (6.00 g, 35.7 mmol) and NBS (6.99 g, 39.2 mmol) in CCI4 (200 mL). The mixture was degassed by bubbling nitrogen through the solvent for 15 min. The mixture was heated to 80 °C for 12 h. Brine (100 mL) was added, and the aq. phase was extracted with DCM (3 x 150 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure. The product was purified by silica gel chromatography (120 g cartridge) eluting with hexanes and EtOAc (0-10%) to provide methyl 2-(bromomethyl)-6-fluoro-benzoate as an oil (5.70 g, 65%). ’H NMR CDCl3500 MHz, δ 7.44-7.33 (m, 1H), 7.22 (dd, J= 7.7, 0.4 Hz, 1H), 7.08 (ddd, J=9.5, 8.4, 1.0 Hz, 1H), 4.65 (s, 2H), 3.98 (s, 3H). m/z (ES+), No ionization. HPLC (A05) tR = 2.40 min.
Step 7: methyl 2-[[2-[bis[(4-methoxyphenyl)methyl]amino]-5-bromo-6-chloro-3pyridyl]methoxymethyl]-6-fliiOΑo-benzoate
[2-[Bis[(4-methoxyphenyl)methyl]amÎno]-5-bromo-6-chloro-3-pyridyl]methanol (2.00 g, 4.19 mmol) was dissolved in THF (20.0 mL), and the mixture was cooled to 0 °C. 60 wt.% NaH in minerai oil (335 mg, 8.37 mmol) was added portion-wise, and the mixture was wanned to 23 °C. After stirring for 10 min, a solution of methyl 2-(bromomethyl)-6-fluoro-benzoate (1.55 g, 6.28 mmol) in THF (10.0 mL) was added drop-wise. The mixture was refluxed for 12 h. After cooling to 0 °C, sat. NH4CI (10.0 mL) was added drop-wise, and the mixture was stirred at 0 °C for 5 min. The
169 aqueous phase was extracted with EtOAc (2 x 100 mL), and the combined organic phases were washed with brine (50.0 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (80 g cartridge) eluting with hexanes and EtOAc (0-25%) to provide methyl 2-[[2-[bis[(4-methoxyphenyl)methyl]ainino]-5-bromo-6-chloro3-pyridyl]methoxymethyI]-6-fiuoro-benzoateas an oil (2.10 g; 78%). !H NMR CDCl3400 MHz, δ 7.79 (s, 1H), 7.41 -7.31 (m, 1H), 7.21-7.00 (m, 6H), 6.89 - 6.74 (m, 4H), 4.60 (s, 2H), 4.39 (s, 2H), 4.30 (s, 4H), 3.82 (s, 3H), 3.79 (s, 6H). m/z (ES+), [M+H]+: 643.1. HPLC (A05) tR = 2.96 min. Step 8: [2-[Ç2-[bls[(4-methoxyphenyl)methyl]amino]-5-bromo-6-chloro-3-pyridyl] methoxymethyl] 6-fliioro-phenyl] methanol
Methyl 2-[[2-[bis[(4-methoxyphenyl)methyl]amino]-5-bromo-6-chloro-3-pyridyl]methoxy methyl]6-fluoro-benzoate (2.10 g, 3.26 mmol) was dissolved in THF (30.0 mL), and the mixture was cooled to -78 °C. 1.0 M DIB AL-H in PhMe (13.0 mL, 13.0 mmol) was added drop-wise. The mixture was warmed to 0 °C and stirred for 1 h. Rochelle's sait was added (50.0 mL). The mixture was warmed to 23 °C and stirred until the solution became clear. The aq. phase was extracted with EtOAc (3 x 100 mL), and the combined organic phases were washed with brine (50.0 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (80 g cartridge) eluting with hexanes and EtOAc (0-40%) to provide [2-[[2-[bis[(4inethoxyphenyl)methyl]amino]-5-biOmo-6-chloro-3-pyridyl] methoxymethyl]-6-fluorophenyl] methanol as an oil (1.90 g; 95%). 'HNMR CDCl3400 MHz, δ 7.78 (s, 1H), 7.28 - 7.21 (m, 1H), 7.15 - 7.09 (m, 4H), 7.07 (t, J= 8.8 Hz, IH), 6.99 (d, J = 7.5 Hz, 1H), 6.86 - 6.78 (m, 4H), 4.72 (dd, J= 6.5, 1.5 Hz, 2H), 4.55 (s, 2H), 4.45 (s, 2H), 4.32 (s, 4H), 3.79 (s, 6H), 2.35 (t, J =6.5 Hz, 1H). m/z (ES+), [M+H]+: 617.0. HPLC (A05) tR = 2.84 min.
Step 9: [2-[(2-ammo-5-bromo-6-chloro-3-pyridyl)methoxymethyl]-6-fluoro-phenyl] methanol
[2-[[2-[Bis[(4-methoxyphenyl)methyl]amino]-5-bromo-6-chioro-3-pyridyl] methoxymethyl]-6fluoro-phenyl]methanol (1.87 g, 3.04 mmol) was dissolved in DCM (15.0 mL). TFA (4.00 mL, 53.8
170 mmol) was added drop-wise, and the mixture was stirred at 23 °C for 3 h. The mixture was concentrated under reduced pressure. 2.0 N NaOH (50.0 ml) was added to the residue, and the aq. phase was extracted with EtOAc (3 x 100 mL). The combined organic phases were washed with brine (100 mL), dried (MgSO^, filtered, and concentrated under reduced pressure. The product was purified by silica gel chromâtography (80 g cartridge) eluting with EtOAc and hexane (0-50%) to provide [2-[(2-amino-5-biOmo-6-chloro-3-pyridyl)methoxymethyl]-6-fluoro-phenyl] methanol as a solid (1.00 g; 87%). *H NMR CDCl3400 MHz, 5 7.50 (s, 1H), 7.34 - 7.27 (m, 11-1),7.15-7.07 (m, 2H), 5.09 (s, 2H), 4.78 (dd, ./=6.4, 1.7 Hz, 2H), 4.63 (s, 2H), 4.47 (s, 2H), 2.26 (t, 6.5 Hz, 1H).
m/z (ES+), [M+H]+: 377.0. HPLC (A05) tR = 2.39 min.
Step 10: 3~bromo-2-chloro-1 I-fluoro-5,7,12,13-tetrahydrobenzo[g]pyrido[3,2-c][1,5]oxazonine
[2-[(2-Amino-5-biOmo-6-chloro-3-pyridyl)methoxymethyl]-6-fluoro-phenyl]methanol (984 mg, 2.62 mmol) was dissolved in THF (15.0 mL). SOC12 (1.60 mL, 21.9 mmol) was added, and the mixture was heated to 50 °C for 40 min (gas évolution). The mixture was concentrated under reduced pressure, and the residue was repeatedly diluted with DCM and concentrated to remove any trace of SOC12. The intennediate (m/z (ES+), [M-C1]+: 394.9. HPLC (A05) tj< = 2.60 m) was dried under high vacuum for 30 m. DMF (15.0 mL) was added to the solid followed by TBAI (968 mg, 2.62 mmol) and Cs2CO3 (2.56 g, 7.86 mmol). The mixture was stirred at 100 °C for 50 min. The mixture was concentrated under reduced pressure. Water (50.0 mL) was added, and the aq. phase was extracted with EtOAc (3 x 100 mL). The combined organic phases were washed with brine (50.0 mL), dried (MgSOQ, filtered, and concentrated under reduced pressure. The product was purified by silica gel chromatography (24 g cartridge) eluting with hexane and EtOAc (0-25%) to provide 3-biOmo-2-chloro-ll-fluoiO-5,7,12,13-tetrahydrobenzo[g]pyrido[3,2-c][l,5]oxazonineas a solid (753 mg; 64%). ’H NMR CDC13 500 MHz, δ 7.59 (s, 1H), 7.30 - 7.24 (m, 1H), 7.05 (t, 8.8
Hz, 1H), 6.96 (d, J =7.6 Hz, 1H), 5.43 (t, 7.2 Hz, lH),4.97(s, 2H), 4.69 (dd, J = 7.5, 2.0 Hz,
2H), 4.35 (s, 2H). m/z (ES+), [M+H]+: 357.0. HPLC (A05) tR = 2.63 min.
Step 11: tert-butyl 3-bromo-2-chloro-ll-fluoro-7,12-dihydrobenzo[g]pyi'ido[3,2-c][1.5]oxazonine13(5H)-carboxylate
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Di-tert-butyl dicarbonate (0.443 mL, 1.93 mmol) was added to a solution of 3-bromo-2-chloro- ί 1 fluoro-5,7,l2,13-tetrahydrobenzo[g]pyrido[3,2-c][l,5]oxazonine (115 mg, 0.322 mmol), NEt3 (0.134 mL, 0.965 mmol), and DMAP (9.82 mg, 0.0804 mmol) in THF (2.00 mL). The mixture was heated to 50 °C for 15 h. Water (5.00 mL) was added, and the aq. phase was extracted with EtOAc (3 x 20.0 mL). The combined organic phases were washed with brine (20.0 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. The product was purified by silica gel chromatography (4 g cartridge) eluting with hexane and EtOAc (0-45%) to provide tert-butyl 3bromo-2-chloro-l l-fluoro-7,12-dihydrobenzo[g]pyrido[3,2-c][l,5]oxazomne-13(5H)-cai'boxylate as a solid (91.0 mg; 62%). Complex NMR (rotamers). m/z (ES+), [M+H-tBu]+: 402.9. HPLC (A05) tR = 2.71 min.
Step 12: tert-butyl 3-bromo-ll-fluoro-2-hydrazineyl-7,12-dihydrobenzo[g]pyrido[3,2c][l, 5] oxazonine-13(5H)-carboxylate
A solution of tert-butyl 3-bromo-2-chloro-l l-fluoro-7,12-dihydrobenzo[g]pyrido[3,2c][l,5]oxazonîne-13(5H)-carboxylate (91.0 mg, 0.199 mmol) and hydrazine monohydrate (0.500 mL, 10.3 mmol) in EtOH (2.00 mL) was heated at 100 °C for 18 h. After cooling to 23 °C, the mixture was concentrated under reduced pressure. The product was purified by silica gel chromatography (4 g cartridge) eluting with DCM and MeOH (0-10%) to provide tert-butyl 3bromo~l l-fluoro-2-hydrazineyl-7,12-dihydrobenzo[g]pyrido[3,2-c][l,5]oxazonine-13(5H)carboxylateas a solid (82.0 mg; 91%). Complex NMR (rotamers). m/z (ES+), [M+H-tBu]: 397.0. HPLC (A05) tR - 2.40 min.
Step 13: tert-butyl 4-bromo-12-fluoro-8,13-dihydro-[1,2,4]triazolo[43’:1,6]pyrido[3,2c]benzo[g] [1,5]oxazonine-14(6H)-carboxyla.te
172
TFA (0.01 mL) was added to a solution of tert-butyl 3-bromo-l l-fiuoro-2-hydrazineyl-7,12dihydrobenzo[g]pyrido[3,2-c][i,5]oxazonine-13(5H)-carboxylate (82.0 mg, 0.181 mmol) in triethyl orthoformate (5.42 mL, 32.6 mmol). The mixture was heated to 100 °C for 1.5 h. After cooling to 23 °C, the mixture was concentrated under reduced pressure. The product was purified by silica gel chromatography (4 g cartridge) eluting with DCM and MeOH (0-10%) to provide tert-butyl 4bromo-12-fluoro-8J13-dihydro-[l,2,4]triazolo[4',3,: l,6]pyrido[3,2-c]benzo[g][l,5]oxazonine14(6H)-carboxylate as a solid (66.0 mg; 78%). Complex NMR (rotamers). m/z (ES+), [M+H-tBu]+: 465.0. HPLC (A05) tR = 2.32 min.
Step 14: tert-butyl 12-fluoro-4-(2-methylpyridln-3-yl)-8,l 3-dihydro[ 1,2,4]triazolo[4',3’:l, 6]pyrido[3,2-c] benzo[g] [1,5] oxazonine-14(6H)-carboxylate
1,4-Dioxane (1.50 mL) and water (0.300 mL) were added to a mixture of tert-butyl 4-bromo-12fluoro-8,13-dîhydro-[ l,2,4]triazoio[4',3': l,6]pyrido[3,2-c]benzo[g][ 1,5]oxazonine- 14(6H)carboxylate (66.0 mg, 0.142 mmol), Pd(dppf)C12 (10.4 mg, 0.0142 mmol), and NaHCOj (35.9 mg, 0.427 mmol) under nitrogen. The mixture was heated to 90 °C for 2 h. After cooling to 23 °C, the mixture was filtered though a silica plug washing with EtOAc. The filtrate was concentrated under reduced pressure. The product was purified by silica gel chromatography (24 g cartridge) eluting with DCM and MeOH (0-10%) to provide tert-butyl 12-fluoro-4-(2-methylpyridin-3-yl)-8,13dihydro-[l,2,4]triazolo[4',3': l,6]pyrido[3,2-c]benzo[g][l,5]oxazonine-14(6H)-carboxylate as a solid (60.0 mg; 89%). Complex NMR (rotamers). m/z (ES+), [M-4-I]+: 476.2. HPLC (A05) tR = 2.24 min. Step 15: tert-butyl 12-fluoro-4-(2-methylpyridin-3-yl)-8,13-dihydro[1,2,4]triazolo[4',3': 1,6]pyrido[3,2-c]benzo[g] [l,5]oxazomne-14(6H)-carboxylate hydrochloride
A solution of tert-butyl 12-fluoro-4-(2-methylpyridin-3-yl)-8,13-dihydro[l,2,4]triazolo[4',3':l,6]pyrido[3,2-c]benzo[g][l,5]oxazonine-14(6H)-carboxylate (53.0 mg, 0.111 mmol) in HF1P ( 1,50 mL) was heated to 100 °C for 15 h. After cooling to 23 °C, the mixture was
173 concentrated under reduced pressure. The product was purified by silica gel chromatography (24 g cartridge) eluting with DCM and MeOH (0-15%) to provide the free base of the title compound as a solid (28.0 mg; 67%). JH NMR (500 MHz, MeOD) Ô 9.50 (s, 1H), 8.48 (dd, J=5.0, 1.7 Hz, 1H), 7.76 (dd,J= 7.7, 1.7 Hz, IH), 7.36 (dd, 7.7, 5.0 Hz, IH), 7.33 - 7.28 (m, 2H), 7.16 (d, J= 7.5 Hz, 1 H), 7.05 (t, J= 9.1 Hz, 1H), 4.90 (d, J= 1.4 Hz, 2H), 4.84 (s, 2H), 4.63 (s, 2H), 2.33 (s, 3H). The compound was converted to the hydrochloride sait by adding 4.0 N HCl in dioxane (18.6 pL, 0.0746 mmol) to a solution of 5-fluoro-15-(2-methyl-3-pyridyl)-l 1 -oxa-2,17,18,20tetrazatetracyclofl 1.7.0.04,9.016,20]icosa-l(13),4(9),5,7,14,16,18-heptaene (28.0 mg, 0.0746 mmol) in DCM (5.00 mL) and MeOH (0.500 mL). The mixture was stirred at 23 °C for 1 h. The mixture was concentrated under reduced pressure to afford the title compound as a solid (25.0 mg, 81%). 'H NMR MeOD 500 MHz, δ 9.62 (s, 1 H), 8.74 (d, J = 5.7 Hz, 1H), 8.45 (d, J =7.8 Hz, 1H), 7.93 - 7.89 (m, III), 7.53 (s, 1H), 7.38 - 7.29 (m, 1H), 7.15 (d, J= 7.5 Hz, IH), 7.09 (t, J= 9.0 Hz, 1H), 4.98 (s, 2H), 4.94 (s, 2H), 4.67 (s, 2H), 2.58 (s, 3H). m/z (ES+), [M+H]+: 376.5. HPLC (A05) tR = 2.03 min.
Example 25: l-(4-(12-tluoro-6,8,13,14-tetrahydro-[l,2,4]triazolo(4’,3,:l,6]pyrido[3,2c]benzo[g][l,5]oxazonin-4-yl)piperidin-l-yl)ethan-l-one
Step 1: tert-butyl 4-(l-acetyl-l,2,3,6-tetrahydropyridin-4-yl)-l 2-fluoro-8,13-dihydro[l,2,4]triazolo[4',3': 1,6]pyrido[3,2-c]benzo[g] [ l ,5] oxazonine-I4(6H)-carboxylate
1,4-Dîoxane (4.00 mL) and water (0.800 mL) were added to a mixture of tert-butyl 4-bromo-12fIuoro-8, L 3-dihydro-[ l,2,4]triazolo[4',3': l,6]pyrido[3,2-c]benzo[g][ 1,5]oxazonine- 14(6H)carboxylate (Example 24; 113 mg, 0.244 mmol), l-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)3,6-dihydro-2H-pyridin-l-yl]ethanone (67.4 mg, 0.268 mmol, Pd(dppf)Cl2 (17.8 mg, 0.0244 mmol), and NaHCO3 (61.5 mg, 0.732 mmol) under nitrogen. The mixture was heated at 90 °C for 2.5 h. The mixture was cooled to 23 °C and filtered though a silica plug, washing with EtOAc and 10% MeOH in DCM. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (12 g cartridge) eluting with DCM and MeOH (0-10%) to provide tert-butyl 4(l-acetyl-l,2,3,6-tetrahydropyridin-4-yl)-12-fluoro-8,13-dihydro-[l,2,4]triazolo[4',3':l,6]pyrido[3,2c]benzo[g][l,5]oxazonine-I4(6H)-carboxylateas a solid (141 mg; 80% pure, 91%). Complex NMR (rotamers). m/z (ES+), [M+H]+: 508.1. HPLC (A05) tR = 2.22 min.
174
Step 2: tert-butyl 4-(l-acetylpiperidin-4-yl)-12-fluoro-8,13-dihydro[ 1,2,4] triazolo]4 3 1,6]pyrido[3,2-c]benzo[g][l,5] oxazonine-14(6H)-carboxylate
A solution of tert-butyl 4~( I -acetyl-1,2,3,6-tetrahydropyridm-4-yl)-12-fluoro-8,13-dihydro[l,2,4]triazolo[4',3':l,6]pyrîdo[3,2-c]benzo[g][l,5]oxazonine-14(6H)-carboxylate (111 mg, 0.175 mmol) in MeOH (12.0 mL) was added at 23 °C to a flask charged with 10% Pd/C (74,0 mg, 0,0695 mmol) under nitrogen atmosphère. The flask was évacuaied and purged with H? gas 3 iimes. The mixture was stirred at 23 °C for 1 h and fïltered through Celite washing with MeOH. The fïltrate was coneentrated under reduced pressure, and the product was purified by silica gel chromatography (24 g) eluting with DCM and MeOH (0-10%) to provide tert-butyl 4-(lacetylpiperidin-4-yl)- 12-fluoro-8,13-dihydro-[ 1,2,4]triazolo[4',3': l ,6]pyrido[3,2c]benzo[g][l,5]oxazonine-14(6H)-carboxyIate as a solid (71.0 mg, 80%). Complex NMR (rotamers). m/z (ES+) [M+Hf: 510.2. HPLC (A05) tR = 2.20 min.
Step 3: 1-(4-( 12-fluoro-6,8,13,14-tetrahydro-f1,2,4]triazolo]4',3 1,6]pyrido[3,2c]benzo[g][ 1,5]oxazomn-4-yl)piperidin-1-yl)ethan-l-one methanesulfonylsait
A solution of tert-butyl 4-(l-acetylpiperidm-4-yl)-12-fluoro-8,13-dihydro[l,2,4]triazolo[4',3': l,6]pyrido[3,2-c]benzo[g][l,5]oxazonine-14(6H)-carboxylate (85.0 mg, 0.167 mmol) in HFIP (4.00 mL) was heated at 100 °C for 12 h. After cooling down to 23 °C, the mixture was coneentrated under reduced pressure. The product was purified by silica gel chromatography (12 g cartridge) eluting with DCM and MeOH (0-10%) to provide the free base of l-(4-(12-fluoro6,8,13,14-tetrahydro-[ 1,2,4]triazolo[4',3': 1,6]pyrido[3,2-c]benzo[g][l,5]oxazonin-4-yl)piperidin-lyl)ethan-l-oneas a solid (40.0 mg; 59%). 'HNMR (500 MHz, MeOD) δ 9.44 - 9.33 (m, IH), 7.337.23 (m, 1H), 7.16 (d, J= 8.6 Hz, 1H), 7.14 (s, 1H), 7.03 (t, J= 9.1 Hz, 1H), 4.73 (s, 2H), 4.72 4.68 (m, 1H), 4.69 (s, 2H), 4.52 (s, 2H), 4.06 (d, J= 13.8 Hz, 1H), 3.39 - 3.33 (m, 1H), 3.30 - 3.24 (m, IH), 2.79 (t, ./ = 13.0 Hz, 1H), 2.14 (s, 3H), 2.07 (d, J= 13.1 Hz, 1 H), 2.00 (d, J= 13.2 Hz, IH), 1.82 - 1.63 (m, 2H). The compound was converted to the methanesulfonyl sait by adding MeSO3H
175 (3.01 pL, 0.0464 mmol) to a solution of 1-(4-( I2-fluoro-6,8,l 3,14-tetrahydro[ 1,2,4]triazolo[4',3': 1,6]pyrido[3,2-c]benzo[g][l ,5]oxazonin-4-yl)pîperidin-1 -yl)ethan-l -one ( 19.0 mg, 0.0464 mmol) in MeCN (2.00 mL). The mixture was stirred at 23 °C for 1 h. The mixture was concentrated underreduced pressure to providc the title compound as a solid (21.0 mg, 89%). 'H NMR MeOD 500 MHz, δ 9.75 (s, 1H), 7.85 (s, 1H), 7.37 (td, J= 7.9, 5.7 Hz, 1H), 7.19 - 7.02 (m, 2H), 4.94 (s, 4H), 4.74 (d, J= 13.5 Hz, 1H), 4.62 (s, 2H), 4.12 (d, J= 13.9 Hz, 1H), 3.36-3.26 (m, 1H), 3.24-3.15 (m, 1H), 2.84-2.75 (m, 1H), 2.70 (s, 3H), 2.17 (s, 3H), 2.06- 1.93 (m, 2H), 1.83 (qd,7 = 12.6, 3.8 Hz, 1H), 1.69 (qd, 7= 12.8,4.2 Hz, 1H). m/z (ES+), [M+H]+: 410.1. HPLC (A05) îr = 2.04 min.
Example 26: 12-fluoro-4-((l-methyl-lH-pyrazol-4-yl)methyl)-6,8,13,14-tetrahydiO[l,2,4]triazolo[4',3':l,6|pyrido|3,2-c]benzo[g][l,5]oxazonine
Step 1 (! 2-fluor O-6,8,13,14-tetrahydro-[l,2,4/ triazolo[4 ',3': 1,6]pyrido[3,2c] benzofg] [ 1,5] oxazonin-4-yl)(l -methyl-lH-pyrazol-4-yl)methanol
‘PrMgCl.LiCl (0.540 mL, 0.703 mmol) was drop wise added to a solution of tert-butyl 4-bromo-12fluoiO-8,13-dihydro-[l,2,4]triazolo[4',3':I,6]pyrido[3,2-c]benzo[g][l,5]oxazonine-14(6H)carboxylate (Exaniple 24; 93.0 mg, 0.201 mmol) in THF (3.00 mL) at -78 °C under nitrogen. The mixture was stirred at -78 °C for 10 min and warmed to 0 °C for 30 min. A solution of 1methylpyrazole-4-carbaldehyde (88.4 mg, 0.803 mmol) in THF ( 1.00 mL) was drop wise added at 0 °C. The mixture was stirred at 0 °C for 30 min and warmed to room température for 2 h. The mixture was diluted with NH4C1 (5 mL) and water (8 mL). The aqueous phase was extracted with ethyl acetate (5X20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (12 g cartridge) eluting with MeOH in DCM (0-15%) to provide (12-fluoro-6,8,13,14-tetrahydro[l,2,4]triazolo[4',3':l,6]pyrido[3,2-c]benzo[g][l,5]oxazonin-4-yl)(l-methyl-lH-pyrazol-4yl)methanol (31 mg, 31%) as a solid. m/z (ES+) [M+H]r: 495.1; HPLC Ir (A05) = 2.13 min.
176
Step 2: 12fluoro-4-((1 -methyl-1 H-pyrazol-4-yl)methyl)-6,8,13,14-tetrahydro[1,2,4] triazolo[4’,3':1,6]pyrido[3,2-c] benzo[g] [1,5] oxazonine
Triethylsilane (0.400 mL, 2.51 mmol) and TFA (0.186 mL, 2.51 mmol) were added to a solution of ( 12-fluoro-6,8,13,14-tetrahydro-[ 1,2,4]trîazolo[4',3’: l,6]pyrido[3,2-c]benzo[g][ 1,5 |oxazonin-4yl)(l-methyl-lFI-pyrazol-4-yl)methanol (31.0 mg, 0.0627 mmol) in MeCN (2.50 mL). The mixture was stirred at 60°C for 3 h and concentrated under reduced pressure. The residue was purified by HPLC (Torus-2PIC 10x250 mm MeOH/CO? 5-55% of MeOH) to afford the title compound as a solid (7.47 mg, 31%) . 'H NMR (500 MHz, MeOD) δ 9.39 (s, IH), 7.45 (s, IH), 7.32 (s, IH), 7.28 (td, J = 7.9, 5.6 Hz, 1 H), 7.15 (d, J = 7.3 Hz, IH), 7.07 (s, IH), 7.02 (t, J = 8.6 Hz, 1 H), 4.73 (d, J = 1.6 Hz, 2H), 4.67 (s, 2H), 4.49 (s, 2H), 4.04 (s, 2H), 3.82 (s, 3H). m/z (ES+) [M+H] +: 379.1; HPLC tR (A05) = 2.05 min.
Exainple 27: (S)-l2-fluoro-4-(2-methylpyridiu-3-yl)-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3':l,6]pyrido|3,2-bjbenzofuro[4,3-fg][l,4]oxazoiiine
Step 1 : (S)-4-bromo-12-fuoro- 7a, 8,13,14-letrahydro-7H-[1,2,4]triazolo[4 ', 3l,6]pyrido[3,2b]benzofuro[4,3-fg] [1,4] oxazonine
F
To a mixture of tert-butyl (S)-4-bromo-12-fluoro-7a,13-dihydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (2.4 g, 4.88 mmol, 1.00 eq; as prepared in Example 17) in DCM (20 mL) was added TFA (9.24 g, 81.0 mmol, 6 mL, 16.6 eq) in one portion at 18°C. The mixture was stirred at 18°C for 12 hrs. TLC (Petroleum ether:Ethyl acetate = 0:1, Rf = 0.2) detected one major new spot with larger polarity. The mixture was evaporated to obtain the product. To the residue was added EtOAc (20 mL), then basified to pH = 8 by saturated aqueous NaHCOj. The precipitate was generated. The mixture was
177 filtered and the filter cake was washed with 10 mL of EtOAc, dried in vacuum to give (S)-4-bromoi2-fluoro-7a,8,13,I4-tetrahydro-7H-[l,2,4]triazolo[4’,3':l,6]pyrido[3,2-b]benzofuro[4,3fg][l,4]oxazonine (1.78 g, 4.55 mmol, 93% yield) as a gray solid.
Step 2: (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H[1,2,4] triazolo[4’,3':l, 6]pyt‘ido[3,2-b] benzofuro[4,3-fg] [1,4] oxazortine
Dioxane (181 mL) and water (39.0 mL) were sequentially added to a mixture of(S)-4-bromo-12fluoro-7a,8,13,14-tetrahydiO-7H-[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3fg][ l,4]oxazonine (2,59 g, 6.62 mmol, 1.00 eq), 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)pyridine (1.74 g, 7.94 mmol, 1.2 eq), Pd(dppf)Cl2 (484 mg, 662 umol, 0.100 eq) and NaHCO3 (2.78 g, 33.1 mmol, 1.29 mL, 5.00 eq) at 20°C under N2. The mixture was heated to 90°C for 2 hrs. LC-MS showed no (S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3': 1,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine was remained. Several new peaks were shown on LC-MS and the desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was combined with other two batches (from 1.82 of (S)-4-bromo-l2-fluoro-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine and LO g of (S)-4-bromo-12fluoro-7a,8,13,i4-tetrahydro-7H-[l,2,4]triazolo[4’,3':l,6]pyrido[3,2-b]benzofuro[4,3fg][l,4]oxazonine ) and to the residue (18 g) was added MeOH (100 mL) and silica-thiol (700 mg, modified Silicon gel for eliminating Pd, irregular silica gel, 100 - 200 mesh, chlorides (Cl), %<0.004, Particle Size Distribution 45-75 um) at 20°C and stirred at 20°C for 12 hrs. The suspension was filtered and the filter cake was washed with 200 mL of MeOH and 20 mL of DMSO, the filtrate was concentrated under reduced pressure to remove MeOH and purified by prepHPLC (HCl condition: column: Phenomenex luna cl8 250 mm * 100 mm * 10 um; mobile phase: [water (0.05% HCl) - ACN]; B%: 1% - 31%, 25 min). The fraction of/?rep-HPLC was concentrated under reduced pressure to remove MeCN at 30°C and the residue was lyophilized. (S)-12-fluoro-4(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[ 1,2,4]triazolo[4',3': 1,6]pyrido[3,2b]benzofuro[4,3-fg][l,4]oxazonine (4.1 g, 9.29 mmol, 99.7% purity, 100% ee, HCl) was obtained as yellow solid. *H NMR DMSO-ίή, 400 MHz, δ = ppm 9.89 (s, 1H), 8.86 - 8.75 (m, 1H), 8.64-8.57
178 (m, 1H), 8.54 - 8.49 (m, 1H), 7.9S - 7.89 (m, 1H), 7.82 - 7.75 (m, 1H), 7.03 - 6.92 (m, 1H), 6.71 (dd, 7=8.6,3.7 Hz, 1H), 5.00-4.91 (m, 1H), 4.84 (br dd, J = 14.7, 5.6 Hz, 1H), 4.58 - 4.45 (m, 2H), 4.25-4.17 (m, IH), 4.11 - 4.00 (m, 1H), 3.95 - 3.83 (m, 1H), 2.64 (s, 3H). LCMS (ESI+): m/z 404.1 (M+H).
Example 28: (S)-l-(4-(ï2-fluoro-7a,8,13,14-tetrahydro-7H-[l,2,4Jtriazolo|4*,3':l,6|pyrido[3,2b]benzofuro[4,3-fg]|l,4joxazoniii-4-yl)pjperidîn-l-yl)ethan-l-one
Step I: tert-butyl (S)-4-(l-acetyl-l,2,3,6-tetrahydropyridin-4-yl)-l 2-fluoro-7a, 13-dihydro-7H[1,2,4]triazolo[4 3 ’:î, 6]pyrido[3,2-b] benzofiirof4,3-fgJ [1,4] oxazonine-14(8H)-carboxylate
Dioxane (2.00 mL) and water (0.400 mL) were added to a mixture of tert-butyl (S)-4-bromo-12fluoro-7a,l 3-dihydro-7H-[ l,2,4]triazolo[4',3’: l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonîne14(8H)-carboxylate (Example 16; 0.122 mol, 60.0 mg), 1-(4-(4,4,5,5-tetramethyl-l,3,2dioxaboiOlan-2-yll-3,6-dihydro-2H-pyridin-J-yl]ethanone (0.128 mmol, 32.1 mg), Pd(dppf)Cl2 (0.0122 mmol, 8.94 mg), and NaHCOj (0.366 mmol, 30.8 mg) under N2. The mixture was stirred at 90 °C for 2.5 h. The mixture was filtered though a short silica pad. The filter cake was washed with EtOAc (3 x 5 mL). The filtra te was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (4 g cartridge) eluting with MeOH in DCM (0-10 %) to afford tert-butyl (S)-4-(l-acetyl-l,2,3,6-tetrahydiOpyridin-4-yl)-12-fluoro-7a,l 3-dihydro-7H[l,2,4]triazolo[4’,3’:l,6]pyrido(3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate as a solid (53.6 mg, 82%). ES+ [M]+:535.63; LC-MS (B05); tR = 2.23 min.
Step 2; tert-butyl (S)-4-(l -acetylpiperidin-4-yl)-l 2-Jluoro-7a, 13-dihydro-7H[ 1,2,4]triazolo[4 3 r:l,6]pyrido[3,2-b] benzofiirof4,3-fgJ[ 1,4]oxazonine-14(8H)-carboxylate
179
A solution of tert-butyl (S)-4-(l-acetyl-l,2J3J6-tetrahydiOpyridin-4-yl)-12-fluoro-7a,i3-dihydro-7H[l,2,4]triazolo[4’,3’: 1,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-i4(8H)-carboxylate (99.0 pmol, 53.0 mg) in MeOH (10.0 mL) was added to a flask eharged with Pd/C (19.8 pmol, 21.1 mg, 10.0 %) under nitrogen atmosphère at room température. The flask was evacuated and purged with FL gas 3 times. The mixture was stiired at rt for 20 h and filtered through Celite. The fdter cake was washed with MeOH (3X8 mL), and the fdtrate was concentrated under reduced pressure. The residue (53 mg) was used as such in the next step without further purification, m/z (ES+) [M]+:537.75. HPLC (B05) tR = 2,09 min.
Step 3: (S)-1-(4-(12-fluoro-7a,8,13,14-tetrahydro-7H-[ 1,2,4]triazolo]4’,3’:1,6]pyrido[3,2b]benzofitro[4,3-fg] [1,4] oxazonin-4-yl)piperidin-l -yljethan- 1-one
A solution of tert-butyl (S)-4-(l-acetylpiperidin-4-yl)-12-fluoiO-7a,13-dihydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-l4(8H)-carboxylate (98.6 pmol, 53.0 mg) in HFIP (2.00 mL) was heated to 100°C for 3 h. The mixture was concentrated under reduced pressure, and the residue was purified by HPLC (BEH C18 30 x 150mm AmBicarb/ACN 25-45%) to afford the title compound as a solid (22.7 mg, 53%). ’H NMR DM S O 500 MHz, δ 9.33 (s, HT), 7.15 (t, J = 6.4 Hz, 1H), 7.07 (s, 1H), 6.97 - 6.84 (m, 1H), 6.66 (dd, J = 8.6, 3.8 Hz, 1H), 4.82 (dd, J = 14.9, 5.9 Hz, 1H), 4.68 (dd, J = 14.9, 6.6 Hz, 1H), 4.51 (t, J = 9.4 Hz, 2H), 4.48 - 4.38 (m, 1H), 4.20 (dd, J = 9.6, 3.3 Hz, 1H), 4.02 - 3.86 (m, 2H), 3.77 (td, J = 11.6, 4.2 Hz, 1H), 3.26-3.09 (m, 2H), 2.67 - 2.55 (m, 1H), 2.02 (d, J = 3.9 Hz, 3H), 1.98- 1.83 (m, 2H), 1.80- 1.67 (m, 1H), 1.67- 1.53 (m, 1H). m/z (ES+) [M+H]T 438.61, HPLC (B05) tR = 1.91 min. Example 29: (S)-12-fluoro-4-((l-methyl-lH-pyrazol-4-yl)methyl)-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3':l,6]pyrido|3,2-blbenzofuro[4,3-fgl|l,4]oxazonine
180
Step 1 tert-butyl (7aS)-12-fluoro-4-(hydroxy(l-methyl-lH-pyrazol-4-yl)methyl)-7a,13-dihydro-7H[1,2,4] triazolo[4 3': 1,6]pyrido[3,2-b] benzofuro[4,3 -fg] [l,4]oxazonine-14(8H)-carboxylate n-nZ
A solution of tert-butyl (S)-4-bromo-12-fluoro-7a,13-dihydro-7H[ 1,2,4]triazolo[4',3': l,6]pyrido[3,2-b]benzofuro[4,3-fg] [l,4]oxazonine-14(8H)-carboxylate (Example 16; 0.122 mmol, 60.0 mg) in THF (2.00 mL) was cooled to -78 °C. 'PrMgCl.LiCl 0.427 mmol, 0.329 mL) was added drop-wise. The mixture was stirred at -78°C for 10 min and warmed to 0 °C for 30 min. A solution of l-methylpyrazole-4-carbaldehyde (0.488 mmol, 53.8 mg) in THF (1.00 mL) was added drop-wise at 0°C. The mixture was stirred at 0 °C for 30 min and warmed to room température for 2 h. The mixture was diluted with NH4CI (5 mL) and water (8 mL). The aqueous phase was extracted with ethyl acetate (5x15 mL), and the combined organic layers were dried over MgSCU, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (4 g cartridge) eluting with MeOH in DCM (0-15%) to provide tert-butyl (7aS)-12-fluoro-4-(hydroxy( I -methyl-1 H-pyrazol-4-yl)methyl)-7a, 13-dihydro7H-[ 1,2,4]triazolo[4',3’: 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ l,4]oxazonme- 14(8H)-carboxylate as a solid (10.5 mg, 17%). LC-MS m/z (ES+) [M+H]+:523.88; (A05) tR = 2.02 min.
Step 2: (S)-l2-fluoro-4-((l-methyl-1 H-pyrazol-4-yl)methyl)-7a,8,13,14-tetrahydro-7H[1,2,4]triazolo[4 , 3 1,6]pyrido[3l2-b]benzofùro[4,3-fg] [1,4] oxazonine
To a solution of tert-butyl 12-fluoro-4-(hydroxy(l-methyl-lH-pyrazol-4-yl)methyl)-8,13-dihydro[l,2,4]triazolo[4’,3':l,6]pyrido[3,2-c]bcnzo[g][l,5]oxazonine-14(6H)-carboxylate (0.0201 mmol, 10.5 mg) in MeCN (1.50 mL) was added Et3SiH (0.804 mmol, 0.0597 mL) and TFA (0.804 mmol,
181
0.128 mL). The mixture was stirred at 60° C for 3 h. The mixture was concentrated under reduced pressure, and the residue was purified by HPLC (BEH C18 30x150mm AmBicarb/ACN 25-45%) to afford the title compound as a solid (5.2 mg, 64%). 'H NMR MeOD 400 MHz, δ 9.23 (s, 1 H), 7.46 (s, IH), 7.36 (s, IH), 7.06 (s, IH), 6.82 (dd, J = 10.3, 8.7 Hz, IH), 6.58 (dd, J = 8.7, 3.8 Hz, IH), 4.95 (d, J= 14.8 Hz, IH), 4.77 (d, J = 14.7 Hz, IH), 4.57 - 4.42 (m, 2H), 4.23 (dd, J = 9.6, 3.0 Hz, IH), 4.04-3.99 (m, 2H), 3.98 -3.89 (m, IH), 3.81 (s, 3H), 3.80-3.72 (m, IH). m/z (ES+) [M+H] +:407.62, HPLC (B05) tR = 1.93 min.
Example 30: (S)-4-((l-methyI-lII-pyrazol·-4-yl)methyl)-7a>8,13,14-tetrahycIro-7H[l,2,4]triazoloI4',3':l,6]pyrÎdo[3,2-b]benzofuro[4,3-fgHl,4Joxazonine and (S)-7a,8,13,14tetrahydro-7H-[l,2,4|triazolo[4’,3’:l,6]pyrido[3,2-b]benzofuro[4,3-fg]|l,4]oxazonine nitrogen (CjHsjîSiH (7.93 mmol, 1.27 mL) and TFA (7.93 mmol, 0.589 mL) were added to a solution of (S)-12-fluoro-4-((1-methyl-lH-pyrazol-4-yl)methyl)~7a,8,13,14-tetrahydro-7H] 1,2,4] triazolo[4',3': 1,6]pyrido[3,2-b] benzofuro[4,3-fg] [1,4] oxazonine (Example 30; 0.198 mmol, 100 mg) in MeCN (2.00 mL). The mixture was heated to 60°C for 3 h. The mixture was concentrated. The residue was purified b y HPLC (BEH 30x150mm ACN/AmBicarb 30-35%) to afford (S)-4-((l-methyl-lH-pyrazol-4-yl)methyl)-7a,8,13,14-tetrahydro-7H-
[ l,2,4]triazolo[4',3': 1,6]pyrido [3,2-b]benzofuro[4,3-fg][ 1,4] oxazonine as a solid (8.00 mg, 10%). ’H NMR (500 MHz, MeOD) δ 9.18 (s, IH), 7.46 (s, IH), 7.36 (s, IH), 7.11 - 7.04 (m, 2H), 6.84 (d, J = 7.6 Hz, IH), 6.62 (d, J = 7.9 Hz, IH), 4.89 - 4.84 (m, 1H),4.75 (d, J= 14.3 Hz, 1 H), 4.49 (t, J = 9.3 Hz, IH), 4.41 (dd,J= 10.5, 4.3 Hz, IH), 4.17 (dd, J = 9.6, 3.4 Hz, 1 H), 4.02 (d, J = 3.0 Hz, 2H), 3.99 - 3.92 (m, IH), 3.81 (s, 3H), 3.78 (dd, J = 11.9, 10.8 Hz, IH). m/z (ES+) [M+H]L 389.95;
HPLC tR (B05) = 2.26 min.
From the preceding purification, (S)-7a,8,I3,14-tetrahydro-7H-[l,2,4]triazolo[4’,3': l,6]pyrido[3,2b]benzofuro[4,3-fg][l,4]oxazonine was isolated as a solid (9.00 mg, 15%). !H NMR (500 MHz, MeOD) δ 9.17 (d, J = 0.8 Hz, IH), 7.37 (d, J = 9.5 Hz, IH), 7.09 (t, J = 7.8 Hz, IH), 7.02 (dd, J = 9.5, 0.9 Hz, IH), 6.86 (d, J = 7.7 Hz, IH), 6.63 (d, J = 7.9 Hz, IH), 4.94 - 4.85 (m, IH), 4.79 (s,
182
IH), 4.51 (t, J = 9.4 Hz, 1 H), 4.47 (dd, J = 10.4, 4.4 Hz, IH), 4.19 (dd, J = 9.6, 3.5 Hz, IH), 3.98 (ddd, J = 13.1, 8.6, 4.0 Hz, IH), 3.88 - 3.81 (m, IH).
Example 31: (S)-4-(2,4-dimethylpynmidin-5-yl)-12-fluoro-7a.,8,13,14-tetrahydro-7H[l,2,4]triazolo[4,,3,:I,6]pyrido|3,2-b]benzofuro[4,3-fg||l,4|oxazonine
Step 1: tert-butyl (S)-4-(2,4-diniethylpyrimidin-5-yl)-12-fluoro-7a,13-dihydro-7H[1,2,4] triazolo[4', 3 1,6]pyrido[3,2-b] benzofuro[4,3-fg] [1,4] oxazonine-14(8H)-carboxylate
Dioxane (1.50 mL) and water (0.300 mL) were added to a mixture of tert-butyl (S)-4-bromo-12fluoro-7a,l 3-dihydro-7H-[ 1,2,4] triazolo[4',3': l,6]pyrido[3,2-b] benzof'uro[4,3-fg] [1,4] oxazonine14(8H)-carboxylate (Example 16; 0.122 mmol, 60.0 mg), 2,4-dimethyl-5-(4,4,5,5-tetramethyll,3,2-dioxaborolan-2-yl)pyrimidine (0.147 mmol, 34.3 mg), Pd(dppf)Cl2 (0.0122 mmol, 8.94 mg), and NaHCO3 (0.366 mmol, 30.8 mg) under N2. The mixture was stirred at 90 °C for 4 h. The mixture was fdtered though a silica pad, and the fdter cake was washed with EtOAc (3X5 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (4 g cartridge) eluting with MeOH in DCM (0-15 %) to afford tert-butyl (S)-4-(2,4dimethylpyrimidin-5-yl)-12-fiuoro-7a, 13-dihydro-7H-[l,2,4]triazolo[4',3': 1,6] pyrido[3,2b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate as a solid (60 mg, 95%). ES+ [M]+:518.47; LC-MS (B05) tR = 2.10 min.
Step 3: (S)-4-(2,4-dimethylpyrimidin-5-yl)-12-]luoro-7a,8,13,14-tetrahydro-7H[ 1,2,4] triazolo[4', 3 1,6]pyrido[3,2-b]benzofuro[4,3-fg] [1,4]oxazonine
A solution of tert-butyl (15R)-21-fluoro-10-(2,4-dimethyl pyrimidyl)-13,l 7-dioxa-3,5,7,8tetrazapentacyclo [13.6.1.04,12.05,9.018,22] docosa-1(21),4( 12),6,8,10,18(22), 19-heptaene-3carboxylate (0.1 16 mmol, 60.0 mg) in HFIP (1.50 mL) was heated to 100 °C for 4 h. The mixture
183 was concentrated under reduced pressure, and the residue was purified by préparative HPLC (BEH Cl8 30x150mm AmForm/ACN 35-45%_13 min) to afford (S)-4-(2,4-dimethylpyrimidin-5-yl)-12fluoiO-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3fg][ 1,4] oxazonine as a solid (11.2 mg, 23%). lH NMR DMSO 400 MHz, δ 9.44 (s, 1H), 8.62 (s, 1H), 7.62 (t, J = 6.3 Hz, IH), 7.41 (s, 1H), 7.04-6.89 (m, 1H), 6.70 (dd, J = 8.6, 3.8 Hz, 1H), 4.92 (dd, J= 15.1,5.7Hz, 11-1),4.79 (dd, J = 15.1,6.7Hz, IH), 4.54 (t, J = 9.4 Hz, 1H), 4.50 - 4.42 (m, 1H), 4.21 (dd, J = 9.6, 3.5 Hz, IH), 4.10 - 3.99 (m, IH), 3.88 (t, J = 11.4 Hz, IH), 2.63 (s, 3H), 2.35 (s, 3H). ES+ [M+H]+:419.88; LC-MS (A05) tR = L91 min.
Example 32: 4-(2,4-diniethylpyrimidin-5-yl)-12-fluoro-7,8,13,14-tetrahydro[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzo[f][l,4Joxazonine, 3MsOH
Step 1: tert-butyl 4-(2,4-dimethylpyrimidin-5-yl)-i 2-fluoro-8,l 3-dihydro[1,2,4]triazolo[4 ',3':1,6]pyrido[3,2-b] benzo[f] [1,4] oxazonine-14(7H)-carboxylate
Dioxane (1.33 mL) and water (0.265 mL) were sequentially added to a mixture of tert-butyl (S)-4bromo-12-fluoro-7a, 13-dihydro-7H-[ 1,2,4]triazolo[4',3’:l,6]pyrido[3,2-b]benzofuro[4,3fg][l,4]oxazonine-14(8H)-carboxylate (Example 16; 50.0 mg, 0.108 mmol), 2, 4-dimethyl-5(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine (35.4 mg, 0.151 mmol), Pd(dppf)Cl2 (11.8 mg, 0.0162 mmol), and NaHCOj (27.2 mg, 0.324 mmol) under N2. The mixture was stirred at 90 °C for 3 h. The mixture was filtered though a short silica pad, washing with DCM (3X5 mL). The filtrate was concentrated under reduced pressure, and the residue was purified b y silica gel chromatography (12 g, cartridge) eluting with MeOH in DCM (0-15 %) to afford tert-butyl 4-(2,4dimethylpyrimidin-5-yl)-12-fluoro-8,13-dihydiO-[l,2,4]triazoIo[4’,3':l,6]pyrido[3,2b]benzo[f][l,4]oxazonine-I4(7H)-carboxylate as a solid (60.0 mg,75% purity, 85%), which was used as such in the next step. ES+ [M+H]+:49L21; HPLC tR = 2.25 min.
Step 2; 4-(2,4-dimethylpyrimidin-5-yl)-12-fluoro-7,8,13,14-tetrahydro[1,2,4] triazolo[4', 3 1,6]pyrido[3,2-b]benzo[f] [1,4] oxazonine
184
A solution of tert-butyl 4-(2,4-dimethylpyrimidin-5-yl)-12-fluoiO-8,i3-dihydiO[l,2,4]triazoIo[4',3,:l,6]pyrido[3,2-b]benzo[f[][l,4]oxazonine-14(7H)-carboxylate (45.0 mg, 0.0917 mmol) in HFIP (3.00 mL) was heated to 100 °C for 4 h. The mixture was concentrated under reduced pressure, and the residue was purified by préparative HPLC (BEH C18 30x150mm AmBicarb/ACN 25-45%) to afford 4-(2,4-dimethylpyrimidin-5-yl)-12-fluoro-7,8,13,14-tetrahydro[l,2,4]triazolo[4',3': l,6]pyrido[3,2-b]benzo[f][l,4]oxazonîne as a solid (14.7 mg, 41%). ES+ [M+H]É 391.2; HPLC tR = 2.08 min.
Step 3: 4-(2,4-dimethylpyrimidm-5-yl)-12-fluoro-7.8,13.14-tetrahydro10 [1,2,4]triazolo[4’,3':l,6]pyrido[3,2-b] benzoff][1,4]oxazonine, 3MsOH
4-(2,4-dimethylpyrimidin-5-yl)- 12-fluoro-7,8,13,14-tetrahydro-[ 1,2,4]triazolo[4',3':l,6]pyrido[3,2b]benzo[f][ 1,4] oxazonine (14.7 mg, 0.0377 mmol) was dissolved in MeOH (4.00 mL). MsOH (7.34 15 uL, 0.113 mmol) was added, and the mixture was stirred for 2 h at rt. The mixture was concentrated under reduced pressure to afford the title compound as a solid (20.6 mg, 81 %). 'H NMR MeOD 500 MHz, δ 9.54 (s, 1H), 8.84 (s, IH), 8.00 (s, 1H), 7.24 (td, 8.0, 5.9 Hz, 1 H), 7.06 (d, J = 6.9 Hz,
185
IH), 7.03-6.98 (m, IH), 5.17 (s, 2H), 4.51 (s, 2H), 3.19 (s, 2H), 2.87 (s, 3H), 2.70 (s, 9H), 2.51 (s, 3 H). ES+ [M+H]+: 391.1; HPLC tR = 1.15 min.
Example 33: (S)-12-fluoro-4-(4-methyl-lH-imiclazoH-yl)-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4,,3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine hydrochloride
Step 1: tert-butyl (S)-12-fluoro-4-(4-methyl-lH-imidazol-l-yl)-7a,I3-dihydro-7H[l, 2,4] triazolo[4',3': 1,6]pyridoft,2-b]benzofuro[4,3-fg] [l,4]oxazonine-14(8H)-carboxylate
A flask was charged with tert-butyl (S)-4-bromo-12-fluoro-7a,13-dihydiO-7H[l,2,4]triazolo[4',3’:l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (Example 16; 0.12 g, 244 umol, 1.00 eq), 4-methyl-lH-imidazole (30.1 mg, 366 umol, 1.5 eq) and K3PO4 (104 mg, 488 umol, 2.00 eq) at 15°C and purged with N2. Another flask was charged with Pd2(dba)3 (11.2 mg, 12.2 umol, 0.05 eq) and ditert-butyl-[2,3,4,5-tetramethyl-6-(2,4,6triisopropylphenyl) phenyl] phosphane (11.7 mg, 24.4 umol, 0.100 eq), toluene (2 mL) and dioxane (0.4 mL) at 15°C, then purged with mtrogen and heated at 120°C for 0.05 hr. Then it was cooled to 15°C. The obtained mixture (per-catalyst) was added to the first mixture via syringe. The resulting mixture was stirred at 120°C for 10 h. LC-MS showed tert-butyl (S)-4-bromo-12-fluoro-7a,13dihydro-7H-[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)carboxylate was consumed completely and the desired mass was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-ALC (SiO2, Ethyl acetate/Methanol = 10/1) to afford tert-butyl (S)-12-fluoro-4-(4-methyl-lH-imidazol-l-yl)-7a,13dihydiO-7H-[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuiO[4,3-fg][l,4]oxazonine-14(8H)carboxylate (40 mg) and (S)-12-fluoro-4-(4-methyI-lH-imidazol-I-yl)-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3’:l,6]pyrido[3,2-b]benzofuro[4,3-fg][I,4]oxazonine (15 mg). They were confirmed by LCMS, respectively. tert-butyl (S)-12-fluoro-4-(4-methyl-lH-imidazol-l-yl)-7a,13dihydro-7H-[l,2,4]triazolo[4,,3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)carboxylate (0.04 g, 81.22 umol, 33% yield) was obtained as a brown solid and used in the next step directly. (S)-l 2-fluoro-4-(4-methyl-lH-imidazol- l-yl)-7a,8,13,14-tetrahydro-7H[ 1,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine was further purified byprepHPLC (formic acid conditions) (column: Luna Cl8 100 * 30 5u; mobile phase: [water (0.2% FA) 186
ACN]; B%: 10% - 25%, 12 min) to afford pure (S)-12-fluoro-4-(4-methyl-lH-imidazol-l-yl)7 a, 8,13,14-tetrahydro-7H-[ 1,2,4]triazolo[4',3': 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4] oxazonine (3.20 mg, 7.15 umol, 2% yield, 97.974% purity, formate sait) as a yellow solid, which was combined with the other batch (de-Boc of tert-butyl (S)-12-iluoiO-4-(4-methyl-lH-imidazol-l-yl)7a,I3-dihydro-7H-[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)carboxylate).
Step 2: (S)-12-fluoro-4-(4-methyl-lH-imidazol-l-yl)-7a,8,13> 14Petrahydro-7H[ 1,2,4]triazolo[4’,3 1,6]pyrido[3,2-b]benzofuro[4.3-fg][1,4]oxazonine hydrochloride
To a solution of tert-butyl (S)-l2-nuoiO-4-(4-methyl-lH-imidazoLl-yl)-7a,13-dihydtO-7H[ l,2,4]triazolo[4',3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (0.03Û g, 60.9 umol, 1.00 eq) in DCM (1 mL) was added TFA (1.54 g, 13.5 mmol, 1.00 mL, 222 eq) at 15°C. The mixture was stirred at 15°C for 1 hr. LC-MS showed tert-butyl (S)-12-fluoiO-4-(4-methyl-lHimidazol-l-yl)-7a, 13-dihydro-7H-[l,2,4]triazolo[4',3': l,6]pyrido[3,2-b]benzofuro[4,3fg][ l,4] oxazonine-14(8H)-carboxylate was consumed completely and one main peak with desired mass was detected. The reaction mixture was blown to dryness by nitrogen stream. The residue was purified by prep-HPLC (formic acid conditions) (column: Lima C18 100 * 30 5u; mobile phase: [water (0.225% FA) - ACN]; B%: 1% - 30%, 12 min). The fraction was combined with batch ((S)12-fl uoro-4- (4-methyl -1 H-imi dazol -1 -yl)-7 a, 8,13,14-tetrahydro- 7H[l,2,4]triazolo[4’,3': 1,6]pyrido[3,2-b]benzoforo[4,3-fg][1,4]oxazonine from previous step, 3.2 mg as formate sait) and lyophilized together. Then one drop of 6 N of aqueous HCl solution was added and lyophilized again. (S)-12-fluoro-4-(4-methyl-lH-imidazol-l-yl)-7a,8,13,14-tetrahydro-7H[ 1,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine (11.5 mg, 26.5 umol, 98.8% purity, HCl) was obtained as a yellow solid. ’H NMR CD3OD 400 MHz, δ = ppm 9.82 (s, IH), 9.33 (s, IH), 8.40 (s, IH), 7.71 (s, IH), 6.93 (t, 7=9.48 Hz, IH), 6.69 (dd,J= 8.68, 3.79 Hz, IH), 5.20 (brd, J= 14.79 Hz, IH), 5.02 (brd, 7 = 14.18 Hz, IH), 4.80 (br s, IH), 4.64 (t, 7= 9.41 Hz, IH), 4.34 (br dd, 7= 9.66, 2.81 Hz, 1 H), 4.11 (br s, IH), 4.06 - 3.93 (m, 1 H), 2.49 (s, 3H). LCMS (ESI+): m/z 393.2 (M+H).
187
Example 34: methyl (S)-4-(12-fluoro-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3':l,6]pyrÎdo[3,2-b]benzofuro[4,3-fg][l,4]oxazonin-4-yl)piperÎdine-lcarboxylate mesylate sait
Step 1: tert-butyl (8)-4-(1-(tert-butoxycarbonyl)-l,2,3,6-tetrahydropyridin-4-yl)-12-fluoro-7a, 135 dïhydro-7H-[l,2,4]tnazol()[4',3': 1,6]pyrido[3,2-b]benzofuro[4,3-fg] [ 1,4] oxazonine-14(8H)carboxylate
Dioxane (2.00 mL) and water (0.400 mL) were added to a mixture of tert-butyl (R)-4-bromo-12fluoro-7a, 13-dihydro-7H-[ 1,2,4]triazolo[4’,3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4]oxazonine10 14(8H)-carboxylate (Example 16; 0.204 mmol, 100 mg), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2dioxaboroIan-2-yD-3,6-dihydiO-2H-pyridine-l-carboxylate (0.305 mmol, 94.4 mg), Pd(dppf)Cl2 (0.0204 mmol, 14.9 mg), and NaHCO3 (0.611 mmol, 51.3 mg) under N2. The mixture was stirred at 90 °C for 2 h. The mixture was filtered though a silica pad. The fïlter cake was washed with EtOAc (3x5 mL), and the fîltrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (4 g cartridge) eluting with MeOH in DCM (0-10 %) to afford tert-butyl (S)-4-(l -(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-12-fluoro-7a, 13-dihydro-7H[l,2,4]triazolo[4',3’: 1,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (102 mg, 84%). ES+ [M]+: 593.48; LC-MS (A05); tR = 2.49 min.
Step 2: tert-butyl (8)-4-(l-(tert-butoxycarbonyl)piperidin-4-yl)-12-fliioro-7a, 13-dihydro-7H20 [1,2,4] triazolo[4 , 3 1,6]pyrido[3,2-b] benzofitro[4,3-fg[[1,4] oxazonine-14(8H)-carboxylate
188
A solution of tert-butyl (S)-4-(l-(tert-butoxycarbonyl)~l,2,3,6-tetrahydropyridin-4-yl)-12-fluoiO7a,13-dihydiO-7H-[l,2,4]triazolo[4',3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)carboxylate (172 pmol, 102 mg) in MeOH (10.0 mL) was added to a flask charged with Pd/C (34.4 pmol, 36.6 mg, 10.0 %) under a nitrogen atmosphère at room température. The flask was evacuated and purged with PL gas 3 times. The mixture was stirred at ri for 20 h. The mixture was fdtered through Celite, and the filter cake was washed with MeOH (3X8 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (4 g cartridge) eluting with MeOH in DCM (0-15 %) to afford tert-butyl (S)-4-(l-(tert-butoxycarbonyl)piperidin-4- yl)-12-fluoro-7a, 13-dihydro-7H-[ l ,2,4]triazolo[4',3’:l,6]pyrido[3,2-b]benzofuro[4,3fg][ l,4]oxazonine-14(8H)-carboxylate as a solid (81.2 mg, 79%). m/z (ES+) [M]1:596.32, LC-MS, (A05) tR = 2.52 min.
Step 3: (S)-12-fhtoro-4-(piperidin-4-yfi7a,8,13,14-tetrahydro-7H[1,2,4] triazolo[4',3 ':1,6]pyrido[3,2-b] benzofuro[4,3-fg][1,4] oxazonine
TFA (2.73 mmol, 0.209 mL) was added to a solution of tert-butyl (S)-4-(l-(tertbutoxycarbonyl)pÎperidin-4-yI)-12-fluoro-7a,13-dihydro-7H-[l,2,4]triazolo[4,,3':l,6]pyrido[3,2b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxyiate (136 pmol, 81.2 mg) in DCM (2.00 mL) at room température. The mixture was stitred at room température for 8.5 h. The mixture was
189 concentrated under reduced pressure and used as such in the next step without further purification, m/z (ES+) [M]+: 395.54; LC-MS (A05), tR = 1.69 min.
Step 5: methyl (S)-4-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4’,3':l,6]pyrido[3,2b]benzofuro[4,3-fg] ]l,4]oxazonin-4-yl)piperidine-l-carboxylate
Methyl chloroformate (150 μιηοΐ, 14.2 mg, 11.6 gL) was added drop wise to a solution of (S)-12fluo!O-4-(piperidin-4-yI)-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4',3': l,6]pyrido[3,2b]benzofuro[4,3-fg][l,4]oxazonine (136 pmol, 53.9 mg) and triethylamine (818 gmol, 82.8 mg, 114 μΕ) in DCM (2.00 mL) at 0 °C. The mixture was stirred at 0 ÛC for 2 h. The mixture was concentrated under reduced pressure, and the residue was purified by HPLC (Gemini C18 3Ox 100mm AmBiCarb/ACN 36-56%) to afford methyl (S)-4-(12-fluoro-7a,8,13,14-tetrahydro-7H[1,2,4]triazolo[4',3': l,6]pyrido[3s2-b]benzoftiro[4,3-fg][l,4]oxazonin-4-yl)piperidine-l-carboxylate as a solid (30.5 mg, 49%). lH NMR DMSO 500 MHz, δ 9.32 (s, 1H), 7.14 (t, J = 6.4 Hz, 1H), 7.07 (s, 1H), 6.92 (dd, J = 10.2, 8.8 Hz, 1H), 6.66 (dd, J = 8.6, 3.8 Hz, 1H), 4.82 (dd, J = 14.9, 5.9 Hz, 1H), 4.68 (dd, J = 15.0, 6.9 Hz, 1H), 4.51 (t, J = 9.4 Hz, 1H), 4.44 (d, J = 6.4 Hz, 1H), 4.20 (dd, J = 9.6, 3.3 Hz, 1H), 4.15 - 4.03 (m, 2H), 4.02 - 3.91 (m, 1H), 3.78 (t, J = 11.5 Hz, 1H), 3.61 (s, 3H), 3.22-3.09 (m, 1 H), 2.91 (brs, 2H), 1.89 (t, J = 13.7 Hz, 2H), 1.76 - 1.60 (m, 2H). m/z (ES+) [Mf:453.25; LC-MS (A05); tR = 2.17 min.
Step 6: methyl (5)-4-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo]4',31,6]pyrido[3,2b] benzofuro]4,3-fg][1,4] oxazonin-4-yl)piperidine-1-carboxylate mesylate sait
190
MeSOjH (0.0529 mmol, 3.44 pL) was added to a stirred suspension of methyl (S)-4-(12-fluoro7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4’,3’:l,6]pyndo[3,2-b]benzofuro[4,3-fg][l,4]oxazonin-4yl)piperidine-1-carboxylate (0.0529 mmol, 24.0 mg) in MeCN (1.00 mL) at room température. The mixture was stirred at room température for 1 h. The solution was concentrated under reduced pressure to afford the title compound as a solid (26.3 mg, 90%). ’H NMR DMSO 500 MHz, δ 9.59 (s, IH), 7.96 (s, IH), 7.68 (s, IH), 6.96 (dd, J = 10.2, 8.8 Hz, IH), 6.70 (dd, J = 8.6, 3.8 Hz, IH), 4.89 (dd, J = 14.9, 5.3 Hz, IH), 4.75 (dd, J = 14.9, 6.8 Hz, IH), 4.61-4.56 (m, IH), 4.54 (t, J = 9.5 Hz, IH), 4.23 (dd, J = 9.7, 3.5 Hz, IH), 4.13 (s, 2H), 4.01 (ddd, J = 13.6, 8.5, 3.9 Hz, IH), 3.82 (t, J = 11.4 Hz, IH), 3.61 (s, 3H), 3.08 (tt, J = 12.0, 3.2 Hz, IH), 2.89 (s, 2H), 2.32 (s, 3H), 1.81 (t, J = 13.4 Hz, 2H), 1.76- 1.50 (m, 2H). m/z (ES+) [M-MsOH] 453.52; LC-MS (A05) tR = 2.04 min.
Exainple 35: (S)-12-fluoro-4-(4-methylpyrimidin-5-yl)-7a,8,13,14-tetrahydro-7H11,2,4] triazolo[4',3’:l,6]pyrido[3,2-b]benzofuro]4,3-fg] [1,4] oxazonine
Step 1: 4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine
To a solution of 5-bromo-4-methylpyrimidine (700 mg, 4.05 mmol, 1.00 eq), 4,4,5,5-tetramethyJ-2(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (1.34 g, 5.26 mmol, 1.3 eq) in dioxane (10 mL) was added KOAc (794 mg, 8.09 mmol, 2.00 eq) Pd(dppf)Cl2 (296 mg, 405 umol, 0.100 eq) at 25°C, then the mixture was stirred al 80°C under nitrogen for 12 h. LCMS showed the reaction was complété, starting material was consumed, desired target MS was detected. The mixture was concentrated, then dissolved with EtOAc (15 mL), fïltered, the filtrate was concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate =1/0 to 0/1 and then Ethyl acetate/MeOH = 1/0 to 0/1). 4-methyl-5-(4,4,5,5-tetramethyl191 l,3,2-dioxaborolan-2-yl)pyrimidine (0.800 g, 3.64 mmol, 89% yield) was obtained as a yellow oil.
*H NMR CDC13 400 MHz, δ = ppm 9.08 (s, 1H), 8.90 (s, 1H), 2.71 (s, 3H), 1.36 (s, 12H).
Step 2: (S)-12-fiuoro-4-(4-methylpyrimidin-5-yl)-7a,8,13,14-tetrahydro-7H[1,2,4] triazo lo[4',3':l, 6]pyrido[3,2-b]benzofuro[4,3-fg] [1,4] oxazonine
To a solution of 4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine (56.3 mg, 256 umol, 2.00 eq), (S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4',3':l,6]pyrido[3,2b]benzofuro[4,3-fg][ 1,4]oxazonine (50.0 mg, 128 umol, 1.00 eq) in dioxane (5 mL), water (0.5 mL) was added NaHCO3 (53.7 mg, 639. umol, 24.9 uL, 5.00 eq), Pd(dppf)Cl2 (9.35 mg, 12.8 umol, 0.100 eq) in 25°C, then the mixture was stirred at 80°C for 6 h. LCMS showed the reaction was complété, starting material was consumed, desired target mass was detected. The mixture was concentrated under reduced pressure, dissolved in Ethyl acetate (20 mL), then filtered, the filtrate was concentrated under reduced pressure to afford cru de product. The cru de product was purified by prep-HPLC (column: Luna Cl 8 100*30 5u; mobile phase: [water (0.225% FA)-ACN]; B%: 20%50%, 12 min). (S)-12-fluoro-4-(4-melhylpyrimidin-5-yl)-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3’:l,6]pyrido[3,2-b]benzofuiO[4,3-fg][l,4]oxazonine (19.8 mg, 48.2 umol, 37% yield, 98.5% purity) was obtained as a white solid. !H NMR DMSO-c/é 400 MHz, δ = ppm 9.46 (s, 1H), 9.06 (s, 1H), 8.76 (s, IH), 7.69 - 7.62 (m, 1H), 7.48 (s, 1H), 6.98 (br t, J = 9.4 Hz, 1H), 6.71 (br dd, J-8.4, 3.5 Hz, 1H), 4.98 - 4.89 (m, 1H), 4.86 - 4.74 (m, 1H), 4.54 (br d, J-9.5 Hz, 1H), 4.52 4.45 (m, 1 H), 4.22 (brdd, 7=9.4, 3.4 Hz, 1H), 4.05 (br d, 7= 3.5 Hz, 1H), 3.95 - 3.83 (m, 1H), 2.41 (s, 3H). LCMS (ESI+): m/z 405.1 (M+H).
Example 36: (S)-12-fluoro-4-(2-methylpyrimidin-5-yl)-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg|[l,4]oxazonine
To a stirred solution of 2-niethyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine (45.0 mg, 205 umol, 2.00 eq), (S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H192
[I,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine (40.0 mg, 102 umol, 1.00 eq) and NaHCO3 (43.0 mg, 511 umol, 19.9 uL, 5.00 eq) in dioxane (3.00 mL) and water (0.60 mL) was added Pd(dppf)Cl2 (7.48 mg, 10.2 umol, O.lOOeq) at 15°C under N2. The resulting mixture was stirred at 90°C for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by neutral prep-HPLC. (S)-12-fluoro-4-(2-methylpyrimidin-5-yI)-7a,8,13,14-tetrahydro7H-[ 1,2,4] triazolo[4',3':l, 6] pyrido[3,2-b]benzofuro[4,3-fg][ 1,4] oxazonine(8.20 mg, 19.5 umol, 19% yield, 96.0% purity) was obtained as a yellow solid. 'H NMR DMSO-> 400 MHz, δ = ppm 9.48 (s, 3H), 7.93 (s, 1H), 7.73 (brs, 1H), 6.96 (t, J=9.3 Hz, 1H), 6.69 (dd. >8.6, 3.9 Hz, IH), 4.97-4.87 (m, 1H), 4.83 (br s, 1H), 4.54 (br t, J=9.2 Hz, 2H), 4.23 (dd, >9.6, 3.2 Hz, 1H), 4.03 (br d, >9.0 Hz, 1H), 3.99 - 3.90 (m, 1H), 2.66 (s, 3H). LCMS (ESI+): m/z 405.1 (M+H).
Example 37: (S)-4-(3-(difluoromethyl)-l-methyI-lH-pyrazol-4-yl)-12-fluoro-7a,8,13,14tetrahydro-7H-[l,2,4[triazolo[4’, 3' :l,6)pyrido|3,2-b]benzofuro[4,3-fg] [1,4] oxazonine Step 1:4-bromo-3-(difluoromethyl)-l-methyl-lI-l-pyrazole
F
The reaction was set up as two separate batches. To a solution of 4-bromo- 1-methyl-lH-pyrazole-3carbaldehyde (450 mg, 2.38 mmol, 1.00 eq) in DCM (8 mL) was added DAST (2.30 g, 14.3 mmol, 1.89 mL, 6 eq) at 0°C, then the mixture was stirred at 20°C for 5 h under nitrogen atmosphère. LCMS indicated that the complété conversion. The batches were combined, aq. NaHCO3 (5%, 6 mL) was added dropwise to the reaction solution under ice bath cooling to adjust pH to 7-8, then the mixture was extracted with EtOAc (10 mL * 3), the organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 1/0 to 3/1; Petroleum ether/Ethyl acetate = 3/1, Rf= 0.4). 4-bromo3-(difluoromethyl)-l-methyl-lH-pyrazole (830 mg, 3.93 mmol, 82% yield) was obtained as a light brown oil.
Step 2: (3-(difluoromethyl)-I-methyl-] H-pyrazol-4-yl)boronic acid
193
To a solution of 4-biOmo-3-(difluoromethyl)-l-methyl-lH-pyrazole (400 mg, 1.90 mmol, 1.00 eq) in THF (10 mL) was added n-BuLi (2.5 M, 910 uL, 1.2 eq) at -78°C, the mixture was stirred at 78°C for 0.5 hr, then triisopropyl borate (1.07 g, 5.69 mmol, 1.31 mL, 3.00 eq) was added to the mixture at -78°C, the mixture was stirred at -78°C for 1.5 h. LCMS showed 4-bromo~3(dîfluoromethyl)-l-methyl-lH-pyrazole was consumed conipletely and the desired mass was detected. Water (10 mL) was added to the mixture, then the mixture was concentrated. The residue was purified by prep-HPLC (column: Xbridge 150*30 mm * 10 um; mobile phase: [water (0.1% TFA) - ACN]; B%: 1% - 20%, 10 min). (3-(difluoromethyl)-l -methyl-lH-pyrazoL4-yl)boronic acid (110 mg, 625 umol, 32% yield) was obtained as a whîte solid.
Step 3: (S)-4-(3-(difluoromethyl)-i-methyl-lH-pyrazol-4-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H[ I,2,4]triazolo[4',3’:1,6]pyrido[3,2-b] benzofuro[4,3-fg] [l,4]oxazonine
F
To a solution of (S)-4-biOmo-12-fluoro-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine (60.0 mg, 153.4 umol, 1.00 eq) in dioxane (1 mL), water (0.1 mL) was added (3-(difluoromethyl)-l-methyl-lH-pyrazol-4yl)boronic acid (67.5 mg, 383 umol, 2.5 eq), Pd(dppf)Cl2 (11.2 mg, 15.3 umol, 0.100 eq) and NaHCOs (64.4 mg, 767 umol, 29.8 uL, 5.00 eq) at 20°C, the mixture was stirred at 80°C for 12 h under N2. LC-MS showed that (S)~4-bromo-12-fIuoro-7a,8,13,14-tetrahydro-7H[ l,2,4]triazolo[4',3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][I,4]oxazonine was consumed completely and the desired mass was detected. The reaction was filtered, the filtrate was concentrated. The residue was purified by /^rep-HPLC (column: Luna C18 100*30 5u; mobile phase: [water (0.2% FA) - ACN]; B%: 35% - 45%, 12 min). (S)-4-(3-(difluoromethyl)-LmethyLlH-pyrazoi-4-yl)-12-fluoiO7a,8,13,I4-tetrahydro-7H-[i,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine (25.0 mg, 56.0 umol, 36% yield, 99.1% purity) was obtained as a yellow solid. 'H NMR DMSO-4 400 MHz, 5 = ppm 9.43 (s, 1H), 8.61 (s, 1H), 7.47 (brt, J= 6.4 Hz, IH), 7.41 (s, 1H), 7.24 (t, J = 54,0 Hz, 1H), 6.99-6.91 (m, IH), 6.69 (dd, J=8.6, 3.9 Hz, 1H), 4.93 - 4.73 (m, 2H), 4.57-4.42 (m, 2H), 4.24 (dd, J= 9.5, 3.3 Hz, IH), 4.04 (br s, IH), 3.96 (s, 3H), 3.89 - 3.80 (m, IH). 'H NMR CDClj 400 MHz, δ = ppm 8.77 (s, IH), 8.73 (s, IH), 7.47 (brt, J =6.4 Hz, IH), 7.41 (s, IH), 6.92
194
6.82 (m, 1H), 6.85 (t, J = 54.0 Hz, 1H), 6.67 (dd, 8.6, 3.9 Hz, 1H), 5.13 - 5.05 (m, 1H), 4.88 4.80 (m, 1 H), 4.70 - 4.60 (m, 2H), 4.30 (dd, 7= 9.5, 3.3 Hz, 1H), 3.99 (s, 3H), 3.97 - 3.80 (m, 2H). LCMS (ESI+): m/z 443.1 (M+H).
Example 38: (S)-4-((S)-12-fluoro-7a,8,13,14-tetraliydro-7H-[l,2,4|triazolo[4',3':l,6]pyrido|3,2b]benzofuro[4,3-fg] [1,4] oxazonin-4-yl)-l-methylpiperidin-2-one and (R)-4-((S)-12-fluoro7a,8,13,14-tetrahydro-7H-[ l,2,4]triazolo [4',3': 1,6)pyrido[3,2-b]benzofuro[4,3-fg] [1,4] oxazonin4-yl)-l-methylpiperidin-2-one
Step 1 : l-methyl-4-(4,4,5,5-tetramethy 1-1,3,2-dioxaborolan-2-yl)pyridin-2( 1 H)-one o
To a solution of 4-bromo-Lmethylpyridin-2(lH)-one (950 mg, 5.05 mmol, 1.00 eq) in dioxane (50 mL) was added KOAc (1.49 g, 15.2 mmol, 3.00 eq), 4,4,4',4',5,5,5,,5'-octamethyl-2,2’-bi(l,3,2dioxaborolane) (1.80 g, 7.07 mmol, 1.4 eq) and Pd(dppf)Cl2.DCM (413 mg, 505 umol, 0.100 eq). The mixture was stin-ed at 110°C for 2 hrs under nitrogen atmosphère. LCMS showed the starting materia) was consumed completely and the desired MS was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Ethyl acetate:Methanol = 0:1 to 1:0). 1 -methyI-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)pyridin-2(lH)-one (650 mg, crude) was obtained as yellow oil. ’H NMR CDC13 400 MHz, δ = ppm 7.27 - 7.21 (m, 1H), 7.01 (s, 1H), 6.40 (d, 7=6.6 Hz, 1H), 3.53 (s, 3H), 1.31 (s, I2H).
Step 2: (3)-4-(12-fluoro-7a, 8,13,14-tetrahydro-7H-[1,2,4]triazolo[4 ', 3 1,6]pyrido[3,2b]benzofuro[4,3-fg] [1,4]oxazonin-4-yl)-l-methylpyridin-2( IHfcme
To a solution of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(lH)-one (397 mg, 1.69 mmol, 2.2 eq) in dioxane (10 mL) and water (2 mL) was added NaHCO3 (193 mg, 2.30 mmol, 89.5 uL, 3.00 eq), (S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4’,3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine (Example 17; 300 mg, 767 umol, 1.00 eq) and Pd(dppf)Cl2 (56.1 mg, 76.7 umol, 0.100 eq) under nitrogen atmosphère. The
195 mixture was stirred at 80°C for 8 hrs. LCMS showed the starting material was consumed completely and the desîred MS was detected. The reaction mixture was filtered and the filter cake was washed by MeOH (20 mL). The filter cake was dried under reduced pressure to give a crude product. The crude product was used to the next step wîthout further purification. (S)-4-(12-fluoro7a, 8,13,14-tetrahydro-7H-[ 1,2,4]triazolo[4',3': 1,6]pyrido[3,2-b]benzofuro[4,3-fg] [l,4]oxazonin-4yl)-l-methylpyrîdin-2(lH)-one (280 mg, ciude) was obtained as a green solid. NMR DMSO-rf0 400 MHz, δ =ppm 9.39 (s, 1H), 7.80 (s, IH), 7.63 (s, 1H), 7.56 (s, iH), 7.01 (s, 1H), 6.92 (s, 1H), 6.65 (s, 1H), 4.89 (s, 2H), 4.51 (s, 2H), 4.04 - 3.90 (m, 2H), 4.04 - 3.89 (m, 3H), 3.32 (s, 3H).
Step 3: (S)-4-((S)-12-fluoro-7a, 8,13,14-tetrahydro-7H-[1,2,4]triazolo[4 3 6]pyrido[3,2b]benzofuro[4,3-fg] [I,4]oxazomnM-yl)-l-methylpiperidin-2-one and (R)-4-((S)-12-fluoro7a, 8,13,14-tetrahydro-7H-[l,2,4] triazolo[4 3':1,6]pyrido[3,2-b] benzofuro[4,3-fg] [1,4] oxazonin-4yl)-1 -methylpiperidin-2-one
To a solution of(S)-4-(12-fluoro-7a,8,I3,14-tetrahydro-7H-[l,2,4]triazolo[4',3,:l,6]pyrido[3,2b]benzofuro[4,3-fg][ l,4]oxazonin-4-yl)-l-methylpyridin-2(!H)-one (190 mg, 453 umol, 1.00 eq) in MeOH (20 mL) was added AcOH (10.5 g, 175 mmol, 10.0 mL, 386 eq) and 10% Pd/C (200 mg, 50% purity at 20°C. The mixture was stirred at 50°C for 5 hrs under FL (15 Psi) atmosphère. LCMS showed most of the starting material was consumed and the desîred MS was detected. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The resîdue was purified byprep-HPLC (formic acid conditions) to give 4-((S)-12-fluoro7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4’,3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonin-4yi)-l-methylpiperidin-2-one (120 mg). The diastereomers were separated by chrial SFC. Column conditions: Waters Prep 80Q SFC; Chiralpak AD, 250*30 mm i.d. lOu; Mobile phase A for CO2; Mobile phase B for MeOH (0.1% NH3H2O)-CH3CN (2:1); Gradient, B% = 50%; Flow rate, 80 g/min; 40°C; 100 bar.
(S)-4-((S)- l2-iluoro-7a,8,13,14-tetrahydro-7H-[ 1,2,4]triazolo[4',3': 1,6]pyrido[3,2-b]benzofuro[4,3fg][L4]oxazonin-4-yi)-l-methylpiperichm2-one (54.4 mg, 126.6 umol, 27% yield, 98.6% purity) (Rt = 1,71 min) was obtained as a yellow solid. ’H NMR DMSO-t4 400 MHz, δ = ppm 9.35 (s, 1H), 7.22 (t, 7= 6.2 Hz, 1H), 7.09 (s, 1H), 6.93 (t,7=9.5 Hz, 1H), 6.68 (dd, 7= 8.6, 3.7 Hz, 1H), 4.874.80 (m, 1H), 4.75 -4.67 (m, 1H), 4.52 (t, 7= 9.4 Hz, 1 H), 4.44 (d,7=6.4 Hz, 1H),4.21 (dd,7 =
196
9.6, 3.1 Hz, IH), 4.04 - 3.95 (m, IH), 3.84 - 3.76 (m, IH), 3.49 - 3.39 (m, 2H), 3.32 - 3.25 (m, IH), 2.86 (s, 3H), 2.60 (d, 8.3 Hz, 2H), 2.16 - 2.06 (m, 2H). LCMS (ESI+): nVz 424.2 (M+H)..
(R)-4-((S)-12-fluoro-7a,8,l3,14-tetrahydro-7H-[l,2,4]triazolo[4',3,:l,6]pyrido [3,2-b]benzofuro[4,3fg][l,4]oxazonin-4-yl)-l-methylpiperidin-2-one (41.6 mg, 93.64 umol, 20% yield, 95.254% purity) (Rt = 2.44 min) was obtained as a white solid. *H NMR ET15715-773-P2B2 DMSO-r/à 400 MHz, S = ppm 9.36 (s, IH), 7.23 (t, J= 6.1 Hz, IH), 7.08 (s, IH), 6.93 (t, J= 9.5 Hz, IH), 6.67 (dd, J = 8.6, 3.7 Hz, IH), 4.84 (dd, J = 15.0, 5.7 Hz, IH), 4.73 - 4.65 (m, IH), 4.52 (t, J= 9.4 Hz, IH), 4.46 (d, J = 5.6 Hz, IH), 4.23 (dd, J = 9.5, 2.8 Hz, IH), 3.98 (br s, IH), 3.85 - 3.77 (m, IH), 3.43 (dd, 10.4, 5.5 Hz, 2H), 3.32 - 3.28 (m, IH), 2.86 (s, 3H), 2.60 - 2.56 (m, 2H), 2.18 - 2.10 (m, 2H). LCMS (ESI+): m/z 424.2 (M+H).
Example 39: methyl 4-(12-fluoro-6,8,13,14-tetrahydro-[l,2,4|triazolo[4’,3’:l,6]pyridol3,2c]benzolgHl,5]oxazonin-4-yl)piperidine-I-carboxylate methanesulfonyl sait
Step 1 : tert-butyl I2-fluoro-4-(l-(methoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-8,13-dihydro[1,2,4]triazolo[4’, 3 ':l,6]pyrido[3,2-c]benzo[g] [l,5]oxazonine-14(6H)-carboxylate
1,4-Dioxane (3.00 mL) and water (0.600 mL) were added to a mixture of tert-butyl 4-bromo-l2fluoro-8,13-dîhydro-[ 1,2,4]triazolo[4',3': l,6]pyrido[3,2-c]benzo[g][ 1,5]oxazonine-14(6H)carboxylate (from Example 24; 99.0 mg, 0.214 mmol), methyl 4-(4,4,5,5-tetramethyl-l,3,2dioxaboiOlan-2-yl)-3,6-dihydro-2H-pyridine-l-carboxylate (68.5 mg, 0.256 mmol), Pd(dppf)Cl2 (15.6 mg, 0.0214 mmol), and NaHCO3 (53.9 mg, 0.641 mmol) under nitrogen. The mixture was heated to 90 °C for 2.5 h. After cooling to 23 °C, the mixture was filtered though a silica plug which was then washed with EtOAc and 10% MeOH in DCM. The combîned filtrâtes were concentrated under reduced pressure. The product was purified by silica gel chromatography (12 g cartridge) eluting with DCM and MeOH (0-10%) to provide tert-butyl 12-fluoro-4-(l-(methoxycarbonyl)i,2,3,6-tetrahydropyridin-4-yl)-8,I3-dihydro-[l,2,4]triazolo[4',3':l,6]pyrido[3,2c]benzo[g][l,5]oxazonine-14(6H)-carboxyiate as a solid (107 mg, 77%). Complex NMR (rotamers). m/z (ES+), [M+H]+: 524.2. HPLC (A05) tR = 2.37 min.
Step 2: tert-butyl 12-fluoro-4-(l ~(methoxycarbonyl)piperidin-4-yl)-8,13-dihydro[1,2,4]triazolo[ 4 3 ':1,6]pyrido[3,2-c] benzo[g][1,5] oxazonine-14(6H)-carboxylate
197
A solution of tert-butyl 12-fluoro-4-(l-(methoxycarbonyl)-l,2,3,6-tetrahydropyridin-4-yl)-8,13dihydro-[ 1,2,4]triazolo[4',3': 1,6]pyrido[3,2-c]benzo[g][ 1,5]oxazonine- 14(6H)-carboxylate ( 102 mg, 156 pmol) in MeOH (12.0 mL) was added at 23 °C to a flask charged with 10% Pd/C (65.9 mg, 0.0619 mmol) under nitrogen atmosphère. The flask was evacuated and purged with H2 gas 3 times. The mixture was stirred at 23 °C for 1.5 h and filtered through Celite washing with MeOH. The filtrate was concentrated under reduced pressure. The product was purified by silica gel chromatography (12 g) eluting with DCM and MeOH (0-10%) to provide tert-butyl 12-fluoro-4-(l(methoxycarbonyl)piperidin-4-yl)-8,13-dihydro-[i,2,4]triazolo[4’,3l: l,6]pyrido[3,2c]benzo[g][l,5]oxazonine-14(6H)-carboxylate as a solid (69.0 mg, 84%). Complex NMR (rotamers). m/z (ES+) 526.2. HPLC (A05) tR = 2.33 min.
Step 3: methyl 4-(12-fluoro-6,8,13.I4-tetrahydro-[l,2,4]triazolo[4',3': l,6]pyrido[3,2c]benzo[g][1,5]oxazonin-4-yl)piperidine-I-carboxylate mesylate
A solution of tert-butyl 12-fluoro-4-(l-(methoxycarbonyl)piperidin-4-yl)-8,13-dihydro[ l,2,4]triazolo[4f,3': 1,6]pyrido[3,2-c]benzo[g][ 1,5]oxazonine-14(6H)-carboxylate (69.0 mg, 0.131 mmol) in HFIP (4.00 mL) was heated to 100 °C for 12 h. After cooling to 23 °C, the mixture was concentrated under reduced pressure. The product was purified by silica gel chromatography (12 g cartridge) eluting with DCM and MeOH (0-10%) to provide the free base of the title compound as a solid (48.0 mg; 86%). *H NMR (500 MHz, MeOD) δ 9.39 (s, IH), 7.29 (td, J= 7.9, 5.7 Hz, IH), 7.16 (d, J =7.6 Hz, 1 H), 7.14 (s, 1 H), 7.03 (t, 9.0 Hz, 1H),4.73 (s, 2H), 4.68 (s, 2H), 4.52 (s,
2H), 4.26 (d, J = 10.7 Hz, 2H), 3.71 (s, 3H), 3.29 - 3.24 (m, IH), 3.08-2.92 (m, 2H), 1.99 (d, J = 12.9 Hz, 2H), 1.70 (qd, J= 12.6, 4.1 Hz, 2H). The compound was converted to the methanesulfonyl sait by addition of MeSO3H (3.36 pL, 51.7 mmol) to a solution the free base (22.0 mg, 0.0517 mmol) in MeCN (2.00 mL). The mixture was stirred at 23 °C for 1 h. The mixture was concentrated under reduced pressure to provide the title compound as a solid (24.0 mg, 89%). *H NMR MeOD
198
500 MHz, δ 9.74 (s, 1H), 7.85 (s, 1 H), 7.37 (td, J = 8.0, 5.7 Hz, 1H), 7.20 - 7.04 (m, 2H), 4.94 (s, 2H), 4.93 (s, 2H), 4.61 (s, 2H), 4.31 (d, J = 12.2 Hz, 2H), 3.72 (s, 3H), 3.19 - 3.07 (m, 1H), 3.062.94 (m, 2H), 2.70 (s, 3H), 1.93 (d,J= 13.1 Hz, 2H), 1.74 (qd, J- 12.4,4.1 Hz, 2H). m/z (ES+), [M+H]+: 426.5. HPLC (A05) tR = 2.15 min.
Example 40: (S)-4-ethyl-12-fluoro-7a,8,13,14-tetrahydro-7H[l,2,4]tnazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fgHl,41oxazonine
Step I: (S)-I2-fluoro-4-vinyl-7a,8,13,14-letrahydro-7H-[l,2,4]triazolo[4',31,6]pyrido[3,2b]benzofwo[4,3-fg] [1,4] oxazonine
To a solution of(S)-4-bromo-12-nuoro-7a,8,13,14-tetrahydro-7H[ l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine (100 mg, 255.63 umol, 1.00 eq), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dîoxaboroIane (78.7 mg, 511 umol, 86.7 uL, 2.00 eq) and NaHCOî (107 mg, 1.28 mmol, 49.7 uL, 5.00 eq) in dioxane (2 mL) and water (0.2 mL) was added Pd(dppf)Cl2 ( 18.70 mg, 25.56 umol, 0.100 eq) at 25°C. The resulting mixture was stirred at 80°C under nitrogen for 2.5 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, EtOAc:MeOH = 20:1). (S)-12-fluoro-4-vinyl-7a,8,13,14tetrahydro-7H-[ 1,2,4]triazolo[4’,3': 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4]oxazonine (100 mg, crude) was obtained as yellow solid.
Step 2: (S)-4-ethyl-12-fluoro- 7 a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4', 3 ':1, 6]pyrido[3,2b]benzofiro[4,3-fg] [1,4] oxazonine
To a solution of (S)-12-fluoro-4-vinyl-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4’,3':l,6]pyrido[3,2b]benzofuro[4,3-fg][l,4]oxazonine (90.0 mg, 266 umol, 1.00 eq) in MeOH (4 mL) was added 10% Pd/C (90.0 mg, 50% purity) at 25°C. The mixture was stirred at 40°C under H2 (15 psi) for 1 hr. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by acidicprep-HPLC (column: Luna Cl 8 100*30 5u; mobile phase: [water (0.225% FA)ACN]; B%: 10%-50%, 12 min). (S)-4-ethyL12-fluoro-7a,8f13,14-tetrahydro-7H199
[l,2,4]triazolo[4,,3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine (11.7 mg, 32.9 umol, 12% yield, 95.6% purity) was obtained as a white solid. ’H NMR. CDC13 400 MHz, δ = ppm 8.68 (s, IH), 6.80 (s, IH), 6.80 - 6.72 (m, IH), 6.56 (dd, J= 8.6, 3.9 Hz, IH), 4.92 (br dd, 14.5, 7.4 Hz, IH), 4.70 (brdd, 7= 14.5, 5.7 Hz, IH), 4.58-4.45 (m, 3H), 4.17 (dd,7= 9.6, 2.6 Hz, IH), 3.86 - 3.71 (m, 2H), 2.97 - 2.82 (m, 2H), 1.27 (t, 7 = 7.5 Hz, 3H). LCMS (ESI+): m/z 341.1 (M+H).
Exampk 41: (S)-12-fluoro-4-(l H-pyrazol-l-yl)-7a,8,13,14-tetrahydro-7H[ 1,2,4] triazolo[4’,3’;l,61pyrido[3,2-b]beiizofuro[4,3-fgni,4] oxazonine Step 1: tert-butyl (S)-12-fluoro-4-(lH-pyrazol-l-yl)-7a,13-dihydro-7H[1,2,4]triazolo[4 3 I,6]pyrido[3,2-b]benzofuro[4,3-fgJ[1,41 oxazonine-14(8H)-carboxylate
A flask was charged with tert-butyl (S)-4-biOmo-12-fluoro-7a,13-dihydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuiO[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (0.120 g, 244 umol, 1.00 eq), IH-pyrazole (24.9 mg, 366 umol, 1.5 eq) and K3PO4 (104 mg, 488 umol, 2.00 eq) at 15°C and purged with N2. Another flask was charged with Pd2(dba)3 (11.2 mg, 12.2 umol, 0.0500 eq) and ditert-butyl-[2,3,4,5-tetramethyl-6-(2,4,6-triisopropylphenyl)phenyl]phosphane (11.7 mg, 24.4 umol, 0.100 eq), toluene (2.00 mL) and dioxane (0.400 mL) were added at 15°C, then purged with nitrogen and heated at 120°C for 0.05 hr, then it cooled to 15°C. The obtained mixture (per-catalyst) was added to the first mixture via syringe. The resulting mixture was stirred at I20°C for 10 h. LC-MS indicated complété conversion. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Petroleum ether/Ethyl acetate = 1 /1 ). tert-butyl (S )-12-fluoro-4-( 1 H-pyrazol-1 -yl)-7a, 13-dihydro-7H[ 1,2,4]triazoïo[4',3': I,6]pyrido[ 3,2-b]benzofuro[4,3-fg][ 1,4] oxazonine-14(8H)-carboxylate (0.070 g, 146 umol, 59% yield) was obtained as a brown solid.
Step 2: (S)-12-fluoro-4-(1 H-pyrazol-1 -yl)-7a,8,13,14-tetrahydro-7H[1,2,4]triazolo[4',3 ':1,6]pyrido[3,2-b]benzoJüro[4,3-fg] [ 1,4] oxazonine
200
A mixture of tert-butyl (S)-12-fluoro-4-(lH-pyrazol-l-yl)-7a,13-dihydro-7H[l,2,4]triazolo[4’,3,:l,6]pyndo[3,2-b]benzofuro[4>3-fg][l,4]oxazonine-14(8H)-carboxylate (0.0700 g, 146 umol, 1.00 eq) in HFIP (2 mL) was stirred at 80°C for 12 h under nitrogen atmosphère. LCMS indicated complété conversion. The reaction mixture was blown to dryness by nitrogen stream. The residue was purified by prep-HPLC (formic acid conditions). (S)-I2-fluoro-4-(lH-pyrazol-lyl)-7a,8,13,14-tetrahydro-7H-[ 1,2,4]triazolo[4',3’: 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4]oxazonine (15.3 mg, 34.9 umol, 23% yield, 96.8% purity, formate sait) was obtained as a yehow solid. lH NMRDMSO-rMOO MHz, δ = ppm 9.52 (s, 1H), 9.05 (d, 7=1.96 Hz, 1H), 7.80 (s, 1H), 7.78 (s, 1H), 7.50 (br t,7=6.11 Hz, 1H), 6.94 (br t, 7=9.54 Hz, 1H), 6.67 (dd, 7=8.56, 3.67 Hz, 1H), 6.56 (d, 7=1.96 Hz, 1H), 4.95 -4.83 (m, 1H), 4.82-4.71 (m, 1H), 4.5S - 4.45 (m, 2H), 4.23 (br dd, 7=9.41, 3.06 Hz, IH), 4.04 (br s, 1H), 3.92-3.81 (m, 1H). LCMS (ESI+): m/z 379.1 (M+H).
Example 42: (S)-4-(l,5-dimethyl-lH-pyrazol-4-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H(l^^ltriazolo^'^kl^lpyridotS^-bîbenzofuro^^-fgKl^loxazonine
N
To a mixture of(S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine (100 mg, 256 umol, 1.00 eq) and l,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yi)-lH-pyrazole (85.2 mg, 383 umol, 1.5 eq) in EtOH (3.5 mL) and water (0.5 mL) was added KOAc (50.2 mg, 511 umol, 2.00 eq), 4ditert-butylphosphanyl-N,N-dimethyl-aniline; dichloropalladiuin (18.1 mg, 25.6 umol, 18.1 uL, 0.100 eq) in one portion at 25°C under N2. The mixture was stirred at 80°C for 16 h under N2. LCMS showed no (S)-4-bromo-l2-iluoro-7a,8,l 3,14-tetrahydro-7H-[ 1,2,4]triazolo[4’,3’:l,6]pyrido[3,2b]benzofuro[4,3-fg][l,4]oxazonine was remained. Several new peaks were shown on LC-MS and the desîred MS was detected. The reaction mixture was fdtered and the filtrate was concentrated under reduced pressure. The residue was purified by /?rep-HPLC (column: Waters Xbridge 150*25 5u; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 10% - 40%, 10 min). (S)-4-(l,5dimethyl-lH-pyrazoL4-yl)- l2-fluoro-7a,8,13,14-tetrahydro-7IT-[l,2,4]triazolo[4’,3': l,6]pyrido[3,2b]benzofuro[4,3-fg][l,4]oxazonine (13.21 mg, 32.13 umol, 12% yield, 98.9% purity) was obtained as a white solid. ’HNMR DMSO-7e 400 MHz, δ = ppm 9.37 (s, 1H), 7.83 (s, 1H), 7.27 (t,7= 6.3 Hz, 1H), 7.16 (s, 1H), 7.01 - 6.89 (m, 1H), 6.68 (dd, 7= 8.7, 3.9 Hz, 1H), 4.92-4.82 (m, 1H), 4.79
201
4.69 (m, 1H), 4.58 - 4.41 (m, 2H), 4.21 (dd, J = 9.6, 3.2 Hz, 1H), 4.11 - 3.96 (m, 1H), 3.92 - 3.83 (m, 1H), 3.80 (s, 3H), 2.37 (s, 3H). LCMS (ESI+): m/z 407.1 (M+H).
Example 43: (S)-4-(2,3-dimethylpyridin-4-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4’,3’:l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
Step 1: 2,3-dimeihyl-4-(4,4,5,5-tetramethy 1-1,3,2-dioxaborolan-2-yl)pyridine
To a mixture of 4-bromo-2,3-dimethylpyridine (0.81 g, 4.35 mmol, 1.00 eq), KOAc (855 mg, 8.71 mmol, 2.00 eq) and 4,4,4',4',5,5,5,,5’-octamethyl-2,2’-bi(l,3,2-dioxaborolane) (2.21 g, 8.71 mmol, 2.00 eq) in dioxane (20 mL) was added Pd(dppf)Cl2 (320 mg, 437 umol, 0.100 eq) in one portion at 18°C under N2. The mixture was stirred at 110°C for 15 h The mixture was evaporated to obtain the product. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 1/0 to 0/1, Petroleum ether/Ethyl acetate = 0:1, Rf = 0.06). 2,3-dimethyl-4-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)pyridine (400 mg, 1.72 mmol, 39% yield) was obtained as a white solid. Step 2: (S)-4-(2,3-dimethylpyridin-4-yl)-12-fluoro-7 a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4', 3 6]pyrido[3,2-b]henzofuro[4,3-fg][l, 4] oxazonine
To a mixture of (S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3';l}6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine (50 mg, 127.81 umol, 1.00 eq), NaHCOj (53.7 mg, 639 umol, 24.9 uL, 5.00 eq) and 2,3-dimethyL4-(4,4,5,5-tetramethyl-l,3,2dioxaborolan-2-yl)pyridine (89.4 mg, 383.4 umol, 3.00 eq) in dioxane (5 mL) and water (0.5 mL) was added Pd(dppf)Cl2 (9.35 mg, 12.8 umol, 0.100 eq) in one portion at 15°C under N2. The mixture was stirred at 80°C for 2 h. LCMS showed that the starting material was consumed completely. The mixture was evaporated to obtain the crude product. The residue was purified by prep-HPLC (neutral condition: column: Nano-micro Kromasil C18 100*30 mm 5 uni; mobile phase: [water (10 mM NH4HCO3) - ACN]; B%: 35% - 52%, 10 min). (S)-4-(2,3-dimethylpyridin-4-yl)-12fluoro-7a,8,13, IT-tetrahydro-TH-fl^^Jtriazolo^S': l,6]pyrido[3,2-b]benzofuro[4,3
202 fg][l,4]oxazonine (25.7 mg, 61.2 umol, 47% yieîd, 99.4% purity) was obtained as a yellow solid. ‘H NMR DMSO-riô 400 MHz, δ = ppm 9.42 (s, 1H), 8.28 (d, J= 5.1 Hz, 1H), 7.54 (br t, J= 6.2 Hz, 1H), 7.28 (s, 1H), 7.20 (d,J= 5.0 Hz, 1H), 7.00 - 6.92 (m, 1H), 6.70 (dd, J= 8.6, 3.9 Hz, 1H), 4.96 4.87 (m, 1H), 4.84-4.74 (m, 1H), 4.54 (t, J=9A Hz, 1H), 4.46 (br d, J= 5.9 Hz, 1H), 4.20 (dd, J = 9.5, 3.5 Hz, 1H), 4.09 - 3.99 (m, 1 H), 3.90 - 3.80 (m, IH), 2.50 (s, 3H), 2.07 (s, 3H). !H NMR CD3OD 400 MHz, δ = ppm 9.71 (s, 1H), 8.65 (d, J=6.1 Hz, 1H), 8.17 (s, 1H), 7.96 (d, J = 6.1 Hz, 1H), 6.99 - 6.88 (m, 1H), 6.69 (dd, J= Ζ.Ί, 3.8 Hz, 1H), 5.23 (br d, J = 14.8 Hz, 1H), 5.02 (br d, J= 14.9 Hz, 1H), 4.78 (br s, 1H), 4.63 (t, J =9.5 Hz, 1H), 4.32 (dd, J=9.7, 3.2 Hz, 1 H), 4.10 (br d, J = 9.5 Hz, 1H), 4.02 - 3.92 (m, 1H), 2.87 (s, 3H), 2.36 (s, 3H). LCMS (ESI+): m/z 418.2 (M+H).
Example 44: (S)-12-tluoro-4-(6-methoxypyridin-3-yl)-7a,8,13,14-tetrahydro-7H[l,2,4|triazolo[4',3*:l,6]pyrido[3,2-b]benzofuro[4,3-fgl[l,4]oxazonme
To a solution of (S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4’,3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine (50.0 mg, 128 umol, 1.00 eq), 2-methoxy-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (90.1 mg, 383 umol, 3.00 eq) in dioxane (3 mL) and water (0.3 mL) were added Na2CO3 (27.1 mg, 256 umol, 2.00 eq) and Pd(PPh3)4 (14.77 mg, 12.78 umol, 0,100 eq) at 25°C. The mixture was stirred at 90°C for 12 h. LCMS showed no (S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-[ 1,2,4]triazolo[4',3': 1,6]pyrido[3,2b]benzofuro[4,3-fg][l,4]oxazonine was remained. Several new peaks were shown on LC-MS and the desired MS was detected. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Waters Xbrîdge 150*25 5u; mobile phase; [water (10 mM NH4HCO3) - ACN]; B%: 20% - 50%, 10 min). (S)-12-fluoro-4(6-methoxypyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[ 1,2,4]triazolo[4’,3': 1,6]pyrido[3,2b]benzofuiO[4,3-fg][l,4]oxazonine (19.10 mg, 44.33 umol, 34% yield, 97.4% purity) was obtained as a white solid. ’H NMR DMSO-^ 400 MHz, δ = ppm 9.44 (s, 1 H), 8.98 (d, J = 2.4 Hz, 1H), 8.48 (dd, J =8.7, 2.5 Hz, 1H), 7.67 (s, 1H), 7.50 (br t, 6.3 Hz, 1H), 6.99 - 6.87 (m, 2H), 6.68 (dd, J = 8.6, 3,7 Hz, 1H), 4.94 - 4.84 (m, 1H), 4.83 -4.72 (m, 1H), 4.58-4.46 (m,2H),4.21 (dd, 9.7, 3.3 Hz, 1H), 4,10-3.98 (m, 1H), 3.94 (br d, J = 11.0 Hz, 1H), 3.90 (s, 3H). LCMS (ESI+): m/z 420.2 (M+H).
203
Example 45: (S)-4-(6-ethyl-4-methylpyridin-3-y])-12-fluoro-7a,8,13,14-tetrahydro-7H [l,2,4]triazolo[4*,3’: 1,6] pyrido[3,2-b]benzofuro[4,3-fg|[ 1,4] oxazonine
Step 1: 5-bromo-2-ethyl-4-methylpyridine
To a stirred solution of 2,5-dibromo-4-methylpyridine (2.00 g, 7.97 mmol, 1.00 eq.) and ZnEt2 (1 M, 4.78 mL, 0.6 eq.) in THF (15.0 mL) was added Pd(PPh3)4 (92.1 mg, 79.7 umol, 0.01 eq.) at 0°C under N2. The resulting mixture was stirred at 70°C for 1 hr. The mixture was added to saturated aqueous NaHCO3 solution (30 mL) and then the mixture was extracted with EtOAc (20 mL * 3) and the combined organic layers were dried overNa2SO4 and then concentrated under reduced pressure.
The mixture was purified by MPLC (SiO2, PE/EtOAc = 1/0 to 5/1). 5-bromo-2-ethyl-4methylpyridine (720 mg, 3.60 mmol, 45% yield) was obtained as colourless oil. ‘H NMR CDC13 400 MHz, δ = ppm 8.54 (s, 1H), 7.05 (s, 1H), 2.75 (q, J= 7.5 Hz, 2H), 2.37 (s, 3H), 1.29 (t, J= 7.6 Hz, 3H).
Step 2: 2-ethyl-4-methyl-5-(4,4,5,5-tetramethyl-l, 3,2-dioxaborolan-2-yl)pyridine p'O
To a stirred solution of 5-bromo-2-ethyl-4-methylpyridine (290 mg, 1.45 mmol, 1.00 eq.), 4,4,5,5tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane ( 1.47 g, 5.80 mmol, 4.00 eq.) and KOAc (285 mg, 2.90 mmol, 2.00 eq) in dioxane (15.00 mL) was added Pd(dppf)Cl2.DCM (237 mg, 290 umol, 0.20 eq) at 15°C under N2. The resulting mixture was stirred 20 at 80°C for 8 h. LCMS showed 5-bromo-2-ethyl-4-methylpyridine was consumed and the desired mass was detected. The mixture was concentrated under reduced pressure. The mixture was purified by MPLC (SiO2, PE/EtOAc = 1/1 to EtOAc/MeOH =1/1). 2-ethyl-4-methyl-5-(4,4,5,5tetramethyl-l,3,2-dioxaboroian-2-yl)pyridine (200 mg, 809 umol, 55% yield) was obtained as brown oil. 'H NMR CDCh 400 MHz, δ = ppm 8.76 (s, 1H), 6.96 (s, 1H), 2.78 (q, J= 7.6 Hz, 2H), 2.50 (s, 25 3H), 1.27- 1.25 (m, 15H).
Step 3: (S)-4-(6-ethyl-4-methylpyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H[ I,2,4] triazolo]4 , 3 1,6]pyrido[3,2-b] benzofitro[4,3-fg] [1,4] oxazonine
204
To a stirred solution of 2-ethyI-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaboiOlan-2-yl)pyridine (126 mg, 511 umol, 4.00 eq), (S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H[ 1,2,4] tr iazolo[4',3l,6]pyrido[ 3,2-b]benzofuro[4,3-fg] [1,4] oxazonine (50.0 mg, 128 umol, 1.00 eq) and NaHCO3 (53.7 mg, 639 umol, 24.9 uL, 5.00 eq) in dioxane (4.00 mL) and water (0.80 mL) was added Pd(dppf)Cl2 (9.35 mg, 12.8 umol, 0.100 eq) at 15°C under N2. The resulting mixture was stirred at 90°C for 5 h. The mixture was concentrated under reduced pressure. The mixture was purified by neutral /jrep-HPLC. (S)-4-(6-ethyl-4-methylpyridin-3-yl)-12-fluoro-7a,8,13,14tetrahydro-7H-[ 1,2,4]triazolo[4',3': 1,6]pyrido[3,2-b]benzofuro[4,3-fg][l ,4]oxazonine (21.7 mg, 49.4 umol, 38% yield, 98.1% purity) was obtained as a white solid. lH NMR OMSO-^ 400 MHz, δ = ppm 9.42 (s, 1H), 8.38 (s, IH), 7.49 (br t, J = 6.4 Hz, IH), 7.30 (s, 1H), 7.22 (s, 1H), 7.02 - 6.92 (m, 1H), 6.71 (dd, J=8.6, 3.9 Hz, IH), 4.96-4.86 (m, 1H),4.83 - 4.75 (m, IH), 4.55 (t, J=9.3 Hz, IH), 4.47 (br d,J= 6.6 Hz, IH), 4.21 (dd, 9.4, 3.3 Hz, IH), 4.05 (br s, IH), 3.91 - 3.82 (m, IH), 2.76 (q, J = 7.5 Hz, 2H), 2.17 (s, 3H), 1.26 (t, J~ 7.6 Hz, 3H). LCMS (ESI+): m/z 432.1 (M+H). Example 46: (S)-4-(2-(difluoromethyl)pyi*îdin3-yI)-12-fluoro-7a,8,13,I4-tetrahydro-7H[ l,2,4]triazolo|4\3':l,6]pyrido|3,2-b]benzofiiro[4,3-fgH l,4]oxazonine Step 1: 3-bromo-2-(difluoromethyl)pyridine
To a solution of 3-bromopicolinaldehyde (1.00 g, 5.38 mmol, 1.00 eq) in DCM (20 mL) was added DAST (1.73 g, 10.8 mmol, 1.42 mL, 2.00 eq) at 0°C under nitrogen atmosphère. The mixture was stirred at 0°C for 2 h. LC-MS showed 3-bromopicolinaldehyde was consumed completely and one main peak with desired mass was detected. The reaction mixture was quenched by addition of water (20 mL), and then diluted with EtOAc (20 mL) and extracted with EtOAc (20 mL * 3). The combined organic layers were washed withim. aq. NaCl (30 mL), dried overNa2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum etherEthyl acetate = 1:0 to 0:1 ; Petroleum ether:Ethyl acetate = 5:1, Rr= 0.4). 3-bromo2-(difluoromethyl)pyridine (480 mg, 2.31 mmol, 42% yield) was obtained as a yellow oil.
205
Step 2: 2-(difluoromethyl)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine
To a solution of 3-bromo-2~(difluoromethyl)pyridine (480 mg, 2.31 mmol, 1.00 eq) in dioxane (6 mL) was added 4,4,4',4',5,5,5',5,-octamethyl-2,2'-bi(l,3,2-dioxaboiOlane) (762 mg, 3.00 mmol, 1.3 eq), KOAc (453 mg, 4.62 mmol, 2.00 eq) and Pd(dppf)Cl2 (169 mg, 231 umol, 0.100 eq) at 25°C under nitrogen atmosphère. The mixture was stirred at 80°C for 12 h. LC-MS indicated presence of the remaining siarting material. To the mixture was added 4,4,4’,4(5,5,5(5'-octaniethyl-2,2'bi( 1,3,2-dioxaborolane) (586.00 mg, 2.31 mmol, 1.00 eq), KOAc (452.96 mg, 4.62 mmol, 2.00 eq) and Pd(dppf)Cl2 (169 mg, 231 umol, 0.100 eq) at 25°C under nitrogen atmosphère. The mixture was stirred at 80°C for 2 h. LC-MS indicated completed conversion. The mixture was concentrated in vacuum. The residue was purified by pre^-TLC (SiO2, Petroleum ether:Ethyl acetate =1:1, Rf= 0.5). 2-(difluoromethyl)-3-(4,4,5,5-tetramethy]-l,3,2-dioxaborolan-2-yl)pyridine (500 mg, crude) was obtained as a yellow solid. !H NMR CDC13 400MHz, δ = ppm 8.78 (br d, J— 3.2 Hz, IH), 8.17 (brd, J=7.6 Hz, IH), 7.43 - 7.37 (m, IH), 7.26 (t,J= 53.2 Hz, IH), 1.37 (s, 12H).
Step 3: (S)-4-(2-(difluoromethyl)pyridin-3-yl)-12-jluoro-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4’,3':l, 6]pyrido[3,2-b]benzofuro[4,3-fg][l, 4] oxazonine
To a solution of 2-(difluoromethyl)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (156 mg, 614 umol, 4.00 eq) in dioxane (4.5 mL) and water (0.5 mL) were added (S)-4-bromo-12-fluoro7a,8,13,i4-tetrahydro-7H-[l,2,4]triazolo[4(3’:l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine (60.0 mg, 153 umol, 1.00 eq), NaHCOj (64.4 mg, 767 umol, 29.8 uL, 5.00 eq) and Pd(dppf)Cl2 (11.2 mg, 15.3 umol, 0.100 eq) at 25°C under nitrogen atmosphère. The mixture was stirred at 80°C for 5 h. LC-MS showed 2-(difluoromethyl)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine was consumed completely and one main peak with desired mass was detected. The réaction mixture was filtered and the iîltrate was dried under high vacuum. The residue was purified by prep-HPLC (neutral condition: column: Waters Xbridge 150 * 25 5 u; mobile phase: [water (10 mM NH4HCOj)
206
- ACN]; B%: 25% - 35%, 10 mm). (S)-4-(2-(difluoromethyl)pyridin-3-yl)-12-iluoro-7a,8,13,14tetrahydiO-7H-[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine (7.64 mg, 17.2 umol, 11% yield, 98.7% purity) was obtained as a yellow solid. 'H NMR DMSO-J6 400 MHz, δ = ppm 9.45 (s, IH), 8.74 (dd, J = 4.6, 1.3 Hz, IH), 8.05 (d, 7= 7.9 Hz, IH), 7.66 (dd, 7= 7.9, 4.4 Hz, 2H), 7.32 (s, 1 H), 6.98 (t, 7 = 10.0 Hz, IH), 6.90 (t, 7= 53.6 Hz, 1H),6.71 (dd, 7= 8.8, 4.0 Ηζ,ΙΗ), 4.97 - 4.89 (m, IH), 4.86 - 4.74 (m, IH), 4.58 - 4.43 (m, 2H), 4.21 (dd, 7= 9.5, 3.5 Hz, IH), 4.04 (br s, IH), 3.93 - 3.83 (m, IH). LCMS (ESI+); m/z 440.1 (M+H).
Example 47: (S)-4-(2,6-dimethylpyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H[1,2,4]triazolo[4',3':l,6|pyrido[3,2-b]benzofuro[4,3-fg] [1,4]oxazonine formate
To a solution of (S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-
[ 1,2,4]tr iazolo[4’,3': 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4]oxazonîne ( 100 mg, 256 umol, 1.00 eq) and 2,6-dimethyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (89.4 mg, 383 umol, 1.50 eq) in water(0.30 mL) and EtOH (2.10 mL) was added 4-ditert-butylphosphanyl-N,Ndimethyl-aniline dicbloropalladium (18.1 mg, 25.6 umol, 18.1 uL, 0.100 eq) and KOAc (50.2 mg, 511 umol, 2.00 eq) at 20°C. The mixture was stirred at 80°C for 12 h. The mixture was filtered and the filtrate was coneentrated under reduced pressure. The residue was purified byprep-HPLC (formic acid conditions). (S)-4-(2,6-dimethylpyridin-3-yl)-12-fiuoro-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4’,3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonme (4.00 mg, 8.48 umol, 3% yield, 98.3% purity, formate sait) was obtained as a yellow solid. *H NMR DMSO-Ti 400 MHz, δ = ppm 9.33 (s, IH), 7.70 (d,7=7.8 Hz, 1 H), 7.34 (s, IH), 7.24 (d, 7= 7.8 Hz, IH), 6.95 -6.82 (m, IH), 6.65 (dd,7= 8.6, 3.9 Hz, 1 H), 5.08 (d,7= 14.8 Hz, I H), 4.86 (s, 1H),4.59 (brt,7=9.4 Hz, 2H), 4.29 (dd, 7= 9.6, 3.1 Hz, IH), 4.11 - 3.97 (m, 1 H), 3.95 - 3.81 (m, IH), 2.58 (s, 3H), 2.38 (s, 3H). LCMS (ESH-): m/z 418.2 (M+H).
Example 48: (S)-12-fluoro-4-(6-methylpyridin-2-yl)-7a,8,13,14-tetrahydro-7H]l,2,4]triazolo[4',3': 1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine formate
207
Step I: tert-butyl (S)-12-fluoro-4-(6-methylpyridin-2-yl)-7a,13-dihydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg] [l,4]oxazonine-I4(8H)-carboxylate
(n-Bu)3Sn
To a solution of 2-bromo-6-methylpyridine (500 mg, 2.91 mmol, 331 uL, 1.00 eq) in THF (20 mL) was added n-BuLi (2.5 Μ, 1.74 mL, 1.5 eq) at -70°C, the mixture was stirred at -70°C for 0.5 hr, then tributyl(chloro)stannane (3.78 g, 11.6 mmol, 3.13 mL, 4.00 eq) was added to the mixture at 70°C, then the mixture was stirred at 20°C for 12 h. TLC (Petroleum ether/Ethyl acetate = 5/1 Rf = 0.5) and LCMS showed the starting material was consumed completely. The residue was poured into water (10 mL) and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (10 mL * 2). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na2SO4, filtered, and concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 1/0 to 1/1). Tert-butyl (S)-12-fluoro-4-(6-methylpyridin-2yl)-7a, 13-dihydro-7H-[ 1,2,4]triazolo[4',3': 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4]oxazonine14(8H)-carboxylate (1.00 g, 2.62 mmol, 90% yield) was obtained as a yellow oil. IH NMR CDC13 400 MHz Ô = ppm 7.36 (t, J = 7.5 Hz, IH), 7.21 -7.15 (m, IH), 6.96 (d, J = 7.7 Hz, IH), 2.54 (s, 3H), 1.70 - 1.51 (m, 12H), 1.43 - 1.22 (m, 6H), 0.95 - 0.87 (td, J = 16.9, 7.4 Hz, 9H).
Step 2: tert-butyl (S)-l 2-jluoro-4-(6-methylpyridin-2-yl)-7a,l 3-dihydro-7H[1,2,4]triazolo[4', 3 1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4] oxazonine-14(8H)-carboxylate
208
To a solution of tert-butyl (S)-4-bromo-12-fluoro-7a,13-dihydro-7H[l,2J4]triazolo[4’,3':l,6]pyrido[3,2-b]benzofuiO[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (150 mg, 305 umol, 1.00 eq) in dioxane (10 mL) was added tert-butyl (S)-12-fluoro-4-(6-methylpyridin-2-yl)7a,13-dîhydro-7H-[l,2,4]triazolo[4',3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)carboxylate (467 mg, 1.22 mmol, 4.00 eq), Cul (23.3 mg, 122 umol, 0.4 eq), LiCl (25.9 mg, 611 umol, 12.5 uL, 2.00 eq) and Pd(PPh3)4 (35.3 mg, 30.5 umol, 0.100 eq) at 20°C under nitrogen atmosphère. The mixture was stirred at 80°C for 12 h under nitrogen atmosphère. The mixture was evaporated to obtain the crude product. The residue was purified by prep-TLC (SiO2, Petroleum ether:Ethyl acetate = 1:2). S)- ! 2-Fiuoro-4-(6-methylpyridin-2-yl)-7a,8,13,14-tetrahydro-7H[ 1,2,4] triazolo[4’,3':l,6]pyrido[ 3,2-b]benzofuro [4,3-fg][ 1,4] oxazonine (120 mg, 238 umol, 78% yield) was obtained as a yellow solid.
Step 3: (S)-12-fluoro-4-(6-methylpyridin-2-yl)-7a,8,13,14-tetrahydfo-H[l,2,4]triazolo[4',3 1,6]pyrido[3,2-b] benzofuro[4,3-fg] [1,4] oxazonine
HCOOH
To a mixture of tert-butyl (S)-12-fluoro-4-(6-methylpyridin-2-yl)-7a,13-dihydro-7H[ l,2,4]triazolo[4',3': 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4]oxazonine-14(8H)-carboxylate (110 mg, 218.46 umol, 1.00 eq) in DCM (10 mL) was added TFA (5.08 g, 44.6 mmol, 3.30 mL, 204 eq) in one portion at 18°C. The mixture was stirred at 18C for 1.5 h. The mixture was evaporated to obtain the crude product. The suspension was filtered, the fdtrate was concentrated and purified by acidic prep-HPLC (fonnic acid conditions; column: Welch Xtimate C18 150*40 mm* 10 um; mobile phase: [water (0.225% FA) - ACN]; B%: 10% - 50%, 12 min). The product-containing fraction was concentrated under reduced pressure to remove most of MeCN at 30°C and the aqueous phase was lyophilized. (S)-12-fluoro-4-(6-methylpyridin-2-yl)-7a,8,13,14-tetrahydro-7H[ l,2,4]triazolo[4',3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine (54.7 mg, 120 umol, 54% yield, 98.3% purity, formate sait) was obtained as an orange solid. IH NMR DMSO-d6 400 MHz δ = ppm 12.74 (br s, 1H), 9.48 (s, 1 H), 8.82 (d, J = 7.9 Hz, 1H), 8.29 (s, 1H), 8.13 (s, 1H), 7.82-7.72 (m, 2H), 7.16 (d, J = 7.6 Hz, IH), 6.99-6.91 (m, 1 H), 6.68 (dd, J = 8.6, 3.8 Hz, IH), 4.97 - 4.88 (m,
209
H), 4.86-4.77 (m, IH), 4.52 (brt, J = 9.4 Hz, 2H), 4.27 (brdd, J = 9.4, 3.1 Hz, IH), 4.05 (br s, IH), 3.95 - 3.84 (m, IH), 2.54 (s, 3H). LCMS (ESI+): m/z 404.2 (M+H).
Example 49: (S)-4-(4,6-dÎmcthylpyridazin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo|4',3’:l,6]pyrido[3,2-b]benzofuro[4,3-fgHl,4]oxazoiiine
Step 1: 6,8-dimethyl-[ 1,2,4]triazolo]4,3 -b]pyridazine
NN K/ NV
To a mixture of 6,8-dimethyl-[l,2,4]triazolo[4,3-b]pyridazine (5.95 g, 59.5 mmol, 6.11 mL, 1.00 eq) and l,2,4-triazol-4-amine (5.00 g, 59.5 mmol, 1.00 eq) in toluene (30 mL) was added TsOH.water (56.6 mg, 297 umol, 0.005 eq) in one portion at 18°C. The mixture was stirred at 120°C for 16 h. TLC (Ethyl acetate/Methanol = 5/1 Rf = 0.5) showed that the starting material was consumed completely. The mixture was evaporated under reduced pressure to obtain the crude product. The residue was purified by re-crystallization from EtOH/TBME (50 mL, v/v = 1/5) to give the pure product. 6,8-Dimethyl-[l,2,4]triazolo[4,3-b]pyridazine (6.60 g, 44.5 mmol, 74% yield) was obtained as a white solid. IH NMR DMSO-d6 400 MHz δ = ppm 9.52 (s, IH), 7.1 I (s, IH), 2.59 (s, 3H), 2.53 (br s, 3H)
Step 2: 4,6-dimethylpyridazin-3~amme
N-~/ N' J ΗξΝ\
To a mixture of 6,8-dimethyl-[l,2,4]triazolo[4,3-b]pyridazine (6.60 g, 44.5 mmol, 1.00 eq) in MeCN (60 mL) was added 2-bromo-l-phenylethan-l-one (8.87 g, 44.5 mmol, 1.00 eq) in one portion at 18°C. The mixture was stirred at 85°C for 6 h. Most of the solvent was removed by évaporation and water (27 mL) was added to the residue followed by addition of NaOI-I (3.00 g, 75.0 mmol, 1.68 eq) in one portion at 18°C. The mixture was stirred at 100°C for 16 h. LCMS indicated formation of the desired product. The suspension was filtered through a pad of Celite and the filter cake was washed with water (40 mL * 2) at 50°C. The filtrâtes were cooled to 18°C and the obtained precipitate was filtered off. The filter cake was washed with 30 mL of water and dried in vacuum to give a afford product. 4,6-Dimethylpyridazin-3-amine (2.00 g, 16.2 mmol, 36% yield) was obtained as a yellow solid. IH NMR DMSO-d6 400 MHz δ = ppm 6.99 (s, IH), 5.91 (br s, 2H), 2.33 (s, 3H), 2.03 (s, 3H).
Step 3: 3-bromo-4,6-dimethylpyridazine
210
To a mixture of 4,6-dîmethyipyridazin-3-amine (1.80 g, 14.6 mmol, 1.00 eq) in HBr (26.8 g, 159 mmol, 18.0 mL, 48% purity, 10.9 eq) was added NaNO2 (1.02 g, 14.8 mmol, 1.01 eq) in water (8 mL) in one portion at 0°C. Then to the mixture was added CuBr (2.94 g, 20.5 mmol, 623 uL, 1.40 eq) in HBr (26.8 g, 159 mmol, 18.0 mL, 48% purity, 10.9 eq) in one portion at 0°C. The mixture was stirred at 100°C for 5 h The aqueous phase layer was made alkaline with aqueous NaOH (10%) till pH = 10. The aqueous phase was extracted with ethyl acetate (10 mL * 2). The combined organic phases were washed with brine (10 mL * 2), dried with anhydrous Na2SO4, filtered, and concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 1/0 to 1/1). Tert-butyl (S)-4-(4,6-dimethylpyridazin-3-yl)-12-fluoro-7a,13dihydro-7H-[l,2,4]triazolo[4',3':L6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)carboxylate (1.20 g, 6.40 mmol, 43% yield) was obtained as a white solid. 1H NMR DMSO-d6 400 MHz δ = ppm 7.57 (s, 1H), 2 .54 (s, 3H), 2.32 (s, 3H).
Step 4\ tert-butyl (8)-4-(4,6-dimethylpyridazin-3-yl)-l 2-fluoro-7a, 13-dihydro-7H[1,2,4]triazolo[4', 3 6]pyrido[3,2-b]benzofuro[4,3-fg] [1,4] oxazonine-14(8H)-carboxylate
To a solution of tert-butyl (S)-12-fluoro-4-(tributylstannyl)-7a,l3-dihydro-7H[L2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (100 mg, 143 umol, 1.00 eq) in dioxane (5 mL) was added 3-bromo-4,6-dimethylpyridazine (66.7 mg, 356 umol, 1.06 uL, 2.50 eq), Cul (10.9 mg, 57.0 umol, 0.400 eq), LiCl (12.1 mg, 285 umol, 5.84 uL, 2.00 eq) and Pd(PPh3)4 (16.5 mg, 14.3 umol, 0.100 eq) at 20°C under nitrogen atmosphère. The mixture was stirred at 80°C for 12 h under nitrogen atmosphère. The mixture was evaporated under reduced pressure to obtain the product. The residue was purified byprep-TLC (SÎO2, EtOAc:MeOH = 10:1). Tert-butyl (S)-4-(4,6-dimethylpyridazin-3-yl)-12-fluoro-7a,13-dihydro-7H211
[l,2,4]triazolo[4,,3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (50 mg,
96.42 umol, 67% yield) was obtained as a yellow solid.
Step 5: (3)-4-(4,6-dimethylpyridazin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H[1,2,4]triazolo[4 3 I,6]pyrido[3,2-b]benzofuro[4,3-fg] [1,4]oxazonine formate
HCOOH
To a mixture of tert-butyl (S)-4-(4,6-dimethylpyridazin-3-yl)-12-iluoiO-7a,13-dihydro-7H[ i ,2,4]triazolo[4',3’: 1,6]pyrido[3,2-b]benzofiiro[4,3-fg][ 1,4]oxazonine-14(8H)-carboxylate (60.0 mg, 116 umol, 1.00 eq) in DCM (10 mL) was added TFA (2.69 g, 23.6 mmol, 1.75 mL, 204 eq) in one portion at 18°C. The mixture was stirred at 18°C for 1.5 h. LCMS showed ~0% of tert-butyl (S)-4-(4,6-dimethylpyi’idazin-3-yl)-12-fluoro-7a,13-dihydro-7H-[l,2,4]triazolo[4,,3,:l,6]pyrido[3,2b]benzofuro[4,3-fg][ 1,4]oxazonîne-14(8H)-carboxylate remained. Several new peaks were shown on LCMS and -74% of a product with the desired mass was detected. The mixture was combined with another batch (from 50 mg of tert-butyl (S)-4-(4,6-dimethylpyridazin-3-yl)- 12-fluoro-7a, 13dihydro-7H-[ l,2,4]triazolo[4', 3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine- 14(8H)carboxylate) and evaporated under reduced pressure. The crude product was dissolved in DMSO (2 mL) and filtered to remove the insoluble material. The filtrate was purified by acidic prep-HPLC (formic acid conditions; column: Weich Xtimate C18 150*40 mmMO um; mobile phase: [water (0.225% FA) - ACN]; B%: 1% - 40%, 12 min). The product-containing fraction was concentrated under reduced pressure to remove most of MeCN at 30°C and the aqueous phase was lyophilized. (S)-4-(4,6-Dimethylpyridazin-3-yI)-12-fluoro-7a,8,13,14-tetrahydro-7H[1,2,4]ίπΗζο1ο[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine (19.5 mg, 40.7 umol, 96.96% purity, formate sait) was obtained as a yellow solid. 1H NMR DMSO-d6 400 MHz δ = ppm 9.46 (br s, 1H), 7.67 (br s, 1H), 7.52 (br s, 1H), 7.47 (s, 1H), 6.97 (t, J = 9.5 Hz, 1H), 6.70 (dd, J = 8.6, 3.8 Hz, 1H), 4.97 - 4.88 (m, 1H), 4.86 - 4.76 (m, 1H), 4.59 - 4.46 (m, 2H), 4.23 (dd, J = 9.7, 3.3 Hz, 1H), 4.06 (br s, 1H), 3.92 - 3.80 (m, 1H), 2.63 (s, 3H), 2.18 (s, 3H). LCMS (ESI+): m/z 419.1 (M+H).
212
Example 50: (S)-12-fluoro-4-(3-methylpyrazin-2-yI)-7a,8,13,14-tetrahydro-7H [l,2,4]triazolo[4',3':l,61pyrido|3,2-b]benzofuro[4,3-fg][l,4]oxazonine
Step 1: tert-butyl (S)-12-fluoro-4-(3-methylpyrazin-2-yl)-7a,13-dihydro-7H[l, 2,4]triazolo[4’, 3 1,6]pyrido[3,2-b]benzofuro[4,3-fg] [ 1,4] oxazonine-14(8H)-carboxylate
A mixture of tert-butyl (S)-12-fluoro-4-(tributylstannyl)-7a,13-dihydiO-7H[l,2,4]triazolo[4,,3':l,6]pyrido[3,2-b]benzolùro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (150 mg, 214 umol, 1.00 eq), 2-bromo-3-methylpyrazine (44.4 mg, 257 umol, 1.20 eq), Cul (16.3 mg, 85.5 umol, 0.400 eq), LiCl (18.1 mg, 428 umol, 8.76 uL, 2.00 eq) and Pd(PPh3)4 (24.7 mg, 21.4 umol, 0.100 eq) in dioxane (4.00 mL) was degassed and purged with nitrogen 3 times at 20°C, and then the mixture was stirred at 80°C for 2.5 h under nitrogen atmosphère. LCMS showed the reaction was complété and the desired mass was detected. The mixture was filtered and the liltrate was concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Petroleum ether: Ethyl acetate = 0:1). Tert-butyl (S)-12-fluoro-4-(3-methylpyrazin-2-yl)-7a,13-dihydro-7H[ 1,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofiiro[4,3-fg][ 1,4]oxazonine-14(8H)-carboxylate (90.00 mg, crude) was obtained as a yellow solid.
Step 2: (S)-12-fluoro-4-(3-methylpyrazin-2-yl)-7a,8,13,14-tetrahydro-7H[1,2,4] triazolo[4',3': 1,6]pyrido[3,2-b] benzofuro[4,3-fg] [1,4] oxazonine formate
To a solution of tert-butyl (S)-12-fluoro-4-(tributylstannyl)-7a,13-dihydro-7H[l,2,4]triazolo[4’,3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (90.0 mg, 17S umol, 1.00 eq) in DCM (1.50 mL) was added TFA (770 mg, 6.75 mmol, 0.500 mL, 37.9 eq) at 20°C. The mixture was stirred at 20 °C for 1 hr. The mixture was concentrated under reduced
213 pressure. The residue was combined with other batch (12 mg of final target with 96.3% purity). The mixture was dissolved in DMSO (3 mL). The suspension was filtered, the filtrate was concentrated and purified by acidic prep-HPLC (formic acid conditions). The product-containing fraction was concentrated under reduced pressure to remove most of MeCN at 30°C and the aqueous phase was lyophilized. (S)-12-Fluoro-4-(3-methylpyrazin-2-yl)-7a,8,l3,l4-tetrahydro-7H[ 1,2,4]triazolo[4’,3':l,6]pyrido[3,2-b]benzofuiO[4,3-fgl[l,4]oxazonine (30.0 mg, 65.7 umol, 36% yield, 98.6% purity, formate sait) was obtained as a yellow solid. IH NMR DMSO-d6 400 MHz δ = ppm 9.44 (s, IH), 8.62 - 8.45 (m, 2H), 7.69 (br t, J = 6.2 Hz, IH), 7.48 (s, IH), 7.04 - 6.87 (m, IH), 6.68 (dd, J = 8.6, 3.7 Hz, IH), 4.96 - 4.86 (m, IH), 4.84 - 4.73 (m, IH), 4.57 - 4.40 (m, 2H), 4.20 (dd, J = 9.5, 3.5 Hz, IH), 4.03 (br s, IH), 3.88 - 3.75 (m, IH), 2.40 (s, 3H). LCMS (ESI+): m/z 405.1 (M+H).
Example 51: (S)-l2-iliioro-4-(5-fluoro-3-methylpyridin-2-yl)-7a,8,]3,14-tetrahydro-7H[l,2,4]triazo]o[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
Step 1: 5-fluoro-3-methyl-2-(trimethylstannyl)pyridine
2-bromo-5-tluoro-3-methylpyiidine (200 mg, 1.05 mmol, 1.00 eq), trimethyl(trimethylstannyl)stannane (690 mg, 2.11 mmol, 437 uL, 2.00 eq) and Pd(PPh3)4 (122 mg, 105 umol, 0.100 eq) were taken up into a microwave tube in dioxane (10 mL) at 18°C under
N2. The sealed tube was heated at 110°C for 3 h under microwave. LCMS showed the réaction was complété. The suspension was filtered through a pad of Celite and the fil ter cake was washed wrth dioxane (1 mL). 5-FluoiO-3-methyl-2-(trimethylstannyl)pyridine (288 mg, 1.05 mmol, 99% yield) in dioxane ( ! 1 mL) was used for the next step without further purification.
Step 2: tert-butyl (S)-12-]luoro-4-(5-fluoro-3-methylpyridin-2-yl)-7a,13-dihydro-7H[1,2,4]triazolo[4’, 3 ’:1, 6Jpyrido[3,2-b] benzofuro]4,3-fg] [1,4] oxazonine-14(8H)-carboxylate
214
To a solution of tert-butyl (S)-4-bromo-12-fluoro-7a,13-dihydro-7H[l,2,4]triazolo[4',3': l,6]pyrido[3,2-b]benzofiiro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (200 mg, 407.08 umol, 1.00 eq) in dioxane ( 10 mL) was added 5-fluoro-3-methyl-2(trimethylstannyl)pyridine (288 mg, 1.05 mmol, 2.59 eq) indioxane(ll mL), Cul (31.0mg, 163 umol, 0.400 eq), LiCl (34.5 mg, 814 umol, 16.7 uL, 2.00 eq) and Pd(PPh3)4 (47.0 mg, 40.7 umol, 0.100 eq) at 20°C under nitrogen atmosphère. The mixture was stirred at 80°C for 2 h under nitrogen atmosphère. LCMS showed tert-butyl (S)-4-bromo-12-fluoro-7a,13-dihydro-7H[l,2,4]tnazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate was consumed completel y. Several new peaks were shown on LCMS and the desired mass was detected. The mixture was evaporated under reduced pressure to obtain the crude product. The residue was purified by prep-TLC (SiO2, Petroleum etherEthyl acetate = 0:1). tert-butyl (S)-12lluoro~4-(5-fluoro-3-methylpyridin-2-yl)-7a,13-dihydro-7H-[l,2,4]triazolo[4',3T: l,6]pyrido[3,2b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (200 mg, 384 umol, 94% yield) was obtained as a yellow solid.
Step 3; (S)-12-fluoro-4-(5-fluoro-3-methylpyridin-2-yl)-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3 1,6]pyrido[3,2-b]benzofuro[4,3-fg] [1,4] oxazonine formate
HCOOH
To a solution of tert-butyl (S)-12-fluoro-4-(5-fluoro-3-methylpyridin-2-yl)-7a,13-dihydro-7H[l,2,4]triazolo[4’,3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine- 14(8H)-carboxylate (150 mg, 288 umol, 1.00 eq) in DCM (3 mL) was added TFA (1.54 g, 13.5 mmol, 1.00 mL, 47.0 eq) at
215
20°C. The mixture was stirred at 20°C for 2 hrTLC (SiO2, PE:EtOAc = 0:1) indicated tert-butyl (S)-12-fluoro-4-(5-fluoro-3-methylpyridin-2-yl)-7a,13-dihydro-7H[l,2,4]triazolo[4,,3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate was consumed completely. The reaction mixture was concentrated under reduced pressure. The crude product was dissolved in MeCN (2 mL) and filtered to remove the insoluble material. The the fdtrate was evaporated and purified by acidic prep-HPLC (fonnic acid conditions; column: Phenomenex Luna Cl8 200*40 mm* 10 um; mobile phase: [water (0.225% FA) - ACN]; B%: 15%45%, 12 min). The product-containing fraction was concentrated under reduced pressure to remove most of MeCN at 30° C and the aqueous phase was lyophilized. (S)-12-Fluoro-4-(5-fluoro-3methylpyridin-2-yI)-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4’,3':l,6]pyrido[3,2-b]benzofuro[4,3fg][l,4]oxazonine (33.4 mg, 78.7 umol, 27% yield, 99.3% purity, formate sait) was obtained as white solid. 1H NMR DMSO-d6 400 MHz δ = ppm 9.43 (s, 1H), 8.45 (d, J = 2.4 Hz, IH), 7.72 (dd, .1 = 9.6, 2.3 Hz, 1H), 7.62 - 7.53 (m, 1H), 7.35 (s, 1H), 6.96 (t, J = 9.4 Hz, 1H), 6.75 - 6.65 (m, IH), 4.97.4.85 (m, IH), 4.84 - 4.71 (m, IH), 4.59 - 4.44 (m, 2H), 4.28 - 4.17 (m, IH), 4.05 (br s, IH), 3.89 - 3.75 (m, 1 H), 2.20 (s, 3H). LCMS (ESI+): m/z 422.2 (M+H).
Example 52: General Procedure A. Préparation of (S)-4-(3,5-dimethylisoxazol-4-yl)-12-fluoro7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofiiro[4,3fgltMloxazonine
O
To a solution of (S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3’:l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine (80.0 mg, 205 umol, 1.00 eq) in dioxane (2.00 mL) and water (0.200 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)isoxazole (57.6 mg, 409 umol, 2,00 eq), Na2CO3 (43,4 mg, 409 umol, 2.00 eq) and Pd(dppf)Cl2 (15.0 mg, 20,4 umol, 0.100 eq) at 20°C. The mixture was stirred at 80°C for 2 h under nitrogen atmosphère. Réaction progress was monitored by LC-MS. The reaction mixture was fdtered, the filtrate was concentrated. The residue was dissolved in MeOH (8 mL) and silica-thiol (500 mg, modified Silicon gel for eliminating Pd, irregular silica gel, 100-200 mesh, Chlorides (Cl), %<0.004, particle size distribution 45-75 um) was added at 20°C and stirred at 20°C for 2 h. The
216 suspension was filtered and the filtrate was evaporated and purified by neutral prep-HPLC (column: Nano-micro Kromasil Cl 8 80*25 mm 3 um; mobile phase: [water (10 mM NH4HCO3) - ACN]; B%: 30% - 50%, 10 min). The product-containing fraction was concentrated under reduced pressure to remove niost of MeCN at 30°C and the residue was lyophilized. (S)-4-(3,55 dimethylisoxazol-4-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4,,3': l,6]pyrido[3,2b]benzofuro[4,3-fg][l,4]oxazonine (58,0 mg, 140 umol, 68% yield, 98,4% purity) was obtained as a white solid. 1H NMR DMSO-d6 400 MHz δ = ppm 9.41 (s, 1H), 7.52 (br s, 1H), 7,35 (s, 1H), 6.98 (t, J = 9.5 Hz, 1H), 6.71 (dd, J = 8.6, 3.7 Hz, 1H), 4.95 - 4.87 (m, 1H), 4.83 - 4.74 (m, 1H), 4.56 4.49 (m, 1H), 4.45 (brd, J = 6.5 Hz, 1H),4.2I (dd, J = 9.5, 3.5 Hz, 1H), 4.05 (br s, 1H), 3.92 - 3.77 (m, 1 H), 2.36 (s, 3H), 2.19 (s, 3H). LCMS (ESI+): m/z 408.1 (M+H)
Compounds 49, 58, 72, 77—78, 91, 94, 96, 103, 105—106, 108—109, 111—112, 114—118, and 142 were prepared according to General Procedure A using the suitable starting materials, precursors, intermediates, and reagents.
Cmpd No. Compound Name Compound Structure Spectral Data
72 (S)-4-(l-ethyl-lH- pyrazol5-yl)-12-fluoro-7a,8,13,14tetrahydro-7H[l,2,4]triazolo [4’, 3’:l,6]pyndo[3,2- b]benzofuro[4,3-fg] [1,4] oxazonine N-N iOh n N F 'θ' 1HNMR DMSO-d6 400 MHz 5 = ppm 9.42 (s, 1H), 7.63 (br t, J = 6.4 Hz, 1 H), 7.50 (d, J = 1.5 Hz, 1H), 7.34 (s, 1H), 6.99-6.90 (m, 1H), 6.68 (dd, J = 8.7, 3.9 Hz, 1H), 6.43 (d, J= 1.5 Hz, 1H), 4.93 - 4.84 (m, 1H), 4.82 - 4.72 (m, 1H), 4.56 - 4.41 (m, 2H), 4.19 (dd, J = 9.6, 3.6 Hz, 1H), 4.08 (q, J = 7.2 Hz, 2H), 4.02 (brs, 1 H), 3.90 - 3.78 (m, 1H), 1.23 (t, J = 7.2 Hz, 3H). LCMS (ES1+): m/z 407.1 (M+H).
49 (S)-4-(12-fluoro-7a,8,13,14tetrahydro-7H~ [l,2,4]triazolo [4',3':l,6]pyrido[3,2b]benzofuro[4,3- fg][l,4]oxazonin-4-yl)-3- met hy 1 b enzo n i tri le CN N'N ΗνΛ HCOOH νχΑ O' 1HNMR DMSO-d6 400 MHz δ = ppm 9.43 (s, 1H),7.81 (s, 1H), 7.75 - 7.69 (m, 1H), 7.63 - 7.55 (m, 2H), 7.34 (s, 1H), 6.98 (dd, J= 10.1, 8.9 Hz, 1H), 6.71 (dd, J = 8.6, 3,7 Hz, 1H), 4.98 - 4.87 (m, III), 4.84 - 4.75 (m, 1H), 4.59 - 4.43 (m, 2H), 4.21 (dd, J = 9.4, 3.5 Hz, 1H), 4.09 - 4.00 (m, 1H), 3.92-3.83 (m, 1H), 2.23 (s, 3H). LCMS (ESI+): m/z 428.1 (M+H)
217
78 ( S)-4-(2-(difluoromethoxy) pyridin-3-yl)-12-fluoro7a,8,13,14 -letrahydro-7H[l,2,4]triazolo [4',3':l,6]pyrido[3,2b]benzofuro[4,3fg][ 1,4] oxazonine AA AA F HN \ F } P HCOOH xy 1HNMR DMSO-d6 400 MHz δ = ppm 9,45 (s, IH), 8.40 (dd, J = 7.5, 1.5 Hz, IH), 8.26 (dd, J = 4.8,1.7 Hz, 11-1),7.73 (t, J = 72.4 Hz, IH), 7.66 (br t, J = 6.4 Hz, IH), 7.56 (s, IH), 7.40 (dd, J = 7.5, 5.0 Hz, IH), 6.97 (t, J = 9.5 Hz, I H), 6.70 (dd, J = 3.7, 8.6 Hz, 1 H), 4.97 - 4.87 (m, IH), 4.86 - 4.77 (m, IH), 4.54 (t, J = 9.5 Hz, 1 H), 4.46 (br s, 1 H), 4.21 (dd, J = 9.5, 3.4 Hz, IH), 4.06 (br s, IH), 3.92 - 3.80 (m, IH). LCMS (ESI+): m/z 456,1 (M+H).
77 (S)-12-fluoro-4-(2- methoxypyridin-3 -yl) - 7a,8,13,14- tetrahydro-7H- [l,2,4]triazolo [4',3':l,6]pyrido[3,2b]benzofuro[4,3-fg] [1,4] oxazonine n-n V N fl P-Vx N b O·^ o HCOOH F, ) s 1HNMR CDC13 400 MHz 5 = ppm 8.93 (s, IH), 8.32 (br d, J = 7.1 Hz, IH), 8.15 (br d, J = 3.9 Hz, IH), 7.57 (s, IH), 6.99 (dd, J = 7.0, 5.2 Hz, IH), 6.85 (br t, J = 9.4 Hz, IH), 6.65 (dd, J = 8.6, 3.7 Hz, IH), 5.36 (brs, IH), 5.07 (br dd, J= 14.6, 6.4 Hz, IH), 4.91 - 4.77 (m, IH), 4.69 4.50 (m, 2H),4.18-4.28 (m, IH), 3.97 (s, 3H), 3.95 - 3.76 (m, 2H). LCMS (ESI+): m/z 420.1 (M+H).
58 (S)-5-(12- fluoro7a,8,13,14-tetrahydro- 7H[l,2,4]triazolo [4',3':l,6]pyrido[3,2b]benzofuro [4,3fg][l,4]oxazonin-4-yl)- N,N,4- trimethylpyrimidine2-carboxamide _ Z N Ν-Ζ^θ T N-N \ N K. N A ΗΝΓο F } P /=\A HCOOH vAa Ό' IH NMR DMSO-d6 400 MHz δ = ppm 9.58 (s, IH), 8.82 (s, IH), 7.98 (brs, 1 H),7.68 (s, 1 H), 6.99(t, J = 9.2 Hz, 1 H), 6.72 (dd, J = 8.4, 3.6 Hz, IH), 5.03 - 4.91 (m, IH), 4.83 (br d, J = 8.4 Hz, 1 H), 4.62 - 4.51 (m, 2H), 4.23 (br d, J = 6.4 Hz, IH), 4.06 (brs, 11-1),3.93 -3.84 (m, IH), 3.04 (s, 3H), 2.86 (s, 3H), 2.44 (s, 3H). LCMS (ES1+): m/z 476.2 (M+H).
96 (S)-4-(2-ethylpyridin -3-yl)12-fluoro-7a,8,13, 14- tetraliydro-7H- [ 1,2,4]triazolo [4', 3': l,6]pyrido[3,2- b]benzofuro [4,3- fg] [ 1,4]oxazonine hcooh A nA aA O \ CT/ 'H NMR DMSO-76 400 MHz δ = ppm 9.41 (s, IH), 8.53 (dd, 7=4.9, 1.5 Hz, IH), 7.68 (dd, 7= 7.6, 1.7 Hz, IH), 7.55 - 7.47 (m, IH), 7.33 7.22 (m, 2H), 7.00 - 6.90 (m, IH), 6.73 - 6.64 (m, IH), 4.95 - 4.84 (m, IH), 4.81 -4.72(m, IH), 4.57 - 4.42 (m, 2H), 4.25 - 4.16 (m, IH), 4.07 3.97 (m, IH), 3.89 - 3.78 (m, IH), 2.60 (q, 7= 7.4 Hz, 2H), 1.06 (t, 7 = 7.5 Hz, 3H). LCMS (ESI+): m/z 418.0 (M+H).
218
105 (S)-12-fluoro- 4-(2methoxy-6-methylpyridm 3-yl)-7a,8,13,14-tetrahydro- 7H-[l,2,4]triazolo [4',3':l,6]pyrido[3,2- b]benzofuro[4,3-fg ][l,4]oxazonine HCOOH .—/ h/ q οΛ 0 ‘H NMR DMSO-î/6 400 MHz δ = ppm 9.40 (d, J = 2.3 Hz, 1 H), 8.17 (d, 7=7.6 Hz, 1H), 7.55 (s, 1H), 7.47 (br t, 7=6.2 Hz, 1H),7.OO6.89 (m, 2H), 6.69 (dd, J = 8.7, 3.8 Hz, 1H), 4.95 - 4.86 (m, 1H), 4.83 4.74 (m, 1H), 4.58 - 4.42 (m, 2H), 4.22 (dd, J= 9.5, 3.5 Hz, 1H), 4.10 3.99 (m, 1H), 3.89 (s, 3H), 3.85 3.78 (m, 1H), 2.45 (s, 3H). LCMS (ESÏ+): m/z 434.1 (M+H).
106 (S)-12-fluoro-4- (6- methoxy-2-methylpyridin3 -yl)-7a,8,13,14-tetrahydro7H- [l,2,4]triazolo [4’,3’:l,6]pyrido[3,2- b]benzofuro [4,3fg][l,4]oxazonine \ 0 \ N N-Λ /=( 't? \ HCOOH HN 0 Fv/ \ Co Ή NMR CDC] 3 400 MHz δ = ppm 8.88 (s, 1H), 7.60 (d, J = 8.4 Hz, 1 H),7.03 (s, 1H), 6.87 (t,7=9.5 Hz, 1H), 6.67 (dd, J= 8.7, 3.9 Hz, 1H), 6.61 (d,7=8.4 Hz, 1H),5.165.03 (m, 2H), 4.83 (br d, J= 9.3 Hz, 1H), 4.64 (t, J= 9.4 Hz, 1H), 4.58 (dd, 7=9.9, 4.2 Hz, 1H),4.25 (dd, J = 9.7, 3.3 Hz, 1H), 4.00 9 Μ, 3H), 3.98 - 3.89 (m, 1H), 3.87 - 3.77 (m, 1H), 2.38 (s, 3H). LCMS (ESI+): m/z 434.2 (M+H)
114 (S)-I2-fluoro- 4-(2- (trifluoromethyl) pyrimidin5-yl)-7a,8,13,14- tetrahydro7H-[l,2,4]triazolo [4',3':l,6]pyrido[3,2b]benzofuro [4,3- fg][ 1,4] oxazonine CF3 /P \ N ν-Λ /=='/ V H N % C£/ Ή NMR DMSO-îL 400 MHz δ = ppm 9.86 (s, 2H), 9.45 (s, 1H), 8.22 (s, 1 H), 7.95 (brs, 1H), 7.03 - 6.89 (m, 1H), 6.78 - 6.65 (m, 1H),4.974.88 (m, 1H), 4.87-4.79 (m, 1H), 4.53 (br t, 7=9.3 Hz, 2H), 4.254.18 (m, 1H), 4.09-4.00 (m, 1H), 3.99 - 3.91 (m, 1H). LCMS (ESI+): m/z 459.2 (M+H).
115 (S)-12-fluoro-4 -(1-methyl3-(trifluoromethyl)- 1Hpyrazol-5-yl)-7a,8,13,I4- tetrahydro-7H- [l,2,4]triazolo [4',3':1,6]pyrido[3,2- b]benzofuro [4,3- fg] [ 1,4] oxazonine CF3 (Pn h t W -N A HN( 0 R/ \ Ci/ ’HNMR DMSO-d6400MHzÔ = ppm 9.47 (s, 1H), 7.81 (br t, J = 6.2 Hz, 1H), 7.57 (s, 1H), 7.02 (s, 1H), 7.00-6.91 (m, 1H), 6.70 (dd, J = 8.6,3.9 Hz, 1H), 4.98 -4.88 (m, 1H), 4.86 - 4.76 (m, 1H), 4.58 - 4.44 (m, 2H), 4.21 (dd, J = 9.6, 3.5 Hz, 1H), 4.10-3.99 (m, 1H), 3.92 (s, 3H), 3.91-3.84 (m, 1H). LCMS (ESI+): m/z 461.2 (M+H).
219
116 (S)-12-fluoro -4-(6morpholinopyridin -3-yl)7a,8,13,14- tetrahydro-7H- [l,2,4]triazolo [4',3':l,6]pyrido[3,2- b]benzofuro [4,3fg] [ 1,4] oxazonine O HCOOH //T \ N HN^ b ΟΓ/ 'H NMR DMSO-îZ6 400 MHz δ = ppm 9.41 (s, 1 H), 8.96 (d,J= 2.3 Hz, IH), 8.36 (dd, J= 9.0, 2.4 Hz, 1 H), 7.60 (s, 1 H), 7.41 (br t,7=6.5 Hz, IH), 6.97 - 6.89 (m, 2H), 6.67 (dd, 8.6, 3.9 Hz, IH), 4.92 - 4.82 (m, 1 H), 4.80 -4.68 (m, 1H),4.564.46 (m, 2H), 4.21 (dd, J = 9.5, 3.2 Hz, IH), 4.07 - 3.86 (m, 2H), 3.76 3.67 (m, 4H), 3.53 - 3.46 (m, 4H). LCMS (ESI+): m/z 475.2 (M+H).
117 (S)-12-fluoro -4-(6-(4- methylpiperazin -1yl)pyridin-3-yl)-7a,8,13,14tetrahydro-7H- [l,2,4]triazolo [4’,3’:l,6]pyrido[3,2- b]benzofuro [4,3- fg][l,4]oxazonine N-Z zn cH )=/ HCOOH H N X o t ΟΓ/ ‘H NMR DMS0-î/6 400 MHz δ = ppm 9.41 (s, 1 H), 8.93 (d, 7=2.4 Hz, IH), 8.37 - 8.30 (m, IH), 8.15 (s, IH), 7.27 (s, IH), 7.44 - 7.33 (m, IH), 7.00 - 6.85 (m, 2H), 6.71 - 6.63 (m, IH), 4.92-4.83 (m, 11-1),4.81 4.71 (m, IH), 4.57 - 4.46 (m, 2H), 4.25 -4.17 (m, IH), 4.09 - 3.99 (m, IH), 3.96 - 3.86 (m, 1 H), 3.57 - 3.52 (m, 4H), 2.43 (br t, J= 4.9 Hz, 4H), 2.24 (s, 3H). LCMS (ESI+): m/z 488.2 (M+H).
118 (S)-12-fluoro -4-(2-(4- methylpiperazin -1y 1 ) p y ri mi din -5 - y 1 ) 7a,8,13,14- tetrahydro-7H- [l,2,4]triazolo [4',3':l,6]pyrido[3,2- b]benzofuro [4,3fg][l,4]oxazonine N-Z A \=/ HCOOH hZ b Fx / 5 Ci) ' H NMR DMSO-dé 400 MHz δ = ppm 9.42 (s, IH), 9.13 (s, 2H), 8.15 (s, IH), 7.66 (s, 1 H), 7.48 (br t,7= 6.4 Hz, IH), 6.99 - 6.90 (m, IH), 6.73 - 6.63 (m, IH), 4.91 - 4.83 (m, IH), 4.80-4.71 (m, IH), 4.56 - 4.42 (m, 2H), 4.25-4.16 (m, 1H),4.O83.97 (m, 111),3.95 -3.86 (m, IH), 3.82 - 3.75 (m, 4H), 2.42 - 2.37 (m, 4H), 2.23 (s, 3H). LCMS (ESI+): m/z 489.2 (M+H).
112 (S)-12-fluoro -4-(6(trifluoromethyl) pyridin-3yl)-7a,8,13,14- tetrahydro7H-[l,2,4]triazolo [4',3':l,6]pyrido[3,2b]benzofuro [4,3fg][l,4]oxazonine cf3 HCOOH / ¾ \ N nA Z HN b Fx_/ À Co ‘H NMR DMSO-76 400 MHz δ = ppm 9.56 (s, IH), 9.51 (s, IH), 8.97 (d, 7=7.0 Hz, IH), 8.51 (s, IH), 8.03 (s, IH), 7.99 (d, 7= 8.3 Hz, IH), 7.89 (s, IH), 6.97 (t,7=9.5 Hz, IH), 6.70 (dd, 7= 8.6, 3.7Hz, IH), 4.98 - 4.90 (m, IH), 4.88 - 4.79 (m, IH), 4.55 (t, 7= 9.3 Hz, 2H), 4.23 (dd, 7= 9.7, 3.0 Hz, IH), 4.06 (s, IH), 4.01 - 3.92 (m, IH). LCMS (ESI+): m/z 458.1 (M+H).
220
109 (S)-4-(2-etlioxypyrimidin 5-yl)-12-fluoro-7a,8,13,14tetrahydro-7H- [l,2,4]triazolo [4',3':l,6]pyrido[3,2bjbenzofuro [4,3fg][ 1,4]oxazonine LL 'H NMR DMSO-di 400 MHz δ = ppm 9.45 (s, IH), 9.35 (s, 2H), 7.82 (s, IH), 7.60 (br s, IH), 6.98 - 6.89 (m, IH), 6.72 - 6.63 (m, IH), 4.94 4.85 (m, IH), 4.82 - 4.72 (m, IH), 4.60 - 4.48 (m, 2H), 4.40 (q, 7= 7.1 Hz, 2H), 4.26-4.17 (m, IH), 4.08 3.86 (m, 2H), 1.36 (t, J = 7.1 Hz, 3H). LCMS (ESI+): m/z 435.1 (M+H).
94 (S)-12-fluoro- 4-(6- methylpyridin-3-yl)-7a,8,13, 14-ietrahydro-7H[l,2,4]triazolo [4’,3':l,6]pyrido[3,2- b]benzofuro [4,3fg][l,4]oxazonine HCOOH N-V F. / \ Qz NV—O Ή NMR DMSO-% 400 MHz δ = ppm 9.45 (s, IH), 9.22 (s, IH), 8.46 (dd, 7= 8.1, 2.3 Hz, IH), 7.75 (s, IH), 7.62 -7.55 (m, IH), 7.33 (d,7 = 8.2 Hz, IH), 6.95 (dd, J= 10.0, 8.9 Hz, IH), 6.68 (dd, 7= 8.6, 3.8 Hz, IH), 4.95 -4.85 (m, IH),4.83 4.74 (m, IH), 4.58 - 4.49 (m, 2H), 4.24-4.18 (m, IH), 4.08 - 3.99 (m, IH), 3.97 - 3.90 (m, IH), 2.52 (br s, 3H). LCMS (ESI+): m/z 404.1 (M+H).
108 (S)-5-(12-fluoiO 7a,8,13,14-tetrabydro-7H[l,2,4]triazolo [4',3':l,6]pyrido[3,2bjbenzofuro [4,3- fg][ 1,4]oxazonin-4-yl)-N,Ndi methy 1 py ri m i di n -2 -ami ne \ N— /A // V \ N nA a HNb HCOOH Qj NV-O ‘H NMR DMSO-76 400 MHz δ = ppm 9.42 (s, IH), 9.12 (s, 2H), 7.64 (s, 1H),7.44 (brt,7=6.5 Hz, IH), 6.99 - 6.90 (m, IH), 6.67 (dd, 7= 8.5,3.9 Hz, IH), 4.92 - 4.83 (m, IH), 4.81 - 4.72 (m, IH), 4.57 - 4.45 (m, 2H), 4.21 (dd, 7= 9.8, 3.2 Hz, 1 H), 4.09 - 3.97 (m, IH), 3.96 - 3.87 (m, IH), 3.17 (s,6H). LCMS (ESI+): m/z 434.1 (M+H).
111 (S)-12-fluoro-4 -(5-fluoro2-methoxypyridin -3-yl)7a,8,13,14-tetrahydro-7H- [l,2,4]triazolo [4',3':l,6]pyrido[3,2b] benzofuro[4,3 -fg] [1,4] oxazonine F \ M A ZZ IL W b'N HN b F' .Z À Oa NV—Q ‘H NMR DMSO-76 400 MHz δ = ppm 9.44 (s, IH), 8.53 - 8.40 (m, IH), 8.14 (s, IH), 7.77 (s, IH), 7.72 - 7.60 (m, IH), 7.01-6.91 (m, IH), 6.74 - 6.65 (m, IH), 4.96 - 4.86 (m, IH), 4.85 - 4.74 (m, IH), 4.58 - 4.42 (m, 21-1), 4.27 - 4.16 (m, IH), 4.11 3.98 (m, IH), 3.94 (s, 3H), 3.87 3.78 (m, 1 H). LCMS (ESI+): m/z 438.1 (M+H).
221
103 (S)-5-(12-fluoro - 7a,8,13,14-tetrahydro-7H- [l,2,4]triazolo [4', 3': 1,6]pyrido[3,2- b]benzoûuO [4,3- fg][l,4]oxazonîn-4-yl)-N,N- dimethy 1 py ri di n-2 - a mi ne \ N— nA j y-/ N A /Λ HCOOH HN X o fx / \ lH NMR DMSO-TXÛO MHz δ = ppm 9.38 (s, 1H), 8.89 (d, J= 2.2 Hz, 1H), 8.28 (dd, 7 = 9.0, 2.4 Hz, 1H), 8.12 (s, 1H), 7.52 (s, 1H), 7.32 (t, 7= 6.4 Hz, 1H), 6.95 - 6.86 (m, 1H), 6.70 (d, 7= 9.0 Hz, 1H), 6.65 (dd, 7= 8.6, 4.0 Hz, 1H), 4.89 - 4.81 (m, 1H), 4.79 - 4.68 (m, 1H), 4.55 4.43 (m, 2H), 4.19 (dd, 7=9.6, 3.2 Hz, 1H), 4.07 - 3.95 (m, 1H), 3.94 3.84 (m, 1H), 3.05 (s, 6H). LCMS (ESI+): m/z 433.1 (M+H).
91 (S)-12-fluoro-4- (pyrimidin5-yl)-7a,8,I3,14-tetrahydro- 7H-[l,2,4]triazolo [4',3':l,6]pyrido[3,2- b]benzofuro [4,3- fg][l,4]oxazonine HCOOH \ N nA A ‘HNMR DMSO-c/s400 MHz δ = ppm 9.61 (s, 2H), 9.51 (s, 1H), 9.12 (s, 1H), 8.00 (s, 1H), 7.82 (t, 7= 6.0 Hz, 1H), 6.97 (t, 7= 9.6 Hz, 1H), 6.70 (dd, J= 8.6, 3.7 Hz, 1H), 5.02 4.88 (m, 1H), 4.84 (s, 1H), 4.55 (t,7 = 9.3 Hz, 2H), 4.23 (dd, 7= 9.6, 3.0 Hz, 1H),4.O5 (s, 1H),4.01 -3.91 (m, 1H), 2.88 - 2.64 (m, 1H). LCMS (ESI+): m/z 391.1 (M+H).
142 (S)-12-fluoro-4-(lHpyrazol-5-yl)-7a,8,13,14tetrahydro-7H[l,2,4]triazolo [4',3':l,6]pyrido [3,2b]benzofuro [4,3fg][l,4]oxazonine O N A >nh Ht/ b FxV y !H NMR ET20970-391-P1C12 DMSO-7, 400 MHz δ = ppm 9.39 (s, 1 H), 7.81 (s, 1H), 7.67 (brs, 1H), 7.32 (br s, IH), 7.20 (br s, 1H), 6.92 (dd,7= 10.4, 8.8 Hz, 1H), 6.66 (dd, 7 = 8.8,4.0 Hz, 1H), 4.98 - 4.89 (m, 1H), 4.87 - 4.78 (m, 1 H), 4.59 - 4.48 (m, 2H), 4.23 (dd, 7= 9.6, 3.6 Hz, 1H), 4.13 - 4.00 (m, 1H), 3.97 - 3.87 (m, 1H). LCMS (ESI+): m/z 379.1 (M+H).
Example 53: (S)- 12-fluoro-4-(3-fluoropyridin-2-yl)-7a,8,13,14-tetrahydro-7H[l,2,4|triazolo[4’,3’:l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
Step 1 : tert-butyl (S)~l 2-fluoro-4-(3-fluoropyridin-2-yl)-7a, 13-dihydro-7H[ 1,2,4]triazolo[4',3 1,6]pyrido[3,2-b]benzofuro[4,3-fg] [1,4] oxaz(mine-14(8H)-carboxylate
To a solution of tert-butyl (S)-12-fluoro-4-(tributylstannyl)-7a,13-dihydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (150 mg, 214 umol, 1.00 eq) and 3-fluoro-2-iodo-pyridine (62.0 mg, 278 umol, 1.30 eq) in dioxane (6 mL)
222 was added LiCl (18.1 mg, 428 umol, 8.76 uL, 2.00 eq), Cul (16.3 mg, 85.5 umol, 0.400 eq) and Pd(PPh3)4 (24.7 mg, 21.4 umol, 0.100 eq) under nitrogen atmosphère. The mixture was stirred at 80°C for 8 h under nitrogen atmosphère. The reaction mixture was filtered, the obtained solid was washed with MeOH (20 mL) and dried under reduced pressure to give 82 mg of the product. The filtrate was concentrated under reduced pressure and the residue was purified by prep-TLC (SiO2, EtOAc:MeOH = 10:1) to give additional 10 mg of the product which was combined with the first batch. tert-butyl (S)-12-fluoro-4-(3-fluoiOpyridin-2-yl)-7a,13-dihydiO-7H[l,2,4]triazolo[4',3’: l,6]pyrido[3,2-b]benzofuiO[4,3-fg][ l,4]oxazonine-14(8H)-carboxy!ate (92.0 mg, 181 umol, 84% yield) was obtained as a yellow oil.
Step 2; (S)-12-fh.toro-4-(3-fluoropyridin-2-ylf7a,8,13,14-tetrahydro-7H[ l,2,4]triazolo[4’,3 M,6]pyrido[3,2-b]benzofùro[4,3-fg] [1,4] oxazonine formate
HCOOH
A mixture of tert-butyl (S)-12-fluoro-4-(3-fluoiOpyridin-2-yl)-7a,13-dihydro-7H[ 1,2,4]triazolo[4',3’: 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4]oxazonine-14(8H)-carboxylate (92.0 mg, 181 umol, 1.00 eq) and HFIP (5 mL) was stirred at 80°C for 8 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (fonnic acid conditions). The product-containing fraction was concentrated under reduced pressure to remove most of MeCN at 30 °C and the aqueous phase was lyophilized. (S)-12-Fluoro-4-(3-fluoropyridin2-yl)-7a,8,13,14-tetrahydro-7H-[ 1,2,4]triazolo[4’,3’: l,6]pyrido[3,2-b]benzofuro[4,3fg][ 1,4] oxazonine (23.0 mg, 50.3 umol, 27% yield, 99.2% purity, formate sait) was obtained as a yellow solid. 1HNMR DMSO-d6 400 MHzô = ppm9.45 (s, 1H), 8.49 (d, J =3.1 Hz, 1H), 7.85 7.70 (m, 2H), 7.56 - 7.45 (m, 2H), 6.93 (t, J = 9.4 Hz, 1H), 6.66 (dd, J = 8.5, 3.2 Hz, 1H), 4.93 - 4.85 (m, 1H), 4.79 (br s, 1H), 4.57 - 4.37 (m, 2H), 4.25 - 4.15 (m, 1H), 4.01 (br s, 1H), 3.88 - 3.75 (m, 1H). LCMS (ESI+): m/z 408.1 (M+H).
Exampk 54: (S)-12-fluoro-4-(pyridin-2-yl)-7a,8,13,I4-tetrahydro-7H]l,2,4|triazolo[4’,3':l,6]pyrido[3,2-b]benzofuro[4,3-fgni,4]oxazonine mesylate sait
223
Step 1: Step 1: tert-butyl (S)-4-bromo-12-fluoro-7a,13-dihydro-7H[1,2,4] trlazolo[4 ' 3 1,6]pyrido[3,2-b]benzofuro[4,3 -fg][l ,4] oxazonine-14(8H) -carboxylate
Tributyl (2-pyridyl) stannane (56.2 mg, 0.153 mmol) was added to a solution of tert-butyl (S)-45 bromo-12-fluoro-7a,13-dihydro-7H-[l,2,4]triazolo[4,,3’:l,6]pyrido[3î2-b]benzofiiro[4,3fg][l,4]oxazonine-14(8H)-carboxylate (Example 16; 50.0 mg, 0.102 mmol) and tetrakis(triphenylphosphine) palladium(O) (35.3 mg, 0.0306 mmol) in toluene (1.00 mL) under nitrogen. The mixture was stirred at 115 °C for 16 h and diluted with sat. aq. NaCl (15.0 mL). The aqueous phase was extracted with DCM (3x15 mL). The combined organic layers were dried over
MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (12 g cartridge) eluting with EtOAc in hexanes (0 -100%) to afford the tert-butyl (S)-4-bromo-12-fluoro-7a, 13-dihydro-7H-[ l,2,4]tnazolo[4',3’: 1,6]pyrido[3,2b]benzofuro[4f3-fg][L4]oxazonine-14(8H)-carboxylate compound as an oil (31.3 mg, 63%). IH NMR (500 MHz, CDC13) δ 9.21 (d, J = S.O Hz, IH), 8.72 (s, IH), 8.67 (d, J = 3.8 Hz, IH), 8.22 (s,
IH), 7.85 (td, J = 7.8, 1.9 Hz, IH), 7.35 - 7.27 (m, IH), 6.60 (s, IH), 6.53 (s, IH), 5.37 (s, IH), 4.74 (s, IH), 4.62 (s, IH), 4.48 (t, J = 8.8 Hz, IH), 4.26 (dd, J = 9.7, 1.2 Hz, IH), 4.18 - 4.11 (m, IH), 3.97 - 3.86 (m, IH), 1.35 (s, 9H). m/z (ES+) [M+H] +: 490.11. HPLC tR (A05) = 2.44 min.
Step 2: (S)-12-fluoro-4-(pyridin-2-yl)-7a,8,13,14-tetrahydro-7H[1,2,4] triazolo[4', 3 1,6]pyrido[3,2-b] benzofuro[4,3-fg] [ 1,4] oxazonine
224
A solution of tert-butyl (S)-4-bromo-12-fluoro-7a, 13-dihydro-7H[ 1,2,4]triazolo[4',3’: 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4]oxazonine-14(8H)-carboxylate (31.3 mg, 0.0639 mmol) in HFIP (2.00 mL) was stirred at 100 °C for 5 h. The solution was concentrated under reduced pressure, and the residue was purified by préparative HPLC (BEI-I C18 30x150mm AmBicarb/ACN 35-55%) to afford (S)-12-fluoiO-4-(pyridin~2-yl)-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][ l,4]oxazonine as a solid (13.0 mg, 52%). IH NMR (400 MHz, DMSO-d6) Ô 9.49 (s, IH), 9.01 (d, J = 8.2 Hz, IH), 8.64 (d, J = 5.0 Hz, IH), 8.31 (d, J = 1.7 Hz, 1 H), 7.90 (t, J = 7.8 Hz, IH), 7.79 (t, J = 6.6 Hz, IH), 7.30 (dd, J = 7.6, 4.7 Hz, IH),
6,95 (t, J = 9.8 Hz, IH), 6.68 (dd, J = 9.7, 3.6 Hz, IH), 4.87 (tdd, J = 16.6, 11.3, 5.2 Hz, 2H), 4.54 (dd, 1 = 20.7, 10.4 Hz, 2H), 4.25 (d, J = 11.4 Hz, IH), 4.05 (s, IH), 3.88 (t, J = 10,9 Hz, lH).m/z (ES+) [M+H] +: 390.2. HPLC tR (A05) = 2.73 min.
Step 3: (S)-12-fluoro-4-(pyridin-2-yl)-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4’,3 1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine monomesylate
Methanesulfonic acid (0.00217 mL, 0.0334 mmol) was added to a suspension of (S)~12-fluoro-4(pyridin-2-yl)-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4',3’: l,6]pyrido[3,2-b]benzofuro[4,3fg][ 1,4] oxazonine (13.0 mg, 0.0334 mmol) in MeCN (2.00 mL). The mixture was stirred at rt for 1
225
h. The mixture was concentrated under reduced pressure to provide the title compound as a solid (15.2 mg, 94%). 1HNMR (500 MHz, DMSO-d6) δ 9.67 (s, IH), 8.74 (d, J = 4.8 Hz, IH), 8.66 8.47 (m, 3H), 8.08 (t, J = 7.5 Hz, IH), 7.49 - 7.42 (m, IH), 6.99 (t, J = 9.0 Hz, IH), 6.73 (d, J = 6.9 Hz, IH), 4.98 (dd, J = 25.9, 15.4 Hz, 2H), 4.65 (s, IH), 4.56 (t, J = 9.0 Hz, IH), 4.25 (d, J = 6.9 Hz, IH), 4.11 (s, IH), 3.99 (s, IH), 2.30 (s, 3H), m/z (ES+) [M+H-MsOH]+: 393.2, HPLC tR (B05) = 1.33 min.
Example 55: General Procedure E. Préparation of(S)-12-fluoro-N,N-dimethyl-7a,8,13,J4tetrahydro-7H-[l,2,4]triazolo|4',3':l,6]pyndo[3,2-b]benzofuro[4,3-fgHl,4]oxazonine-4carboxamide
Step 1: tert-butyl (S)-12-fluoro-4-vinyl-7a, 13-dihydro-7H-[l,2,4]triazolo[4’,3’:l,6]pyrido[3,2b] benzofuro[4,3-fg] [1,4] oxazonine-14 (8H)-carboxylate
A mixture of tert-butyl (S)-4-bromo-12-fluoro-7a,13-dihydro-7H[ 1,2,4]triazolo[4',3': 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ l,4]oxazonine-l 4(8H)-carboxylate (Example 16; 300 mg, 0.611 mmol), potassium vinyltrifluoroborate (164 mg, 1.22 mmol), Pd(dppf)CI2 (44.7 mg, 0.0611 mmol), and NaHCO3 (256 mg, 3.05 mmol) in 1,4-dioxane/waler (5.00/0.500 mL) deoxygenated by applying vacuum and refiliing with nitrogen. Two additional deoxygenation cycles were applied. The mixture was stirred at 90 °C for 4 h. The mixture was diluted with water (15.0 mL) at room température, and the aqueous phase was extracted with EtOAc (4 x 25.0 mL). The combined organic layers were washed with sat. aq. NaCl (15.0 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified b y silica gel chromatography (24 g cartridge) eluting with MeOH in DCM (0-15 %) to provide tert-butyl (S)-12fluoro-4-vinyl-7a,13-dihydro-7H-[l,2,4]triazolo[4',3’:l,6]pyrido[3,2-b]benzofuro[4,3fg][l,4]oxazonine-14(8H)-carboxylate as a solid (0.258 g, 96 %). ES+ [M]+: 438.37; HPLC tR (A05) = 2.27 min.
226
Step 2: tert-butyl (S)-l2-fluoro-4~formyl-7a, 13-dihydro-7H-[1,2,4]triazolo]4',3L6]pyrido]3,2bjbenzofuro]4,3-fg] [1,4] oxazonine-14(8H)-carboxylate
NaIO4 (755 mg, 3.53 mmol) and 2,6-lutidine (0.137 mL, LIS mmol) were sequentially added to a stirred solution of aq. OsO4 (0.187 mL, 29.4 pmol, 4.00%) and tert-butyl (S)-12-fluoro-4-vinyl7a,13-dihydro-7H-[l,2,4]triazolo[4’,3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)carboxylate (258 mg, 0.588 mmol) in 1,4-dioxane/water (6.00 mL/2.00 mL) under N2. The mixture was stirred at room température for 4.5 h. Water (15.0 mL) and EtOAc (20.0 mL) were added. The aqueous phase was extracted with EtOAc (3X30 mL). The combined organic layers were washed with sat. aq. NaCl (15.0 mL), dried over MgSO4, filtered, and coneentrated under reduced pressure. The residue was purified by silica gel chromatography (24 g cartridge) with EtOAc in hexanes (1090%) to afford tert-butyl (S)-12-fluoro-4-formyL7a,13-dihydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazor]me-14(8H)-carboxylate (159 mg, 61%) as a solid. IH NMR (400 MHz, CDC13) δ 10.63 (s, IH), 8.72 (s, IH), 7.66 (s, IH), 6.72 - 6.47 (m, 2H), 5.34 (bs, IH), 4.74 (bs, IH), 4.63 (bs, IH), 4.48 (dd, J = 9.6, 7.8 Hz, IH), 4.27 (dd, J = 9.7, 1.4 Hz, 1 H), 4.01 (t, J = 11.5 Hz, IH), 3.96-3.85 (m, IH), 1.36 (s, 9H). m/z (ES+) [M+H]+: 441.62; HPLC tR (A05) = 2.13 min.
Step 3: (S)-14-(tert-butoxycarbonyl)-12-fluoro-7a,8,13,14-tetrahydro-7H]1,2,4] triazolo]4\3 ':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l, 4]oxazonine-4-carboxylic acid
2-Methyl-2-butene (0.373 mL, 3.52 mmol) was added to a solution of tert-butyl (S)-12-fluoro-4formyl-7a,13-dihydro-7H-[l,2,4]triazolo[4,,3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
227
14(8H)-carboxylate (155 mg, 0.352 mmol) in tBuOH (4.50 mL). A solution ofNaCIO? (95.5 mg, 1.06 mmol) and NaH2PO4 (76.0 mg, 0.633 mmol) in water (3.00 mL) was added dropwise. The mixture was stirred at room température for 2 h. The mixture was concentrated under reduced pressure. Water (10.0 mL) was added, and the aqueous phase was extracted with EtOAc (4 x 20.0 mL). The combined organic layers were washed with sat. aq. NaCl (S.00 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (12 g, cartridge) with MeOH in DCM (0-30%) to afford (S)-14-(tertbutoxycarbonyl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[ l,2,4]triazolo[4',3': 1,6]pyrido[3,2b]benzofuro[4,3-fg][l,4]oxazonine-4-carboxylic acid as a solid (128 mg, 80%). m/z (ES+) [M]+: 456.73; HPLC tR (A05) = 1.98 min
Step 4: tert-butyl (S)-4-(dimethylcarbamoyl)-12-fluoro-7a,l 3-dihydro-7H[1,2,4] triazolo[4’,3 ':1,6]pyrido[3,2-b]benzofttro[4,3-fg] [l,4]oxazomne-14(8H)-carboxylate
N, N-Diisopropylethylamine (22.9 qL, 0.13 1 mmol) was added to a solution of (S)-14-(tertbutoxycarbonyl)-12-fluoiO-7a,8,13,i4-tetrahydro-7H-[ 1,2,4]triazolo[4',3’: l,6]pyrido[3,2b]benzofuro[4,3-fg][ J ,4]oxazonine-4-carboxylic acid (30.0 mg, 0.0657 mmol) and dimethylamine hydrochloride (8.04 mg, 0.0986 mmol) in DMF (1.00 mL). HATU (50.0 mg, 0.131 mmol) was added. The mixture was stirred at room température for 2 h. Reaction completion was monitored by chromatography. The mixture was concentrated under reduced pressure. Water (10.0 mL) was added, and the aqueous phase was extracted with EtOAc (3x20.0 mL). The combined organic layers were washed with sat. aq. NaCl (8.00 mL), dried over MgSÛ4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (4 g, cartridge) with MeOH in DCM (0-10%) to provide tert-butyl (S)-4-(dimethylcarbamoyl)-12-fluoro-7a,13-dihydro-7H[l^NJtriazoIofT^’:l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate as a solid (25.0 mg, 79%). m/z (ES+) [M+H]+: 484.78; HPLC tR (A05) = 2.05 min.
228
Step 5: (S)-12-fluoro-N,N-dimethyI-7a,8J3,14-tetvahydro-7H-[1,2,4]triazolof431,6]pyrido[3,2b] benzofuro[4,3-fg] [I,4] oxazonine-4-carboxamide
A solution of tert-butyl (S)-4-(dimethylcarbamoyl)-12-fluoro-7a,13-dihydro-7H5 [l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (25.0 mg, 0.0517 mmol) in HFIP (1.00 mL) was heated to 100 °C for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by préparative HPLC (Gemini C18 30xI00mm AmBicarb/ACN 25-45%) to afford the title compound as a solid (4.50 mg, 23%). IH NMR (400 MHz, CD3OD) δ 9.30 (s, IH), 7.51 (s, IH), 6.86 (dd, J = 10.3, 8.7 Hz, IH), 6.62 (dd, J = 8.7, 3.9
Hz, IH), 5.05 (d, J = 14.8 Hz, IH), 4.86 (d, J = 14.6 Hz, IH), 4.57 (t, J = 9.3 Hz, 2H), 4.27 (dd, J = 9.6, 3.3 Hz, IH), 3.99 (ddd, J = 12.9, 9.8, 4.8 Hz, 1 H), 3.92 - 3.77 (m, IH), 3.13 (s, 3H), 2.94 (s, 3H). m/z (ES+) [M]+: 383.38; HPLC tR (A05) = 1.83 min.
Compounds 38 and 64 were prepared according to General Procedure E using the suitable starting materials, precursors, intermediates, and reagents.
Cmpd No. Compound Naine Structure Spectral Data
64 (S)-12-fluoro-Nmethyl-N(tetrahydro-2H pyran-4-yl)* 7a,8,13,14tetrahydro-7H[l,2,4]triazolo [4’,3':l,6]pyrido[3,2b]benzofuro [4,3fg][l,4] oxazonine4-carboxamide 0 0 UN L F-^ IH NMR (500 MHz, MeOD) δ 9.31 (s, IH), 7.49 (s, IH), 6.86 (dd, J - 10.3, 8.7 Hz, IH), 6.62 (dd, J = 8.7, 3.8 Hz, IH), 5.05 (d,J = 14.8 Hz, IH), 4.86 (m, 2H), 4.56 (t, J = 9.3 Hz, 2H), 4.27 (dd, J = 9.6, 3.2 Hz, IH), 4.09 - 3.93 (m, 2H), 3.85 (t, J = 11.2 Hz, 2H), 3.56 (bs, IH), 3.11-2.72 (m, 3H), 2.20-2.10 (m, IH), 1.98 - 1.85 (m, 2H), 1.79 (bs, 2H) (rotamers); m/z (ES+) [M]+: 453.35; LC-MS (A05) tR= 1.85 min.
229
38 (S)-12-fluoro-NmethyLN-(2,2,2trifluoroethyl)7a,8,13,14tetrahydro- 7H[l,2,4]triazolo [4',3': 1,6]pyrido[3,2b] benzo furo [4,3 fg][l ,4]oxazonîne4-carboxamide U- UL, 1. —\ / pÆ) \ / έ u- ° H IH NMR (500 MHz, DMSO) δ 9.42 (s, IH), 7.79 (s, IH), 7.45 (s, IH), 6.96 (dd, J= 10.2, 8.8 Hz, IH), 6.69 (dd, J = 8.7, 3.8 Hz, IH), 4.90 (d, J = 15.0 Hz, IH), 4.80 (d, J= 15.4 Hz, IH), 4.52 (t, J = 9.4 Hz, IH), 4.46 (bs, IH), 4.35 (bs, 2H), 4.21 (dd, J = 9.5, 3.7 Hz, IH), 4.02 (t, J = 10.8 Hz, IH), 3.80 (t, J = 11.4 Hz, IH), 3.02 (s, 3H) (rotamers); m/z (ES+) [M]+: 451.21; LC-MS (A05) tR = 2.03 min.
Example 56: (S)-12-fluoro-4-(l-methyl-lH-pyrazol-3-yl)-7a,8,13,14-tetrahydro-7H [l,2,4]triazolo[4',3':l,6|pyrido[3,2-b]benzofiiro[4,3-fg][l,4]oxazonine mesylate
Step 1 : lributyl-(l-methylpyrazol-3-yl)stannane
SnBuj n-BuLi in THF (0,960 mL, 2.40 mmol, 2.50 M) was added dropwise to a solution of 5-bromo-lmethyl-lH-pyrazole (0.322 g, 2.00 mmol) în THF (10.0 mL) at -78 °C. The mixture was stirred at 78 °C for 30 min. Tributyltin chloride (0.651 mL, 2.40 mmol) was added dropwise. The mixture was stirred at -78 °C for I h, warmed to room température, and stirred for 2 h. Sat. NH4C1 (10 mL) was added, and the aqueous phase was extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with brine (20 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (40 g cartridge) elutîng with hexanes and EtOAc (0-20%) to provide the title compound as an oil (0.142 g, 19%). IH NMR (500 MHz, CDC13) δ 7.42 (d, J = 2.0 Hz, IH), 6.32 (d, J = 2.1 Hz, IH), 3.96 (s, 3H), 1.60 - 1.52 (m, 6H), 1.38 - 1.28 (m, 6H), 1.10-1.04 (m, 6H), 0.88 (t, .1 = 7.3 Hz, 9H); m/z (ES+) [M]+: 371.06 (multiple Sn isotopes), HPLC tR (A05) =
3.03 min.
Step 2: tert-butyl (S)-12-fluoro-4-(I-methyl-lH-pyrazol-3-yl)-7a,13-dihydro-7H[ 1,2,4] triazolo[4',3' : 1,6]pyrido[3,2-b] benzofuro[4,3-fg] [1,4] oxazonine-14(8H)-carboxylate
230
A solution oftributyl-(l-methylpyrazol-3-yl) stannane (51.0 mg, 0.137 mmol) in toluene (1.50 mL) was added to a mixture of tert-butyl (S)-4-bromo-12-fluoro-7a,13-dihydro-7H[ 1,2,4] tri azolo[4',3l,6]pyrido[ 3,2-b]benzofuro[4,3-fg][ 1,4] oxazonine-14(8H)-carboxylate (Example 16; 50.0 mg, 0.102 mmol) and Pd(PPh3)4 (23.5 mg, 0.0204 mmol) under nitrogen. The mixture was heated at 110 °C for 20 h. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (4 g cartridge) eluting with MeOH in DCM (0-15%) to provide tert-butyl (S)-12-fluoro-4-(l-methyl-lH-pyrazol-3-yl)-7a,13-dihydro-7H[ l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3~fg][l,4]oxazonine-14(8H)-carboxylateas a solid (37.0 mg, 74%). m/z (ES+) [M+H]+:493.49; HPLC tR (A05) = 2.21 min.
Step 3: (S)-12-fluoro-4-(l-methyl-lH-pyrazol-3-yl)-7a,8,13,14-tetrahydro-7H[1,2,4] triazolo[4',3':l, 6]pyrido[3,2-b]benzofuro[4,3-fg] [1,4] oxazonine
A solution of tert-butyl (S)-12-fluoro-4-(l-methyl-lH-pyrazol-3-yl)-7a,13-dihydro-7H[l,2,4]triazolo[4',3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (37.0 mg, 75.1 pmol) in HF1P (2.00 mL) was heated at 100 °C for 16 h. The mixture was concentrated under reduced pressure, and the residue was purified by HPLC (Gemini C18 30x100mm AmBicarb/ACN 27-47%) to afford the deprotected material as a solid (20.8 mg, 71%) . IH NMR (500 MHz, DMSO) δ 9.41 (s, IH), 7.74 (d, J = 2.1 Hz, IH), 7.73 (s, IH), 7.44 (t, J = 5.3 Hz, IH), 7.22 (d, J = 2.2 Hz, IH), 6.99-6.88 (m, IH), 6.66 (dd, J = 8.6, 3.8 Hz, 1H),4.88 (d, J = 11.4 Hz, IH), 4.76 (d, J = 11.6 Hz, IH), 4.55-4.50 (m, 2H), 4.24 (dd, J = 9.6, 3.4 Hz, IH), 4.06 - 3.97 (m,
231
IH), 3.90 (s, 3H), 3.84 (t, J = 11.5 Hz, IH). m/z (ES+) [M+H]+: 392.38; HPLC tR (A05) - 1.97 min.
Step 4: (S)-12-fluoro-4-(l-methyl- lH-pyrazol-3-yl)- 7a, 8,13,14-tetrahydro-7H[1,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-jg][1,4]oxazonine mesylate sait
Methanesulfonic acid (1.90 μL, 29.3 μιηοΐ) was added to a suspension of (S)-12-fluoro-4-(LmethyllH-pyrazoL3-yl)-7a,8,13!14-tetrahydro-7H-[l,2,4]triazolo[4',3': l,6]pyrido[3,2-b]benzoturo[4,3fg][l,4]oxazonine (11.5 mg, 29.3 μιηοΐ) in MeCN (1,50 mL). The mixture was stirred at room température for 1 h. The mixture was concentrated under reduced pressure to provide the title compound as a solid (13.5 mg, 94%). IH NMR (400 MHz, CD3OD) δ 9.47 (s, IH), 8.28 (s, IH), 7.70 (d, J = 2,4 Hz, IH), 6.89 (dd, J = 10.3, 8,7 Hz, IH), 6.85 (d, J = 2.4 Hz, IH), 6.66 (dd, J = 8.7, 3.9 Hz, IH), 5.14 (d, J = 14.8 Hz, JH), 4.94 (d, J = 14.9 Hz, 1H),4.76 (dd, J = 9.9, 4.1 Hz, IH), 4.60 (t, J = 9.3 Hz, IH), 4.31 (dd, J = 9.7, 3.3 Hz, IH), 4.09 - 4.02 (m, IH), 4.01 (s, 3H), 4,01 -3.92 (m, IH), 2.70 (s, 3H). m/z (ES+) [M-MeSO3H]+: 392.1; HPLC tR (B05) = 1.53 min.
Example 57: General Procedure B. Préparation of (S)-4-(3,5-difluoropyridîn-2-yl)-12-fluoro7a,8,13,14-tetrahydro-7H-fl,2,4]triazolo[4’,3':l,6jpyrido[3,2-b]benzofuro[4,3fg] [l,4]oxazonine
Step 1: tert-butyl (5)-4-(3,5-difluoropyridin-2-yl)-l2-fluoro-7a,l3-dihydro-7H[1,2,4] triazolo[4',3 6]pyrido[3,2-b]benzofuro[4,3-fg] [1,4] oxazonine-14(8H)-carboxylate
232
To a solution of tert-butyl (S)-12-fluoro-4-(tributylstannyI)-7a,13-dihydro-7H[ 1,2,4] triazolo[4,,3':l,6]pyrido[3,2-b]benzofuiO[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (200 mg, 285 umol, 1.00 eq) indioxane (5 mL) was added 2-bromo-3,5-difluoro-pyridine (55.3 mg, 285 umol, 1.00 eq), Cul (21.7 mg, 114 umol, 0.400 eq), Pd(PPh3)4 (33.0 mg, 28.5 umol, 0.100 eq) and LÎCl (24.2 mg, 570 umol). Reaction completion was monitored by LC-MS. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (SiO?, Petroleum ether/Ethyl acetate = 1/4). tert-butyl (S)-4-(3,5-difluoropyridin-2-yl)-12-fluoro-7a,13dihydro-7H-[ 1,2,4]triazoio[4',3’: 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ l,4]oxazonine- 14(8H)~ carboxylate (140 mg, crude) was obtained as a yellow solid.
Step 2: (S)-4-(3,5-difluoropyridin-2-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H[1.2,4] triazo lo[4',3':l, 6]pyrido[3,2-b] benzofuro[4,3 -fg] [1,4] oxazon ine
HCOOH
To a solution of tert-butyl (S)-4-(3,5-difluoropyridin-2-yl)-12-fluoro-7a,13-dihydro-7H[l,2,4]triazolo[4’,3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (120 mg, 228 umol, 1.00 eq) in DCM (3 mL) was added TFA (1.5 mL) at 15°C. The mixture was stirred at 15°C for 2 h. Reaction completion was monitored by LC-MS. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (FA System). (S)4-(3,5-difluoropyiidin-2-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[ l,2,4]triazolo[4',3’: 1,6]pyrido[3,2b]benzofuro[4,3-fg][l,4]oxazonine (50 mg, 104.59 umol, 45% yield, 98.607% purity, formate sait) was obtained as a yellow solid. 1H NMR ET20970-310-P1C11 DMSO-d6 400 MHz δ = ppm 9.46 (s, 1 H), 8.62 (s, 1H), 8.08 (br t, J = 9.2 Hz, 1H), 7.75 (br t, J = 5.6 Hz, 1H), 7.54 (s, 1H), 6.97 (t, J = 9.6 Hz, 1H), 6.70 (dd, J = 8.8, 3.6 Hz, 1H), 4.98 - 4.88 (m, 1H), 4.87 - 4.76 (m, 1H), 4.60 - 4.46 (m, 2H), 4.22 (br dd, J = 9.4, 3.2 Hz, 1H), 4.05 (br s, 1H), 3.92 - 3.79 (m, 1H). LCMS (ESI+): m/z 426.1 (M+H).
Compounds 83, 93, 95, 101, 123, 135, 144, and 149 were prepared according to General Procedure B using the suitable starting materials, precursors, intermediates, and reagents.
233
Cmpd No. Compound Naine Structure Spectral Data
95 (S)-12-fluoro-4- (3methyl pyridin-2-y))7a,8,13,14-tetrahydro- 7H-[l,2,4]triazolo [4',3': 1,6]pyrido[3,2b] benzofuro [4, 3fg] [ 1,4]oxazonine A 0 N J ' HN \ F ) P MJ, HCOOH 1H NMR DMSO-d6 400 MHz δ = ppm 9.48 (br s, IH), 8.49 (br s, IH), 7.80 (br s, 1H),7.71 (brs, IH), 7.48 (s, 1H),7.41 (br s, IH), 7.07 - 6.91 (m, IH), 6.71 (dd, J = 8.7, 3.8 Hz, IH), 4.98 - 4.88 (m, IH), 4.88 - 4.75 (m, IH), 4.60 - 4.47 (m, 2H), 4.24 (dd, J = 9.6, 3.5 Hz, IH), 4.05 (br s, IH), 3.91 - 3.79 (m, IH), 2.24 (s, 3H). LCMS (E SI+): m/z 404.1 (M+H).
101 (S) -4-(5 -chloropyridin -2-yl)-12-fluoro-7a,8, 13,14-tetrahydro -7H[l,2,4]trîazolo [4',3':l,6]pyrido[3,2-b] benzofuro [4,3fg][ 1,4] oxazonine Cl nK nA \=/ HCOOH HN 0 F,/ \ OJ> ‘H NMR CDjOD 400 MHz. δ = ppm 9.50 (br s, IH), 8.71 (br s, IH), 8.60 (s, IH), 8.17 (br s, IH), 7.99 (s, 1 H), 6.90 (t, J= 9.6 Hz, IH), 6.66 (dd, J= 8.6, 3.7 Hz, IH), 5.19(d,7 = 14.8 Hz, IH), 4.97 (br d,7= 15.0 Hz, IH), 4.79 (brd, 7= 6.2 Hz, IH), 4.62 (t, 7 = 9.2 Hz, IH), 4.32 (dd, 7= 9.5, 2.9 Hz, IH), 4.13 - 3.92 (m, 2H). LCMS (ES1+): m/z 424.0 (M+H).
144 (S)-4-(3- ( d i flu oromethy 1 ) -6 methylpyridin-2-yl)12-fluoro-7a,8,13,14tetrahydro-7H[l,2,4]triazolo[4',3':l, 6]pyrido[3,2b]benzofuro[4,3fg][l,4]oxazonine cCma oT>—% ΤΊ 'H NMR DM S O-7, 400 MHz δ = ppm 9.43 (s, IH), 8.01 (d, 7= 8.2 Hz, IH), 7.67 (br t, 7= 6.3 Hz, IH), 7.44 (d, 7= 8.2 Hz, IH), 7.41 (s, IH), 7.05 (t, 7= 52.8 Hz, IH), 6.99 - 6.90 (m, IH), 6.68 (dd, J = 8.6, 3.7 Hz, IH), 4.96 - 4.87 (m, IH), 4.83 4.74 (m, IH), 4.56 - 4.46 (m, 2H), 4.22 (dd, 7= 9.7, 3.5 Hz, IH), 4.08 - 3.98 (m, 1 H), 3.86 - 3.80 (m, 1 H), 2.54 (s, 3H). LCMS (ESI+): m/z 454.1 (M+H).
83 (S)-12-fluoro-4-(2 (tri fl uoromethoxy) pyridin-3-yl)-7a, 8,13,14-terrahydro- 7H-[l,2,4]triazolo [4',3':l,6]pyrido[3,2b]benzofuro [4,3fg] [ 1,4]oxazonine On nA 0 F / F h/ b Fx / y 'H NMR DMSO-<MOOMHzÔ = ppm 9.40 (brd, 7= 1.2 Hz, IH), 8.36 (dd,7= 5.2, 3.2 Hz, 2H), 7.68 (br t, 7 = 6.2 Hz, IH), 7.58 -7.48 (m, 2H), 6.96 (t,7= 9.5 Hz, IH), 6.70 (dd,7= 8.6,3.7 Hz, IH), 4.90 (br d, 7= 5.6 Hz, IH), 4.81 (br s, IH), 4.61 -4.41 (m, 2H), 4.24 - 4.15 (m, IH), 4.04 (brs, IH), 3.87 (brd,7= 11.5 Hz, IH). LCMS (ES1+): m/z 474.2 (M+H).
93 (S)-f2-fluoro-4 - (thiazol-5-yl)- 7a, 8,13,14tetrahydro-7H[1,2,4]triazolo [4’,3’:l,6]pyrido [3,2b]benzofuro[4,3-fg] [1,4] oxazonine S^N nAv O HN\/° Fx / y CD lHNMR DMSO-76400 MHz δ = ppm 9.49 (s, IH), 9.08 (s, IH), 8.70 (s, IH), 7.87 (s, IH), 7.75 (br t, 7 = 6.4 Hz, IH), 6.95 (dd, 7= 10.1,8.8 Hz, 1 H), 6.68 (dd,7 = 8.7, 3.9 Hz, IH), 4.95 - 4.86 (m, IH), 4.85 - 4.76 (m, 1 H), 4.59 - 4.47 (m, 2H), 4.22 (dd, 7=9.6, 3.4 Hz, IH), 4.09 - 3.99 (m, IH), 3.97 - 3.87 (m, IH). LCMS (ESI+): m/z 396.1 (M+H).
234
135 (S)-4-( 1,4-dimethyllH-imidazoL2-yl)-12fluoro-7a,8,13,14tetrahydro-7H- [ 1,2,4] triazolo[4',3':l, 6]pyrido[3,2b]benzofuro[4,3fg][ 1,4] oxazonine TY O ! p LL ‘H NMR CDjOD 400 MHz δ = ppm 9.54 (s, 1H), 8.04 (s, 1H), 7.45 (s, 1H), 6.95 6.87 (m, 1H), 6.68 (dd, 7= 8.7, 3.9 Hz, IH), 5.20 (d,7= 14.8 Hz, 1H),4.96 (br d, 7= 14.7 Hz, 1H), 4.74 (br d,7=6.2 Hz, IH), 4.62 (t,7=9.4 Hz, IH), 4.31 (dd,7 = 9.7, 3.2 Hz, 1H), 4.06 (br d, 7= 2.8 Hz, 1H), 3.93 (brd,7= 10.9 Hz, 1H), 3.83 (s, 3H), 2.42 (s, 3H). LCMS (ESI+): m/z 4Û7.2 (M+H).
149 (S)-12-fluoro-4-(4methylpyridi n-2 -yl)7a,8,13,14tetrahydro-7H[l,2,4]triazolo Î4',3':l,6]pyrido[3,2b]benzofuro [4,3fg][l ,4]oxazonine O nA HN b - / \ ‘H NMR CD3OD400 MHz δ = ppm 9.86 (brs, 1H), 8.65 (br s, 2H), 8.34 (bis, 1H), 7.61 (br s, IH), 6.90 (br 1,7=9.3 Hz, 1H), 6.71 - 6.61 (m, 1H), 5.28 - 5.08 (m, 1H), 5.04 -4.96 (m, 1H), 4.81 (brs, 1H),4.62 (br t, 7= 7.8 Hz, 1H), 4.32 (br d, 7= 8.9 Hz, 1H), 4.03 (br s, 2H), 2.67 (s, 3H). VTNMR DMSO-7û 400 MHz δ = ppm 8.81 (brs, 1H), 8.63 (brs, 1H), 7.02 - 6.88 (m, IH), 6.70 (br dd, 7= 8.3, 3.3 Hz, 1H), 5.07 -4.87 (m, 2H), 4.66 - 4.51 (m, 2H), 4.25 - 4.18 (m, 1H), 4.15 - 4.06 (m, 1H), 4.02 (br d, 7= 10.8 Hz, 1H), 2.54 (s, 3H). LCMS (ESI+): m/z 404.1 (M+H).
123 (S)-12-nuoro-4-(6methylpyridazin-4-yl)7a,8,13, 14tetrahydro-7H[l,2,4]triazolo [4',3':l,6]pyrido [3,2b]benzofuro [4,3fg][ 1,4] oxazonine n-N \ N il N Λ hn\ hcooh O (J 1H NMR DMSO-d6 400 MHz δ = ppm 9.92 (d, J = 1.8 Hz, 1H), 9.50 (s, 1H), 8.47 (d, J = 2.0 Hz, 1H), 8.18 (s, 1H), 8.06 7.96 (m, IH), 6.99 - 6.90 (m, 1H), 6.68 (dd, J = 8.7, 3.9 Hz, 1H), 4.97 - 4.89 (m, 1H), 4.84 (br s, 1H), 4.53 (br t, J = 9.3 Hz, 2H), 4.20 (dd, J = 9.3, 3.3 Hz, 1 H), 4.04 (brs, IH), 3.99 - 3.88 (m, 1H), 2.65 (s, 3H). LCMS (ESI+): m/z 405.1 (M+H)
Example 58: (S)-12-fluoro-4-(5-niethylpyriniidin-2-yl)-7a,8,13,I4-tetrahydro-7H|l,2,4|triazolo[4’,3*:l,6|pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
Step 1: 24odo-5-methylpyrimidÎne
A mixture of 2-chloro-5-methylpyrimidine (1.00 g, 7.78 mmol, 1.00 eq) in HI (13.6 g, 50.0 mmol, 8.00 mL, 47% purity, 6.42 eq) was stirred at 0°C for 1 hr under nitrogen atmosphère. LC-MS showed some of the starting material remained. The mixture was stirred at 15°C for additional 2 h. The reaction mixture was adjusted pH to 8-9 by added sat. aq. NaHCOj and extracted with EtOAc (50 mL * 3). The combined organic layers were dried over anhydrous Na2SO4, fdtered and
235 coneentrated under reduced pressure. Then the residue was purified by flash silica gel (PE/MTBE 1/1) to give 2-iodo-5-methylpyrimidine (400 mg, crude) as a white solid.
Step 2: tert-butyl (S)-12-fluoro-4-(5-methylpyrimidin-2-yl)-7a,l 3-dihydro-7H[1, 2,4] triazolo [4', 3 ':l,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4] oxazonine-14(8H)-carboxylate
To a solution of tert-butyl (S)-12-fluoro-4-(tributylstannyl)-7a,13-dihydro-7H[ 1,2,4]triazolo[4's3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4]oxazonine- 14(8H)-carboxylate ( 150 mg, 214 umol, 1.00 eq) in dioxane (4 mL) was added Cul (16.3 mg, 85.5 umol, 0.400 eq), 2-iodo-5methylpyrimidine (56.5 mg, 257 umol, 1.20 eq), Pd(PPh3)4 (24.7 mg, 21.4 umol, 0.100 eq) and LiCl (18.1 mg, 428 umol, 8.76 uL, 2.00 eq) at 15°C. The mixture was stirred at 80°C for 12 h under nitrogen atmosphère. The reaction mixture was coneentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Petroleum ether/Ethyl acetate = 0/1). (S)-12-fluoro-4-(5methylpyrimidin-2-yi)-7a,8,13,14-tetrahydro-7H-[ l,2,4]triazolo[4',3': 1,6]pyrido[3,2b]benzofuro[4,3-fg][l,4]oxazonine (55.0 mg, crude) was obtained as yellow solid.
Step 3: (S)-12-fluoro-4-(5-methylpyrimidin-2~yl)- 7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine hydrochloride
To a solution of tert-butyl (S)-12-fluoro-4-(5-methylpyrimidin-2-yl)-7a,13-dihydro-7H[l,2,4]triazolo[4,,3,:l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (55.0 mg, 109 umol, 1.00 eq) in DCM (2 mL) was added TFA (1.54 g, 13.5 mmol, 1.00 mL, 124 eq) at 15°C. The mixture was stirred at 15°C for 2 h The reaction mixture was coneentrated under reduced
236 pressure. The residue was purified by prep-HPLC (column: Welch Xtimate Cl 8 150 * 40 mm * 10 um; mobile phase; [water (0.225% FA) - ACN]; B%: 10% - 50%, 12 min). (S)-12-fluoro-4-(5m ethylpyrimidin-2-yl)-7a,8,13,14- tetrahydro-7H-[ 1,2,4] triazolo[4',3':l, 6]pyrido[3,2b]benzofuro[4,3-fg][l,4]oxazonine (29.5 mg, 46.1 umol, 42% yield, 99.1% purity, formate sait) was obtained as a yellow solid. The compound was additionally purified by prep-HPLC (column: Phenomenex Luna Cl 8 150 * 30 mm * 5 um; mobile phase: [water (0.04% HCl) - ACN]; B%: 15% - 50%, 10 min). (S)-12-fluoro-4-(5-methylpyrimidin-2-yl)-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine (25.0 mg, 56.5 umol, 51% yield, 99.6% purity, HCl sait) was obtained as a yellow solid. 1H NMR CD3OD 400 MHz δ = ppm 9.55 (s, 1H), 8.88 (s, 1H),8.79 (s, 2H), 6.93 (t, J = 9.4 Hz, 1H), 6.69 (dd, J = 8.5, 3.7 Hz, 1H), 5.24 (br d, J = 14.8 Hz. 1H), 5.01 (br d, J = 15.6 Hz, 1H), 4.85 - 4.80 (m, 1H), 4.70 - 4.61 (m, 1H), 4.35 (br d, J = 6.8 Hz, 1 H), 4.09 (br s, 1H), 4.04 - 3.94 (m, 1 H), 2.41 (s, 3H). LCMS (ESI+): m/z 405.2 (M+H).
Example 59: (S)-4-(3,5-dimethylpyrazin-2-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3“fg][l,4]oxazonine
Step 1: 3,5-dimethylpyrazin-2-yl trifluoromethanesidfonate
To a solution of 3,5-dimethylpyrazin-2-ol (200 mg, 1.61 mmol, 1.00 eq) and TEA (326 mg, 3.22 mmol, 448 uL, 2.00 eq) in DCM (5 mL) was added Tf2O (682 mg, 2.42 mmol, 399 uL, 1.50 eq) at 0°C under nitrogen atmosphère. The mixture was stirred at 0°C for 0.5 hr and then at 25°C for 12 h. LC-MS showed 3,5-dimethylpyrazin-2-ol was consumed completely and one main peak with desired mass was detected. The reaction mixture was quenched by addition of ice water (5 mL), and then diluted with DCM (5 mL) and extracted with DCM (5 mL * 3). The combined organic layers were washed with sat. aq. NaCl (10 mL), dried overNa2SO4, filtered and blown to dryness by nitrogen stream. The residue was purified by prep-TLC (SiO2, Petroleum ether:Ethyl acetate = 3:1, Rf = 0.5). 3,5-dimethylpyrazîn-2-yl trifluoromethanesulfonate (200 mg, 781 umol, 48% yield) was obtained as a yellow oil.
Step 2: tert-butyl (S)-4-(3,5-dimethylpyrazin-2-yl)-l 2-fluoro-7a,l 3-dlhydro-7H[ 1,2,4]triazolo[4', 3 6]pyrido[3,2-b] benzofuro]4,3-fg][l, 4] oxaz(mine-14(8H)-carboxylate
237
A mixture of tert-butyl (S)-12-fluoiO-4-(tributylstannyl)-7a,13-dihydro-7H[l,2,4]triazolo[4',3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(SH)-carboxylate (200 mg, 285 umol, 1.00 eq), 3,5-dimethylpyrazin-2-yI trifluoromethanesulfonate (110 mg, 428 umol, 1.50 eq), LiCl (36.3 mg, 855 umol, 17.5 uL, 3.00 eq), Pd(PPh3)4 (33.0 mg, 28.5 umol, Û.100 eq) in dioxane (5 mL) was degassed and purged with nitrogen for 3 times at 25°C, and then the mixture was stirred at 100°C for 17 h under nitrogen atmosphère. LC-MS showed presence of the starting material. The mixture was stirred at 100°C for 7 h The reaction was still incomplète by LC-MS. To the mixture was added 3,5-dimethylpyrazin-2-yl trifluoromethanesulfonate (110 mg, 428 umol, 1.500 eq), LiCl (36.3 mg, 855 umol, 17.5 uL, 3.00 eq), Pd(PPh3)4 (33.0 mg, 28.5 umol, 0.100 eq) at 25°C under nitrogen atmosphère. The mixture was stirred at 100°C for 16 h. The reaction mixture was quenched by addition of water (5 mL), and then diluted with EtOAc (5 mL) and extracted with EtOAc (5 mL * 3). The combined organic layers were washed with sat. aq. NaCl (10 mL), dried over Na2SO4, fïltered and concentrated under reduced pressure. The residue was purified by prepTLC (SiO2, Ethyl acetate:Methanol = 10:1, Rf = 0.5). tert-butyl (S)-4-(3,5-dimethylpyrazin-2-yl)12-fluoro-7a, 13-dihydiO-7H-[l,2,4]triazolo[4',3,:l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine14(8H)-carboxylate (130 mg, 251 umol, 87% yield) was obtained as a yellow oil.
Step 3.· (S)-4-(3,5-dimethylpyrazin-2-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H[1,2,4]triazolo[4', 3 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4] oxazonine formate
HCOOH
238
A mixture of tert-butyl (S)-4-(3,5-dimethylpyrazin-2-yl)-12-nuoro-7a,I3-dihydro-7H[l,2,4]triazolo[4’,3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (120 mg, 23 1.42 umol, 1.00 eq) in HFIP (5 mL) was degassed by purging with nitrogen 3 times at 25°C, and then the mixture was stirred at 80°C for 12 h under nitrogen atmosphère. The mixture was concentrated in vacuum. The residue was purified by prep-HPLC (formic acid conditions: column: Phenomenex Luna Cl 8 200 * 40 mm * 10 um; mobile phase: [water (0.225% FA) - ACN]; B%: 10% - 40%, 12 min). (S)-4-(3,5-dimethylpyrazin-2-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3,:l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine (24.5 mg, 52.2 umol, 22% yield, 99.0% purity, formate) was obtained as a yellow solid. 1H NMR CDC13 400 MHz δ = ppm 9.02 (s, 1H), 8.33 (s, ÎH), 7.33 (s, 1H), 6.83 (t, J = 9.4 Hz, 1H), 6.64 (dd, J = 8.6, 3.9 Hz, 1H), 5.67 (brs, 1H), 5.06 (brdd, J = 14.5, 7.0 Hz, 1H), 4.84 (br dd, J = 14.6, 6.1 Hz, 1 H), 4.65 - 4.54 (m, 2H), 4.22 (br d, J = 7.8 Hz, 1H), 3.97 - 3.86 (m, 2H), 2.58 (s, 3H), 2.53 (s, 3H). LCMS (ESI+): m/z 419.2 (M+H)
Example 60: (S)-12-fluoro-4-(l-(2-methoxyethyl)-lH-pyrazoM-yl)-7a,8,13,14-tetrahydro-7H|l,2,4]triazolo[4',3':l,6]pyrido[3,2-blbenzofiiro[4,3-fg][l,4]oxazonhie
Step 1: tert-butyl {S)-l2-fluoro-4-(l-(2-methoxyethyl)-lH-pyrazol-4-yl)-7a,l 3-dihydro-7H[1,2,4]triazolof4 ',3':l,6]pyndo[3,2-b] benzofiirof4,3-fg] f1,4] oxazonine-14(8H)-carboxylate
Pd(PPh3)4 (25.9 mg, 0.0224 mmol) was added to a mixture of tert-butyl (S)-4-bromo-12-fluoro7a,13-dihydro-7H-[I,2,4]triazolo[4',3,:l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)carboxylate (Example 16; 55.0 mg, 0.112 mmol), l-(2-methoxyethyl)-3,5-dimethyl-4-(4,4,5,5tetramethyl-l,3,2-dîoxaboroïan-2-yl) pyrazole (50.2 mg, 0.179 mmol), and NaHCO3 (47.0 mg, 0.560 mmol) in 1,4-dioxane (1.00 mL) and water (0.200 mL). Nitrogen was bubbled through the mixture for 5 minutes. The mixture was stirred at 110 °C for 3 h. The mixture was cooled to room température and concentrated under reduced pressure. The residue was purified by silica gel chromatography (40 g cartridge) eluting with MeOH in DCM (0-10%) to provide tert-butyl (S)-12
239 fluoro-4-(l-(2-methoxyethyl)-lH-pyrazol-4-yl)-7a,13-dihydro-7H[ 1,2,4]triazolo[4',3I,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4]oxazonine-14(8H)-carboxylate as a solid (56.0 mg, 87 %). IH NMR (400 MHz, cdcl3) (rotamers, partial characterization) δ 8.66 (s, 1 H), 6.77 (s, IH), 6.56 (s, 2H), 4.18 (t, J = 5.6 Hz, 2H), 3.75 (t, J = 5.6 Hz, 2H), 3.33 (s, 3H), 2.18 (s, 3H), 2.13 (s, 3H), 1.36 (s, 9H).m/z(ES+) [M+H]+: 565.5. HPLC tR (A05) = 2.18 min.
Step 2: (S)-12-fluoro-4-(l-(2-methoxyethyl)-lH-pyrazol-4-yl)-7a,8,I3,14-tetrahydro-7H[1,2,4] triazo lo[4',3':l, 6]pyrido[3,2-b]benzofuro[4,3-[g] [1,4] oxazonine
A solution of tert-butyl (S)-12-fluoro-4-(l-(2-methoxyethyl)-lH-pyrazol-4-yl)-7a,13-dihydro-7H[l,2,4]triazoIo[4',3,:l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (56.0 mg, 99.2 μιηο!) in HFIP (2.00 mL) was heated at 100 °C for 5 h. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (24 g cartridge) eluting with MeOH in DCM (0-10%) to afford the title compound 4 as a solid (37.0 mg, 80%). IH NMR (400 MHz, CDC13) δ 8.93 (s, IH), 6.94 (s, IH), 6.84 (dd, J = 10.1, 8.8 Hz, IH), 6.64 (dd, J = 8.7, 3.9 Hz, IH), 5.35 (s, IH), 5.05 (dd, J = 14.7, 7.0 Hz, IH), 4.81 (dd, J = 14.8, 5.8 Hz, IH), 4.61 (t, J = 9.4 Hz, IH), 4.53 (dd, J = 10.0, 4.3 Hz, IH),4.22 (dd, J = 9.7, 3.2 Hz, 1 H), 4.17 (t, J = 5.7 Hz, 2H), 3.93 (dt, J = 8.3, 6.2 Hz, 1H),3.81 (dd, J = 11.9, 10.1 Hz, IH), 3.75 (t, J = 5.7 Hz, 2H), 3.32 (s, 3H), 2.21 (s, 3H), 2.18 (s, 3H). m/z (ES+) [M+H]+: 466.1. HPLC tR (A05) = 2.03 min.
Example 61: (S)-12-fluoro-4-(4-methyl-lH-pyrazol-l-yl)-7a,8,13,14-tetrahydro-7H[l^^ltriazolo^hS'rijôlpyridolS^-blbenzofuro^^-fgJIl^loxazoïiine
Step 1: tert-butyl (S)-12-fluoro-4-(4-methyl-lH-pyrazol-l-yl)-7a,13-dihydro-7H[1,2,4] triazolo[4\3 6]pyrido[3,2-b]benzofuro[4,3-fg] [1,4] oxazonine-14(8H)-carboxylate
240
Toluene (2.00 mL) and dioxane (0.400 mL) were added to a mixture of Pd2(dba)3 (5.85 mg, 10.2 pmol) and di-tert-butyl-[2,3,4,5-tetramethyl-6-(2,4,6-triisopropylphenyl) phenyl] phosphane (9.79 mg, 20.4 pmol) in a sealed tube. Nîtrogen was bubbled through the mixture. The mixture was heated at 120 °C for 4 min and added to a mixture of tert-butyl (S)-4-bromo-12-fluoro-7a,13dihydro-7H-[l,2,4]triazolo[4’,3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)carboxylate (Example 16; 100 mg, 204 pmol), 4-methyl-lH-pyrazole (25.3 pL, 305 pmoî), and K3PO4 (86.4 mg, 407 pmol) under N2. The mixture was stirred at 120 °C for 7 h. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (40 g cartridge) eluting with MeOH in DCM (0-10%) to afford tert-butyl (S)-12-fiuoro-4-(4-methyl-lHpyrazol-l-yl)-7a,l3-dÎhydro-7H-[l,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3fg][l,4]oxazonine-14(8H)-carboxylate as a solid (56.0 mg, 56%). m/z (ES+) [M+H]+: 493.8, HPLC tR (A05) = 2.39 min.
Step 2: (S)-12-fluoro-4-(4-methyl-lH-pyrazol-l-yl)-7a, 8,13,14-tetrahydro-7H[1,2,4] triazolo[4',3’:l, 6]pyrido[3,2-b]benzofuro[4,3-fg] [1,4] oxazonine
A solution of tert-butyl (S)-12-fluoro-4-(4-methyl-lH-pyrazol-l-yl)-7a,13-dihydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine- 14(8H)-carboxylate (45.0 mg, 91.4 pmol) in HFIP (2.00 mL) was heated ai 100 °C for 5 h. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (24 g cartridge) eluting with MeOH in DCM (0-10%) to afford the title compound as a solid (26.0 mg, 73%). IH
241
NMR (500 MHz, DMSO) δ 9.51 (s, 1H), 8.86 (s, 1H), 7.74 (s, III), 7.60 (s, 1H), 7.44 (t, J = 6.4 Hz, ] H), 6.94 (dd, J = 10.3, 8.7 Hz, 1H), 6.67 (dd, J = 8.6, 3.8 Hz, 1H), 4.89-4.85 (m, 2H), 4.52 (t, J = 9.4 Hz, 2H), 4.23 (dd, J = 9.6, 3.5 Hz, 1 H), 4.07 - 3.99 (ni, 1H), 3.87 (t,J = 11.4 Hz, 1H), 2.13 (s, 3H). m/z (ES+) [M+H]+: 393.1. HPLC tR (A05) = 2.16 min.
Example 62: (S)-4-(l,4-dimethyl-lH-pyrazol-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H11,2,4]triazolo[4',3':l,6]pyrido[3,2-b]bcnzofuro[4,3-fg](l,4]oxazonine hydrochloride
To a stirred solution of (S)-4-bromo-12-Îluoro-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3’: l,6]pyrido[3,2-b]benzofuiO[4,3-fg][l,4]oxazonine (120 mg, 307 umol, 1.00 eq), l)4-dimelhyl-5-(4,4,5,5-tetramethyI-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (136 mg, 614 umol, 2.00 eq) and NaHCO3 (129 mg, 1.53 mmol, 5.00 eq) in dioxane (4.00 mL) and water (0.800 mL) was added Pd(dppf)C12 (22.5 mg, 30.7 umol, 0.100 eq) at 15°C under N2. The resulting mixture was stirred at 80°C of 12 h. LCMS showed (S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazoninewas remained and the desired mass was detected. The mixture was stined at 80°C for 6 h. LCMS showed (S)-4-bromo-12-fluoro7a, 8,13,14-tetrahydro-7H-[ 1,2,4]triazolo[4’,3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][ l,4]oxazonine remained. To the mixture was added Pd(dppf)C12 (0,100 eq) at 15°C under N2. The resulting mixture was stirred at 80°C for 12 h. To the mixture was added silica-thiol (400 mg, modified Silicon Gel for Eliminating Pd, Irregular Silica Gel, 100 - 200 mesh, Chlorides (Cl), %<0.004, Particle Size Distribution 45 - 75 um) at !5°C and stirred at 15°C for 4 h. The suspension was filtered off and the filter cake was washed with MeOH (5 mL *3). The filtrate was concentrated under reduced pressure. The residue was purified by acidic prep-HPLC (HCl conditions). The product-containing fraction was concentrated under reduced pressure to remove most of MeCN at 30°C and the aqueous phase was lyophilized. (S)-4-(l,4-dimethyl-lH-pyrazol-5-yl)-12-fluoro7a,8,13,14-tetrahydro-7H-[ l,2,4]triazolo[4’,3 ’ : 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4]oxazonine (25.8 mg, 56.8 umol, 18% yield, 97.5% purîty, HCl sait) was obtained as a yellow solid. 1H NMR DMSO-d6 400MHzÔ=ppm 10.19 (brs, 1H), 9.17(brs, 1H), 7.98 (s, 1H), 7.44 (s, 1 H), 7.02 (br t,
242
J = 9.4 Hz, IH), 6.75 (br dd, .1 = 8.5, 3.4 Hz, IH), 5.09-4.97 (m, IH), 4.92 (brs, IH), 4.62-4.49 (m, 2H), 4.27 - 4.20 (m, IH), 4.12 (br s, IH), 3.91 (brs, IH), 3.65 (s, 3H), 1.90(s,3H). LCMS (ESI+): m/z 407.2 (M+H).
Example 63: (S)-4-(4-(difluoromethyl)pyrimidin-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H[ 1,2,4]triazolo[4',3':l,6] pyrido [3,2-b]benzofuro[4,3-fg][l,4| oxazonine
To a solution of (S)-4-bromo-12-fluoiO7a,8,13,14-tetrahydro-7H[ l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4]oxazonine (150 mg, 383 umol, 1.00 eq) in EtOH (10.0 mL), water (2.00 mL) were added 4-(difiuoromethyl)-5-(4,4,5,5-tetramethyl-l,3,2dioxaborolan-2-yl)pyrimidine (1.13 g, 4.39 mmol, 11.5 eq), Pd(Amphos)2C12 (27.2 mg, 38.3 umol, 0.100 eq) and KOAc (75.3 mg, 767 umol, 2.00 eq) at 20°C. The mixture was stirred at 80°C for 2 h. LCMS indicated complété conversion. The réaction misture was filtered and the filtrate was concentrated. The residue was dissolved in MeOH (8.00 mL) and silica-thiol (600 mg, modified Silicon gel for eliminating Pd, irregular silica gel, 100-200 mesh, Ch 1 ondes (Cl), %<0.004, particle size distribution 45-75 um) was added at 20°C and stirred at 20°C for 12 h. The suspension was filtered and the filtrate was evaporated. The residue was purified by neutral prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40 mm* 10 um; mobile phase: [water (10 mM NH4HCO3)ACN]; B%: 20%-50%, 8 min). The product-containing fraction was concentrated under reduced pressure to remove most of MeCN at 30°C and the aqueous phase was lyophilîzed. (S)-4-(4(difluoromethyl)pyrimidin-5-yi)- 12-fluoro-7a,8,13,14-tetrahydro-7H[ l,2,4]triazolo[4',3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][ l,4]oxazonine (40.0 mg, 87.9 umol, 22% yîeld, 96.7% purity) was obtained as a yellow solid. IH NMR DMSO-d6 400 MHz δ = ppm 9.48 (s, IH), 9.38 (s, IH), 9.15 (s, IH), 7.79 (br t, J = 6.4 Hz, 1H),7.51 (s, IH), 7.06 (t, J = 53.2 Hz, IH), 7.99 (t, J = 10.0 Hz, IH), 6.72 (dd, J = 8.7, 3.8 Hz, IH), 5.01 - 4.89 (m, IH), 4.87 - 4.72 (m, IH), 4.61 - 4.46 (m, 2H), 4.23 (dd, .1 = 9.6, 3.5 Hz, IH), 4.05 (br s, IH), 3.96 - 3.86 (m, IH). LCMS (ESI+): m/z 441.1 (M+H).
243
Example 64: (S)-4-(2-(difliioromethyl)-4-methylpyrimidin-5-yi)-12-iluoro-7a,8,13,14tetrahydro-7H-[ 1,2,4] triazolo]4',3':Î,6]pyrido[3,2-b]benzofuro[4,3-fg] [1,4] oxazonine
To a solution of 2-(difluoromethyl)-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)pyrimidine (104 mg, 383 umol, 2.50 eq) in EtOH (4.00 mL) and water (0.560 mL) was added 4ditert-butylphosphanyl-N,N-dimethyl-aniline dichloropalladium (10.9 mg, 15.3 umol, 0.100 eq), (S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-[ 1,2,4]triazolo[4',3': 1,6]pyrido[3,2b]benzofuro[4,3-fg][l,4]oxazonine (60.0 mg, 153 umol, 1.00 eq) and KOAc (45.2 mg, 460 umol, 3.00 eq) at 20°C under nitrogen atmosphère. The mixture was stirred at 80°C for 8 h under nitrogen atmosphère. LCMS showed the starting material was consumed completely and the desired MS was detected. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in MeOH (10.0 mL) and silica-thiol (100 mg, modîfied Silicon gel for eliminating Pd, inegular silica gel, 100-200 mesh, Chlorides (Cl), %<0.004, particle size distribution 45-75 um) was added at 20°C and stirred at 20°C for 4 h. The suspension was filtered and the filtrate was concentrated and then purified by neutral prep-HPLC. The product-containing fraction was concentrated under reduced pressure to remove most of MeCN at 30°C and the aqueous phase was lyophilized. (S)-4-(2-(difhioromethyI)-4-methylpyrimidin-5-yl)-12-fluoro-7a,8,13,14-tetrahydro7H-[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine (30.0 mg, 65.4 umol, 42% yield, 99.1% purity) was obtained as a yellow solid. IH NMR. CDC13 400 MHz δ = ppm 8.95 (s, IH), 8.76 (s, IH), 7.11 (s, IH), 6.91 - 6.84 (m, IH), 6.68 (dd, J = 8.8, 4.8 Hz, IH), 6.67 (t, J = 54.4 Hz, IH), 5.37 (t, J = 6.8 Hz, IH), 5.11 (dd, J = 14.7, 7.4 Hz, IH), 4.85 (dd, J = 14.4, 6.3 Hz, IH), 4.70 - 4.57 (m, 2H), 4.26 (dd, J = 9.7, 3.3 Hz, IH), 4.01 - 3.88 (m, IH), 3.86 - 3.76 (m, IH), 2.57 (s, 3H). LCMS (ESI+): m/z 455.1 (M+H).
Example 65: (S)-12-fluoro-4-(l-(2,2,2-trifluoroethyl)-lH-pyrazol-3-yl)-7a,8,13,14-tetrahydro 7H-[l,2,4]triazolo[4’,3’:l,6]pyrido[3,2-b]benzofuro[4,3-fg]Îl,4]oxazonme
Step 1: tert-butyl (S)-l 2-fluoro-4-(lH-pyrazol-3-yl)-7a,l 3-dihydro-7H[1,2,4]triazolo[4 3 1,6]pyrido[3,2-b] benzofuro[4,3-fg] [1,4] oxazonine-14(8H)-carboxylate
244
To a solution of tert-butyl (S)-4-bromo-12-fluoro-7a,13-dihydro-7H[l,2,4]triazolo[4',3,:l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (220 mg, 448 umol, 1.00 eq), 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (130 mg, 672 umol, 1.50 eq) and Na2CO3 (94.9 mg, 896 umol, 2.00 eq) in dioxane (1.00 mL) and water (0.100 mL) was added Pd(dppf)CI2 (32.8 mg, 44.8 umol, 0.100 eq) under nitrogen at 25°C. The resulting mixture was stirred at 80°C under nitrogen for 10 h. LCMS indicated incomplète conversion. To the mixture was added 5-(4,4,5,5-tetramethyI-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (130 mg, 672 umol, 1.50 eq) and Pd(dppf)C12 (32.8 mg, 44.8 umol, 0.100 eq) at 25°C. The resulting mixture was stirred at 80QC under nitrogen for 3 h. The réaction mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, EtOAc:MeOH = 5:1). tert-butyl (S)-l2fluoro-4-(lH-pyrazol-3-yl)-7a, 13-dihydro-7H-[ 1,2,4]triazolo[4’,3': 1,6]pyrido[3,2-b]benzofuro[4,3fg][l,4]oxazonine-14(8H)-carboxyiate (280 mg, crude) was obtained as yellow solid.
Step 2: tert-butyl (S)-l 2-fluoro-4-(l-(2,2,2-trifluoroethyl)-I H-pyrazol-3-yl)-7a, 13-dihydro-7H[l,2,4]triazolo[4',3':l, 6]pyrido[3,2-b]benzofuro[4,3-fg] [1,4] oxazonine-14(8H)-carboxylate
A mixture of tert-butyl (S)-12-fiuoiO-4-(lH-pyrazol-3-yl)-7a,13-dihydro-7H[l,2,4]triazolo[4',3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (80.0 mg, 167 umol, 1.00 eq) and Cs2CO3 (109 mg, 334 umol, 2.00 eq) in DMF (2.Ü0 mL) was stirred at 25°C for 0.5 hr. 2,2,2-trifluoroethyl trifluoromethanesulfonate (58.2 mg, 251 umol, 1.50 eq) was added and the mixture was stirred at 25°C for 10 h The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, PE:EtOAc = 0:1). tert-butyl (S)
245
12-fluoro-4-(l-(2,2,2-trifluoroethyl)-lH-pyrazol-3-yl)-7a,13-dihydro-7H[l,2,4]triazolo[4’,3’:l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (65.0 mg, crude) was obtained as yellow oil.
Step 3: (S)-12-fluoro-4-(l-(2,2,2-trifluoroethyl)-lH-pyrazol-3-yl)-7a,8,13.14-tetrahydro-7H[1,2,4] triazolo[4', 3 1,6]pyrido[3,2-b]benzqfuro[4,3-fgj[1,4] oxazonine
To tert-butyl (S)-12-fluoro-4-( 1-(2,2,2-trifluoroethyl)-1 H-pyrazol-3-yl)-7a,13-dihydro-7H[1,2,4]triazolo[4',3’:l,6]pyndo[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate (85.0 mg, 152 umol, 1.00 eq) in DCM (1.50 mL) was added TFA (0.500 mL) at 15°C. The mixture was stirred at 15°C for 10 h. The reaction mixture was coneentrated under reduced pressure. The suspension was filtered and the filtrate was coneentrated and then purified by acidic prep-HPLC (column: Phenomenex Luna Cl 8 100*30 mm*5 uni; mobile phase: [water (0.2% FA)-ACN]; B%: 20%-45%, 12 min). (S)-12-fluoro-4-(l-(2,2,2-trifluoroethyl)-iH-pyrazol-3-yl)-7a,8,13,14tetrahydro-7H-[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][ l,4]oxazonine (22.7 mg, 43.8 umol, 28% yield, 97.7% purity, formate) was obtained as a white solid. IH NMR CD3OD 400 MHz δ = ppm 9.40 (s, IH), 8.12 (s, 1 H), 7.86 (d, J = 2.0 Hz, IH), 7.15 - 7.10 (m, IH), 6.91 -6.83 (m, IH), 6.67 - 6.60 (m, IH), 5.12 - 5.01 (m, 3H), 4.92 (s, IH), 4.69 (brdd, J = 9.9, 3.7 Hz, IH), 4.58 (t, J = 9.2 Hz, IH), 4.29 (dd, J = 9.7, 3.2 Hz, IH), 4.07 - 3.99 (m, IH), 3.99 - 3.90 (m, IH). LCMS (ESI+): m/z 461.1 (M+H)
Example 66; (S)-4-(4-(difluoromethyl)-2-methylpyrimidin-5-yl)-12-fluoro-7a,8,13,14tetrahydro-7H-[l,2,4]triazolo[4',3':l,6|pyrîdo[3,2-b]benzofuro[4,3-fg][l,4]oxazoninc
246
To a solution of (S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4’,3': l,6]pyrido[3,2-b]benzoiuro[4,3-fg][l,4]oxazonine (100 mg, 256 umol, 1.00 eq) in EtOH (5.00 mL) and water (1.00 mL) were added 4-(dill uoromethyl)-2-me thyl-5-(4,4,5,5tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine (690 mg, 2.56 mmol, 10.0 eq), KOAc (50.2 mg, 511 umol, 2.00 eq) and 4-ditert-butylphosphanyl-N,N-dimethyl-aniline dichloropalladium (18.1 mg, 25.6 umol, 0.100 eq) at 25°C under nîtrogen atmosphère. The mixture was stirred at 80°C for 2 h under nîtrogen atmosphère. The reaction mixture was filtered and the filtrate concentrated under high vacuum. The residue was dîssolved in MeOH (5.00 mL) and silica-thiol (260 mg, modîfied Silicon gel for eliminating Pd, irregular silica gel, 100-200 mesh, Chlorides (Cl), %<0.00400, particle size distribution 45.0-75.0 um) was added at 25°C and stirred at 25°C for 3 h. The suspension was filtered and the filtrate was concentrated and purified by FA prep-HPLC (column: Phenomenex Luna C18 100 * 30.0 mm * 5.00 um; mobile phase: [water (0.200% FA)-ACN]; B%: 20.0%-45.0%, 12.0 min). The fraction containing the product was concentrated under reduced pressure to remove most of MeCN at 30°C and the aqueous phase was lyophilized. (S)-4-(4(difluoromethyl)-2-methylpyrimidîn-5-yl)-I2-fluoiO-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine (29.6 mg, 58.6 umol, 22% yield, 99.0% purity, formate) was obtained as a yellow solid. 1H NMR DMSO-d6 400 MHz δ = ppm 9.46 (s, 1H), 9.00 (s, 1H), 7.73 (brt,J = 6.2 Hz, 1H), 7.44 (s, 1H), 6.98 (t, J - 9.6 Hz, 1H), 6.98 (t, J = 53.0 Hz 1H), 6.71 (dd, J = 8.6, 3.7 Hz, 1H), 4.99 - 4.89 (m, 1H), 4.86 - 4.75 (m, 1H), 4.59 4.52 (m, 1H), 4.49 (br d, J = 6.1 Hz, 1 H), 4.22 (dd, J = 9.6, 3.4 Hz, 1H), 4.10 - 3.98 (m, 1H), 3.95 3.83 (m, 1H), 2.76 (s, 3H). LCMS (ESI+): m/z 455.1 (M+H)
Example 67: (S)-4-(2-(difluoromethoxy)pyrimidin-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazomiie
Step 1: 5-bromo-2-(diflitoromelhoxy)pyrimidine
F
N N
Br
To 5-bromopyrimidin-2-ol (5.00 g, 28.6 mmol, 1.00 eq), sodium;2-chloro-2,2-difluoro-acetate (8.71 g, 57.2 mmol, 2.00 eq), K2CO3 (8.29 g, 60.0 mmol, 2.10 eq) was added in DMF (33.3 mL) at 20°C. The mixture was degassed and purged with nîtrogen 3 tîntes, and then the mixture was stirred at
247
65°C for 1.5 h under nitrogen atmosphère. LC-MS showed 5-bromopyrimidin-2-ol was consumed completely and one main peak with desired mass was detected. Water (150 mL) was added and the mixture was extracted with EtOAc (150 mL * 4). The combined organic layers were dried over anhydrous Na2SO4, fdtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 1/0 to 1/1). 5-bromo-2(difluoromeÎhoxy)pyrimidine (191 mg, crude) was obtained as yellow oîl. 'H NMR CD3OD 400 MHz δ = ppm 8.78 (s, 2H), 7.52 (t, 7= 71.6 Hz, 1H)
Step 2: 2-(diftuoromethoxy)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine
F
F -(
O
To 5-bromo-2-(difluoromethoxy)pyrimidine (190 mg, 844 umol, 1.00 eq), 4,4,4’,4',5,5,5',5'octamethyl-2,2'-bi(l,3,2-dioxaborolane) (429 mg, 1.69 mmol, 2.00 eq), Pd(dppf)Cl2.DCM (69.0 mg, 84.5 umol, 0.100 eq), KOAc (166 mg, 1.69 mmol, 2.00 eq) was added dioxane (3.00 mL) at 20°C. The mixture was degassed and purged with nitrogen 3 times, and then the mixture was stirred at 80°C for 4 h under nitrogen atmosphère. The reaction mixture was concentrated under reduced pressure to give 2-(difiuoromethoxy)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaboiOlam2-yl)pyrimidine (200 mg, crade) as brown solid.
Step 3: (S)-4-(2-(difluoromethoxy)pyrimidin-5-yl)-12-fliioro-7a,8,13,14-tetrahydro-7H[1,2,4]triazolo[4’,3 6]pyrido[3,2-b] benzofuro[4,3-fg] [l,4]oxazonine
To (S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4',3':l,6]pyrido[3,2b]benzofuro[4,3-fg][l,4]oxazonine (180 mg, 460 umol, 1.00 eq), 2-(di fl uoromethoxy)-5-(4,4,5,5tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine (200 mg, 736 umol, 1.60 eq), Na^COj (97.5 mg,
248
920 umol, 2.00 eq), Pd(dppf)Cl2 (33.7 mg, 46.0 umol, 0.100 eq) was added dioxane (3.00 mL) and water (0.300 mL) at 20°C. The mixture was degassed and purged with nitrogen 3 times, and then the mixture was stirred at 80°C for 3 h under nitrogen atmosphère. The reaction mixture was fïltered and the filtrate was concentrated under reduced pressure. The residue was dissolved in dioxane (10.0 mL) and silica-thiol (500 mg, modified Silicon gel for eliminating Pd, îrregular silica gel, 100200 mes h, Chlorides (Cl), %<0.004, parti cle size distribution 45-75 um) was added at 20°C and stirred at 20°C for 3 h. The suspension was fïltered and the filtrate was concentrated under reduced pressure. The residue was purified by acidic prep-HPLC (fomiic acid conditions). The producteontaîning fraction was concentrated under reduced pressure to remove most of MeCN at 30°C and the aqueous phase was lyophilized. (S)-4-(2-(difluoromethoxy)pyrimidin-5-yl)-12-fluoro7a,8,13,14-tetrahydro-7H-[l ,2,4]triazolo[4',3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4]oxazonine (23.5 mg, 45.2 umol, 9% yield, 96.7% purity, formate) was obtained as yellow solid. ’H NMR DMSO-î/6 400 MHz δ = ppm 9.49 (s, 2H), 9.46 (s, IH), 7.99 (s, IH), 7.72 (t, J=7L6 Hz, IH), 7.71 (br s, IH), 6.95 (t, J = 9.5 Hz, IH), 6.74 - 6.63 (m, IH), 4.96 - 4.87 (m, IH), 4.85 - 4.75 (m, IH), 4.60 - 4.48 (m, 2H), 4.27 - 4.17 (m, IH), 4.09 - 3.99 (m, IH), 3.98 - 3.88 (m, IH). LCMS (ESI+): m/z 457.1 (M+H).
Example 68: (S)-12-fluoro-4-(6-methoxy-4-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H[l,2,4]triazofo[4',3':l,6]pyrido[3,2-b]benzofuro|4,3-fg][l,4]oxazonine
To a solution
of (S)-4“bromo-12-fluoro-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine (90.0 mg, 230 umol, 1.00 eq) in dioxane (5.00 mL) and water (0.500 mL) was added (6-methoxy-4-methyl-3-pyridyl)boronic acid (76.8 mg, 460 umol, 2,00 eq), Pd(dppt)Cl2 (16.8 mg, 23.0 umol, 0.100 eq) and Na2COj (48.8 mg, 460 umol, 2.00 eq) at 20°C. The mixture was stirred at 80°C for 2 h under nitrogen atmosphère. LCMS showed (S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4',3':l,6]pyrido[3,2b]benzofuro[4,3-fg][l,4]oxazonine was consumed completely and the desired mass was detected. The reaction was fïltered, the filtrate was concentrated. The residue was dissolved in MeOH (5.00
249 mL) and silica-thiol (600 mg, modified Silicon gel for elimînating Pd, inegular silica gel, 100-200 mesh, Chlorîdes (Cl), %<0.004, particle size distribution 45-75 um) was added at 20°C and stirred at 20°C for 12 h. The suspension was filtered, the filtrate was concentrated and purified by acidic pre/>-HPLC (column: Phenomenex Luna C18 200*40 mm* 10 um; mobile phase: [water (0.225% F A)-ACN]; B%: 25%-45%, 12 min). The product-containing fraction was concentrated under reduced pressure to remove most of MeCN at 30°C and the aqueous phase was lyophilized, (S)-12fluoro-4- (6-methoxy-4-methylpyridin-3 -yl)-7 a, 8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine (65.0 mg, 136 umol, 58% yield, 100% purity, formate sait) was obtained as a white solid. ’H NMR DMSO-rfi 400 MHz. δ = ppm 9.41 (s, IH), 8.09 (s, IH), 7.48 (br t, J= 6.2 Hz, IH), 7.26 (s, IH), 7.03 - 6.92 (m, IH), 6.79 (s, IH), 6.75 - 6,66 (m, IH), 6.71 (dd, J= 8.6, 3.8 Hz, IH), 4.97 - 4.86 (m, IH), 4.82 - 4.74 (m, IH), 4.58.4.40 (m, 2H), 4.22 (dd, 7= 9.5, 3.3 Hz, IH), 4.04 (br s, IH), 3.87 (s, 3H), 3.83 - 3.80 (m, IH), 2.15 (s, 3H). LCMS (ES1+): m/z 434.1 (M+H).
Example 69: (S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolol4',3’:l,6]pyrido[3,2 b]benzofuro[4,3-fg]ll,4]oxazonin-4-yl)-l-methyïpyridin-2(lH)-one
To a stirred solution of (S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H
[l,2,4]triazolo[4',3': 1,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonîne (100 mg, 256 umol, 1.00 eq), l-methyl-5-(4,4,5,5-tetramethyl-I,3,2-dioxaborolan-2-yl)pyridin-2-one (120 mg, 511 umol, 2.00 eq) and Na2CO3 (54.2 mg, 512 umol, 2.00 eq) in dioxane (2.50 mL) and water (0.500 mL) was added Pd(dppf)Cl2 (18.7 mg, 25.6 umol, 0.100 eq) at 15°C under N2. The resulting mixture was stirred at 80°C for 3 h. The mixture was concentrated under reduced pressure. The mixture was purified by prep-ALC (SiO2, EtOAc/MeOH = 4/1) to give the crude product and the crude product was purified b y acidic /vvp-HPLC (FA). The product-containing fraction was concentrated under reduced pressure to remove most of MeCN at 30°C and the aqueous phase was lyophilized. (S)-5(12-fluoro-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3fg][l,4]oxazonin-4-yl)-l-methylpyridin-2(IH)-one (18.8 mg, 39.6 umol, 15% yield, 98.1% purity,
250 fonnate sait) was obtained as a yellow solid. ’H NMR DMSO-rfô 400 MHz δ - ppm 9.44 (s, 1H), 8.82 (d, 7=2.4 Hz, 1H), 8.23 (dd, 7= 9.6, 2.6 Hz, 1H), 7.60 (s, 1H), 7.45 (brt,7= 6.1 Hz, IH), 6.94 (dd, 7= 10.1,9.0 Hz, 1H), 6.68 (dd, 7= 8.6, 3.9 Hz, 1H), 6.50 (d, 7= 9.5 Hz, 1H), 4.92 - 4.83 (m, 1H), 4.81 - 4.72 (m, 1H), 4.57 - 4.48 (m, 2H), 4.22 (dd, 7 = 9.4, 3.1 Hz, 1H), 4.07 - 3.98 (m, 1H), 3.97 - 3.88 (m, 1H), 3.53 (s, 3H). LCMS (ESI+): m/z 420.1 (M+H).
Example 70: (S)-12-tluoro-4-(2-(trîfluoromethyl)pyridin-3-yl)-7a,8,13,14-tetrahydro-7H|l,2,41triazolo|4’,3':l,6]pyrido[3,2-b]benzofuro|4,3-fg][l,4]oxazonine
F
To a solution of (S)-4-biOmo42-fluoiO-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuiO[4,3-fg][l,4]oxazonine (100 mg, 256 umol, L00 eq) in dioxane (3.60 mL) and water (0.400 mL) were added [2-(trifluoromethyl)-3-pyridyl]boronic acid (195 mg. 1.02 mmol, 4.00 eq), Na2CO3 (67.7 mg, 639 umol, 2.50 eq) and Pd(dppf)Cl2 (18.7 mg, 25.6 umol, 0.100 eq) at 25°C under nitrogen atmosphère. The mixture was stirred at 80°C for 12 h under nitrogen atmosphère. LC-MS showed (S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H[l}2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine was remained and one main peak with desired mass was detected. To the mixture were added [2-(trifluoiOmethyI)-3pyridyi]boronic acid (97.6 mg, 511 umol, 2.00 eq), Na2CO3 (67.7 mg, 639 umol, 2.50 eq) and Pd(dppf)Cl2 (18.7 mg, 25.7 umol, 0.100 eq) at 25°C under nitrogen atmosphère. The mixture was stirred at 80°C for 3 h under nitrogen atmosphère. The réaction mixture (combined with another batch from 50 mg of (S)-4-bromo-12-fluoiO-7a,8,13,14-tetrahydro-7H[l/^triazolofT’/1:L6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4]oxazonine) was filtered and the filtrate concentrated under high vacuum. The residue was dissolved in MeOH (5.00 mL) and silica-thiol (540 mg, modified Silicon gel for eliminating Pd, irregular silica gel, 100-200 mesh, Chlorides (Cl), %<0.004, particle sîze distribution 45-75 um) was added at 25°C and stirred at 25°C for 3 h. The suspension was filtered, the filtrate was concentrated and purified by jWep-HPLC (column: Phenomenex Luna C18 200 * 40 mm *10 um; mobile phase: [water (0.225% FA)-ACN]; B%: 20.0%-50.0%, 12 min. The product-containing fraction was concentrated under reduced pressure to
251 remove most of MeCN at 30°C and the aqueous phase was lyophilized. (S)-12-fluoro-4-(2(trifluoromethyl)pyi’idin-3-yl)-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4,,3':l,6]pyrido[3,2b]benzofuro[4,3-fg][l,4]oxazonine (24.2 mg, 46.6 umol, 18% yield. 96.9% purity, formate sait) was obtained as a yellow solid. 'H NMR DMSO-74 400 MHz δ = ppm 9.44 (s, 1H), 8.80 (br d, J — 3.8 Hz, 1H), 8.09 (br d, 7= 7.5 Hz, 1H), 7.79 (dd, 7 = 7.8, 4.7 Hz, 1H), 7.62 (br s, 1H), 7.30 (s, 1H), 6.97 (t, 7= 9.5 Hz, 1H), 6.71 (dd, 7= 8.6, 3.7 Hz, 1H), 4.99 - 4.86 (m, 1H), 4.83 - 4.69 (m, 1H), 4.59 _ 4.40 (m, 2H), 4.21 (br dd, 7= 9.6, 3.2 Hz, 1H), 4.02 (br s, 1H), 3.88 - 3.70 (m, 1H). LCMS (ESI+): m/z 458.1 (M+H).
Exampie 71: (S)-12-fliioro-4-(2-methoxy-4-inethylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H| l,2,4]triazolo[4',3’:l,6]pyrido[3,2-b]beiizofuro[4,3-fg][l,4]oxazonÎne
F
Two parallel reactions were set up (each of 100 mg (S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro7H-[l,2,4]triazolo[4’,3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine). To a solution of (S)-4bromo-12-fluoiO-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4,,3':l,6]pyrido[3,2-b]benzofuro[4,3fg][l,4]oxazonine (100 mg, 256 umol, 1.00 eq), 2-methoxy-4-methyl-3-(4,4,5,5-tetrarnethyl-1,3,2dioxaborolan-2-yl)pyridine (127 mg, 511 umol, 2.00 eq) in water (0.400 mL), EtOH (4.00 mL) was added 4-ditert-butylphosphanyl-N,N-dimethyl-aniline dichloropalladium (36.2 mg, 51.1 umol, 0.200 eq), KOAc (75.3 mg, 767 umol, 3.00 eq) at 25°C, then the mixture was stirred at 80°C for 12 h under N2. The batches were combined. The resulting mixture was concentrated, the residue was dîssolved in MeOH (4.0 mL) and silica-thiol (40.0 mg, modîfied Silicon gel for eliminating Pd, irregular silica gel, 100-200 mesh, Chlorides (Cl), %^0.004, particle size distribution 45-75 um) was added at 20°C and stirred at 20°C for 2 h. The suspension was filtered, the filtrate was concentrated and purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150 * 40 mm * 10 um; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 30%-40%, 8 min). The fraction was then blown to dryness by nitrogen stream to remove most of MeCN and the aqueous phase was lyophilized. (S)- 12-fluoiO-4-(2-methoxy-4-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H[I,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine (25.0 mg, 56.7 umol, 11%
252 yield, 98.3% purity) was obtained as a white solid. 'H NMR DMSO-c/ô 400 MHz δ — ppm 9.38 (s, 1H), 8.08 - 8.04 (m, 1H), 7.46 - 7.35 (m, 1H), 7.17 (d, J = 2.2 Hz, 1H), 7.00 - 6.90 (m, 2H), 6.73 6.63 (m, 1H), 4.94 - 4.85 (m, 1H), 4.80-4.68 (m, 1H), 4.57 - 4.48 (m, 1H), 4.43 (brdd,7 = 10.0, 4.1 Hz, 1H), 4.24 - 4.15 (m, 1H), 4.07 - 3.96 (m, 1H), 3.72 (br s, 1H), 3.65 (s, 1.5H), 3.71 (s, 1.5H), 2.03 (s, 1.5H), 1.92 (s, 1.5H). LCMS (ESI+): m/z 434.2 (M+H).
Example 72: (S)-12-fluoro-4-(l-(2,2,2-trifluoroethyl)-lH-pyrazol-5-yl)-7a,8,13,14-tetrahydro7H-|l,2,4]trîazolo[4',3':l,61pyrido[3,2-b[benzofuro[4,3-fg][ï,4]oxazonine
Step 1: (I-(2,2,2-trifluoroethyl)-lH-pyrazol-5-yl)boronic acid
To a solution of 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (2.00 g, 10.3 mmol, 1.00 eq) in MeCN (50.0 mL) was added Cs2CO3 (6.72 g, 20.6 mmol, 2.00 eq) and 2,2,2trifluoroethyl trifluoromethanesulfonate (3.59 g, 15.5 mmol, 1.50 eq) at 20°C. The mixture was stirred at 20°C for 3 h. LC-MS showed no 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-lHpyrazole was remained. Several new peaks were shown on LC-MS and desired m/s was detected. The reaction mixture was filtered, and the filtrate was diluted with water (50.0 mL) and extracted with DCM (40.0 mL * 3). The combined organic layers were washed with water (90.0 mL * 4), dried over Na2SÛ4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: WelchXtimate C18 250 * 50 mm * 10 um; mobile phase: [water (0.225% FA) - ACN]; B%: 0% - 20%, 20 min). (1-(2,2,2-trifluoroethyI)-lH-pyrazol-5-yl)boronic acid (200 mg, crude) was obtained as a yellow oîl. ( 1-(2,2,2-trifluoiOethyl)-lH-pyrazol-3-yl)boronic acid (900 mg, crude) was obtained as a white solid. lH NMR DMSO-^ 400 MHz δ = ppm 7.93 - 7.84 (m, 1H), 6.73 - 6.61 (m, 1H), 5.27 - 5.19 (m, 2H).
Step 2: (S)-I2-fluoro-4-(l-(2,2,2-trifluoiOethyl)-lH-pyrazol-5-yl)-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
253
cf3
To a solution (S)-4-bromo- 12-fluoro-7a,8,13,14-tetrahydro-7H-[ 1,2,4]triazolo[4',3':l,6] pyrido[3,2b]benzofuro[4,3-fg][l,4]oxazonine (90.0 mg, 230 umol, 1.00 eq) in dioxane (5.00 mL) was added Pd(dppf)Cl2.DCM (18.8 mg, 23.0 umol, 0.100 eq), Na2CO3 (73.2 mg, 690 umol, 3.00 eq), (1-(2,2,2trifluoroethyl)-lH-pyrazol-5-yl)boronic acid (89.2 mg, 460 umol, 2.00 eq) and water (0.500 mL) at 20°C under N2. The mixture was stirred at 80°C for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in MeOH (3.00 mL) and silica-thiol (50.0 mg, modified Silicon gel for elîminating Pd, irregular silica gel, 100 - 200 mesh, Chlorides (Cl), %< 0.004, particle size distribution 45 - 75 um) was added at 20°C and stirred at 20°C for 2 h. The suspension was filtered, the filtrate was concentrated and purified by ^>rep-HPLC (column: Phenomenex Luna C18 100 * 30 mm * 5 um; mobile phase: [water (0.2% FA) - ACN]; B%: 35% 65%, 10 min). The product-containing fraction was concentrated under reduced pressure to remove most of MeCN at 30°C and the aqueous phase was lyophilized. (S)-12-fluoro-4-(l-(2,2,2trifluoroethyl)-lH-pyrazol-5-yl)-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4',3':l,6]pyrido[3,2b]benzofuro[4,3-fg][l,4]oxazonine (65.0 mg, 141 umol, 61% yield, 99.7% purity) was obtained as a white solid. lH NMR DMSO-^ 400 MHz δ = ppm 9.48 (s, IH), 7.77 (br l, J= 6.4 Hz, IH), 7.68 (d, J = 1.6 Hz, IH), 7.47 (s, IH), 6.97 (dd, J= 10.0, 8.8 Hz, IH), 6.71 (dd, J= 8.7, 3.6 Hz, IH), 6.61 (d, J = 1.8 Hz, IH), 5.37 - 5.24 (m, 2H), 4.97 - 4.88 (m, IH), 4.85 - 4.75 (m, IH), 4.59 - 4.46 (m, 2H), 4.23 (dd. J = 9.6, 3.6 Hz, IH), 4.04 (br s, IH), 3.93 - 3.81 (m, IH). LCMS (ESI+): m/z 461.1 (M+H).
Exampk 73: (S)-12-fluoro-4-(5-fluoro-6-methylpyridin-2-yl)-7a,8,13,14-tetrahydro-7H [l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
Step 1: 3-fluoro-2-methyl-6-(lrimethylstannyl)pyridine
To a solution of 6-bromo-3-fluoro-2-methylpyridine (1.00 g, 5.26 mmol, 1.00 eq) in dioxane (20.0 mL) were added trimethyl(trimethylstannyl)stannane (3.44 g, 10.5 mmol, 2.18 mL, 2.00 eq) and Pd(PPh3)4 (608 mg, 526 umol, 0.100 eq) at 20°C, the mixture was stirred at 100°C for 4 h under
254 nitrogen atmosphère. The obtained solution of 3-fluoro-2-methyl-6-(trimethylstannyl)pyridine (1.44 g, 5.26 mmol theoretical yield) in dioxane (20.0 mL) was used in the next step directly.
Step 2: tert-butyl (S)-12fluoro-4-(5fluoro-6-methylpyridin-2-yl)-7a,13-dihydro-7H[l,2,4]triazolo[4 3 1,6]pyrido[3,2-b]benzofuro[4,3-fg] [1,4] oxazonine-14(8H)-carboxylate
F
To a solution of 3-fluoro-2-methyl-6-(trimethylstannyi)pyridine (2.85 mmol, 7.00 eq. based on the theoretical yield in the previous step) in dioxane were added tert-butyl (S)-4-bromo-12-fluoro7a, 13-dihydro-7H-[ 1,2,4]triazoio[4',3': 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4]oxazonine- 14(8H)carboxylate (200 mg, 407 umol, 1.00 eq), Pd(PPh3)4 (47.0 mg, 40.7 umol, 0.100 eq). Cul (31.0 mg, 163 umol, 0.400 eq) and LiCl (34.5 mg, 814 umol, 2.00 eq) at 20°C. The mixture was stirred at 80°C for 12 h under nitrogen atmosphère. LC-MS showed tert-butyl (S)-4-bromo-12-fluoro-7a,13dihydro-7H-[ 1,2,4]triazolo[4',3': 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4]oxazonine- I4(8H)carboxylate was consumed completely and the desired mass was detected. The reaction mixture was filtered, the filtrate was concentrated. The residue was purified by prep-TLC (SiO2, Petroleum ether/Ethyl acetate = 1/1). tert-butyl (S)-12-fluoro-4-(5-fluoro-6-methylpyridin-2-yl)-7a,13dihydro-7H-[ 1,2,4]triazolo[4',3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4]oxazonine- 14(8H)carboxylate (150 mg, 288 umol, 70% yield) was obtained as a yellow oil.
Step 3: (S)-12-fluoro-4-(5-fluoro-6-methylpyridin-2-yl)- 7a, 8,13,14-tetrahydro-7H[1,2,4]triazolo[4', 3 1,6]pyrido[3,2-b] benzofuro[4,3-fg] [1,4] oxazonine
A mixture of tert-butyl (S)-12-fluoro-4-(5-fluoro-6-methylpyridin-2-yl)-7a,13-dihydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (140 mg, 268 umol, 1.00 eq) in TFA (3.00 mL) and DCM (6.00 mL) was stirred at 20°C for 2 h. The reaction
255 mixture was concentrated. The residue was dissolved in DMSO (4.00 mL). The solution was purified by acidic prep-HPLC (column: Phenomenex Luna C18 100*30 mm*5 um; mobile phase: [water (0.2% FA)-ACN]; B%: 20%-50%, 12 min). The product-containing fraction was concentrated under reduced pressure to remove most of MeCN at 30°C and the aqueous phase was lyophilized. (S)-12-fluoro-4-(5-fluoro-6-methylpyridin-2-yl)-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3’:l,6]pyrido[3,2-b]benzofuiO[4,3-fg][l,4]oxazonine (33.0 mg, 70.3 umol, 26% yield, 99.6% purity, formate sait) was obtained as a yellow solid. *H NMR DMSO-<4 400 MHz δ = ppm 9.42 (br s, 1H), 8.77 (br d, J = 5.1 Hz, 1H), 8.13 (s, 1H), 7.73 (br s, 1H), 7.65 (t, J = 8.9 Hz, IH), 6.86 (br t, J = 9.5 Hz, 1H), 6.58 (dd, J = 8.6, 3.7 Hz, 1H), 4.87 - 4.68 (m, 2H), 4.42 (br t, J = 9.4 Hz, 2H), 4.20 - 4.10 (m, 1H), 3.95 (br s, 1H), 3.85 - 3.74 (m, 1H), 2.44 (s, 3H). LCMS (ESI+): m/z 422.1 (M+H).
Example 74: (S)-4-(4,5-dimethyl-4H-l,2,4-triazol-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3’:l,6]pyndo[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
Step 1: tert-butyl (S)-4-(4,5-dimethyl-4H-l,2,4-triazol-3-yl)-l2-fluoro-7a, 13-dihydro-7H[1.2,4] triazolo[4 ',3’:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4] oxazonine-14(8H)-carboxylate
Pd(OAc)2 (34.3 mg, 0.153 mmol) and di(l-adamantyl)-n-butylphosphine hydriodide (149 mg, 0.305 mmol) were added to a solution of 3,4-dimethyl-l,2,4-triazole (74.1 mg, 0.763 mmol), (Example 16; 150.0 mg, 0.305 mmol), 2,2-dimethylpropanoic acid (31.2 mg, 0.305 mmol), and K2CO3 (127 mg, 0.916 mmol) in tohiene (2.50 mL). The mixture was stirred at 120 °C for 6 h. Water (0.5 mL) was added. The mixture was extracted with ethyl acetate (3 x 25 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (4 g cartridge) elutîng with MeOH in DCM (0-10%) to provide tert-butyl (S)-4-(4,5-dimethyl-4H-l,2,4-triazoI-3-yl)-12-fluoro-7a,13dihydro-7H-[l,2,4]triazolo[4',3,:l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)carboxylateas a solid (66.0 mg, 30%, 70% purity). 1HNMR (400 MHz, MeOD) δ 9.19 (br, 1H),
256
7.73 (s, 1H), 6.74-6.62 (m, ÎH), 6.59 (dd, J = 8.5, 3.7 Hz, 1H), 5.35-5.20 (m, 1H), 4.72-4.63 (m, 1H), 4.47 (dd, J = 9.6, 7.7 Hz, 1H), 4.34 (d, J = 9.6 Hz, 1H), 4.18-4.08 (m, IH), 4.08-4.01 (m, 2H), 3.77 (s, 3H), 2.37 (s, 3H), 1.56-1.33 (m, 9H). m/z (ES+) [M+H]+: 508.6; HPLC tR (A05) = 2.01 min,
Step 2: (S)-4-(4,5-dimethyl-4H-l, 2,4-triazol-3-yl)-12-fluoro- 7a,8,13,l 4-tetrahydro- 7H[2,2,4] triazo lo[4’,3':l, 6]pyrido[3,2-b]benzofuro [4,3-fg] [2,4] oxazonine
A solution of tert-butyl (S)-4-(4,5-dimethyl-4H-l,2,4-triazol-3-yl)-12-fhioro-7a,13-dihydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (66.0 mg, 70% pure, 91.0 pmol) in HFIP (2.50 mL) was heated at 100 °C for 15 h. After evaporating the solvent under reduced pressure, the residue was purified b y HPLC (Gemini C18 30x100mm AmBicarb/ACN 23-43%) to afford the title compound as a solid (16.3 mg, 44%). ‘H NMR (500 MHz, DMSO) Ô 9.48 - 9.39 (s, 1H), 7.83 (t, J = 5.4 Hz, 1H), 7.54 (s, 1H), 7.02-6.91 (m, 1H), 6.70 (dd, J = 8.6, 3.8 Hz, 1H), 4.93 (dd, J = 15.0, 6.1 Hz, 1H), 4.85 - 4.75 (m, 1H), 4.54 (t, J = 9.5 Hz, 1H), 4.51 - 4.41 (m, 1H), 4.22 (dd, J = 9.6, 3.6 Hz, IH), 4.05 (s, 1H), 3.91 - 3.78 (m, 1H), 3.49 (s, 3H), 2.42 (s, 3H). m/z (ES+) [M+H]+: 408.6; HPLC tR (A05) = 1.80 min.
Example 75: (S)-12-iluoro-4-(5-mcthyl-l,3,4-oxadiazol-2-yl)-7a,8,13,14-tetrahydro-7H [1,2,4]triazoloI4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4| oxazonine
Step 1: tert-butyl (S)-i2-fluoro-4-(5-methyl-l,3,4-oxadiazol-2-yl)-7a,13-dihydro-7H[1,2,4]triazolo[4’,3':l, 6]pyrido[3,2-b] benzofuro[4,3-fg] [1,4] oxazonine-14(8H)-carboxylate
257
Pd(OAc)2 (36.3 mg, 0.162 mmol) and di(l-adamantyl)-n-butylphosphine hydriodide (157 mg, 0.324 mmol) were added to a solution of 2-methyl-l,3,4-oxadiazole (68.0 mg, 0.809 mmol) and tert-butyl (S)-4-bromo-12-fluoiO-7a,13-dihydro-7H-[l,2,4]triazolo[4’,3':l,6]pyrido[3,2-b]benzofuro[4,35 fg][l,4]oxazonine-14(8H)-carboxylate (Example 16; 159 mg, 0.324 mmol), 2,2-dimethylpropanoic acid (33.1 mg, 0.324 mmol), K2CO3 (134 mg, 0.971 mmol) in toluene (2.50 mL). The mixture was stirred at 120 °C for 6 h. Water (0.5 mL) was added, The aqueous phase was extracted with ethyl acetate (3X15 mL). The combined organic layers were dried over Na2SO4, fïltered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (4 g cartridge) eluting with MeOH in DCM (0-10%) to provide tert-butyl (S)-12-fluoro-4-(5-methyl-l,3,4oxadiazol-2-yl)-7a,13-dihydiO-7H-[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3fg][ 1,4] oxazonine-14(8H)-carboxylate as a solid (99.0 mg, 43%, 70% purity). m/z (ES+) [M+H] : 495.4; (A05) tR = 2.09 min.
Step 2: (S)-12-fluoro-4-(5-methyl-l, 3,4-oxadiazol-2-yl)-7a, 8,13,14-tetrahydro-7H15 [1,2,4]triazolo[4 3': 1,6]pyrido[3,2-b] benzofuro[4,3 -fg] [1,4] oxazonine
A solution of tert-butyl (S)- 12-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)-7a, 13-dihydro-7H[l,2,4]triazolo[4',3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4] oxazonine-14(8 H)-carboxylate (99,0 mg, 70% pure, 140 gmol) in HFIP (2.50 mL) was heated at 100 °C for 15 h. After evaporating the
258 solvent under reduced pressure, the residue was purified by HPLC (BEH C18 30x150 mm ACN/AmBic 25-45%) to afford the tîtle compound as a solid (18.6 mg, 34%). “H NMR (500 MHz, DMSO) δ 9.51 (s, IH), 8.17 (s, IH), 7.97 (s, IH), 7.03 - 6.90 (m, IH), 6.70 (dd, J = 8.7, 3.8 Hz, IH), 4.99 - 4.90 (m, IH), 4.90 - 4.81 (m, IH), 4.53 (t, J = 9.4 Hz, 2H), 4.26 - 4.15 (m, IH), 4.09 4.00 (m, IH), 3.94- 3.83 (m, IH), 2.59 (s, 3H). m/z (ES+) [M+H]+: 395.5; HPLC tk (A05) = 1.88 min.
Examplc 76: (S)-4-(6-(difluoromethyl)-2-methylpyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro7H-[l,2,4]triazolo[4’,3':l,6]pyridol3,2-b]benzofuro[4,3-fg][l,4Ioxazonine
Step 1: 3-bromo-2-methyl-6-vinylpyridine
To a stirred solution of 3,6-dibromo-2-methylpyridine (8.60 g, 34.3 mmol, 1.00 eq), 4,4,5,5tetramethyl-2-vinyLl,3,2-dioxaborolane (5.28 g, 34.3 mmol, 1.00 eq) and Na2CO3 (7.27 g, 68.6 mmol, 2.00 eq) in dioxane (90.0 mL) and water (18.0 mL) was added Pd(dppf)Cl2 (2.51 g, 3.43 mmol, 0.100 eq) at 15°C under N2. The resulting mixture was stirred at 80°C for 12 h. The mixture was concentrated under reduced pressure. The mixture was purified by MPLC (SiO2, ΡΕ/EtOAc = 1/0 to 1/1). 3-bromo-2-methyl-6-vinylpyridine (5.70 g, 28.8 mmol, 84% yield) was obtained as colourless oil.
Step 2: 5-bromo-6-methylpicolinaldehyde
Ozone (15 psi) was bubbled înto a solution of 3-bromo-2-methyl-6-vinylpyridme (5.70 g, 28.8 mmol, 1.00 eq) in DCM (100 mL) at -78°C for 0.5 hr. After excess O3 was purged with O2 for 0.5 hr, to the mixture was added Me2S (35.8 g, 576 mmol, 42.3 mL, 20.0 eq) at -78°C. The resulting mixture was stirred at 15°C for 12 h. The mixture was concentrated under reduced pressure. The mixture was purified by MPLC (SiO2, ΡΕ/EtOAc = 1/0 to 10/1). 5-bromo-6-methylpicolinaldehyde (1.60 g, 8.00 mmol, 27% yield) was obtained as a yellow solid. 'H NMR DMSO-î4 400 MHz δ = ppm 9.92 (s, IH), 8.27 (d, 7 = 8.1 Hz, IH), 7.67 (d, 7= 8.1 Hz, IH), 2.68 (s, 3H).
259
Step 3: 3-bromo-6-(difiuoromethyl)-2-methylpyridine
F 2^F
Br
To a stirred solution of 5-bromo-6-methylpicolinaldehyde (1.60 g, 8.00 mmol, 1.00 eq) in DCM (50.0 mL) was added DAST (2.84 g, 17.6 mmol, 2.32 mL, 2.20 eq) at -78°C under N2. The resulting mixture was stirred at 15°C for 12 h. The mixture was basified by saturated aqueous NaHCO3 solution to pH = 7-8 and then the mixture was extracted with EtOAc (20 mL * 3). The combined organic layers were dried over Na2SO4 and then concentrated under reduced pressure. The mixture was purified by MPLC (SiO2, PE/EtOAc = 1/0 to 1/1). 3-bromo-6-(dîfhioromethyl)-2methylpyridine (1.40 g, 6.31 mmol, 78% yield) was obtained as coiourless oil.
Step 4: 6-(difluoromethyl)-2-methyl-3-(tributylstannyl)pyridine
To a solution of 3-bromo-6-(difluoiOmethyl)-2-methylpyridine (1.30 g, 5.86 mmol, 1.00 eq) in THF (15.0 mL) was added n-BuLi (2.50 M, 2.58 mL, 1.10 eq) at -78°C under nitrogen and the mixture was stirred at -78°C for 0.5 hr under N2. Then tnbutyl(chloro)starmane (5.72 g, 17.6 mmol, 4.73 mL, 3.00 eq) was added to the mixture under nitrogen atmosphère at -78°C and the resulting mixture was stirred at -78°C for 2 h under N2. The mixture was quenched with saturated aqueous NH4Cl solution (20.0 mL) and the mixture was extracted with EtOAc (20.0 mL * 3). The combined organic layers were dried over Na2SO4 and then concentrated under reduced pressure. The mixture was purified by MPLC (SiO2, PE/EtOAc = 1/0 to 1/1). 6-(difluoromethyl)-2-methyl-3(tributylstannyl)pyridine ( 1.00 g, 2.3 1 mmol, 39% yield) was obtained as yeiïow oil.
Step 5: tert-butyl (S)-4-(6-(difluoromethyl)-2-methylpyridin-3-yl)-12-fluoro-7a,13-dihydro-7H[1,2,4] triazolo[4 ',3':l,6]pyrido[3,2-b]benzo]itro[4,3-fg] [1,4] oxazonine-14(8H)-carboxylate
260
To a stirred solution of tert-butyl (S)-4-bromo-12-fluoro-7a,13-dihydro-7H[l,2,4]triazolo[4',3’:l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (130 mg, 265 umol, 1.00 eq), 6-(difluoromethyl)-2-methyl-3-(tributyIstannyl)pyridme (263 mg, 609 umol, 5 2.30 eq), Cul (20.2 mg, 106 umol, 0.400 eq) and LiCl (22.4 mg, 529 umol, 2.00 eq) in dioxane (4.00 mL) was added Pd(PPh3)4 (30.6 mg, 26.5 umol, 0.100 eq) at 15°C under N2. The resulting mixture was stirred at 80°C for 12 h. The mixture was concentrated under reduced pressure. The mixture was purified by /ire/i-TLC (SiO2, ΡΕ/EtOAc = 0/1). tert-butyl (S)-4-(6-(difluoromethyl)-2methylpyridin-3-yl)- 12-fluoro-7a, 13-dihydro-7H-[ 1,2,4]triazolo[4',3': 1,6]pyrido[3,210 b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (200 mg, crude) was obtained as yellow oil.
Step 6: (Sj-4-(6-(difluoromethyl)-2-methylpyridin-3-yl)-I2-fliioro- 7 a, 8,13,14-tetrahydro-7H[ 1,2,4]triazolo[4', 3 1,6]pyrido[3,2-b]benzofuro[4,3-fg] [1,4] oxazonine
F
ΛΛ H /A LAMA
F
To tert-butyl (S)-4-(6-(difluoromethyl)-2-methylpyridin-3-yl)- !2-fluoro-7a, 13-dihydiO-7H15 [l,2,4]triazolo[4',3': 1,6]pyrido[3,2-b]benzofùro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (200 mg,
361 umol, 1.00 eq) was added HFIP (3.00 mL) at 15°C. The resulting mixture was stirred at 80°C for 12 h. LCMS showed the reactant was consumed and the desired mass was detected. The mixture was concentrated under reduced pressure. The mixture was purified by neutral pi'ep-HPLC. The fraction was concentrated under reduced pressure to remove most of MeCN at 30°C and the 20 aqueous phase was lyophilized. (S)-4-(6-(difluoromeihyl)-2-methylpyridin-3-yl)-12-fluoro7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine (15.2 mg, 31.6 umol, 8% yield, 94.2% purity) was obtained as a yellow solid. *H NMR DMSO-î/6
261
400 MHz δ = ppm 9.42 (s, IH), 7.97 (d, 7= 7.7 Hz, 1H), 7.63 - 7.53 (m, 2H), 7.39 (s, 1H), 6.96 (t, J = 54.8 Hz, IH), 6.96 (t, 7= 10.6 Hz, 1H), 6.68 (dd, 7= 8.6, 3.7 Hz, IH), 4.95 - 4.87 (m, IH), 4.84 4.73 (m, IH), 4.57 - 4.41 (m, 2H), 4.19 (dd, 7= 9.7, 3.5 Hz, IH), 4.09 - 3.97 (m, IH), 3.91 - 3.81 (m, IH), 2.41 (s, 3H). LCMS (ES1+): m/z 454.2 (M+H).
Example 77: (S)-4-(5-(difluoromethyl)-6-methylpyridm-2-yl)-12-fluoro-7a,8,13,14-tetrahydro7H-[ 1,2,4] triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg] [l,4]oxazonine
Step 1: 6-bromo-2-methylnicotinaldehyde
To a solution of 3,6-dibromo-2-methylpyridine (10.0 g, 39.9 mmol, 1.00 eq) in Et2O (230 mL) was 10 added n-BuLÎ (2.50 M, 18.3 mL, 1.15 eq) at -78°C and the reaction mixture was stirred at -78°C for hr. TLC (SiO2, ΡΕ/EtOAc = 10/1) showed 3,6-dibromo-2-methylpyridine was consumed completely and new spots were formed. To the mixture was added DMF (5.15 g, 70.5 mmol, 5.42 mL, 1.77 eq) at -78 °C and the reaction mixture was stirred at -78°C for 1 hr. Then the mixture was stirred at 15°C for I hr. TLC (SiO2, ΡΕ/EtOAc = 10/1) showed the intennediate was consumed 15 completely and new spots were formed. The mixture was quenched with saturated aqueous NH4C1 solution (80.0 mL) and the mixture was extracted with EtOAc (50.0 mL * 3). The combined organic layers were dried over Na2SO4 and then concentrated under reduced pressure. The mixture was purified by MP LC (SiO2, ΡΕ/EtOAc = 1/0 to 1/1). 6-bromo-2-methylnicotinaldehyde (5.20 g, 26.0 mmol, 65% yield) was obtained as a yellow solid. 'H NMR DMSO-(4 400 MHz δ = ppm 20 10.22 (s, IH), 8.05 (d, 7= 8.2 Hz, IH), 7.69 (d, 7= 8.2 Hz, IH), 2.75 (s, 3H).
Step 2: 6-bromo-3-(difluoromethyl)-2-methylpyridine
To a stirred solution of 6-bromo-2-methylnicotinaldehyde (2.00 g, 10.0 mmol, 1.00 eq) in DCM (80.0 mL) was added DAST (3.55 g, 22.0 mmol, 2.91 mL, 2.20 eq) at -78°C under N2. The resulting mixture was stirred at 15°C for 12 h. LCMS showed 6-bromo-2-methylnicotmaldehyde was consumed and the desired mass was detected. The mixture was basified by saturated aqueous
262
NaHCOj solution to pH = 7-8 and then the mixture was extracted with EtOAc (50 mL * 3). The combined organic layers were dried over Na2SO4 and then concentrated under reduced pressure. The mixture was purified by MPLC (SiO2, ΡΕ/EtOAc = 1/0 to 1/1). 6-bromo-3-(difluoromethyl)-2methylpyridine (1.70 g, 7.66 mmol, 76% yield) was obtained as yellow oiL
Step 3: 3-(difluoromethyl)-2-methyl-6-(trimethylstannyl)pyridine
To a solution of 6-bromo-3-(difluoromethyl)-2-methylpyridine (500 mg, 2.25 mmol, 1.00 eq) in dioxane (15.0 mL) was added trimethyl(trimethylstannyl)stamiane (1.49 g, 4.50 mmol, 943 uL, 2.00 eq), Pd(PPh3)4 (260 mg, 225 umol, 0.100 eq) at 25°C under nitrogen atmosphère. The sealed tube was heated at 110°C for 3 h under microwave irradiation. The suspension was filtered through a pad of Celite gel and the filter cake was washed with dioxane (1.00 mL). 3-(difluoromethyl)-2-methyl6-(trimethylstannyl)pyridine (680 mg, 2.22 mmol, 98% yield) was obtained as yellow oil (in 16.0 mL of dioxane).
Step 4: tert-butyl (S)-4-(5-(difluoromethyl)-6-methylpyridm-2-yl)-I2-fluoro-7a, 13-dihydro-7H[ 1,2,4] triazolo[4\3 ’:1,6]pyrido[3,2-b]benzoJùro[4,3-fg][1,4] oxazonine-14 (8H)-carboxylate
F
To a solution of 3-(difluoromethyl)-2-rnethyl-6-(trimethylstannyl)pyridme (340 mg, 1.11 mmol, 5.46 eq) in dioxane (8.00 mL) was added tert-butyl (S)-4-bromo-12-fluoro-7a,13-dihydro-7H[l,2,4]triazolo[4’,3':l,6]pyrido[3,2-b]benzofiiro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (100 mg, 204 umol, 1.00 eq), LiCl (17.3 mg, 407 umol, 8.34 uL, 2.00 eq), Cul (15.5 mg, 81.4 umol, 0.400 eq) and Pd(PPh3)4 (23.5 mg, 20.4 umol, 0.100 eq) at 15°C under nitrogen atmosphère. The mixture was stirred at 80°C for 3 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, ΡΕ/EtOAc = 1/1). tert-butyl (S)-4-(5-(difluoromethyl)-6263 methyl pyridin-2-yl)- 12-fluoro-7a, 13-dihydro-7H-[ 1!2,4]ti-iazolo[4,,3’:l,6]pyrido[3,2b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (150 mg, crude) was obtained as a yellow oil.
Step 5: (S)-4-(5-(difluoromethyl)-6-methylpyridin-2-yl)-12-fluoro- 7a, 8,13,14-tetrahydro-7H[1,2,4]triazolo[4 ', 3 1,6]pyrido[3,2-b]benzofttro[4,3-fg] [1,4] oxazonine
F
To tert-butyl (S)-4-(5-(difluoiOmethyJ)-6-methylpyridin-2-yl)-12-fluoro-7aJ13-dihydiO-7H[ 1,2,4]triazolo[4',3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate (150 mg, 271 umol, 1.00 eq) was added HFIP (4.0Ü mL) at 15°C. The resulting mixture was stirred at 80°C for 12 h. The mixture was coneentrated under reduced pressure. The mixture was purified by neutral /wep-HPLC, The fraction was coneentrated under reduced pressure to remove most of MeCN at 30°C and the aqueous phase was lyophilized. (S)-4-(5-(difluoromethyl)-6-methylpyridin2-yl)-12-nuoiO-7a,8,13,14-tetraliydro-7H-[l,2,4]triazolo[4',3':l,6]pyi-ido[3,2-b]benzofuiO[4s3fg][ 1,4] oxazonine (14.0 mg, 29.7 umol, 11% yield, 96.1% purity) was obtained as yellow solid. 'H NMR DMSO-76400 MHz δ = ppm 9.49 (s, IH), 8.96 (d, J = 8.4 Hz, IH), 8.35 (s, IH), 8.01 (d, J = 8.4 Hz, IH), 7.90 (br s, IH), 7.24 (t, J = 54.8 Hz, IH), 6.94 (t, J= 9.5 Hz, IH), 6.67 (dd, 7 = 8.7, 3.6 Hz, IH), 4.98 - 4.75 (m, 2H), 4.50 (br t, 7= 9.4 Hz, 2H), 4.31 - 4.20 (m, IH), 4.10 - 3.99 (m, IH), 3.95 - 3.82 (m, IH), 2.63 (s, 3H). LCMS (ESI+): m/z 454.2 (M+H).
Example 78: (S)-4-(3-(12-fluoro-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4',3':l,6[pyrido [3,2b]benzofuro[4,3-fg[[l,4)oxazonin-4-yl)pyridiii-2-yl)-2-mcthylbutan-2-ol
Step 1: 4-(3-bromopyridin-2-yl)-2-methylbut-3-yn-2-ol
To a solution of 3-bromo-2-iodopyridîne (2.00 g, 7.04 mmol, 1.00 eq) in THF (20.0 mL), EtjN (20.0 mL) were added 2-methylbut-3-yn-2-ol (652 mg, 7.75 mmol, 757 uL, 1.10 eq), PdfPPhjjaCh (494 264 mg, 704 umol, 0.100 eq) and Cul (134 mg, 704 umol, 0.100 eq) at 20°C. The mixture was stirred at 70°C for 12 h under nitrogen atmosphère. The reaction was filtered, the filtra te was concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 1/0 to 0/1). 4-(3-bromopyridin-2-yl)-2-methylbut-3-yn-2-ol (1.51 g, 6.29 mmol, 89% yield) was obtained 5 as a yellow oil.
Step 2: 3-hromo-2-(3-((tert-butyldimethylsilyi)oxy)-3-methylbut-l-yn-l-yl)pyridîne
To a solution of 4-(3-bromopyridin-2-yl)-2-methylbut-3-yn-2-ol (600 mg, 2.50 mmol, 1.00 eq), 2,6dimethylpyridine (535 mg, 4.99 mmol, 582 uL, 2.00 eq) in MeCN (10.0 mL) was added TBDMS10 OTf (1.06 g, 4.00 mmol, 919 uL, 1.60 eq) at 0°C. Then the mixture was stirred at 60°C for 12 h under nitrogen atmosphère. The reaction was concentrated. The residue was purified by pre^-TLC (SiO2, Petroleum ether/Ethyl acetate = 3/1). 3-biOmo-2-(3-((tert-buÎyldimethylsilyl)oxy)-3methylbut-l-yn-l-yl)pyndîne (800 mg, 2.26 mmol, 90% yield) was obtained as a yellow oil.
Step 3: 2-(3-((tert-butyldimethylsifyl)oxy)-3-methyîbut-I-yn-l-yl)-3-(tribiitylstannyl)pyridine
To a solution of 3-bromo-2-(3-((Îert-butyidimethylsilyl)oxy)-3-methylbut-l-yn-l-yi)pyridine (1.00 g, 2.82 mmol, 1.00 eq) in THF (10.0 mL) was added rî-BuLi (2.50 M, 1.24 mL, 1.10 eq) at -70°C under nitrogen atmosphère. The reaction mixture was stirred at -70°C for 0.5 hr under nitrogen atmosphère, then tributyl(chloro)stannane (2.76 g, 8.48 mmol, 2.28 mL, 3.00 eq) was added under 20 nitrogen atmosphère and the resulting mixture wa stirred at -70° C for 2 h under nitrogen atmosphère. The reaction solution was poured into water (10.0 mL), the mixture was extracted with ethyl acetate (10 mL * 3), the combined organic layers were dried overNa2SO4, and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Petroleum ether/Ethyl acetate = 10/1). 2-(3-((tert-butyldimethylsilyl)oxy)-3-methylbut-l-yn-l-yl)-3-(tributylstannyl)pyridine 25 (1.30 g, 2.30 mmol, 81% yield) was obtained as a yellow oil.
265
Step 4: tert-butyl (S)-4-(2-(3-((tert-butyldimethylsilyl)oxy)-3-methylbut-l-yn-l-yl)pyridin-3-yl)-l2fluoro-la, 13-dihydro- 7H-[1,2,4]triazolo[4',3 /, 6]pyrido[3,2-b]benzofuro[4,3-fg] [1,4] oxazonine14(8H)-carboxylate
To a solution of tert-butyl (S)-4-bromo-12-fluoro-7a,!3-dihydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][i,4]oxazonine-14(8H)-carboxylate (240 mg, 488 umol, 1.00 eq) in dioxane (8.00 mL) was added 2-(3-((tert-butyIdimethylsilyl)oxy)-3m ethylbut-1-yn-l-yl)-3-(tri butylstaimyl)pyri dîne (551 mg, 976 umol, 2.00 eq), Cul (37.2 mg, 195 umol, 0.400 eq), LiCl (41.4 mg, 977 umol, 2.00 eq) and Pd(PPh3)4 (56.5 mg, 48.9 umol, 0.100 eq) at 20°C under nitrogen atmosphère. The mixture was stirred at 80°C for 12 h under nitrogen atmosphère. The reaction was concentrated. The residue was purified by prep-TLC (SiO2, Petroleum ether/Ethyl acetate = 1/2). tert-butyl (S)-4-(2-(3-((tert-butyldimethylsilyl)oxy)-3methyibut- 1-yn-1 -yl)pyridin-3-yl)- 12-fluoro-7a, 13-dihydro-7H-[ l,2,4]triazolo[4',3': 1,6]pyrido[3,2b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (300 mg, 437 umol, 89% yield) was obtained as a yellow oil.
Step 5: tert-butyl (S)-l2-fluoro-4-(2-(3-hydroxy-3-methylbut-l-yn-1 -yl)pyridin-3-yl)-7a, 13-dihydro7H-[l,2,4]triazolo[4', 3 ':l,6]pyrido[3,2-b]benzofttro[4,3-fg][1,4] oxazonine-14 (8H)-carboxylate
To a solution of tert-butyl (S)-4-(2-(3-((tert-butyldimethylsilyl)oxy)-3-methylbut-l-yn-l-yl)pyridin3-yl)-12-fluoro-7a,13-dihydro-7H-[l,2,4]triazolo[4',3’:l,6]pyrido[3,2-b]benzofuro[4,3fg][l,4]oxazonine-14(8H)-carboxylate (280 mg, 408 umol, 1.00 eq) in THF (8.00 mL) was added
TB AF (1.00 M, 815 uL, 2.00 eq) at 20°C. The mixture was stirred at 40°C for 12 h. LCMS showed
266 tert-butyl (S)-4-(2-(3-((tert-butyldimethylsilyl)oxy)-3-methylbut-l-yn-l-yl)pyridin-3-yl)-12-fluoiO7a, 13-dihydro-7H-[ 1,2,4]triazolo[4’,3’: 1,6]pyrido[3J2-b]benzofuro[4J3-fg][ i ,4] oxazonine-14(8H)carboxylate was consumed completely and the desired mass was detected. Water (10.0 mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (10.0 mL * 3), the combined organic layers were dried over Na2SO4, and concentrated under reduced pressure, tertbutyl (S)-12-fluoro-4-(2-(3-hydroxy-3-methylbut-l-yn-l-yl)pyridin-3-yl)-7a,13-dihydro-7H[ l,2,4]triazoio[4',3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (230 mg, crude) was obtained as a brown oîl.
Step 6: tert-butyl (S)-l 2-fluoro-4-(2-(3-hydroxy-3-methylbutyl)pyridin-3-yl)-7a,l 3-dihydro- 7H[1,2,4] triazolo[4’,3 ':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4] oxazonine-14 (8H)-carboxylate
To a solution of tert-butyl (S)-12-fluoro-4-(2-(3-hydroxy-3-methylbut-l-yn-l-yl)pyridin-3-yl)7a, 13-dihydro-7H-[ 1,2,4]triazolo[4’,3’: 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ l,4]oxazonine- 14(8H)carboxylate (200 mg, 350 umol, 1.00 eq) in MeOH (15.0 mL) was added 10% Pd/C (80.0 mg, 50% purity) at 20°C under nitrogen atmosphère. The suspension was degassed and purged with H2 three times. The mixture was stirred under H2 (15 Psi) at 40°C for 3 h. The reaction was filtered, the filtrate was concentrated. tert-butyl (S)-I2-fIuoro-4-(2-(3-hydroxy-3-methylbutyl)pyridin-3-yl)7a,13-dihydro-7H-[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)carboxylate (200 mg, crude) was obtained as a yellow oil.
Step 7: (5)-4-(3-( 12-fluoro-7a, 8,13,14-tetrahydro- 7H-[ 1,2,4] triazolo[4 3 ’:1,6]pyrido[3,2b]benzofuro[4,3-fg] [1,4]oxazonin-4-yl)pyridin-2-yl)-2-methylbutan-2-ol
267
A mixture of tert-butyl (S)-12-fluoro-4-(2-(3-hydiOxy-3-methylbutyl)pyridin-3-yl)-7a,13-dihydro7H-[I,2,4]triazolo|4',3’:l,6]pyrido[3,2-b]benzofuro[4,3-fg][î,4]oxazonine-14(8H)-carboxylate (200 mg, 347 umol, 1.00 eq) in HFIP (20.0 mL) was stirred at 80°C for 12 h. LCMS showed tert-butyl (S)- 12-fluoro-4-(2-(3-hydroxy-3-methylbutyl)pyridin-3-yl)-7a, 13-dihydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate remained and the desired mass was detected. The mixture was stirred at 100°C for 3.5 h at which time LCMS showed complété conversion. The reaction mixture was concentrated. The residue was dissolved in DMSO (8.00 mL). The solution was purified by neutral prep-HPLC. The fraction containing the product was concentrated under reduced pressure to remove most of MeCN at 30°C and the aqueous phase was lyophilized. (S)-4-(3-(12-fluoiO-7a,8,13,14-tetrahydro-7H[ 1,2,4]triazolo[4',3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4]oxazonin-4-yl)pyridin-2-yl)-2methylbutan-2-ol (24.0 mg, 49.4 umol, 14% yield, 97.9% purity) was obtained as a white solid. ’H NMR CDCh 400 MHz δ = ppm 8.77 (s, IH), 8.47 (br d, J = 3.4 Hz, IH), 7.61 (br d, J = 7.8 Hz, IH), 7.13 (dd, 7 = 7.6, 5.0 Hz, IH), 6.99 (s, IH), 6.81 (t,7 = 9.4 Hz, IH), 6.60 (dd, 7=8.6, 3.9 Hz, IH), 5.08 - 4.91 (m, 2H), 4.76 (br dd, 7= 14.1, 4.6 Hz, IH), 4.59 - 4.47 (m, 2H), 4.17 (dd, 7= 9.8, 2.7 Hz, IH), 3.91 - 3.63 (m, 3H), 2.79 (br t, J-7.2 Hz, 2H), 1.85 (br t, J= 7.4 Hz, 2H), 1.07 (s, 6H). LCMS (ES1+): m/z 476.0 (M+H).
Exainple 79: (S)-12-fluoro-4-(l,3,5-trimethyLlH-pyrazol-4-yl)-7a,8,13,14-tetrahydro-7H|l,2,4]triazolo[4',3': 1,6] pyrido[3,2-b] benzofuro[4,3-fg] [l,4]oxazonine
Step 1: tert-butyl (S)-4-(2,4-dioxopentan-3-yl)-12-fluoro-7a,13-dihydro-7H[1,2,4] triazolo]4', 3 1,6]pyrido[3,2-b] benzofuro[4,3-fg] [1,4]oxazomne-14(8H)-carboxylate
F
To a solution of tert-butyl (S)-4-bromo-12-iluoro-7a,13-dihydro-7H[L2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (250 mg, 509 umol, 1.00 eq), pentane-2,4-dione (509 mg, 5.09 mmol, 523 uL, 10.0 eq) in toluene (5.00 mL) was added /-BuONa (2.00 M, 509 uL, 2.00 eq), LBuXPhos Pd G3 (40.4 mg, 50.9 umol, 0.100 eq) at 20°C. The mixture was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 100°C for 12 h under nitrogen atmosphère. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, EtOAc:MeOH = 10:1). tert-butyl 268 (S)-4-(2,4-dioxopentan-3-yl)-12-fluoro-7a,l 3-dihydro-7H-[ 1,2,4]triazoLo[4’,3': 1,6]pyrido[3,2b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (59.7 mg, crude) was obtained as yellow solid.
Step 2: tert-butyl (S)-12-fluoro-4-(l,3,5-trimethyl-IH-pyrazol-4-yl)-7a,13-dihydro-7H[1,2,4]triazolo[4\ 3 ':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4] oxazonine-14(8H)-carboxylate
To a solution of tert-butyl (S)-4-(2,4-dioxopentan-3-yl)-12-f1uoro-7a,13-dihydro-7H[l,2,4]triazolo[4’,3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (59.7 mg, 117 umol, 1.00 eq) tn EtOH (2.00 mL) was added mcthylhydrazîne (269 mg, 2.34 mmol, 308 uL, 20.0 eq) at 20°C. Then the mixture was stirred at 80°C for 4 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prepTLC (SiO2, EtOAc:MeOH = 5:1). tert-butyl (S)-12-fiuoiO-4-(l,3,5-trimethyl-lH-pyrazol-4-yl)7a,13-dihydro-7H-[l,2,4]iriazolo[4',3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)carboxylate (15 mg, crude) was obtained as yellow oil.
Step 3: (S)-l 2fhtoro-4-(l ,3,5-trimethyl-l H-pyrazol-4-yl)-7a,8,l 3,14-tetrahydro-7H[l,2,4]triazolo[4',3':l, 6]pyrido[3,2-b]benzofwo[4,3-fg] [1,4] oxazonine formate
To tert-butyl (S)-12-fluoro-4-(l,3,5-trimethyl-lH-pyrazol-4-yl)-7a,13-dihydro-7H[ 1,2,4]triazolo[4', 3 ': l,6]pyrido[ 3,2-b]benzofuro[4,3-fg] [1,4] oxazonine-14(8 H)-carboxylate (15.0 mg, 28.8 umol, 1.00 eq) was added HF1P (2.00 mL) at 20°C. The mixture was stirred at 100°C for 12 h. LC-MS showed tert-butyl (S)-12-fluoro-4-(l,3,5-trimethyl-lH-pyrazol-4-yl)-7a,13-dihydro7H-[l,2,4]triazolo[4',3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][ l,4]oxazonine-14(8H)-carboxylate was
269 consumed completely and one main peak with desîred mass was detected. The reaction mixture was concentrated under reduced pressure. The crude product was purified by /?rep-HPLC (fonnic acid conditions). (S)-12-fluoro-4-(l,3,5-trimethyl-lH-pyrazol-4-yl)-7a,8,13,14-tetrahydro-7H[l^TltriazoloHLSkLôjpyridotS^-bJbenzofiiroiAS-fgJIT^oxazonine (5.00 mg, 10.6 umol, 36% 5 yield, 98.6% purity, formate sait) was obtained as yellow solid. ‘H NMR CDC13 400 MHz δ = ppm 8.81 (s, 1H), 7.27 (s, 1H), 6.91 - 6.84 (m, 1H), 6.70 - 6.64 (m, 1H), 5.19 - 5.00 (m, 1H), 4.89 4.78 (m, 2H), 4.72 - 4.50 (m, 2H), 4.32 - 4.20 (m, 1H), 3.98 - 3.89 (m, 1H), 3.86 - 3.79 (m, 1H), 3.77 (s, 3H), 2.21 (s, 3H), 2.20 (s, 3H). LCMS (ES1+): m/z 421.2 (M+H).
Exampk 80: (S)-l-(5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4’,3':l,6]pyrido[3,210 b|benzofuro[4,3-fgHl,4]oxazonin-4-yl)-lH-pyrazol-l-yl)-2-methylpropan-2-ol
Step 1: l-(lH-pyrazol-l-yl)propan-2-one
O
To a solution of IH-pyrazole (10.0 g, 147 mmol, 1.00 eq) in 1-chloropropan-2-one (20.4 g, 220 mmol, 5.00 mL, 1.50 eq) was added Cs2CO3 (14.4 g, 44.2 mmol, 3.01e-l eq) at 20°C. The mixture 15 was stirred ai 90°C for 6 h. TLC (Petroleum etherEthyl acetate = 1:1) îndicated no IH-pyrazole was remained, and one new spot with lower polarity was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 1/0 to l/l). l-(lH-pyrazoI-l-yl)propan-2-one (5.30 g, crude) was obtained as yellow oil.
Step 2: 2-methyl-l-(lH-pyrazol-l-yl)propan-2-ol
To a solution of l-(lH-pyrazol-l-yl)propan-2-one (5.00 g, 40.3 mmol, 1.00 eq) in toluene (100 mL) was added A1(CH3)3 (2.00 M, 60.4 mL, 3.00 eq) at 0°C under N2. The mixture was stirred at 50°C for 6 h. The reaction mixture was quenched by addition of MeOH (100 mL) at 0°C, and then 25 the mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 1/0 to 3/2). 2-methyl-l(lH-pyrazol-l-yl)propan-2-ol (2.80 g, crude) was obtained as a white solid. ]H NMR DMSO-î4 400 MHz δ = ppm 7.63 (d, 7= 2.2 Hz, 1H), 7.39 (d, 7= 0.8 Hz, 1H), 6.21 (t, 7 = 1.6 Hz, 1H), 4.65 (s, IH), 3.99 (s, 2H), 1.01 (s, 6H).
Step 3: 2-methyl-l-(5-(tributylstannyl)-lH-pyrazol-l-yl)propan-2-ol
270
To a solution of 2-methyl-1-(1 H-pyrazol-1-yl)propan-2-oi (200 mg, 1.43 mmol, 1.00 eq) in THF (5.00 mL) was added n-BuLi (2.50 M, 1.14 mL, 2.00 eq) and TMEDA (332 mg, 2.86 mmol, 431 uL, 2.00 eq) at -70°C under N2. The mixture was stirred at -70°C for 30 mîns. Then tributyl(chloro)stannane (697 mg, 2.14 mmol, 576 uL, 1.50 eq) was added to the mixture at -70°C and the mixture was stirred at 0°C for 1 hr. The reaction mixture was quenched b y addition of MeOH (3.00 mL) at 0°C. And the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 1/0 to 10/1). 2-methyl-l-(5-(tributylstannyl)-l H-pyrazol-l-yI)propan-2-ol (350 mg, crude) was obtained as a yellow liquid.
Step 4: (S)-l-(5-(12-fluoro- 7a,8,13,14-tetrahydro- 7H-[1,2,4] triazolo[4', 3 1,6]pyrido[3,2bjbenzofitro]4,3-fg][ 1,4]oxazonin-4-yl)-l H-pyrazol-1 -yl)-2-methylpropan-2-ol
To a solution of (S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuiO[4,3-fg][l,4]oxazonine (90.0 mg, 230 umol, 1.00 eq) in DMF (4.00 mL) was added LiCl (19.5 mg, 460 umol, 2.00 eq), Pd(PPh3)4 (26.6 mg, 23.0 umol, 0.100 eq), Cul (18.4 mg, 96.6 umol, 0.420 eq) and 2-methyl-l-(5-(tributylstannyl)-1 H-pyrazol-1yl)propan-2-ol (148 mg, 345 umol, 1.50 eq) at 20°C under N2. The mixture was stirred at 80°C for 6 h. The réaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 100 * 30 mm * 5 um; mobile phase: [water (0.2% FA) - ACN]; B%: 15% - 45%, 12 min). (S)-I-(5-(12-fluoro-7a,8,13,14-tetrahydro-7H[ 1,2,4]triazolo[4’,3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonin-4-yl)-l H-pyrazol-l-yl)-2methylpropan-2-ol (28.0 mg, 55.4 umol, 24% yield, 98.3% purity, formate sait) was obtained as a yellow solid. 'H NMR DMSO-7ri 400 MHz δ = ppm 9.45 (s, IH), 7.64 (br t, J= 6.4 Hz, IH), 7.56 (s, IH), 7.50 (s, IH), 6.96 (dd, J- 10.2, 8.8 Hz, IH), 6.70 (dd, J- 8.6, 4.0 Hz, IH), 6.48 (s, IH), 4.96
271
4.87 (m, IH), 4.84 - 4.74 (m, IH), 4.58 - 4.50 (m, 2H), 4.22 (dd, 7= 9.5, 3.6 Hz, IH), 4.10 - 3.99 (m, 3H), 3.90 - 3.79 (m, IH), 0.93 (s, 6H).
Example 81: (S)-Î2-fiuoro-4-(5-(trifluoromethyl)pyridm-2-yI)-7a,8,13,14-tetrahydro-7H[l,2,4]iriazolo[4\3':l,6]pyrido[3,2-b]beiizofuri>[4,3-fg][l,4]oxazonine
Step 1: 5-(trifluoromethyl)-2-(trimethylstannyl)pyridine
CF3 Φ SnMej
To a solution of 2-bromo-5-(trifluoromethyl)pyndine (240 mg, 1.06 mmol, 1.00 eq) and trimethyl (trimethylstannyl) stannane (696 mg, 2.12 mmol, 440 uL, 2.00 eq) in dioxane (8.00 mL) was added Pd(PPh3)4 (61.4 mg, 53.1 umol, 0.0500 eq) under nitrogen atmosphère. The mixture was stirred at 100°C for 2 h under nitrogen atmosphère. LCMS showed the 2-bromo-5(trifluoromethyl)pyridine was consumed completely and the desired MS was detected. 5(trifluoromethyl)-2-(trimethylstannyl)pyridine (329 mg, crude) was obtained as yellow liquid (in 8.00 mL of dioxane), which was used to the next step directly.
Step 2: tert-butyl (S)-12-fluoro-4-(5-(trifluoromethyl)pyridm-2-yl)-7a,l 3-dihydro-7H[1,2,4]triazolo[4', 37,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4] oxazonine-14(8H)-carboxylate
A mixture of tert-butyl (S)-4-bromo-12-fluoro-7a,13-dihydro-7H
[l,2,4]triazolo[4,,3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (158 mg, 322 umol, 1.00 eq), 5-(trifluoromethyl)-2-(trimethylstannyl)pyridine (329 mg, 1.06 mmol, 3.30 eq), LiCl (27.3 mg, 643 umol, 2.00 eq), Cul (24.5 mg, 129 umol, 0.400 eq) and Pd(PPh3)4 (37.2 mg, 32.2 umol, 0.100 eq) in dioxane (8.00 mL) was degassed and purged with nitrogen 3 limes, and the mixture was stirred at 80°C for 8 h under nitrogen atmosphère. LCMS indieated incomplète conversion. Pd(PPh3)4 (37.2 mg, 32.2 umol, 0.100 eq) was added to the mixture under nitrogen atmosphère. The mixture was stirred at 100°C for 2 h under nitrogen atmosphère. The réaction mixture was diluted with water (5.00 mL) and extracted with EtOAc (3.00 mL * 3). The combined
272 organic layers were washed with brine (5.00 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, PE:EtOAc = 1:1). tert-butyl (S)-12-fluoro-4-(5-(trifluoromethyl)pyridin-2-yl)-7a,13-dihydro-7H[ 1,2,4]triazolo[4',3’: 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4]oxazonîne- I4(8H)-carboxylate (50.0 mg, crude) was obtained as yellow oil.
Step 3: (S)-12-fluoro-4-(5-(trifluoromethyl)pyridin-2-yl)-7a, 8,13,14-tetrahydro-7H[1,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4] oxazonine
F
A mixture of tert-butyl (S)-I2-fluoro-4-(5-(trifluoromethyl)pyridin-2-yl)-7a,13-dihydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][ls4]oxazonine-14(8H)-carboxylate (50.0 mg, 89.7 umol, 1.00 eq) and HFIP (2.00 mL) was stirred at 80°C for 8 h. LCMS indicated small amount of the starting material remaining. The mixture was stin'ed at 100°C for 2 h. LCMS indicated complété conversion. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (neutral conditions). The product-containing fraction was concentrated under reduced pressure to remove most of MeCN at 30°C and the aqueous phase was lyophilized. QC indicated insufficient purity. The material was re-purîfied by ρπφ-HPLC (formic acid conditions). The product-containing fraction was concentrated under reduced pressure to remove most of MeCN at 30°C and the aqueous phase was lyophilized. (S)-12-fluoro-4-(5(trifluoromethyl)pyridin-2-yI)-7a,8,13,14-tetrahydro-7H-[l ,2,4]triazolo[4’,3': 1,6]pyrido[3,2b]benzofuro[4,3-fg][ 1,4] oxazonine (22.3 mg, 43.5 umol, 48% yield, 98.2% purity, formate sait) was obtained as a yellow solid. ]HNMR DMSO-7ri 400 MHz δ = ppm 9.56 (s, IH), 9.26 (d, 7= 8.4 Hz, IH), 9.00 (s, IH), 8.43 (s, IH), 8.36 - 8.30 (m, IH), 8.11 (br s, IH), 6.98 (t,7=9.5 Hz, IH), 6.71 (dd, 7= 8.7, 3.9 Hz, IH), 5.03 - 4.94 (m, IH), 4.89 (s, IH), 4.60 (br s, IH), 4.55 (t, 7= 9.5 Hz, IH), 4.30 - 4.25 (m, IH), 4.08 (br s, IH), 3.98 - 3.84 (m, IH). LCMS (ES1+): m/z458.1 (M+H).
Example 82: (S)-l-(3-(12-fluoro-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4’,3':l,6]pyrido[3,2b]benzofuro[4,3-fg][l,4]oxazonm-4-yI)-lH-pyrazol-l-yl)-2-methylpropan-2-ol
Step 1: l-(3-iodo-!H-pyrazoÎ-l-yl)propan-2-one
273
To a solution of 3-iodo-lH-pyrazole (2.00 g, 10.3 mmol, 1.00 eq) in MeCN (20.0 mL) was added Cs2CO3 (6.72 g, 20.6 mmol, 2.00 eq) and l-chloropropan-2-one (1.43 g, 15.5 mmol, 1.50 eq) at 20°C. The mixture was stirred at 60°C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18 250 * 50 mm * 15 um; mobile phase: [water (0.225% FA) - ACN]; B%: 5% - 35%, 20 min). l-(3-iodolH-pyrazol-l-yl)propan-2-one (385 mg, crude) was obtained as a white solid. l-(5-îodo-lHpyrazol-l-yi)propan-2-one (310 mg, crude) was obtained as a white solid. ’H NMR CDC13 400 MHz δ = ppm 7.20 (d, J = 2.8 Hz, 1H), 6.44 (d, 7= 2.0 Hz, 1H), 4.85 (s, 2H), 2.08 (s, 3H).
Step 2: l-(3-iodo-lH-pyrazol-l-yl)-2-methylpropan-2-ol
To a solution of l-(3-iodo-lH-pyrazol-l-yl)propan-2-one (380 mg, 1.52 mmol, 1.00 eq) in toluene (10.0 mL) was added AlMe3 (2.00 M, 3.80 mL, 5.00 eq) at 2Ü°C under N2. The mixture was stirred at 60°C for 12 h. LC-MS showed sonie of l-(3-iodo-lH-pyrazol-l-yl)propan-2-one remained. The reaction mixture was quenched by addition of MeOH (5.00 mL) at 0°C. Then the mixture was fdtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2. Petroleum ether/Ethyl acetate = 1/0 to 4/1). l-(3-iodolH-pyrazol-l-yl)-2-methylpropan-2-ol (127 mg, crude) was obtained as yellow oil.
Step 3: tert-butyl (S)-l2-flu(}ro-4-(l-(2-hydroxy-2-methylpropyl)-IH-pyrazol-3-yl)-7a, 13-dihydro7H-[1,2,4] triazolo[4 3 ':1,6]pyrido[3,2-b] benzofuro[4,3-fg] [1,4] oxazonine-14(8H)-carboxylate
To a solution of tert-butyl (S)-12-fluoro-4-(tributylstannyl)-7a,13-dihydro-7H[l,2,4]triazolo[4T,3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (110 mg.
274
157 umol, 1.00 eq) in dioxane (5.00 mL) was added L(3-iodo-lH-pyrazol-l-yl)-2-methyIpropan-2ol (83.5 mg, 314 umol, 2.00 eq), LiCl (13.3 mg, 314 umol, 2.00 eq), Pd(PPh3)4 (18.1 mg, 15.7 umol, 9.99e-2 eq) and Cul (11.9 mg, 62.5 umol, 3.98e-l eq) at 20°C under N2. The mixture was stirred at 80°C for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate - 1/0 to 1/1). tert-butyl (S)-12-iluoro-4-(l-(2-hydroxy-2-methylpropyl)-lH-pyrazol-3-yl)-7a,13-dihydro-7H[l,2,4]triazolo[4',3’:l,6]pyi-ido[3,2-b]benzoiüro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (80.0 mg, crude) was obtained as a yellow solid.
Step 4: (S)-l-(3-(I2-fluoro-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4',3’:l, 6]pyrido[3,2b]benzofuro[4,3-fg] [l,4]oxazomn-4-yl)-lH-pyrazol-l-yl)-2-methylpropan-2-ol
F
OH
A mixture of tert-butyl (S)-12-fluoro-4-(I-(2-hydroxy-2-methylpropyl)-lH-pyrazol-3-yl)-7a,13dihydro-7H-[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuiO[4,3-fg][l,4]oxazonine-14(8H)carboxylate (80.0 mg, 145 umol, 1.00 eq) in HFIP (2.00 mL) was stirred at 100°Cfor 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prepHPLC (column: Phenomenex Luna Cl 8 200 * 40 mm * 10 um; mobile phase: [water (0.2% FA) ACN]; B%: 10% - 50%, 10 min). The product-containing fraction was concentrated under reduced pressure to remove most of MeCN at 30°C and the aqueous phase was lyophilized to give a yellow solid. The material was additionally purified byprep-HPLC (column: Phenomenex Luna Cl8 200 * 40 mm * 10 um; mobile phase: [water (0.2% FA) - ACN]; B%: 20% - 40%, 10 min). (S)-l-(3-(12fluoro-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4',3'; 1,6] pyrido[3,2-b]benzofuro[4,3fg][l,4]oxazonm-4-yl)-lH-pyrazol-l-yl)-2-methylpropan-2-ol (4.00 mg, 7.80 umol, 5% yield, 96.8% purity, formate sait) was obtained as a yellow solid. lH NMR DMSO-i/é 400 MHz δ = ppm 9.42 (s, IH), 7.81 - 7.68 (m, 2H), 7.46 (br s, IH), 7.25 (s, IH), 6.99 - 6.88 (m, IH), 6.67 (dd, J= 8.8, 3.6 Hz, IH), 4.93 - 4.84 (m, IH), 4.82 - 4.70 (m, 2H), 4.59 - 4.48 (m, 2H), 4.26 (dd, J = 9.5, 3.2 Hz,
275
IH), 4.09 (s, 2H), 4.03 (br s, IH), 3.91 - 3.80 (m, IH), 1.10 (s, 6H) LCMS (ESI+): m/z 451.1 (M+H).
Example 83: (S)-12-fluoro-4-(l-methyl-lH-imidazol-2-yl)-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4’,3,:l,61pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
Step 1: tert-butyl (S)-12-fluoro-4-(l-methyl-lH-imidazol-2-yl)-7a,13-dihydro-7H[1,2,4] triazolo[4', 3r: 1,6]pyrido[3,2-b] benzofuro[4,3-fg] [ 1,4] oxazonine-14(8H)-carboxylate
To tert-butyl (S)-12-fluoro-4-(tributylstannyl)-7a,13-dihydro-7H-[l,2,4]triazolo[4,,3':l,6]pyrido[3,2b]benzofuro[4,3-fg][ 1,4] oxazonine-I4(8H)-carboxylate (200 mg, 285 umol, L00 eq) in dioxane (3.00 mL) was added 2-bromo-1-methyl-îmidazole (91.8 mg, 570 umol, 2.00 eq), Pd(PPh3)4 (33.0 mg, 28.5 umol, 0,100 eq), Cul (21.7 mg, 114 umol, 0.400 eq), LiCl (24.2 mg, 570 umol, 2.00 eq) at 20 °C. The mixture was degassed and purged with nitrogen 3 times, then the mixture was stirred at 100°C for 12 h under nitrogen atmosphère. The reaction mixture was fïltered and the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, EtOAc:MeOH = 10:1). tert-butyl (S)-12-fluoiO-4-(l-methyl-lH-imidazol-2-yl)-7a,13-dihydiO-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (140 mg, crude) was obtained as a yellow solid.
Step 2: (S)-12-fluoro-4-( 1 -methyl-1 H-imidazol-2-yl)-7a,8,13,14-tetrahydro-7H
[1,2,4] triazolo]4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4] oxazonine
To tert-butyl (S)-12-fluoro-4-(l-methyl-lH-imidazol-2-yl)-7a,13-dihydro-7H[l,2,4]triazolo[4f,3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-I4(8H)-carboxylate (140 mg, 284 umol, 1.00 eq) was added HFIP (2.00 mL) at 20°C. The mixture was stirred at 100°C for 12 h. The reaction mixture was concentrated under reduced pressure. The crude product was purified by
276 prep-HPLC (fonnic acid conditions). The product-containing fraction was concentrated under reduced pressure to remove most ol MeCN at 30°C and the aqueous phase was lyophilized. (S)-12nuoiO-4-(Lmethyl-lH-imidazol-2-yI)-7a,8,13,14-tetrahydiO-7H-[L2,4]tnazolo[4T,3': l,6]pyrido[3,2b]benzofuro [4,3-fg] [1,4] oxazonine (26.2 mg, 59.8 umol, 21% yield, 100% purity, formate sait) was obtained as yellow solid. ]H NMR CD3OD 400 MHz δ = ppm 9.84 (s, IH), 8.38 (s, IH), 7.83 (s, IH), 7.79 (s, IH), 6.93 (t, J = 9.6 Hz, IH), 6.69 (dd, J = 8.6, 3.9 Hz, IH), 5.26 (br d, J = 14.7 Hz, IH), 5.07 (br s, IH), 4.78 (br s, IH), 4.63 (br t, J = 9.5 Hz, IH), 4.31 (br d, J= 6.1 Hz, IH), 4.20 4.06 (m, IH), 4.04 - 3.92 (m, IH), 3.89 (s, 3H). LCMS (ESI+): m/z 393.1 (M+H).
Example 84: (S)-12-fluoro-4-(5-fluoro-2-methylpyridin-4-yI)-7a,8,13,14-tetrahydro-7H[l,2,4]triazolol4',3’:l,6]pyrido[3,2-b]benzofuro|4,3-fg][l,4]oxazonine
Step 1: 5-fluoro-2-methyl-4-(trimethylstannyl)pyridine
To a mixture of 4-bromo-5-fluoiO-2-methylpyridine (150 mg, 789 umol, 1.00 eq), trimethyl(trimethylstannyl)stannane (517 mg, 1.58 mmol, 327 uL, 2.00 eq) and Pd(PPh3)4 (91.2 mg, 78.9 umol, 0.100 eq) was added dioxane (3.00 mL) at 20°C under N2. Then the mixture was stirred at 100°C for 12 h under nîtrogen atmosphère. LC-MS showed 4-bromo-5-fluoro-2-methylpyridme was consumed completely and one main peak with desired mass was detected. The obtained solution of 5-fluoro-2-methyl-4-(trimethylstannyl)pyridine was used in the next step directly.
Step 2: tert-butyl (S)-12-fluoro-4-(5-fluoro-2-methylpyridin-4-yl)-7a,13-dihydro-7H[1,2,4]triazolo[4 3 l, 6]pyrido[3,2-b]benzofiiro[4,3-fg] [1,4] oxazonine-14(8H)-carboxylate
F
To a solution of 5-fluoro-2-methyl-4-(trimethylstannyl)pyridine (216 mg, 789 umol, 3.23 eq) in dioxane (3.00 mL) was added tert-butyl (S)-4-bromo-12-fluoro-7a,13-dihydro-7H[l,2,4]triazolo[4’,3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (120 mg, 244 umol, 1.00 eq), Pd(PPh3)4 (28.2 mg, 24.4 umol, 0.100 eq), LiCl (20.7 mg, 488 umol, 2.00 eq)
277 and Cul (18.6 mg, 97.7 umol, 0.400 eq) at 20°C. The mixture was degassed and purged with nitrogen 3 times, and then the mixture was stirred at 100°C for 3 h under nitrogen atmosphère. The reaction mixture was filtered and the fiitrate was concentrated under reduced pressure. The residue was purified by prep-TTC (SiO2, EtOAc). tert-butyl (S)-12-fluoiO-4-(5-fluoro-2-methylpyridin-4yl)-7a,I3-dihydro-7H-[l,2,4]triazolo[4',3,:l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine14(8H)-carboxylate (130 mg, crude) was obtained as a yellow solid.
Step 3: (S)-12-fluoro-4-(5-fluoro-2-methylpyridin-4-yl)- 7a, 8,13,14-tetrahydro- 7H[1,2,4] triazolo[4 ', 3!:1,6]pyrido[3,2-b] benzojùro[4,3-fg] [1,4] oxazonine
To tert-butyl (S)-12-fluoiO-4-(5-fluoro-2-methylpyridin-4-yl)-7a, 13-dihydro-7H[l,2,4]triazolo[4',3’:l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (130 mg, 249 umol, 1.00 eq) was added HFIP (2.00 mL) at 20°C. The mixture was stirred at 100°C for 12 h. The reaction mixture was concentrated under reduced pressure. The crude product was purified by prep-HPLC (formic acid conditions). (S)-12-fluoro-4-(5-fluoro-2-methylpyridin-4-yl)-7a, 8,13,14tetrahydro-7H-[ 1,2,4] triazolo[4',3’: l,6]pyrido [3,2-b]benzofuro[4,3-fg][l,4]oxazonine (57.3 mg, 122 umol, 49% yield, 99.6% purity, formate sait) was obtained as yellow solid. ’H NMR CDjOD 400 MHz δ = ppm 9.79 (s, IH), 9.04 (d, J= 4.0 Hz, 1 H), 8.42 (s, IH), 8.33 (d, 7=6.5 Hz, IH), 6.93 (dd, 7= 10.1, 8.9 Hz, IH), 6.70 (dd, 7= 8.7, 3.9 Hz, IH), 5.27-5.21 (m, IH), 5.13 -4.97 (m, IH), 4.92 4.75 (m, IH), 4.68 - 4.56 (m, IH), 4.38 - 4.27 (m, IH), 4.19 - 3.94 (m, 2H), 2.89 (s, 3H). LCMS (ES1+): m/z 422.2 (M+H).
Example 85: (S)-4-(6-(difluoromethyl)-4-methylpyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro7H-[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
Step 1: 5-bromo-2-(di[luoromethyl)-4-methylpyridine
278
To a solution of 5-biOmo-4-methylpicolinaldehyde (1.00 g, 5.00 mmol, 1.00 eq) in DCM (10.0 mL) was added DAST (3.22 g, 20.0 mmol, 2.64 mL, 4.00 eq) at -78°C. The mixture was stirred at 78°C for 30 min. The reaction mixture was quenched by addition of sat. aq. Na2CO3 (80.0 mL) at 0°C, diluted with water (30.0 mL) and extracted with DCM (30.0 mL * 3). The combined organic layers were washed with brine (30.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 1/0 to 15/1). 5-biOmo-2-(difluoromethyl)-4-methylpyridine (812 mg, crude) was obtained as a yellow oîl.
Step 2: 2-(difluoromethyl)-4-melhyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine
A mixture of 5-bromo-2-(diiluorornethyl)-4-methylpyridine (200 mg, 901 umol, 1.00 eq), 4,4,5,5tetramethyl-2-(4,4,5,5-teÎramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (343 mg, 1.35 mmol, 1.50 eq), KOAc (265 mg, 2.70 mmol, 3.00 eq), Pd(dppf)Cl2 (65.9 mg, 90.1 umol, 0.100 eq) in dioxane (2.00 mL) was degassed and purged with nitrogen 3 times at 20°C, and then the mixture was stirred at 80°C for 2 h under nitrogen atmosphère. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 1/0 to 10/1). 2-(difluoromethyl)-4-methyl-5-(4,4,5,5-tetramethyll,3,2-dioxaborolan-2-yl)pyridine (180 mg, 669 umol, 74% yield) was obtained as yellow oil.
Step 3: (S)-4-(6-(difluoromethyl)-4-methylpyridin-3-yl)-l 2-fluoro-7a,8,13,14-tetrahydro-7H[1,2,4] triazolo[4’,3 ’:l,6]pyrido[3,2-b] benzofuro[4,3-fg] [1,4] oxazonine
To solution
of (S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3’: I,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine (Example 17; 80.0 mg, 205
279 umol, 1.00 eq) and 2-(difluoromethyl)-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)pyridine (165 mg, 614 umol, 3.00 eq) in dioxane (2.00 mL) and water (0.400 mL) was added Na2CO3 (65.0 mg, 614 umol, 3.00 eq) and Pd(dppf)C12 (15.0 mg, 20.5 umol, 0.100 eq). The mixture was stirred at 80°C for 2 h under nitrogen atmosphère. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in MeOH (10.0 mL) and silicathiol (20.0 mg, modified Silicon gel for eliminating Pd, irregular silica gel, 100-200 mesh, Chlorides (Cl), % <0.004, partie le size distribution 45-75 um) was added at 20°C and stirred at 20°C for 4 h. The suspension was fdtered, the filtrate was concentrated and purified by prep-HPLC (formic acid conditions). The product-containing fraction was concentrated under reduced pressure to remove most of MeCN at 30°C and the aqueous phase was lyophilized. (S)-4-(6-(difluoromethyl)-4methylpyridin-3-yl)-12-fluoiO-7a,8,13,ï4-tetrahydro-7H-[l,2,4]triazo!o[4’,3': l,6]pyrido[3,2b]benzofuro[4,3-fg][l,4]oxazonine (32.8 mg, 62.7 umol, 30% yield, 95.4% purity, formate sait) was obtained as a yellow solid. !HNMR DMSO-îX 400 MHz δ = ppm 9.45 (s, IH), 8.62 (s, 1H), 7.68 (s, 1H), 7.62 (t, 7= 6.4 Hz, 1H), 7.43 (s, 1H), 6.99 (t, 7= 60.8 Hz, 1H), 7.03 - 6.94 (m, 1H), 6.71 (dd, 7= 8.7, 3.5 Hz, 1H), 4.98 - 4.89 (m, 1H), 4.86 - 4.74 (m, 1H), 4.59 - 4.52 (m, 1H), 4.48 (d, J = 8.1 Hz, 1H), 4.22 (dd, 7= 9.5, 3.5 Hz, 1H), 4.05 (s, 1H), 3.94 - 3.83 (m, IH), 2.30 (s, 3H). LCMS (ESI+): m/z 454.2 (M+H).
Example 86: (S)-12-fluoro-4-(3-fluoro-2-methylpyridin-4-yl)-7a,8,13,14-tetrahydro-7H [1,2,4 |triazolo|4*,3’: 1,6] pyrido[3,2-b]benzofuro[4,3-fgl [1,4] oxazonine
Step 1: 3-fluoro-2-methyl-4-(trimethylstannyl)pyridine # A_
Me3Sn F
To a stirred solution of 4-bromo-3-fluoiO-2-methylpyridine (70.0 mg, 368 umol, 1.00 eq) and trimethyl(trimethylstannyl)stannane (241 mg, 737 umol, 153 uL, 2.00 eq) in dioxane (3.00 mL) was added Pd(PPh3)4 (42.6 mg, 36.8 umol, 0.100 eq) at 15°C under N2. The resulting mixture was stirred at I00°C for 12 h. 3-fluoro-2-methyl-4-(trimethylstannyl)pyridine (100 mg, crude) was obtained as brown liquid (in 3.00 mL dioxane), which was used to the next step directly.
Step 2: tert-butyl (S)-12-fluoro-4-(3-fluoro-2-methylpyridin-4-yl)-7a,13-dihydro-7H[l,2,4]triazolo[4!, 3 ’:1,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4]oxazonine-14(8H)-carboxylate
280
To a solution of 3-fluoro~2-methyl-4-(trimethylstannyl)pyridine (100 mg, 365 umol, 2.00 eq) in dioxane (3.00 mL) was added tert-butyl (S)-4-bromo-12-fluoro-7a,13-dihydro-7H[1,2,4] triazolo[4',3':l, 6] pyrido[3,2-b]benzofuro[4,3-fg] [1,4] oxazonine-14(8H)-carboxylate (89.7 mg, 183 umol, 1.00 eq), LiCl (15.5 mg, 365 umol, 2.00 eq), Cul (13.9 mg, 73.0 umol, 0.400 eq) and Pd(PPh3)4 (21.1 mg, 18.3 umol, 0.100 eq) at 15°C under nitrogen atmosphère. The mixture was stirred at 100°C for 12 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, ΡΕ/EtOAc = 0/1). tert-butyl (S)-12-fluoro-4-(3-fluoro-2methylpyridin-4-yl)-7a, 13-dihydro-7H-[ 1,2,4]triazolo[4’,3': 1,6]pyrido[3,2-b]benzofuro[4,3fg] [1,4] oxazonine-14(8H)-carboxylate (60.0 mg, crude) was obtained as a brown solid.
Step 3 ; (S)-l 2-fluoro-4-(3-fluoro-2-methylpyridin-4-yl)- 7a,8,13,l 4-tetrahydro-7H[ l, 2,4]lriazolo[4’, 3 ':l,6]pyrido[3,2-b] benzofuro[4,3-fg] [ 1,4] oxazonine
To tert-butyl (S)-12-fluoro-4-(3-fluoro-2-methylpyridin-4-yl)-7a,13-dihydro-7H-
[1 ,2,4] tri azolo[4’,3':l, 6] pyrido[ 3,2-b]benzofuro[4,3-fg] [1,4] oxazonine-14( 8 H)-carboxylate (60.0 mg, 115 umol, 1.00 eq) was added HFIP (2.00 mL) at 15°C. The resulting mixture was stirred at 80°C for 12 h. LCMS showed tert-butyl (S)-12-fluoro-4-(3-iluoro-2-methylpyridin-4-yl)-7a,13dihydiO-7EI-[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)carboxylate was consumed and the desired mass was detected. The mixture was concentrated under reduced pressure. The mixture was purified by acidic prep-HPLC (FA). The fraction was concentrated under reduced pressure to remove most of MeCN at 30°C and the aqueous phase was lyophilized. The title compound (7.10 mg, 14.9 umol, 13% yield, 98.1% purity, formate sait) was obtained as a yellow solid. ’HNMR DMSO-c/è 400 MHz δ = ppm 9.45 (s, IH), 8.32 (d, J = 5.1 Hz, IH), 7.94 (t, J = 5.2 Hz, IH), 7.84 - 7.76 (m, IH), 7.64 (s, IH), 7.00 - 6.89 (m, IH), 6.68 (dd, J =
281
8. 8, 3.7 Hz, IH), 4.95 - 4.86 (ni, IH), 4.85 - 4.75 (m, IH), 4.55 - 4.42 (m, 2H), 4.22 - 4.16 (m, IH), 4.09 - 3.96 (m, IH), 3.90 - 3.79 (m, IH), 2.50 (s, 3H). 'H NMR CDC13 400 MHz δ = ppm 8.84 8.77 (m, IH), 8.41 - 8.33 (m, IH), 8.07 - 7.99 (m, IH), 7.58 - 7.52 (m, IH), 6.92 - 6.82 (m, LH), 6.72 - 6.63 (m, IH), 5.19 - 5.08 (m, IH), 4.98 - 4.81 (m, 2H), 4.69 - 4.61 (m, 2H), 4.31 - 4.21 (m, IH), 3.95 - 3.80 (m, 2H), 2.59 (d, 7= 3.3 Hz, 3H). LCMS (ESI+): m/z 422.1 (M+H).
Example 87: (S)-l-(3-(12-fluoro-7a,8,13,14-tetrahydro-7H-fl,2,4]triazolo|4',3':l,61pyrido[3,2b]benzofuro[4,3-fgHl,4joxazonin-4-yl)pyridin-2-yI)-2-methylpropan-2-ol
Step J: l-(3-hromopyridin-2-yl)-2-methylpropan-2-ol jOn
Br γ pOH
To a solution of N-isopropylpropan-2-amine (765 mg, 7.56 mmol, 1.07 mL, 1.30 eq) in THF (15.0 mL) was added n-BuLi (2.50 M, 2.79 mL, 1.20 eq) at -70°C under N2, and stirred at -70°C for 0.5 hr. 3-Bromo-2-methylpyridine (1.00 g, 5.81 mmol, 1.00 eq) was added to the mixture at -70°C and stirred at -70°C for 0.5 hr. Acetone (675 mg, 11.6 mmol, 854 uL, 2.00 eq) was added to the mixture at -70°C, and stirred at 0°C for 1 hr. The reaction mixture was quenched by addition of MeOH (7.00 mL) at 0°C. Then the mixture was coneentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 1/0 to 5/1). l-(3bromopyridin-2-yl)-2-methy!propan-2-ol (1.00 g, crude) was obtained as yellow oil. 'H NMR CDC13 400 MHz δ = ppm 8.38 (d, 7 = 4.4 Hz, IH), 7.81 (d, 7 = 8.0 Hz, IH), 7.00 (dd, 7 = 8.0, 4.8 Hz, IH), 5.70 (s, 1 H), 3.06 (s, 2H), 1.20 (s, 6H).
Step 2; 2-methyl-l-(3-(tributylstannyl)pyridin-2-yl)propan-2-ol
JQ (n-Bu)3Sn τ
[OH
To a solution of l-(3-bromopyridin-2-yl)-2-methylpropan-2-ol (500 mg, 2.17 mmol, 1.00 eq) in THF (9.00 mL) was added n-BuLi (2.50 M, 1.74 mL, 2.00 eq) and TMEDA (504 mg, 4.34 mmol, 654 uL, 2.00 eq) at -70°C under N2. The mixture was stirred at -70°C for 30 min. Sn(nBu)3Cl (1.06 g, 3.26 mmol, 877 uL, 1.50 eq) was added at -70°C and the reaction mixture was stirred at 0°C for I hr. The réaction mixture was quenched by addition of MeOFI (2.00 mL) at 0°C, and then mixture was coneentrated under reduced pressure. The residue was purified by column
282 chromatography (SiO2, Petroleum ether/Ethyl acetate — 1/0 to 10/1). 2-methyl-l-(3(tributylstannyl)pyridin-2-yl)propan-2-ol (190 mg, crude) was obtained as a yellow liquid.
Step 3: tert-butyl (S)-12-fluoro-4-(2-(2-hydroxy-2-melhylpropyl)pyridm-3-yl)-7a,13-dihydro-7H[1,2,4]triazolo[4’,3 6]pyrido[3,2-b]benzofuro[4,3-fg] [1,4] oxazonine-I4(8H)-carboxylate
To a solution of (S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[l,2,4]lriazolo[4’,3':l,6]pyrido[3,2b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (140 mg, 285 umol, 1.00 eq) in dioxane (3.00 mL) was added 2-methyl-l-(3-(tributylstannyl)pyridin-2-yl)piOpan-2-ol (188 mg, 427 umol, 1.50 eq), LiCi (24.2 mg, 571 umol, 2.00 eq), Pd(PPh3)4 (36.2 mg, 31.3 umol, 0.110 eq) and Cul (21.7 mg, 114 umol, 0.400 eq) at 20°C under N2. The mixture was stirred at 80°C for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-fCC (SiO2, Petroleum ether/Ethyl acetate = 1/2). tert-butyl (S)-12-fluoro-4-(2-(2-hydroxy-2methylpropyl)pyridin-3-yl)-7a,13-dihydro-7H-[l,2,4]triazolo[4,,3,:l,6]pyrido[3,2-b]benzofuro[4,3fg][ 1,4] oxazonine-14(8 H )-carboxylate (80.0 mg, crude) was obtained as a brown solid.
Step 4: (S)-l-(3-(12fluoro-7a,8,13,14-tetrahydro-7H-[ l,2,4]triazolo[4',3':l, 6]pyrido[3,2b]benzofuro[4,3-fg] [1,4]oxazomn-4-yl)pyridin-2-yl)-2-methylpropan-2-ol
A mixture of tert-butyl (S)-12-fluoro-4-(2-(2-hydroxy-2-methylpropyl)pyridin-3-yl)-7a,13-dihydro7H-[l,2,4]triazolo[4',3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (60.0 mg, 107 umol, 1.00 eq) in HF1P (2.00 mL) was stirred at 100°C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 100 * 30 mm * 5 um; mobile phase: [water (0.2% FA) - ACN]; B%: 1%
283
25%, 12 min). The title compound (23.0 mg, 45.3 umol, 42% yield, 99.9% purity, formate sait) was obtained as a yellow solid. ‘H NMR DMSO-A 400 MHz δ = ppm 9.43 (s, IH), 8.56 (dd, J = 4.6, 1.2 Hz, IH), 7.78 (dd, J-7.6, 1.6 Hz, IH), 7.52 (br t, J = 6.4 Hz, IH), 7.37 - 7.34 (m, IH), 7.33 (s, IH), 7.00 - 6.93 (m, IH), 6.70 (dd, J= 8.6, 4.0 Hz, IH), 5.43 (br s, IH), 4.97 - 4.87 (m, IH), 4.85 - 4.74 (m, IH), 4.59 - 4.51 (m, IH), 4.48 (br d, 7= 6.4 Hz, IH), 4.21 (dd, 7= 9.6, 3.6 Hz, IH), 4.08 - 3.99 (m, IH), 3.90 - 3.81 (m, IH), 2.76 (s, 2H), 0.95 (s, 6H). LCMS (ESI+): m/z 462.2 (M+H).
Example 88: (S)-4-(l,3-dimethyl-lH-pyrazol-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H [l,2,4]triazolo[4',3':l,6|pyrido[3,2-b]benzofuro[4,3-fg|[l,4|oxazonine niesylate
Step 1: (S)-4-(l,3-dimethyl-lH-pyrazol-5-yl)-12-fluoro- 7 a, 8,13,14-tetrahydro-7H]l,2,4]triazolo]4 ', 3 1,6]pyrido]3,2-b] benzofuro]4,3-fg] ] 1,4] oxazonine
To a stirred solution of (S)-4-bromo-12-fluoiO-7a,8,13,14-tetraliydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuiO[4,3-fg][l,4]oxazonine (852 mg, 3.83 mmol, 1.50 eq) and Na2CO3 (542 mg, 5.11 mmol, 2.00 eq) in dioxane (20.0 mL) and water (4.00 mL) was added Pd(dppf)Cl2 (187 mg, 256 umol, 0.100 eq) at 15°C under N2. The resulting mixture was stirred at 80°C for 3 h. The mixture was concentrated under reduced pressure. The residue was dissolved in DMSO (10.0 mL), MeOH (20.0 mL) and silica-thiol (1.20 g, inodified Silicon Gel for Eliminating Pd, Irregular Silica Gel, 100-200 mesh, Chlorides (Cl), %<0.004, Particle Size Distribution 4575um) was added to the mixture at 15°C and stirred at 15°C for 12 h. The suspension was filtered and the fil ter cake was washed with MeOH (20.0 mL). The tiltrate was concentrated under reduced pressure to remove MeOH and purified by acidic prep-HPLC (FA). The product-containing fraction was concentrated under reduced pressure to remove most of MeCN at 30°C and the aqueous phase was lyophilized. (S)-4-(l,3-dimethyI-lH-pyrazol-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H[ 1,2,4]tri azol o[4',3': l,6]pyrido[ 3,2-b]benzofuro[4,3-fg] [1,4] oxazonine (480 mg, 1.18 mmol, 46% yield) was obtained as a white solid.
Step 2: (5)-4-(1,3-dimethyl-lH-pyrazol-5-yl)-l 2-ftuoro- 7a, 8,13,14-tetrahydro-7H[ 1,2,4]triazolo]4 3 ':l,6]pyrido]3,2-b] benzofuro]4,3-fg][1,4]oxazonine mesylate
284
To (S)-4-(l,3-dimethyl-lH-pyrazol-5-yl)-12-fluoiO-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine (480 mg, 1.18 mmol, 1.00 eq) in MeCN (20.0 mL) was added CH3SO3H (114 mg, 1.18 mmol, 84.1 uL, 1.00 eq) at 15°C. Water (50.0 mL) was added to the mixture at I5°C. The solution was concentrated under reduced pressure to remove most of MeCN and the aqueous phase was lyophilized. (S)-4-(l,3-dimethyl-lH-pyrazol5-yl)-12-fluoiO-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4',3':l,6]pyndo[3,2-b]benzofuiO[4,3fg][ 1,4] oxazonine (525 mg, 1.17 mmol, 99% yield, 99.1% purity, 0.4 eq. CH3SO3H) was obtained as a yellow solid. 'H NMR DMSO-76 400 MHz δ = ppm 9.51 (s, 1H), 7.96 (br s, 1H), 7.59 (s, 1H), 6.96 (t, J =9.5 Hz, 1H), 6.69 (dd, 7= 8.6, 3.7 Hz, 1H),6.31 (s, 1H ), 4.99 - 4.87 (m, 1H), 4.86 - 4.75 (m, 1H), 4.58 - 4.45 (m, 2H), 4.19 (br dd, 7= 9.6, 3.4 Hz, 1H), 4.04 (br d, 7 = 9.9 Hz, 2H), 3.89 3.82 (m, )H), 3.69 (s, 3H), 2.28 (s, 1.2H), 2.17 (s, 3H). LCMS (ESI+): m/z 407.1 (M+H).
Example 89: (S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-|l,2,4]triazolo[4’,3':l,6]pyrido[3,2b]benzoiurol4,3-fg][l,4]oxazonin-4-yI)-N,l-dimetliyl-lH-pyrazol-3-ainine
Step 1: tert-butyl (5-bromo-l-methyl-lH-pyrazol-3-yl)carbamate
NHBoc
To a solution of 5-bromo-l-methyl-lH-pyrazol-3-amine (300 mg, 1.70 mmol, 1.00 eq') in THF (8.00 mL) was added TEA (345 mg, 3.41 mmol, 475 uL, 2.00 eq) and Boc2O (893 mg, 4.09 mmol, 940 uL, 2.40 eq) at 20°C. The mixture was stirred at 80°C for 6 h. The reaction was concentrated. The residue was purified by ^rep-TLC (SiO2, Petroleum ether/Ethyl acetate = 3/1 ). tert-butyl (5-bromol-methyl-IH-pyrazol-3-yl)carbamate (270 mg, 978 umol, 57% yield) was obtained as a white solid.
Step 2: tert-butyl (5-bromo-l-methyl-lH-pyrazol-3-yl)(methyl)carbamate
285
To a mixture of tert-butyl (5-bromo-l-methyl-lH-pyrazol-3-yl)carbamate (270 mg, 978 umol, 1.00 eq) in THF (6.00 mL) was added NaH (78.2 mg, 1.96 mmol, 60.0% purity, 2.00 eq) at 0°C. The mixture was stirred at 0°C for 0.5 hr. Then Mei (278 mg, 1.96 mmol, 122 uL, 2.00 eq) was added to the mixture at 0°C, the mixture was stirred at 20°C for 12 h. Water (5.00 mL) was added to the 5 reaction solution, the mixture was extracted with ethyl acetate (5.00 mL * 3), the combined organic layers were dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Petroleum ether/Ethyl acetate = 3/1). tert-butyl (5-bromo-l-methyl- 1Hpyrazol-3-yl)(methyl)carbamate (150 mg, 517 umol, 52% yield) was obtained as a yellow oil.
Step 3: tert-butyl methyl(l-methyl-5-(tributylstannyl)-lH-pyrazol-3-yl)carbamate \ ^Boc N î0 (n-Bu)3Sn X
To a solution of tert-butyl (5-bromo-l-methyl-lH-pyrazol-3-yl)(methyl)carbamate (150 mg, 517 umol, 1.00 eq) in THF (5.00 mL) was added n-BuLi (2.50 M, 620 uL, 3.00 eq) at -70°C. The mixture was stirred at -70°C for 0.5 hr. Then tributyl(chloro)stannane (673 mg, 2.07 mmol, 556 uL, 4.00 eq) was added to the mixture at -70°C under nitrogen atmosphère and the mixture was stirred at 15 20°C for 12 h. Water (5.00 mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (5.00 mL * 3), the combined organic layers were dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 3/1). tert-butyl methyl(l-methyl-5-(tributylstannyI)-lH-pyrazol-3yl)carbamate (200 mg, 400 umol, 77% yield) was obtained as a yellow oil.
Step 4: tert-butyl (S)-4-(3-((tert-butoxycarbonyl)(methyl)amino)-l-methyl-lH-pyrazol-5-yl)-12]luoro-7a, 13-dihydro-7H-[1,2,4]triazolo[4’, 3 1,6]pyrido[3,2-b]benzofttro[4,3-fg] [1,4] oxazonine14(8H)-carboxylate
To a solution of tert-butyl (S)-4-bromo-12-fluoro-7a,13-dihydro-7H25 [l,2,4]tnazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (100 mg,
286
204 umol, 1.00 eq} in dioxane (6.00 mL) were added tert-butyl methyl(l-methyl-5-(tributylstannyl)lH-pyrazol-3-yl)carbamate (175 mg, 350 umol, L72 eq), Cul (15.5 mg, 81.4 umol, 0.400 eq) and LiCl (17.3 mg, 407 umol, 2.00 eq) Pd(PPh3)4 (23.5 mg, 20.4 umol, 0.100 eq) at 20°C under nitrogen atmosphère. The mixture was stirred at 90°C for 12 h under nitrogen atmosphère. The reaction was fïltered, the filtrate was concentrated. The residue was purified by prep-TLC (SiO2, Petroleum ether/Ethyl acetate = 0/1). tert-butyl (S)-4-(3-((tert-butoxycarbonyl)(methyl)amino)-l-methyl-lHpyrazol-5-yl)- 12-fluoro-7a, 13-dihydro-7H-[ l,2,4]triazolo[4',3’: 1,6]pyrido[3,2-b]benzofuro[4,3fg][l,4]oxazonine-14(8H)-carboxylate (120 mg, 193 umol, 94% yield) was obtained as a yellow solid. In addition, 60 mg of crude product and 30 mg of crude deprotected material were obtained.
Step 5: (8)-5-(12-fluoro- 7a,8,13,I4-tetrahydro- 7H-[1,2,4]triazolo[4',3’:1,6]pyrido[3,2b] benzofuro [4,3-fg] [1,4] oxazonin-4-yl)-N,l-dimethyl~lH-pyrazol-3-amine
A mixture of tert-butyl (S)-4-(3-((tert-butoxycarbonyl)(methyl)amino)-l-methyl-lH-pyrazol-5-yl)12-iluoro-7a,I3-dihydro-7H-[l,2,4]triazolo[4',3': l,6]pyrido[3,2-b]benzoiuro[4,3-fg][l,4]oxazonine14(8H)-carboxylate (120 mg, 193 umol, 1.00 eq) in DCM (4.00 mL) and TFA (2.00 mL) was stirred at 20°C for 12 h. The reaction was concentrated. The residue was dissolved in DMSO (3.00 mL). The suspension was purified by acidic prep-HPLC (column: Phenomenex Luna C18 100*30 mm*5 um; mobile phase: [water (0.04% HC1)-ACN]; B%: 15%-40%, 10 min). The product-containing fraction was concentrated under reduced pressure to remove most of MeCN at 30°C and the aqueous phase was lyophilized. (S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonin-4-yl)-N,l-dimethyl-]Hpyrazol-3-amine (37.0 mg, 76.6 umol, 39% yield, 94.8% purity, HCl sait) was obtained as a yellow solid. 'H NMR CH3OD 400 MHz δ = ppm 9.55 (s, IH), 8.05 (s, IH), 7.02 - 6.89 (m, IH), 6.70 (dd, 7=8.7, 3.9 Hz, IH), 6.44 (s, IH), 5.22 (d,7= 14.5 Hz, IH), 4.98 (brd, 7= 14.8 Hz, IH), 4.78 (brs, IH), 4.64 (t, 7=9.5 Hz, IH), 4.33 (dd, 7=9.7, 3.3 Hz, IH), 4.06 (brd, 7= 8.8 Hz, IH), 3.97 - 3.86 (m, IH), 3.77 (s, 3H), 3.07 (s, 3H). LCMS (ESI+): m/z 422.2 (M+H).
Example 90: (R)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H[ 1,2,4] triazolo[4’,3’:l,6]pyrido[3,2-b]benzofuro[4,3-fg] [1,4] oxazonine
287
F
A mixture of (S)-4-bromo- 12-fluoro-7a,8,13,14-tetrahydro-7H-[ 1,2,4]triazolo[4',3': 1,6]pyrido[3,2b]benzofuro[4,3-fg][ l,4]oxazonine (enantiomer of Example 17; obtained via the sanie sequence using (R)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate in the Example 6 procedure) (200 mg, 511 umol, 1.00 eq), 2-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (224 mg, 1.02 mmol, 2.00 eq), Pd(dppf)Cl2 (37.4 mg, 51.1 umol, 0.100 eq) and NaHCO3 (85.9 mg, 1.02 mmol, 39.8 uL, 2.00 eq) in dioxane (4.00 mL) and water (0.400 mL) was degassed and purged with nitrogen 3 times at 20°C, and then the mixture was stirred at 80°C for 12 h under nitrogen atmosphère. Silica-thiol (100 mg, modiiîed Silicon gel for eliminating Pd, irregular silica gel, 100200 mesh, Chlorides (Cl), %<0.004, particle size distribution 45-75 um) was added to the reaction mixture at 20°C and stirred at 20°C for 2 h. The mixture was concentrated under reduced pressure. The residue was dissolved in DMSO (4.00 mL), the suspension was filtered, the filtrate was concentrated and purified by acidic /?re/>-HPLC (HCl conditions, column: Phenomenex Luna Cl8 150 * 30 mm *5 um; mobile phase: [water (0.04% HCl) -ACN]; B%: 20%-40%, 10 min. The fraction was lyophilized. (R)-12-fluoro-4-(2-methyIpyridin-3-yl)-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine (68.5 mg, 155 umol, 30% yield, 99.8% purity, HCl sait) was obtained as a yellow solid. ’H NMR DMSO-i4400 MHz δ = ppm 9.70 (d, J = 2.4 Hz, IH), 8.81 (d, J = 5.5 Hz, IH), 8.52 (brd, 7.3 Hz, IH), 8.32 - 8.23 (m, IH), 7.92 (br t, J= 6.8 Hz, IH), 7.72 (s, IH), 7.06 - 6.93 (m, IH), 6.71 (dd, J = 8.7, 3.9 Hz, IH), 5.02 - 4.91 (m, IH), 4.89 - 4.77 (m, IH), 4.60 - 4.47 (m, 2H), 4.22 (dd, J = 9.7, 3.3 Hz, IH), 4.12 4.00 (m, IH), 3.92 - 3.85 (m, IH), 2.64 (s, 3H).
Example 91: (S)-5-(12-iliioro-7a,8,13,14-tetraliydro-7H-[l,2,4]triazolo[4',3':l,6]pyrido[3,2 b]benzofuro|4,3-fg][l,4]oxazonin-4-yI)-N,N,l-trimethyl-lH-pyrazol-3-amine
Step 1: 5-bromo-N,N,l-trimethyl-l H-pyrazol-3-amine
288
To a solution of 5-bromo-l-methyl-lH-pyrazol-3-amine (200 mg, 1.14 mmol, 1.00 eq) and 37% aqueous HCHO (369 mg, 4.55 mmol, 338 uL, 4,00 eq) in MeOH (5.00 mL) was added AcOH (6.82 mg, 114 umol, 6.50 uL, 0.100 eq) at 20°C. The mixture was stirred at 20°C for 1 hr. Then NaBH3CN (179 mg, 2.84 mmol, 2.50 eq) was added to the mixture, and the mixture was stirred at 20°C for 10 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved with DCM (8.00 mL), washed with saturated aqueous sodium bicarbonate (3.00 mL). The organic layer was dried over Na2SO4 and then concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Petroleum ether:Ethyl acetate = 2:1). 5-bromo-N,N,l-trimethyL lH-pyrazol-3-amine (180 mg, 882 umol, 77% yield) was obtained as a light yellow oil.
Step 2: Ν,Ν, 1 -trimethyl-5-(tributylstannyl)-1 H-pyrazol-3-amine
To a solution of 5-bromo-N,N,l-trimethyl-lH-pyrazol-3-amine (180 mg, 882 umol, 1.00 eq) in THF (6.00 mL) was added dropwised ri-BuLi (2.50 M, 529 uL, 1.50 eq) at -78°C. The mixture was stirred at -78°C for 0.5 hr. Then tributyl(chloro)stannane (861 mg, 2.65 mmol, 712 uL, 3.00 eq) was added to the mixture at -78°C, and the mixture was stirred at -78°C for i hr. The reaction mixture was quenched by saturated aqueous NH4C1 solution (2.00 mL) at 0°C, then diluted with water (5.00 mL), extracted with ethyl acetate (4.00 mL * 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the fdtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Petroleum edrer:Ethyl acetate = 4:1). N,N-l-trimethyl-5(tributylstannyl)-lH-pyrazol-3-amine (200 mg, 483 umol, 54% yield) was obtained as a colourless oil.
Step 3: tert-butyl (S)-4-(3-(dimethylamino)-l-methyl-lH-pyrazol-5-yl)-12-fluoro-7a, 13-dihydro-7H[ 1,2,4]triazolo[4 3 ':J, 6]pyrido[3,2-b] benzofuro[4,3-fg][1,4] oxazonine-14(8H)-carboxylate
289
A mixture of N,N,l-trimethyl-5-(tributylstannyl)-lH-pyrazol-3-amine (194 mg, 468 umol, 1.15 eq), tert-butyl (S)-4-bromo- 12-fluoro-7a, 13-dihydro-7H-[ 1,2,4]triazolo[4',3': 1,6]pyrido[3,2b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (200 mg, 407 umol, 1.00 eq), LiCl (25.9 mg, 611 umol, 1.50 eq), Cul (38.8 mg, 204 umol, 0.500 eq) and Pd(PPh3)4 (23.5 mg, 20.4 umol, 0.0500 eq) in dioxane (5.00 mL) was degassed and purged with nitrogen 3 times at 20’'C, and then the mixture was stirred at 80°C for 10 h under nitrogen atmosphère. The reaction mixture was filtered and the filtrat e was concentrated under reduced pressure. The residue was purified by ^rep-TLC (SiO2, Ethyl acetate;M éthanol = 8:1). tert-butyl (S)-4-(3-(dimethylamino)-l-methyl-IH-pyrazol-5yl)-12-fluoro-7a, 13-dihydro-7H-[ l,2,4]triazolo[4’,3': 1,6]pyrido[3,2-b]benzofuro[4,3fg][l,4]oxazonine-14(8H)-carboxylate (200 mg, 373 umol, 91% yield) was obtained as a yellow solid.
Step 4: (S)-5-(12-fliioro-7a,8J3J4-tetrahydro-7H-[1,2,4]triazolo[4>,3';l,6]pyrido[3,2b]benzofuro[4,3-fg] [l,4]oxazonin-4-yl)-N,N, l-trimethyl-lH-pyrazol-3-amine
To a solution of tert-butyl (S)-4-(3-(dimethylamîno)-l-methyl-lH-pyrazol-5-yl)-12-fluoiO-7a,13dihydro-7H-[l,2,4]triazolo[4,,3’:lJ6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)carboxylate (200 mg, 373 umol, 1.00 eq) in DCM (4.00 mL) was added TFA (4.62 g, 40.5 mmol, 3.00 mL, 109 eq) at 20°C. The mixture was stirred at 20°C for 3 h. LC-MS showed tert-butyl (S)4-(3-(dimethylamino)-l-methyl~lH-pyrazol-5-yi)-12-fluoro-7a,13-dihydro-7H[l,2,4]triazolo[4ff3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate was consumed completely and one main peak with desired mass was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (fonnic acid conditions) (column: Phenomenex Synergi C18 150*25 mm* 10 um; mobile phase: [water (0.225% FA)-ACN]; B%: 20%-50%, 12 min). (S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4,,3,:l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonin-4-yl)-N,N,l-tnmethyl-lHpyrazol-3-amine (102 mg, 210 umol, 56% yield, 99.6% purity, formate sait) was obtained as a white solid. ‘H NMR DMSO-^400 MHz 0 = ppm 9.43 (s, IH), 8.13 (s, IH), 7.67 - 7.58 (m, IH), 7.37 (s, IH), 6.96 (t, 7= 9.6 Hz, IH), 6.69 (dd, 7= 8.5, 3.6 Hz, IH), 5.94 (s, IH), 4.94 - 4.85 (m,
290
IH), 4.83 - 4.71 (m, IH), 4.58 - 4.39 (m, 2H), 4.20 (br d, J= 9.7 Hz, IH), 4.03 (br s, IH), 3.92 3.79 (m, IH), 3.62 (s, 3H), 2.75 (s, 6H). LCMS (ESI+): m/z 436.2 (M+H).
Example 92: (S)-12-iluoro-4-(6-methoxypyndin-2-yl)-7a,8,13,14-tetrahydro-7H [l,2,4]triazolo[4’,3':l,6]pyrido[3,2-bjbenzofuro[4,3-fg][l,4]oxazonine
Step 1: 2-methoxy-6-(tributylstannyl)pyridine
To a solution of 2-bromo-6-methoxypyridine (300 mg, 1.60 mmol, 196 uL, 1.00 eq) in THF (6.00 mL) was added o-BuLi (2.50 M, 1.28 mL, 2.00 eq) at -78°C. Then the mixture was stirred at -78°C for 0.5 hr. Tributyl(chloro)stannane (779 mg, 2.39 mmol, 644 uL, 1.50 eq) was added to the mixture, and the mixture was stirred at -78°C for 2 h. The reaction mixture was quenched by saturated aqueous NH4C1 solution (2.00 mL) at 0°C then diluted with water (6.00 mL) and extracted with ethyl acetate (5.00 mL * 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Petroleum ether:Ethyl acetate = 10:1). 2-methoxy-6-(tributylstannyl)pyridine (300 mg, 753 umol, 47% yield) was obtained as a colouriess oil.
Step 2: tert-butyl (S)-12-fluoro-4-(6-methoxypyridin-2-yl)-7a,13-dihydro-7H[1,2,4] triazo lo[4', 3 1,6]pyrido[3,2-b] benzofuro[4,3-fgJ [1,4] oxazonine-14 (8H)-carboxylate
A mixture of 2-methoxy-6-(tributylstannyl)pyridine (146 mg, 366 umol, 1.20 eq), tert-butyl (S)-4bromo- 12-fluoro-7a, 13-dihydro-7H-[l ,2,4]triazolo[4',3': 1,6]pyrido[3,2-b]benzofiiiO[4,3fg][l,4]oxazonîne-14(8H)-carboxyIate (150 mg, 305 umol, 1.00 eq), LiCl (19.4 mg, 458 umol, 9.38 uL, 1.50 eq), Cul (29.1 mg, 153 umol, 0.500 eq) and Pd(PPh3)4 (17.6 mg, 15.3 umol, 0.0500 eq) in dioxane (4.00 mL) was degassed and purged with nîtrogen for 3 times at 20°C, and then the mixture was stirred at 80°C for 10 h under nitrogen atmosphère. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (SiCh, Petroleum ether:Ethyl acetate
291 = 1:1). tert-butyl (S)- 12-fluoro-4-(6-methoxypyridin-2-yl)-7a, 13-dihydro-7H[I,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonme-14(8H)-carboxylate (130 mg, 250 umol, 82% yield) was obtained as a yellow solid.
Step 3/ (S)-12-fluoro-4-(6-methoxypyridin-2-yl)-7a,8,13,14-tetrahydro-7H[1,2,4]triazolo[4',3 1,6]pyrido[3,2-bJ benzofuro]4,3-fg][l, 4] oxazonine
F
A mixture of tert-butyl (S)-12-iluoro-4-(6-methoxypyridin-2-yl)-7a,13-dihydiO-7H[ l,2,4]triazolo[4',3’: 1,6] pyrido[3,2-b]benzofuro[4,3-fg][ 1,4] oxazonine-l4(8H)-carboxylate (100 mg, 192 umol, 1.00 eq) in HFIP (3.00 mL) was stirred at 80°C for 3 h under nitrogen atmosphère. The réaction mixture was coneentrated under reduced pressure. The residue was purified by /vep-HPLC (formic acid conditions) (column: Phenomenex Luna Cl8 200*40 mm* 10 um; mobile phase: [water (0.2% FA)-ACN]; B%: 30%-60%, 10 min). (S)-12-fluoro-4-(6-methoxypyridin-2-yl)-7a,8,13,14tetrahydro-7H-[ 1,2,4]triazolo[4',3': 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4]oxazonine (34.9 mg, 74.5 umol, 38% yield, 99.3% purity, formate sait) was obtained as a yellow solid. !H NMR DMSO-4 400 MHz Ô = ppm 9.50 (s, IH), 8.66 (d, J= 7.5 Hz, IH), 8.32 (s, IH), 7.85 - 7.75 (m, 2H), 7.01 6.94 (m, IH), 6.74 (d, J = 8.2 Hz, IH), 6.70 (dd, J- 8.7, 3.6 Hz, IH), 4.98 - 4.80 (m, 2H), 4.53 (br t, J = 9.4 Hz, 2H), 4.26 (br d, J = 6.2 Hz, IH), 4.08 (br s, IH), 4.00 (s, 3H), 3.98 - 3.90 (m, IH). LCMS (ESI+): m/z 420.1 (M+H).
Example 93: (S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4',3':l,6]pyrido[3,2b]benzofuro]4,3-fg][l,4Joxazonin-4-yl)-l-methyl-lH-pyrazol-3-amine
Step 1: tert-butyl (5-bromo-I-methyl-lH-pyrazol-3-yl)carbamate
Two parallel reactions were set up. To a solution of 5-bromo-l-methyl-lH-pyrazol-3-amine (350 mg, 1.99 mmol, LOÛ eq) in THF (6.00 mL) was added TEA (403 mg, 3.98 mmol, 554 uL, 2.00 eq) and Boc2O (1.04 g, 4.77 mmol, 1.10 mL, 2.40 eq) at 20°C. The mixture was stirred at 80°C for 12 h. The batches were combined and the obtained mixture was coneentrated. The residue was
292 purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate — 1/0 to 3/1). tert-butyl (5-bromo-l-methyl-1 H-pyrazol-3-yl)carbamate (760 mg, 2,75 mmol, 69% yield) was obtained as a white solid.
Step 2: tert-butyl ( 1 -methyl-5-(trimethylstannyl)-l H-pyrazol-3-yl)carbamate
N HBoc
A /—N
Me3Sn
To a solution of tert-butyl (5-bromo-l-methyl-IH-pyrazol-3-yl)carbamate (240 mg, 869 umol, 1,00 eq) in dioxane (15,0 mL) was added trimethyl(trimethylstannyl)stannane (570 mg, 1.74 mmol, 361 uL, 2.00 eq) and Pd(PPh3)4 (100 mg, 86.9 umol, 0.100 eq) at 20°C. The mixture was stirred at 100°C for 12 h under nitrogen atmosphère. LCMS showed tert-butyl (5-bromo-l-methyl-lI-Ipyrazol-3-yl)carbamate was remained and the desired mass was detected. tert-butyl ( 1 -methyl-5(trimethyistannyl)-lH-pyrazol-3-yl)carbamate (310 mg, crude) in dioxane (15.0 mL) as a brown liquid used for next step directly.
Step 3: tert-butyl (S)-4-(3-((tert-butoxycarbonyl)amino)-l-methyl-lH-pyrazol-5-yl)-12-fluoro-7a, 13dihydro-7H-[1,2,4]triazolo[4’,3’:1,6]pyrido[3,2-b] benzofuro[4,3-fg] [1,4] oxazonine-14 (8H)carboxylate
To a solution of tert-butyl (l-methyl-5-(trimethylstannyl)-lH-pyrazol-3-yl)carbamate (300 mg, 833 umol, 2.00 eq) in dioxane (14.5 mL) was added tert-butyl (S)-4-bromo-12-fluoro-7a,13~dihydro-7H[l,2,4]triazolo[4',3': 1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine- 14(8H)-carboxylate (205 mg, 417 umol, 1.00 eq), Pd(PPh3)4 (48.1 mg, 41.7 umol, 0.100 eq), Cul (31.7 mg, 167 umol, 0.400 eq) and LiCl (35.3 mg, 833 umol, 17.1 uL, 2.00 eq) at 20°C, The mixture was stin-ed at I00°C for 12 h under nitrogen atmosphère. The reaction was fïltered, the filtrate was concentrated. The residue was purified by /ir^-TLC (S1O2, Petroleum ether/Ethyl acetate = 1/1). tert-butyl (S)-4-(3-((tertbutoxycarbonyl)amino)-I-methyl-lH-pyrazol-5-yl)-12-fluoro-7a,13-dihydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (270 mg, crude) was obtained as a yellow oil.
293
Step 4: (8)-5-(12-fluoro-7a,8,13,I4-tetrahydro-7H-[l,2,4]triazolo[4',3':l,6]pyrido[3,2b]benzofuro[4,3-jg][1,4]oxazonin-4-yl)-l-methyl-lH-pyrazol-3-amine
A mixture of tert-butyl (S)-4-(3-((tert-butoxycarbonyl)amino)-l-methyl-IH-pyrazol-5-yl)-l 2-fluoro7a, 13-dihydro-7H-[ 1,2,4]triazolo[4',3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4] oxazonine-14(8H)carboxylate (270 mg, 444 umol, 1.00 eq) in TFA (2.50 mL) and DCM (5.00 mL) was stirred at 20°C for 6 h. The reaction was concentrated. The residue was dissolved in MeOH (5.00 mL), the suspension was filtered, the filtrate was concentrated and purified by neutral prep-HPLC (column: Waters Xbridge Prep OBD Cl 8 150*40 mm* 10 um; mobile phase: [water (0.04% NH3H2O+W mM NH4HCO3)-ACN]; B%: 5%-35%, 10 min). The product-containing fraction was concentrated under reduced pressure to remove most of MeCN at 30°C and the aqueous phase was lyophilized. (S)-5( 12-fluoro-7a,8,13,14-tetrahydro-7H-[ 1,2,4]triazolo[4's3': 1,6]pyrido[3,2-b]benzofuro[4,3fg][l,4]oxazonin-4-yl)-l -methyl- lH-pyrazol-3-amine (20.3 mg, 49.7 umol, 11% yield, 99.7% purity) was obtained as a white solid. lH NMR DMSO-<4 400 MHz δ = ppm 9.42 (s, IH), 7.59 (br t, 7= 6.4 Hz, IH), 7.34 (s, IH), 6.97 (t, 7 = 9.5 Hz, IH), 6.70 (dd,7= 8.6, 3.8 Hz, IH), 5.76 (s, IH), 4.97 - 4.86 (m, IH), 4.84 - 4.73 (m, IH), 4.59 (s, 2H), 4.54 (br t, 7= 9.4 Hz, IH), 4.49 (br s, IH), 4.21 (br dd, 7= 9.7, 3.4 Hz, IH), 4.04 (br s, IH), 3.91 - 3.82 (m, IH), 3.56 (s, 3H). LCMS (ESI+): m/z 408.1 (M+H).
Example 94: (S)-12-fluoro-4-(l-methyl-lH-imidazol-4-yl)-7a,8,13,14-tetrahydro-7H [l,2,4]triazolo[4',3':l,6]pyrido[3,2-b|benzofuro[4,3-fg][l,4]oxazonine
Step 1: tert-butyl (S)-12-jluoro-4-(l-methyl-lH-imidazol-4-yi)-7a,13-dihydro-7H[1,2,4] triazolo[4’,3 ':1,6]pyrido[3,2-b]benzofttro[4,3-fg] [ 1,4] oxazonine-14(8H)-carboxylate
294
Two parallel réactions were set up. A mixture of tert-butyl (S)-12-fluoro-4-(tributylstannyl)-7a,13dihydro-7H-[ 1,2,4]triazolo[4',3’: 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4] oxazonine-14(8H)carboxylate (120 mg, 171 umol, 1.00 eq), 4-bromo-l-methyl-imidazole (82.6 mg, 513 umol, 3.00 eq), palladium tritert-butylphosphane (8.74 mg, 17.1 umol, 0.100 eq) in dioxane (2.00 mL) was degassed and purged with nitrogen for 3 times at 20°C, and then the mixture was stirred at 100°C for 4 h under nitrogen atmosphère. The batches were combined. The reaction mixture was diluted with water (5.00 mL) and extracted with EtOAc (5.00 mL * 3). The combined organic layers were washed with brine (3.00 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, EtOAc:MeOH = 5:1). tert-butyl (S)-12-fluoro-4-(lmethyl-1 H-imidazol-4-yl)-7a, 13-dihydro-7H-[ 1,2,4]triazolo[4’,3': l,6]pyrido[3,2-b]benzofuro[4,3fg][l,4]oxazonine-14(8H)-carboxylate (50 mg, crude) was obtained as a yellow oil.
Step 2: (S)-12-fluoro-4-(l -methyl-lH-imidazol-4-yl)- 7a, 8,13,14-tetrahydro- 7H[1,2,4] triazo lo[4(341,6]pyrido[3,2-b]benzofuro[4,3-fg] [1,4] oxazonine
A mixture of tert-butyl (S)-12-fluoro-4-(l-methyl-lH-imidazol-4-yl)-7a,13-dihydro-7H[l,2,4]triazolo[4T,3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (50.0 mg, 102 umol, 1.00 eq) and HFIP (2.00 mL) was stirred at 80°C for 8 h under nitrogen atmosphère. The reaction mixture was concentrated under reduced pressure. The residue was purified by prepHPLC (HCl condition). The product-containing fraction was concentrated under reduced pressure to remove most of MeCN at 30°C and the aqueous phase was lyophilized. (S)-12-fluoro-4-(lmethyl~lH-imidazoi-4-yl)-7a,8,13,i4-tetrahydro-7H-[l,2,4]tnazolo[4',3':l,6]pyrido[3,2-
b] b enzofuro[4,3-fg] [1,4] oxazonine (16.0 mg, 37.1 umol, 36% yield, 99.3% purity, HCl) was obtained as a yellow solid. 'HNMR DMSO4 400 MHz δ = ppm 9.61 (s, IH), 9.17 (s, IH), 8.36 (s, IH), 8.18 (s, 1 H), 8.10 - 8.00 (m, IH), 6.93 (t, J = 9.5 Hz, IH), 6.67 (dd, J= 8.5, 3.9 Hz, IH), 4.93 - 4.85 (m, IH), 4.80 (s, IH), 4.56 - 4.45 (m, 2H), 4.21 (d, 7= 9.7 Hz, IH), 4.03 (s, IH), 3.92 (s, 3H), 3.88 -3.80 (m, IH). ‘HNMR CD3OD 400 MHz δ = ppm 9.60 (s, 1H),9.O7 (s, IH), 8.11 (s, IH), 8.06 (s, IH), 6.88 (t, 7=9.5 Hz, IH), 6.65 (dd,7=8.6, 3.7 Hz, IH), 5.14 (d,7 = 15.0 Hz, 1 H), 4.93
295 (d, J = 15.0 Hz, IH), 4.76 (d, 7= 5.3 Hz, IH), 4.61 (t, 7= 9.3 Hz, IH), 4.31 (dd, 7= 9.6, 2.8 Hz, IH), 4.10-4.04 (m, IH), 4.03 (s, 3H), 3.98 - 3.90 (m, IH). LCMS (ESI+): m/z 393.2 (M+H).
Example 95: (S)-4-(l,2-dimctliyl-lH-imidazol-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo|4',3':l,6|pyrido[3,2-b]benzofuro[4,3-fg|[l,4| oxazonine
Step 1:i,2-dimethyl-5-(tributylstannyl)-lH-imidazole (n-Bu)3Sn
To a solution of 5-bromo-l,2-dimethyl-IH-imidazoIe (250 mg, 1.43 mmol, 1.00 eq) in THF (2.00 mL) was added w-BuLi (2.50 M, L14 mL, 2.00 eq) at -78°C under nitrogen atmosphère. The mixture was stirred at -78°C for 0.5 hr'. Then tributyl(chloro)stannane (L86 g, 5.71 mmol, 1.54 mL, 10 4.00 eq) was added to the mixture under nitrogen atmosphère at -78°C, and the mixture was stirred at -78°C for 1 lu- under nitrogen atmosphère. Then the mixture was warmed slowly to 20°C. The mixture was stirred at 20°C for 10 h under nitrogen atmosphère. The reaction mixture was quenched by saturated aqueous NH4C1 solution (4.00 mL) at 0°C, then diluted with water (5.00 mL), and extracted with ethyl acetate (5.00 mL * 3). The combined organic layers were dried over 15 anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a crude product. l,2-dimethyl-5-(tributylstannyl)-lH-imidazole (500 mg, crude) was obtained as a yellow gum.
Step 2: iert-butyl (S)-4-(l,2-dimethyl-lH-imidazol-5-yl)-12-flttoro-7a,13-dihydro-7H[ 1,2,4] triazolo[4’,3’:1,6]pyrido[3,2-b] benzo]uro[4,3-fg] [ l,4]oxazonÎne-14(8H)-carboxylate
A mixture of l,2-dimethyi-5-(tributylstannyl)-lH-imidazole (470 mg, 1.22 mmol, 4.00 eq), tertbutyl (S)-4-bromo-l2-fluoro-7a,13-dihydro-7H-[l,2,4]triazolo[4',3,:l,6]pyrido[3,2-b]benzofuro[4,3fg][ 1,4] oxazonine-14(8H)-carboxylate (150 mg, 305 umol, 1.00 eq), LiCl (19.4 mg, 458 umol, 1.50 eq), Cul (29.1 mg, 153 umol, 0.500 eq) and Pd(PPh3)4 (17.6 mg, 15.3 umol, 0.0500 eq) in dioxane 25 (6.00 mL) was degassed and purged with nitrogen 3 times at 20°C, and then the mixture was stirred at 80°C for 10 h under nitrogen atmosphère. The reaction mixture was concentrated under reduced
296 pressure. The residue was purified by column chromatography (SiO?, Ethyl acetate/Methanol = 1/0 to 3/1). tert-butyl (S)-4-(i,2-dimethyl-lH-imidazol-5-yl)-12-fluoro-7a,l3-dihydro-7H[l,2,4]triazolo[4,,3,:l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (150 mg, 296 umol, 97% yield) was obtained as a yellow solid.
Step 3: (S)-4-(l,2-dimethyl-lH-imidazol-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4', 3 ’:1,6]pyrido[3,2-b]benzofuro[4,3-fg] [1,4] oxazonine
F
To a solution of tert-butyl (S)-4-(l,2-dimethyl-lH-imklazoL5-yl)-12-fIuoro-7a,13-dihydiO-7H[l,2,4]triazolo[4',3':l,6]pyrido[3}2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate3 (130 mg, 257 umol, 1.00 eq) in DCM (3.00 mL) was added TFA (2.31 g, 20.3 mmol, 1.50 mL, 78.9 eq) at 20°C. The mixture was stirred at 20°C for 3 h The reaction mixture was concentrated under reduced pressure. The residue was purified by /jrep-HPLC (formic acid conditions). (S)-4-(l,2-dimethyllH-imidazol-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[ 1,2,4]triazolo[4',3': 1,6]pyrido[3,2b]benzofuro[4,3-fg][l,4]oxazonine (79.5 mg, 174 umol, 67% yield, 99.2% purity, formate sait) was obtained as a light yellow solid. lH NMR DMSO-c/9400 MHz δ = ppm 9.49 (s, 1H), 7.89 (br t, J — 6.1 Hz, 1H), 7.75 (s, 1H), 7.51 (s, 1H), 7.02 - 6.90 (m, 1H), 6.71 (dd, J = 8.7, 3.8 Hz, 1H) 4.99 4.89 (m, 1H), 4.87 - 4.74 (m, 1H), 4.60 - 4.43 (m, 2H), 4.22 (br dd, J = 9.5, 3.3 Hz, 1H), 4.04 (br s, 1H), 3.87 (brt, 10.9 Hz, 1H), 3.65 (s, 3H), 2.66 (s, 3H). LCMS (ES I+): m/z 407.1 (M+H).
Example 96: (S)-4-(4,6-diinethylpyridin-3-yl)-12-iluoro-7a,8,13,14-tetrahydro-7H 20 [l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg] [1,4] oxazonine
Step 1: (4,6-dimethylpyridin-3-yl)boronic acid
O —F N
HO—E(
OH
To a solution of 5-bromo-2,4-dimethylpyridme (400 mg, 2.15 mmol, 1.00 eq) in THF (10.0 mL) was added n-BuLÎ (2.50 M, 1.12 mL, 1.30 eq) at -65°C and stirred at -65°C for 0.5 hr. Triisopropyl 25 borate (809 mg, 4.30 mmol, 989 uL, 2.00 eq) was added to the solution and the reaction mixture was 297 stirred at -65°C for 1 hr. MeOH (2.00 mL) was added to the solution and the mixture was concentrated. (4,6-dimethylpyridin-3-yl)boronic acid (400 mg, crude) was obtained as a white solid.
Step 2: (S)-4-(4,6-dimethylpyridin-3-yl)-l2-fluoro-7a,8,13,14-tetrahydro-7H[ l,2,4]triazolo[4’,3': 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4]oxazonine
F
To a solution of (4,6-dimethylpyridin-3-yl)boromc acid (116 mg, 767 umol, 3.00 eq) in EtOH (5.00 mL) and water (1.00 mL) was added (S)-4-bromo-12-fluoiO-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4’,3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine (100 mg, 256 umol, 1.00 eq), KOAc (75.3 mg, 767 umol, 3.00 eq) and 4-ditert-butylphosphanyl-N,N-dimethyl-aniline dichloropalladium (18.1 mg, 25.6 umol, 18.1 uL, 0.100 eq) at 20°C under nitrogen atmosphère. The mixture was stirred at 80°C for 2 h under nitrogen atmosphère. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in MeOEI (10.0 mL) and silicathiol (20.0 mg, modified Silicon gel for eliminating Pd, irregular silica gel, 100-200 mesh, Chlorides (Cl), %<0.004, particle size distribution 45-75 um) was added at 20°C and stirred at 20°C for 4 h. The suspension was filtered, the filtrate was concentrated and purified by ^re/7-HPLC (formic acid conditions). The product-containing fraction was concentrated under reduced pressure to remove most of MeCN at 30°C and the aqueous phase was lyophihzed. (S)-4-(4,6-dimethylpyridin-3-yl)12-fluoro-7a,8,13,14-tetrahydro-7H-[l ,2,4]triazolo[4',3’: 1,6]pyrido[3,2-b]benzofuro[4,3fg][l,4]oxazonine (26.0 mg, 56.1 umol, 22% yîeld, 100% purity, formate sait) was obtained as a yellow solid. 'HNMR DMSO-^400 MHz δ = ppm 9.39 (s, IH), 8.33 (s, IH), 7.48 (t, J=6.3 Hz, IH), 7.26 (s, IH), 7.18 (s, IH), 6.95 (dd, J = 10.3, 8.9 Hz, IH), 6.68 (dd, J= 8.6, 3.7 Hz, 1H),4.95 4.83 (m, IH), 4.82 - 4.71 (m, IH), 4.57 - 4.49 (m, IH), 4.45 (d,J=5.7 Hz, IH), 4.19 (dd, J = 9.5, 3.5 Hz, IH), 4.00 (d, J = 9.3 Hz, IH), 3.90 - 3.76 (m, IH), 2.45 (s, 3H), 2.14 (s, 3H). LCMS (ES1+): m/z 418.1 (M+H).
Example 97: (S)-4-(4-(difluoromethyl)-6-metliylpyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro7H-[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg|[l,4]oxazonîne
Step 1: 5-bromo-4-iodo-2-methylpyridine
298
To a stiired solution of 5-bromo-2-methylpyridm-4-amine (2.05 g, 11.0 mmol, 1.00 eq) and diiodomethane (5.87 g, 21.9 mmol, 1.77 mL, 2.00 eq) in MeCN (20.0 mL) was added isopentyl nitrite (2.82 g, 24. i mmol, 3.25 mL, 2.20 eq) in MeCN (10.0 mL) at 0°C. The resulting mixture was stirred at 0°C for 1 hr and then stirred at 60°C for 12 h. The mixture was concentrated under reduced pressure. The mixture was purified by MPLC (SÎO2, ΡΕ/EtOAc = 1/0 to 3/1). 5-bromo-4iodo-2-methylpyridine (1.50 g, 5.03 mmol, 45% yield) was obtained as a yellow solid.
Step 2: 5-bromo-2-methyl-4-vinylpyridme
To a stirred solution of 5-bromo-4-iodo-2-methylpyrîdine (1.50 g, 5.03 mmol, 1.00 eq), 4,4,5,5tetramethyl-2-vinvl-l,3,2-dioxaborolane (620 mg, 4.03 mmol, 683 uL, 0.800 eq) and Na2CO3 (1.07 g, 10.1 mmol, 2.00 eq) in dioxane (20.0 mL) and water (4.00 mL) was added Pd(dppf)Cl2 (369 mg, 504 umol, 0.100 eq) at 15°C under N2. The resulting mixture was stirred at 80°C for 12 h. LCMS indicated incomplète conversion. To the mixture was added 4,4,5,5-tetramethyl-2-vinyl-l,3,2dioxaborolane (0.200 eq) and Pd(dppf)Cl2 (0.100 eq) at 15°C under N2. The resulting mixture was stirred at 80°C for 2 h. LCMS showed that 5-bromo-4-iodo-2-methylpyridme was consumed completely. The mixture was concentrated under reduced pressure. The mixture was purified by MPLC (SiO2, PE'EtOAc = 1/0 to 3/1). 5-bromo-2-methyl-4-vinylpyridine (900 mg, 4.54 mmol, 90% yield) was obtained as yellow oil.
Step 3: 5-bromo-2-methylisonicotinaldehyde
Ozone (15 psi) was bubbled into a solution of 5-bromo-2-methyl-4-vînylpyridine (900 mg, 4.54 mmol, 1.00 eq) in DCM (30.0 mL) at -78°C for 0.5 hr. After excess O3 was purged by O2 (15 psi) for 0.5 hr, to the mixture was added Me2S (5.65 g, 90.9 mmol, 6.67 mL, 20.0 eq) at -78°C. The resulting mixture was stirred at 15°C for 2 h. The mixture was concentrated under reduced pressure.
299
The mixture was purified by MPLC (SiO2, PE/EtOAc — 1/0 to 1/1). 5-bromo-2methylisonicotinaldehyde (450 mg, 2.25 mmol, 49% yield) was obtained as a whîte solid.
Step 4: 5-bromo-4-(difluoromethyl)-2-methylpyridine
Sr F
F
To a stirred solution of 5-bromo-2-methylisonicotinaldehyde (450 mg, 2.25 mmol, 1.00 eq) in DCM (5.00 mL) was added DAST (798 mg, 4.95 mmol, 654 uL, 2.20 eq) at -78°C under N2. The resulting mixture was stirred at 15°C for 12 h. The mixture was basified by saturated aqueous NaHCO3 solution to pH = 7-8 and the mixture was extracted with EtOAc (10.0 mL * 3). The combined organic layers were dried over Na2SÛ4 and concentrated under reduced pressure. The mixture was purified by MPLC (SÎO2, PE/EtOAc = 1/0 to 3/1). 5-bromo-4-(difhioromethyl)-2methylpyridine (210 mg, 946 umol, 42% yield) was obtained as yellow oil. *H NMR CDC13 400 MHz δ = ppm 8.66 (s, IH), 7.40 (s, IH), 6.79 (t, J= 54.4 Hz, IH), 2.58 (s, 3H).
Step 5: 4-(difluoromethyl)-2-methyl-5-(tributylstannyl)pyridine (n-Bu)3Sn y1—F
F
To a solution of 5-bromo-4-(difluoiOmethyl)-2-methylpyridine (190 mg, 856 umol, 1.00 eq) in THF (5.00 mL) was added ?i-BuLi (2.50 M, 377 uL, 1.10 eq) at -78°C under nîtrogen and the mixture was stirred at -78°C for 0.5 hr under N2. Tributyl(chloro)stannane (836 mg, 2.57 mmol, 691 uL, 3.00 eq) was added to the mixture under nîtrogen atmosphère at -78°C and the resulting mixture was stirred at -78°C for 2 h under N2. The mixture was quenched with saturated aqueous NH4C1 solution (5.00 mL) and the mixture was extracted with EtOAc (5.00 mL * 3). The combined organic layers were dried over Na2SO4 and then concentrated under reduced pressure. The mixture was purified by MPLC (SiO2, PE/EtOAc = 1/0 to 1/1). 4-(difiuoromethyl)-2-methyl-5-(tributylstannyl)pyridine (120 mg, 278 umol, 32% yield) was obtained as yellow oil.
Step 6: tert-butyl (S)-4-(4-(dijluoromethyl)-6-methylpyridin-3-yl)-12-fluoro-7a, 13-dihydro~7H[1,2,4] triazolo[4 3 1,6]pyrido[3,2-b]benzofuro[4,3-fg] [1,4] oxazonine-14(8H)-carboxylate
300
To a stirred solution of 4-(difluoromethyl)-2-methyl-5-(tributylstannyl)pyridine (120 mg, 27S umol, 1.00 eq) and tert-butyl (S)-4-biOmo-12-fluoro-7a,13-dihydro-7H-[l,2,4]triazolo[4,,3’:l,6]pyrido[3,2b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (136 mg, 278 umol, 1.00 eq) in dioxane (4.00 mL) was added Cul (21.2 mg, 111 umol, 0.400 eq), LiCl (23.5 mg, 555 umol, 11.4 uL, 2.00 eq) and Pd(PPh3)4 (32.1 mg, 27.8 umol, 0.100 eq) at 20°C under N2. The resulting mixture was stirred at 100°C for 12 h. The mixture was concentrated under reduced pressure. The mixture was purified by prep-JLC (SiO2, PE/EtOAc = 0/1). tert-butyl (S)-4-(4-(difluoromethyl)-6methylpyridin-3-yl)-I241uoro-7a,13-dihydro-7H-[l,2,4]ti-iazolo[4’,3':l,6]pyrido[3,2b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (150 mg, crude) was obtained as a yellow solid.
Step 7: (S)-4-(4~(difluoromethyl)-6-methylpyridin-3-yl)-l 2-fluoro-7a, 8,13,14-tetrahydro-7H[ 1,2,4]triazolo[4', 3 1,6]pyrido[3,2-b] benzofuro]4,3-fg] [ 1,4] oxazonine
To tert-butyl (S)-4-(4-(difluoromethyl)-6-methylpyridin-3-yl)-12-fluoro-7a, 13-dihydro-7H[l,2,4]triazolo[4’,3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (150 mg, 271 umol, 1.00 eq) was added HFIP (3.00 mL) at 20°C. The mixture was concentrated under reduced pressure. The mixture was purified by acidic prep-HPLC (HCl conditions). HPLC analysis indicated insufficient purity. The material was additionally purified by acidic yjrejp-HPLC (FA). The product-containing fraction was concentrated under reduced pressure to remove most of MeCN at 30°C and the aqueous phase was lyophilized. (S)-4-(4-(difluoromethyl)-6-methylpyrîdin3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofiiro[4,3fg][l,4]oxazonine (20.9 mg, 45.5 umol, 16% yield, 98.6% purity) was obtained as a yellow solid. 'H
301
NMR DMSO-t4 400 MHz δ = ppm 9.42 (s, IH), 8.63 (s, IH), 7.61 (br t, J= 6.4 Hz, IH), 7.56 (s, IH), 7.34 (s, IH), 7.05 (t, J = 54.4 Hz, IH), 6.96 (dd, 7= 10.0, 8.8 Hz, IH), 6.69 (dd, J= 8.7, 3.9 Hz, IH), 4.96 - 4.87 (m, IH), 4.85 - 4.72 (m, IH), 4.58 - 4.42 (m, 2H), 4.20 (dd, 9.6, 3.4 Hz, IH), 4.07 - 3.96 (m, IH), 3.93 - 3.84 (m, IH), 2.59 (s, 3H). LCMS (ESI+): m/z 454.2 (M+H).
Example 98: (S)-(5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[l,2,4|triazolo[4’,3':l,6]pyrido[3,2b]benzofuro|4,3-fgHl,4]oxazonin-4-yl)-l-methyl-lH-pyrazol-3-yl)methanamine
Step 1: (5-bromo-l-methyl-lH-pyrazol-3-yl)methanol
OH
O /—N Br X
To a solution of methyl 5-bromo-1-methyl-lH-pyrazole-3-carboxylate (5.20 g, 23.7 mmol, 1.00 eq) in DCM (200 mL) was added DIBAL-H ( 1.00 M, 47.5 mL, 2.00 eq) at -65°C under N2 and stirred at -65°C for 1 hr. TLC (Petroleum ether/Ethyl acetate = 3/1) showed that the reaction was complété. The mixture was added dropwise to sat. aq. potassium sodium tartrate (200 mL), stirred for 0.5 hr at 20°C, then extracted with DCM (200 mL * 3). The combined organic layers were dried overNa2SO4 and concentrated. (5-bromo-l-methyl-lH-pyrazol-3-yl)methanol (4.50 g, crude) was obtained as yellow oil.
Step 2: 5-bromo-l-methyl-lH-pyrazole-3-carbaldehyde
To a solution of (5-bromo-l-methyl-lH-pyrazol-3-yl)methanol (4.50 g, 23.6 mmol, 1.00 eq) in DCM (100 mL) was added DMP (20.0 g, 47.1 mmol, 14.6 mL, 2.00 eq) at 0°C, stirred at 20°C for 12 h. The mixture was filtered, the filtrate was concentrated. The residue was purified by MPLC (SiO2, Petroleum ether/Ethyl acetate = 1/0 to 0/1). 5-Bromo-l-methyl-lH-pyrazole-3-carbaldehyde (2.70 g, 14.3 mmol, 60% yield) was obtained as a white solid.
Step 3: 5-bromo-l-methyl-lH-pyrazole-3-carbaldehyde oxime
302
OH ΐ
Br x
To a solution of 5-bromo-l-methyl-lH-pyrazole-3-carbaklehyde (1.00 g, 5.29 mmol, 1.00 eq) in DCM (10.0 mL) was added hydroxylamine hydrochloride (735 mg, 10.6 mmol, 2.00 eq), TEA (2.14 g, 21.2 mmol, 2.95 mL, 4.00 eq) at 20°C, and the mixture was stirred at 20°C for 1 hr. TLC (Petroleum ether/Ethyl acetate = 3/1 ) showed that the reaction was complété. Water (5.00 mL) was added to the solution and the mixture was extracted with DCM (10.0 mL * 3). The combined organic layers were dried over Na2SO4 and concentrated. 5-bromo-I-methyl-lH-pyrazole-3carbaldehyde oxime (1.15 g, crude) was obtained as a yellow oil.
Step 4: (5-bromo-l-methyl-lH-pyrazol-3-yl)methanamine
NH2
Cï
Br
To a solution of 5-bromo-1-methyl-lH-pyrazole-3-carb aldéhyde oxime (1.00 g, 4.90 mmol, 1.00 eq) in AcOH (10.0 mL) was added to Zn (3.21 g, 49.0 mmol, 10.0 eq) at 20°C and the mixture was stirred at 20°C for 12 h. MeOH (10.0 mL) was added to the solution which was tlien fïltered and the filtrate was concentrated. 1.20 g of crude (5-bromo-1-methyl-1 H-pyrazol-3-yI)methanamine (AcOH sait) including (1 -methyl-lH-pyrazol-3-yl)methanamine was obtained as a yellow oil.
Step 5: tert-butyl {(5-bromo-1 -methyl-lH-pyrazol-3-yl)methyl)carbamate
To a solution of (5-bromo-1-methyl-lH-pyrazol-3-yi)methanamine (1.20 g, 4.80 mmol, 1.00 eq, HOAc) in DCM (20.0 mL) was added TEA (3.88 g, 38,4 mmol, 5.34 mL, 8.00 eq), (Boc)2O (1.57 g, 7.20 mmol, 1.65 mL, 1.50 eq) at 20°C, then the mixture was stirred at 20°C for 2 h. The mixture was concentrated. The residue was purified by MPLC (SiO2, Petroleum ether/Ethyl acetate = 1/0 to 0/1). tert-butyl ((5-bromo-1-methyl-lH-pyrazol-3-yl)methyl)carbamate (300 mg, 1.03 mmol, 21% yield) was obtained as a yellow oil.
303
Step 6: tert-butyl (( 1 -methyl-5-(tributylstannyl)-l H-pyrazol-3-yl)methyl)carbamate NHBoc y-N (n-Bu)3Sn
To a solution of tert-butyl ((5-bromo-l-methyl-lH-pyrazol-3-yl)methyl)carbamate (250 mg, 862 umol, 1.00 eq) in THF (6.00 mL) was added n-BuLi (2.50 M, 689 uL, 2.00 eq) at -65°C under N2 and the reaction mixture was stirred at -65°C for 0.5 hr. Snfn-BuECl (1.12 g, 3.45 mmol, 927 uL, 4.00 eq) was added to the solution at -65°C and the mixture was stirred at -65°C for 1 hr under N2. LCMS showed the reaction was complété. Sat. aq. NH4CI (4.00 mL) was added to the solution, then the mixture was ex tract ed with EtOAc (4.00 mL * 3), the combined organic layers was dried over Na2SO4, then concentrated. tert-butyl ((l-methyl-5-(tributylstannyl)-1 H-pyrazol-3yl)methyl)carbamate (430 mg, crude) was obtained as a yellow oil.
Step 7: tert-butyl (5)-4-(3-(((tert-butoxycarbonyl)amino)methyl)-l-methyl-lH-pyrazol-5-yl)-l 2fluoro-7a, J 3-dihydro- 7H-] 1,2,4] triazolo]4', 3’: 1,6]pyrido]3,2-b] benzofuro]4,3-fg] ]1,4] oxazonine14(8H)-carboxylate
To a solution of tert-butyl ((l-methyl~5-(tributylstannyl)-lH-pyrazol-3-yl)methyl)carbamate (430 mg, 859 umol, 1.92 eq), tert-butyl (S)-4-bromo-12-fiuoro-7a,13-dîhydro-7H[l,2,4]triazolo[4',3’:l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (220 mg, 448 umol, 1.00 eq) in dioxane (4.00 mL) was added LiCl (1.90 mg, 44.8 umol, 0.100 eq), Cul (8.53 mg, 44.8 umol, 0.100 eq) and Pd(PPh3)4 (51.7 mg, 44.8 umol, 0.100 eq) at 20°C and the mixture was stirred at 80°C for 12 h under N2. LCMS showed the reaction was complété. The mixture was concentrated. The residue was purified by prep-TLC (SiO2, Petroleum ether/Ethyl acetate = 0/1). tert-butyl (S)-4-(3-(((tert-butoxycarbonyl)amino)methyl)-l-methyl-lH-pyrazol-5-yl)-12-fluoiO7a,13-dihydro-7H-[l,2,4]triazolo[4',3,: 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ l,4]oxazonine-14(8H)carboxylate (260 mg, crude) was obtained as a yellow oil.
304
Step 8: (S)-(5-(l 2-fluora- 7a, 8,13,14-tetrahydro-7H-[ 1,2,4] triazolo[4 3 ’:1,6]pyrido[3,2b] benzafuro[4,3-fg] [1,4] oxazonin-4-yl)-l -methyl- lH-pyrazol-3-yl)methananùne
A solution of tert-butyl (S)-4-(3-(((tert-butoxycarbonyl)amino)methyl)-l-methyl-lH-pyrazol-5-yl)12-fluoro-7a, 13-dihydro-7H-[ 1,2,4]triazolo[4',3’: 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1 ,4]oxazonine14(8H)-carboxylate (100 mg, 161 umol, 1.00 eq) în TFA (1.50 mL) and DCM (3.00 mL) was stirred at 20°C for 1 hr. The mixture was concentrated. The mixture was purified by /?rep-HPLC (column: Phenomenex Luna C18 150 * 30 mm * 5 um; mobile phase: [water (0.04% HC1)-ACN]; B%: 10%45%, 10 min). The fraction was blown to dryness by a nitrogen stream to remove most of MeCN and the aqueous phase was lyophilized. (S)-(5-(12-fluoro-7a,8,13,I4-tetrahydro-7H[ l,2,4]triazolo[4',3': l,6]pyrido[3,2-b]benzofuiO[4,3-fg][l,4]oxazonin-4-yl)-l-methyl-lH-pyrazol-3yl)methanamine (45.0 mg, 98.0 umol, 60% yield, 99.7% purity, HCl sait) was obtained as a yellow solid. ’H NMR CD3OD 400 MHz δ = ppm 9.51 (s, IH), 7.98 - 7.89 (m, IH), 6.93 (t, J = 9.4 Hz, IH), 6.70 (dd, 7=8.6, 3.7 Hz, IH), 6.61 (s, IH), 5.19 (br d, 7= 14.7 Hz, IH), 4.99 - 4.93 (m, IH), 4.80-4.71 (m, 1 H), 4.63 (t, 7=9.4 Hz, IH), 4.32 (br dd, 7 = 9.6, 3.0 Hz, IH), 4.19 (s, 2H), 4.13 4.02 (m, IH), 3.97 - 3.86 (m, IH), 3.83 (s, 3H). LCMS (ESI+): m/z 422.2 (M+H).
Example 99: (S)-l-(5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4',3’:l,6]pyrido[3,2b|benzofuro|4,3-fg][l,4]oxazonii]-4-yl)-l-methyl-lH-pyrazol-3-yl)-N,N-dimethylmcthanamine
To a solution of (S)-(5-(12-fluoiO-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4',3':l,6]pyrido[3,2b]benzofuro[4,3-fg][l,4]oxazonin-4-yl)-l-methyl-lH-pyrazol-3-yl)methanamine (86.1 mg, 161 umol, 1.00 eq, TFA) in MeOH (3.00 mL) was added AcOH (96.6 ug, 1.61 umol, 0.0920 mL, 0.0100 eq), formaldéhyde (26.1 mg, 322 umol, 23.9 uL, 2.00 eq) at 20°C and stirred at 20°C for 0.5 hr. NaBH3CN (20.2 mg, 321 umol, 2.00 eq) was added to the solution at 20°C and stirred at 20^0 for 1
305 hr. LCMS showed that the reaction was complété. The mixture was concentrated. The mixture was purified by prep-HPLC (column: Phenomenex Luna C18 100 * 30 mm * 5 uni; mobile phase: [water (0.04% HCl) -ACN]; B%: 5%-35%, 10 min), the fraction was blown to dryness by a nitrogen stream to remove most of MeCN and the aqueous phase was lyophilized. (S)-l-(5-(12-tluoro7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonin-4yl)-l-methyl-lH-pyrazol-3-yl)-N,N-diniethylmethanamine (35.0 mg, 69.7 umol, 43% yield, 96.7% purity, HCl sait) was obtained as a yellow solid. *H NMR CD3OD 400 MHz δ = ppm 9.56 (s, IH), 8.06 (s, IH), 6.94 (t, J= 9.5 Hz, IH), 6.74 (s, IH), 6.70 (dd, J = 8.7. 3.9 Hz, IH), 5.22 (d, 14.9
Hz, IH), 4.98 (brd,7 = 15.0 Hz, IH), 4.81 -4.75 (m, IH), 4.68 - 4.59 (m, IH), 4.39 (s, 2H), 4.33 (br dd, 7 = 9.7, 3.2 Hz, IH), 4.12-4.03 (m, IH), 3.98 -3.89 (m, IH), 3.85 (s, 3H), 2.96 (s, 6H). LCMS (ESI+): m/z 450.2 (M+H).
Example 100: (S)-4-(4-cyclopropylpynmidÎn-5-yl)-12-fluoro-7a,8,13,14-tctrahydro-7H[l,2,4]triazolo[4’,3’:l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
Step 1: 4-cyclopropyl-5-(trimethylstannyl)pyrimidine
O
Me3Sn
A mixture of 5-bromo-4-cyclopropyIpyrimidine (200 mg, 1.00 mmol, 1.00 eq), Îrimethyl(trimethylstannyl)stannane (658 mg, 2.01 mmol, 417 uL, 2.00 eq), Pd(PPh3)4 (116 mg, 100 umol, 0.100 eq) in dioxane (8.00 mL) was degassed and purged with nitrogen 3 times at 20°C, and the mixture was stirred at 100°C for 2 h under nitrogen atmosphère. 4-cyclopropyl-5(trimethylstannyl)pyrimidme (284 mg, 1.00 mmol, 99% yield) was obtained as yellow liquid in dioxane (8.00 mL), which was used to the next step directly.
Step 2: tert-butyl (S)-4-(4-cyclopropylpyrimidin-5-yl)-I2-fluoro-7a,13-dlhydro-7H[ 1,2,4]triazolo[4',3 ':1,6]pyrido[3,2-b] benzofuro]4,3-fg] [1,4] oxazomne-14(8H)-carboxylate
306
A mixture of tert-butyl (S)-4-bromo-12~fluoro-7a,13-dihydiO-7H[l,2,4]triazolo[4',3’: l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (164 mg, 335 umol, 1.00 eq), 4-cyclopiOpyl-5-(trimethylstannyI)pyrimidine (284 mg, 1.00 mmol, 3.00 eq), LiCl (28.4 mg, 669 umol, 13.7 uL, 2.00 eq), Cul (25.5 mg, 134 umol, 0.400 eq) and Pd(PPh3)4 (38.7 mg, 33.5 umol, 0.100 eq) in dioxane (8.00 mL) was degassed and purged with nitrogen 3 times at 20°C, and then the mixture was stirred at 80°C for 2 h under nitrogen atmosphère. The reaction mixture was diluted with water (3.00 mL) and extracted with EtOAc (3.00 mL * 3). The combined organic layers were washed with brine (3.00 mL), dried over Na2SO4, fïltered, and concentrated under reduced pressure. The residue was purified by //rep-TLC (SiO2, PE:EtOAc = 3:1). tert-butyl (S)-4-(4-cyclopiOpylpyrimidin-5-yl)-l 2-fluoro-7a, 13-dîhydro-7H[],2,4]triazolo[4’,3': 1,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (150 mg, 283 umol, 84% yield) was obtained as a yellow oil.
Step 3: (S)-4-(4-cyclopropylpyrimidin-5-yl)-l 2-fluoro-7a,8,13,14-tetrahydro-7H[ 1,2,4]triazolo[4 3 ’:1,6]pyrido[3,2-b] benzofuro[4,3-fgJ [1,4] oxazonine
To HFIP (4.00 mL) was added tert-butyl (S)-4-(4-cyclopiOpylpyrÎmidin-5-yl)-12-fluoro-7a,l3dihydro-7H-[l,2,4]triazolo[4',3': l,6]pyrido[3,2-b]benzofuiO[4,3-fg][l,4]oxazonine-14(8H)carboxylate (150 mg, 283 umol, 1.00 eq) at 20°C, then the mixture was stirred at 80°C for 12 h. The mixture was concentrated. The mixture was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30 mm* 10 um; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 28%-48%, 10 min). 50.0 mg of the product was obtained, which was then purified by prep-HPLC (column: Phenomenex Luna Cl8 200*40 mm* 10 um; mobile phase: [water (0.2% FA)-ACN]; B%: 10%-45%, 10 min). (S)-4-(4-cyclopropylpyrimidin-5-yl)-12-fl uoro-7a, 8,13,14-tetrahydro-7 H[l,2,4]triazolo[4')3':l,6]pyrido[3,2-b]benzofÎiiO[4J3-fg][l,4]oxazonine (33.6 mg, 77.4 umol, 27% yield, 99.2% purity) was obtained as a white solid. 'H NMR DMSO-ιή, 400 MHz δ = ppm 9.44 (s, IH), 8.97 (s, IH), 8.65 (s, IH), 7.61 (br t, J = 6.4 Hz, IH), 7.45 (s, IH), 7.02 - 6.92 (m, IH), 6.70 (dd, 7 = 8.7, 3.9 Hz, IH), 4.98 - 4.89 (m, IH), 4.86 - 4.74 (m, IH), 4.59 - 4.43 (m, 2H), 4.21 (br dd,
307 ./=9.1, 3.4 Hz, IH), 4.11 - 3,99 (m, IH), 3.93 - 3.81 (m, IH), 2.00 - 1.87 (m, IH), 1.10 (br d, J = 3.5 Hz, 2H), 0.95 (br dd, J-7.6, 2.8 Hz, 2H). LCMS (ESI+): m/z 431.1 (M+H).
Example 101: (S)-12-iluoro-4-(5-fluoro-6-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H[l,2,4|triazolo(4,,3':l,6]pyrido[3,2-blbenzofuro[4,3-fgni,4]oxazonine
Step /; 3-fhioro-2-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine E /
To a solution of 5-bromo-3-fluoro-2-methylpyridine (100 mg, 526 umol, 1.00 eq), 4,4,5,5tetramethyi-2~(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaboiOlane (200 mg, 789 umol, 1.50 eq) in dioxane (4.00 mL) was added KOAc (103 mg, 1.05 mmol, 2.00 eq), Pd(dppf)Cl2 (38.5 mg, 52.6 umol, 0.100 eq) at 20°C, stirred at 100°C for 2 h under N2. The mixture was concentrated. 3-fluoro-2-methyi-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine ( 124 mg, crude) as obtained as black oil.
Step 2: (S)-12-fluoro-4-(5-fluoro-6-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H[ 1,2,4]triazolo[4 3 1,6]pyrido[3,2-b] benzofurof4,3-fg] [1,4] oxazonine
To a solution of 3-fiuoro-2-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (96.9 mg, 409 umol, 2.00 eq), (S)-4-bromo-12-fluoro-7a,8,l 3,14-tetrahydro-7H[l,2,4]Îriazolo[4l,3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine (80.0 mg, 205 umol, 1.00 eq), 4-ditert-butylphosphanyl-N,N-dimethyl-aniline dichloropalladium (14.5 mg, 20.5 umol, 14.5 uL, 0.100 eq) in EtOH (4,00 mL) and water (0.400 mL) was added KOAc (40.1 mg, 409 umol, 2.00 eq) at 20°C and the reaction mixture was stirred at 100°C for 12 h. The residue was dissolved in MeOH (3.00 mL) and silica-thiol (100 mg, modified Silicon gel for eliminating Pd, irregular silica gel, 100 200 mesh, Chlorides (Cl), %<0.004, particle size distribution 45-75 um) was added at 20°C and stirred at 20°C for 3 h. The mixture was filtered, the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100 * 25
308 mm * 5 um; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 20%-50%, 8 min). The fraction was blown to dryness by a nitrogen stream to remove most of MeCN and the aqueous phase was lyophilized, then the product dissolved in MeOH (10.0 mL) and water (3.00 mL). Aq. HCl (2.00 mL, 1.00 M) was added to the solution which was then lyophilized. (S)-12-fluoro-4-(5-fluoro-6methylpyridin-3-yI)-7a,8,13,14-tetrahydro-7H-[ 1,2,4]triazolo[4’,3’: 1,6]pyiido[3,2-b]benzofuro[4,3fg][ 1,4] oxazonine (23.8 mg, 50.1 umol, 24% yield, 96.3% purity, HCl sait) was obtained as a yellow solid. 'H NMR CDjOD 400 MHz δ = ppm 9.63 (s, 1H), 8.96 (d, 7= 1.5 Hz, 1H), 8.51 (dd, 7= 9.7, 1.2 Hz, 1H), 8.23 (s, 1H), 6.92 (dd,7= 10.1, 8.8 Hz, 1H), 6.69 (dd,7= 8.6, 3.9 Hz, 1H), 5.20 (d,7= 14.7 Hz, 1H), 5.01 - 4.96 (m, 1H), 4.87 - 4.78 (m, 1H), 4.68 - 4.59 (m, 1H), 4.35 (dd,7=9.7, 2.9 Hz, 1 H), 4.12 - 3.95 (m, 2H), 2.76 (d, 7= 2.4 Hz, 3H). LCMS (ESI+): m/z 422.0 (M+H).
Example 102: (S)-4-(3-(difluoroinethyl)-l-methyl-lH-pyrazol-5-yl)-12-fluoro-7a,8,13,14tetrahydro-7H-[l,2,4]triazolo[4’,3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
Step 1: 5-bromo-3-(difhioromethyl)-l-methyl-1 H-pyrazole
To a solution of 5-biOino-l-methyl-lH-pyrazole-3-carbaldehyde (300 mg, 1.59 mmol, 1.00 eq) in DCM (3.00 mL) was added DAST (512 mg, 3.17 mmol, 419 uL, 2.00 eq) at -78°C. The mixture was stirred at 20°C for 12 h. The reaction mixture was quenched by addition of saturated aqueous NaHCO3 (3.00 mL), concentrated under reduced pressure to remove DCM, and extracted with EtOAc (2.00 mL * 3). The combined organic layers were washed with brine (3.00 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 5-bromo-3-(difluoromethyl)-lmethyl-IH-pyrazole (300 mg, crude) as a yellow oil.
Step 2: 3-(difluoromethyl)-l-methyl-5-(tribiitylstannyl)-lH-pyrazoie
F^ ^F
(n-Bu)3Sn v
To a solution of 5-bromo-3-(difluoromethyl)-l-methyl-IH-pyrazole (290 mg, 1.37 mmol, 1.00 eq) in THF ( 10.0 mL) was added n-BuLÎ (2.50 M, 715 uL, 1.30 eq) at -78°C under N2. The mixture was stirred at -78°C for 0.5 hr. To the mixturte was added tributyl(chloro)stannane (1.79 g, 5.50 mmol,
309
1.48 mL, 4.00 eq) at -78°C under N2. The mixture was stirred at -78°C for 2 h. LC-MS showed that 5-bromo-3-(difluoromethyl)-l-methyl-lH-pyrazole was consumed completely and the desired mass was detected. The reaction mixture was quenched by addition of saturaied aqueous NH4C1 (5.00 mL). THF layer was separated and the aqueous layer was extracted with EtOAc (3.00 mL * 3). The combined organic layers were washed with brine (5.00 mL), dried over Na2SÛ4, filtered, and concentrated under reduced pressure to afford 3-(difluoromethyl)-l-methyl-5-(tributylstannyl)-lHpyrazole (570 mg, crude) as a yellow oil.
Step 3: tert-butyl (S)-4-(3-(difluoromethyl)-l-methyl-lH-pyrazol-5-yl)-12-fluoro-7a,13-dihydro-7H[1,2,4]triazolo[4',3 1,6]pyrido[3,2-b] benzofitro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate
A mixture of 3-(difluoromethyl)-l-methyl~5-(tributylstannyl)-lH-pyrazole (560 mg, 1.33 mmol, 2.50 eq), tert-butyl (S)-4-bromo-12-fhioro-7a,13-dihydro-7H-[l ,2,4]triazolo[4',3':l,6]pyrido[3,2b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (261 mg, 532 umol, 1.00 eq), Pd(PPh3)4 (61.5 mg, 53.2 umol, 0.100 eq), Cul (40.5 mg, 213 umol, 0.400 eq) and LiCJ (45.1 mg, 1.06 mmol, 21.8 uL, 2,00 eq) in dioxane (10.0 mL) was degassed and purged with nitrogen 3 times at 20°C. The réaction mixture was stirred at 80°C for 12 h under nitrogen atmosphère. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SÎO2, Petroleum ether/Ethyl acetate = 1/0 to 0/1). tert-butyl (S)-4-(3-(difluoromethyl)-l-methyl-lHpyrazol-5-yl)- 12-fluoro-7a, 13-dîhydro-7H-[ 1,2,4]triazolo[4',3': 1,6]pyrido[3,2-b]benzofuiO[4,3fg][l,4]oxazonine-14(8H)-carboxylate (230 mg, crude) was obtained as a brown solid.
Step 4: (S)-4-(3-(difluoromethyl)-l-methyl-lH-pyrazol-5-yl)-I2-fluoro- 7 a, 8,13,14-tetrahydro-7H[ 1,2,4]triazolo[4', 3 1,6]pyrido[3,2-b] benzofuro[4,3-fg] [1,4] oxazonine
F
310
To the HFIP (5.00 mL) was added tert-butyl (S)-4-(3-(difluoiOmelhyl)-l-methyl-1H-pyrazol-5-yl)I2-fluoro-7a, 13-dihydro-7H-[ l,2,4]triazolo[4’,3': 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4]oxazonine14(8H)-carboxylate (200 mg, 369 umol, 1.00 eq) at 20°C, the mixture was stirred at 100°C for 12 h The reaction mixture was concentrated under reduced pressure. The mixture was dissolved in DMSO (5.00 mL). The mixture was purified by neutral prep-HPLC (column: Welch Xtimate Cl 8 150 * 25 mm * 5 um; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 35%-60%, 10 min). The fraction was lyophilized. 70 mg of crude product was obtained and dissolved in DMSO (5.00 mL). The obtained sample was purified by acidic prep-HPLC. (column: Phenomenex Luna Cl8 200*40 mm* 10 um; mobile phase: [water (0.2% FA)-ACN]; B%: 20%-60%, 10 min). (S)-4-(3(difluoromethyl)-1 -methyl-1 H-pyrazol-5-yl)-12-fluoro-7a,8,13,I4-tetrahydro-7H[l,2,4]triazolo[4',3’: l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine (58.3 mg, 126 umol, 34% yield, 95.9% purity) was obtained by lyophilization as a white solid. JH NMR DMSO-r/^OO MHz δ = ppm 9.46 (s, IH), 7.75 (br t,./= 6.2 Hz, IH), 7.53 (s, IH), 7.00 (t, J= 54.8 Hz, IH), 6.99 - 6.93 (m, IH), 6.82 (s, IH), 6.70 (dd, J = 8.7, 3.8 Hz, IH), 4.96 - 4.88 (m, IH), 4.86 - 4.76 (m, IH), 4.60 4.45 (m, 2H), 4.24 - 4.17 (m, IH), 4.10 - 3.98 (m, IH), 3.93 - 3.88 (m, IH), 3.87 (s, 3H). LCMS (ESI+): m/z 443.1 (M+H).
Exainple 103: (S)-4-(l,5-dimethyl-lH-imidazol-4-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H|l,2,4]triazolo[4’,3': 1,6] pyrido[3,2-b] benzofuro[4,3-fg] [l,4|oxazonine
Step 1: (l,5-dimethyl-lH-imidazol-4-yl)boronic acid / n hob>n I OH
To a solution of 4-bromo-l,5-dimethyl-lH-imidazole (800 mg, 4.57 mmol, 1.00 eq) in THF (6.00 mL) was added n-BuLi (2.50 M, 3.66 mL, 2.00 eq) at 0°C under N?. The mixture was stirred at 20°C for 1 hr. Then triisopropyl borate (2.58 g, 13.7 mmol, 3.15 mL, 3.00 eq) was added to the mixture at 0°C and stirred at 0°C for 1 hr. The reaction mixture was quenched by addition of MeOH (5.00 mL) at 0°C. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 200 * 40 mm * 10 um; mobile phase: [water (0.2% FA) - ACN]; B%: 1% - 20%, 10 min). (l,5-dimethyl-lH-imidazol-4-yl)boronic acid (450 mg, crude) was obtained as yellow oil.
Step 2: tert-butyl (S)-4-( 1,5-dimethyl-lH-imidazol-4-yl)-12-fluoro-7a, 13-dlhydro-7H[1,2,4]triazolo[4 3 ’:1,6]pyrido[3,2-b]benzofuro[4,3-fg][l, 4] oxazonine-l4(8H)-carboxylate
311
F
To a solution of tert-butyl (S)-4-bromo-12-fluoro-7a,13-dihydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (197 mg, 401 umol, 1.00 eq) in dioxane (5.00 mL) was added (l,5-dimethyl-lH-imidazol-4-yl)boronic acid (280 mg, 2.00 mmol, 5.00 eq), Pd(dppf)Cl2 DCM complex (65.3 mg, 80.0 umol, 0.200 eq), water (0.500 mL) and Na2CO3 (106 mg, 1.00 mmol, 2.98 uL, 2.50 eq) at 20°C under N2. The mixture was stirred at 80°C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Ethyl acetate/MeOH = 10/1). tert-butyl (S)-4-(l,5dimethyl-lH-imidazol-4-yl)-12-fluoiO-7a,13-dihydro-7H-[l,2,4]triazolo[4',3':l,6]pyrido[3,2bjbenzofuiO^S-fgHLdJoxazonme-MiSHj-carboxylate (80.0 mg, crude) was obtained as a brown solid.
Step 3: (5)-4-(1,5-dimethyl-lH-imidazol-4-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H[ 1,2,4]triazolo[4 3 1,6]pyrido[3,2-b]benzofuro[4,3-fg] [1,4] oxazonine
F
A mixture of tert-butyl (S)“4-(l,5-dimethyl-lH-imidazol-4-yl)-12-fluoro-7a,13-dihydro-7H
[l,2,4]tnazolo[4',3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (80.0 mg, 158 umol, 1.00 eq) in HFIP (2.00 mL) was stirred at I00°C for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by jPrep-HPLC (column: Phenomenex Luna C18 100 * 30 mm * 5 um; mobile phase: [water (Ü.2% FA) - ACN]; B%: 10% 35%, 10 min). (S)-4-(l,5-dimethyl-lH-imidazol-4-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine (9.50 mg, 20.8 umol, 13% yield, 99.1% purity, formate sait) was obtained as a white solid. H NMR DMSO-tfô 400 MHz δ = ppm 9.38 (br s, 1H), 7.63 (br s, 1H), 7.41 - 7.26 (m, 2H), 6.94 (t, >9.6 Hz, 1H), 6.67 (dd, >3.6, 8.8 Hz, 1H), 4.88 (br dd, >5.6, 15.1 Hz, 1H), 4.75 (br dd, >6.8, 14.8 Hz, 1H), 4.56 - 4.47 (m, 2H),
312
4.28 - 4.21 (m, 2H), 4.02 (br s, IH), 3.90 - 3.78 (m, IH), 3.59 (s, 3H), 2.35 (s, 3H). LCMS (ESI+): m/z 407.16 (M+H).
Example 104: (S)-4-(l,2-dimethyl-lH-iinidazol-4-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H[l,2,4]trÎazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
Step 1: 4-bromo-1,2-dimethyl- ÎH-imidazole
Br
To a solution of 5-bromo-2-methyl-lH-imidazole (2.00 g, 12.4 mmol, 1.00 eq) and Mel (2.12 g, 14.9 mmol, 928 uL, 1.20 eq) in DMF (10.0 mL) was added K2CO3 (3.78 g, 27.3 mmol, 2.20 eq) at 20°C. The mixture was stirred at 20°C for 12 h. The reaction mixture was diluted with water (30.0 mL), extracted with ethyl acetate (15.0 mL * 3). The combined organic layers were dried over anhydrous sodium sulfate, fïltered and the filtrate was concentrated under reduced pressure. The residue was purified by /ire/i-TLC (SiO2, Ethyl acetate:Methanol = 20:1). 4-bromo- 1,2-dimethyL IH-imidazole (500 mg, 2.86 mmol, 23% yield) was obtained as a white solid. ’H NMR CDjOD 400 MHz 5 = ppm 6.97 (s, IH), 3.58 (s, 3H), 2.31 (s, 3H).
Step 2: tert-butyl (S)-4-( 1,2-dimethyl- lH-imidazol-4-yl)-12-fluoro-7a, 13-dihydro-7H[l, 2,4]triazolo[4 3 l, 6]pyrido[3,2-b] benzofuro[4,3-fg] [1,4] oxazonine-14(8H)-c.arboxylate
A mixture of 4-bromo-1,2-dimethyl-IH-imidazole (60.0 mg, 343 umol, 1.00 eq), tert-butyl (S)-4bromo-12-fluoro-7a,13-dihydiO-7H-[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3fg] [1,4] oxazonine-14(8H)-carboxylate (Ex. 16; 241 mg, 344 umol, 1.00 eq), Pd(t-Bu3?)2 (17.6 mg, 34.4 umol, 0.100 eq) in dioxane (1.00 mL) was degassed and purged with nitrogen 3 times at 20°C, and the mixture was stirred at 100°C for 2 h under nitrogen atmosphère. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Ethyl acetate/Methanol = 5/1). tert-butyl (S)-4-(l,2-dimethyl-lH-imidazol-4-yl)-12-fluoro-7a,13-dihydro7H-[L2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuiO[4,3-fg][ 1,4]oxazonine-14(8H)-carboxylate (90.0 mg, 178 umol, 51% yield) was obtained as a yellow solid.
Step 3: (S)-4-(l,2-dimethyl-lH-imidazol-4-yi)-12-fluoro-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3l:l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
313
F
A solution of tert-butyl (S)-4-( 1,2-dimethyl-1 H-imidazoL4-yl)-12-fluoro-7a,13-dihydro-7H[l,2,4]triazolo[4',3':L6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxyIate (90.0 mg, 178 umol, 1.00 eq) in HFIP (3.00 mL) was stirred at 80°C for 1 hr. The reaction mixture was coneentrated under reduced pressure. The residue was purified by prep-HPLC (HCl conditions). The product-containing fraction was coneentrated under reduced pressure to remove most of MeCN at 30°C and the aqueous phase was lyophilized. (S)-4-(l,2-dimethyl-lH-imidazol-4-yl)-12-fluorO“ 7a,8)13,14-tetrahydro-7H-[l,2,4]triazolo[4,,3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine (15.5 mg, 34.1 umol, 19% yield, 97.5% purity, HCl sait) was obtained as a yellow solid. ’l-I NMR CD3OD 400 MHz 5 = ppm 9.54 (s, IH), 8.01 (s, IH), 7.99 (s, IH), 6.88 (dd, 7= 10.1, 8.9 Hz, IH), 6.64 (dd, 7 = 8.7, 3.8 Hz, IH), 5.11 (d,7= 14.7 Hz, IH), 4.93 (br s, IH), 4.74 (br d, 7= 6.0 Hz, IH), 4.60 (t, 7= 9.3 Hz, 1H),4.31 (dd,7 = 9.7, 3.0 Hz, IH), 4.09 - 3.99 (m, IH), 3.95 (br d, 7= 10.3 Hz, IH), 3.89 (s, 3H), 2.73 (s, 3H). LCMS (ESI+): m/z 407.1 (M+H).
Example 105: (S)-4-(2-(difluoromethyl)-6-methylpyridin-3-yl)-12-fluoro-7a,8,13,14tetrahydro-7H-[l)2,4)triazolo[4',3’:l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine Step 1: 3-bromo-2-iodo-6-methylpyridine
To a solution of L (5.43 g, 21.4 mmol, 4.31 mL, 2.00 eq), Cul (2.65 g, 13.9 mmol, 1.30 eq), isopentyl nitrite (1.88 g, 16.0 mmol, 2.16 mL, 1.50 eq) in MeCN (30.0 mL) was added 3-bromo-6methylpyridin-2-amîne (2.00 g, 10.7 mmol, 1.00 eq) at 0°C. The mixture was stirred at 60°C for 2 h The reaction mixture was quenched by Na^SOj -30.0 g at 20°C, and then filtered and the filtrate was coneentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 1/0 to 10/1). 3-bromo-2-iodo-6-methylpyridine (1.60 g, 5.37 mmol, 50% yield) was obtained as a yellow solid.
Step 2: 3-bromo-6-methyl-2-vinylpyridine
314
A mixture of 3-bromo-2-iodo-6-methylpyridine (1.60 g, 5.37 mmol, 1.00 eq), 4,4,5,5-letramethyl-2vinyLl,3,2-dioxaborolane (744 mg, 4.83 mmol, 820 uL, 0.900 eq), Na2CO3 (1.14g, 10.7 mmol, 2.00 eq) and Pd(dppf)Cl2 (196 mg, 269 umol, 0.0500 eq) in dioxane (20.0 mL) and water (2.00 mL) was degassed and purged with nitrogen 3 times at 20°C, and the mixture was stirred at 80°C for 2 h under nitrogen atmosphère. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 1/0 to 10/1). 3-bromo-6-methyl-2-vinylpyridine (600 mg, 3.03 mmol, 56% yield) was obtained as a yellow oil.
Step 3: 3-bromo-6-methylpicolinaldehyde
C N Br \=O
Ozone was bubbled into a solution of 3-biOrno-6-rnethyl-2-vinylpyridine (600 mg, 3.03 mmol, 1.00 eq) in DCM (35.0 mL) at -78°C for 0.5 hr. After excess O3 was purged by O2, Me2S (2.82 g, 45.5 mmol, 3.34 mL, 15.0 eq) was added to the mixture at 20°C. The mixture was stirred at 20°C for 8 h. LC-MS showed 3-broino-6-methyl-2-vinylpyridine was consumed completely and one main peak with desired mass was detected. The mixture was concentrated and water (10.0 mL) was added to the solution. The mixture was extracted with EtOAc (10.0 mL * 3), the combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0—11% Ethyl acetate/Petroleum ether gradient @ 40 mL/min). 3-bromo-6-methylpicolinaldehyde (250 mg, 1.25 mmol, 41% yield) was obtained as a whîte solid.
Step 4: 3-bromo-2-(difluoromethyl)-6-meihylpyridine fi
C N
Br y—F
F
To a solution of 3-bromo-6-methylpicolma]dehyde (250 mg, 1.25 mmol, LOÛ eq) in DCM (4.00 mL) was added DAST (403 mg, 2.50 mmol, 330 uL, 2.00 eq) at 0°C. The mixture was stirred at 20°C for 10 h. Cold water (2.ÛÛ mL) was added to the solution, then the mixture was extracted with EtOAc (3.00 mL * 3), the combined organic layers were dried over Na2SO4 and concentrated. The
315 residue was purified by prep-TLC (SiO2, Petroleum ether/Ethyl acetate = 5/1). 3-bromo-2(difluoromethyl)-6-methylpyridine (100 mg, 450 umol, 36% yield) was obtained as a yellow gum.
Step 5: tert-butyl (S)-4~(2-(difluoromethyl)-6-methylpyridin-3-yl)-12-fluoro-7a, 13-dihydro-7H[1,2,4]triazolo[4’,3':l, 6]pyrido[3,2-b]benzofuro[4,3-fg] [1,4] oxazonine-14(8H)-carboxylate
F
F
A mixture of 3-bromo-2-(dîfluoromethyl)-6-methylpyridine (70.0 mg, 315 umol, 1.00 eq), tert-butyl (S)-12-fluoro-4-(tributylstannyl)-7a, 13-dihydro-7H-[ 1,2,4]triazolo[4',3': l,6]pyrido[3,2b]benzofuiO[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (221 mg, 315 umol, 1.00 eq) and Pd(tBu3P)2 (16.1 mg, 31.5 umol, 0.100 eq) in dioxane (1.00 mL) was degassed and purged with nitrogen 3 times at 20°C, and the mixture was stirred at 100°C for 10 h under nitrogen atmosphère. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Petroleum ether/Ethyl acetate = 1/3). tert-butyl (S)-4-(2-(difluoromethyl)-6-methylpyridin-3yl)-12-fluoro-7a,13-dÎhydro-7H-[l,2,4]triazolo[4,,3':l,6]pyrido[3,2-b]benzofuro[4,3fg][l,4]oxazonine-14(8H)-carboxylate (80.0 mg, 145 umol, 45% yield) was obtained as a yellow solid.
Step 6: (S)-4-(2-(difluoromethyl)-6-methylpyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H[1,2,4] triazolo[4’, 3 ’:1,6]pyrido[3,2-b] benzo]uro[4,3-fg][l, 4] oxazonine
A mixture of tert-butyl (S)-4-(2-(difluoromethyl)-6-methylpyridin-3-yl)-12-fluoro-7a,13-dihydro7H-[I,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuiO[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (80.0 mg, 145 umol, 1.00 eq) in HFIP (2.00 mL) was stirred at 80°C for 5 h under nitrogen atmosphère. The reaction mixture was concentrated under reduced pressure. The residue was purified by prepHPLC (HCl conditions). !H NMR indicated insufficient purity. The product was further purified by prep-HPLC (formic acid conditions). The product-containing fraction was concentrated under reduced pressure to remove most of MeCN at 30° C and the aqueous phase was lyophilized. (S)-4
316 (2-(difluoromethy 1)-6-meÎhylpyridin-3-yl)-l 2-fluoro-7a, 8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine (18.0 mg, 38.0 umol, 26% yield, 95.6% purity) was obtained as a yellow solid. 'H NMR DMSO-A400 MHz δ = ppm 9.42 (s, IH), 7.90 (d, 7= 7.9 Hz, IH), 7.59 (brt,7=6.3 Hz, IH), 7.49 (d,7=7.9 Hz, IH), 7.24 (s, IH), 6.96 (br t, J = 9.6 Hz, IH), 6.83 (t, J= 54.8 Hz, IH), 6.72 - 6.65 (m, IH), 4.96 - 4.86 (m, IH), 4.82 - 4.71 (m, IH), 4.52 (br t, 7= 9.4 Hz, IH), 4.44 (br s, IH), 4.19 (br dd, 7= 9.5, 3.5 Hz, IH), 4.02 (brs, IH), 3.91 - 3.79 (m, IH), 2.57 (s, 3H). LCMS (ES I+): m/z 454.1 (M+H).
Example 106: (S)-12-fluoro-4-(5-methylpyridin-2-yl)-7a,8,13,14-tetrahydro-7H“ [l,2,4]triazolo[4’,3':l,6|pyrido[3,2-b]benzofuro(4,3-fg][l,4]oxazonine
Step 1: 5-methyl-2-(tributylstannyl)pyridine
O
An (n-Bu)3Sn
To a solution of 2-bromo-5-methylpyridine (1.00 g, 5.81 mmol, 1.00 eq) in THF (10.0 mL) was added n-BuLi (2.50 M, 2.81 mL, 1.21 eq) at -70°C under N2. The mixture was stirred at -70°C for 0.5 hr. Tributyl(chloiO)stannane (2.84 g, 8.72 mmol, 2.35 mL, 1.50 eq) was added to the mixture at -70°C and the mixture was stirred at 0°C for 1 hrThe reaction mixture was quenched by addition of water (10.0 mL) at 20°C, and extracted with PE (15.0 mL * 3). The combined organic iayers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified b y column chromatography (SiO2, Petroleum ether/Ethyl acetate = 1/0 to 20/1). 5-methyl-2(tributylstannyl)pyridine (500 mg, crude) was obtained as a yellow liquîd.
Step 2: tert-butyl (S)-12-fluoro-4-(5-methylpyridin-2-yl)-7a,13-dihydro-7H[1,2,4] triazolo ]4', 3 1,6]pyrido [3,2-b] benzofuro]4,3-fg]]l, 4] oxazonine-14(8H)-carboxylate / Boc CA
To a solution of tert-butyl (S)-4-bromo-l2-fIuoro-7a,13-dihydiO-7H[l,2,4]triazolo[4,,3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (200 mg, 407 umol, 1.00 eq) in dioxane (6.00 mL) was added 5-methyl-2-(tributylstannyl)pyridine (311 mg, 814 umol, 2.00 eq), Pd(PPh3)4 (47.0 mg, 40.7 umol, 9.99e-2 eq) and LiCl (40.0 mg, 944 umol, 19.3 uL, 2.32 eq), Cul (30.0 mg, 158 umol, 3.87e-l eq) at 20°C under N2. The mixture was stirred at 100°C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Petroleum ether/Ethyl acetate = 1/3). tert-butyl (S)-l2-fluoro-4-(5
317 methylpyridin-2-yl)~7a, 13-dihydro-7H-[ 1,2,451032010(4^3^ 1,6]pyrido[3,2-b5benzofuro[4,3fg][l,4]oxazonine-14(8H)-carboxylate (100 mg, crude) was obtained as a yellow solid.
Step 3: (S)-12-fluoro-4-(5-methylpyridin-2-yl)-7a,8,13,14-tetrahydro-7H[1,2,4] tri azoîo [4 3 1,6]pyrido[3,2-b] benzofuro[4,3 -fgj[l, 4] oxazonine
A mixture of tert-butyl (S)-12-fluoro-4-(5-methylpyridin-2-yl)-7a,13-dihydro-7H[l,2,4]triazolo[4’,3':l,6]pyri do [3,2-b]benzofuro[4,3-fg][ 1,4] oxazonine-14(8H)-carboxylate (100 mg, 199 umol, 1.00 eq) in HFIP (2.00 mL) was stirred at 100°C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: 10 Phenomenex Synergi C18 150 * 25 * 10 um; mobile phase: [water (0.04% HCl) - ACN]; B%: 10% 35%, 10 min). (S)-12-fluoro-4-(5-methylpyridin-2-yl)-7a,8,13,14-tetrahydiO-7H[ 1,2,4]triazolo[4',3’:l,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4]oxazonine (38.0 mg, 84.1 umol, 42% yield, 97.3% purity, HCl) was obtained as a brown solid. 'H NMR CD3OD 400 MHz S = ppm 9.65 (brs, IH), 8.67 (s, 1 H), 8.58 (s, IH), 8.26 (br s, IH), 8.10 (br s, IH), 6.91 (br t, 7= 9.4 Hz, 1H),6.67 15 (brdd, 7=8.4, 3.0 Hz, IH), 5.18 (brs, IH), 5.07 - 4.99 (m, IH), 4.81 (brs, IH), 4.64 (brt, 7= 8.9
Hz, IH), 4.33 (br d, 7= 9.2 Hz, IH), 4.07 (br s, 2H), 2.51 (br s, 3H). ‘H NMR DMSO-î/î 400 MHz δ = ppm 9.93 (brs, IH), 8.96 (brs, IH), 8.66 (brs, 2H), 8.44 (brs, IH), 8.02 (brs, IH), 7.09 - 6.94 (m, 1 H), 6.74 (br d, 7 = 6.0 Hz, 1 H), 4.95 (br s, 2H), 4.57 (br d, 7 = 9.2 Hz, 2H), 4.24 (br d, J = 7.2 Hz, IH), 4.11 (brs, IH), 4.00- 3.95 (m, 1 H), 2.40 (s, 3H). LCMS (ESI+): m/z 404.0 (M+H).
Example 107: (S)-4-(5-chloro-6-methylpyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
Step 1: 3-chloro-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine
Cl /
O
C N
0=8
To 5-bromo-3-chIoro-2-methylpyridine (150 mg, 727 umol, 1.00 eq) in dioxane (5.00 mL) were 25 added 4,4,5,5-tetramethyl-2-(4,4,5,5-teîramethyl-1,3,2-dioxaborolan-2-yi)-1,3,2-dioxaboroIane (369 mg, 1.45 mmol, 2.00 eq), Pd(dppf)Cl2 (53.2 mg, 72.7 umol, 0.100 eq), KOAc (143 mg, 1.45 mmol,
2.00 eq) at 20°C. Then the mixture was stirred at 100°C for 2 h under nitrogen atmosphère. The
318 reaction mixture was concentrated under reduced pressure to give 3-chloro-2-methyl-5-(4,4,5,5tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (200 mg, crude) as brown solid,
Step 2: tert-butyl (S)-4-(5-chloro-6-methylpyridin-3-yl)-12-fluoro-7a,13-dihydro-7H[I,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg] [l,4]oxazonine-14(8H)-carboxylate
To 3-chloro-2-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (155 mg, 611 umol, 2,00 eq) in EtOH (3.00 mL) and water (0.600 mL) was added KOAc (89.9 mg, 916 umol, 3.00 eq), 4-ditert-butylphosph any l-N,N-dimethyl-ani line dichloropalladium (21.6 mg, 30.5 umol, 21.6 uL, 0.100 eq) and tert-butyl (S)-4-bromo-12-fluoiO-7a,13-dihydro-7H[ l,2,4]triazolo[4',3': 1,6]pyrido [3,2-b] b enzofuro[4,3-fg] [1,4] oxazonine-14(8H)-carboxylate (150 mg, 305 umol, 1.00 eq) at 20 °C. The mixture was stirred at 80°C for 2 h under nitrogen atmosphère. The reaction mixture was concentrated under reduced pressure. The residue was purified by prepTLC (SiO2, PE:EtOAc = 0:1). tert-butyl (S)-4-(5-chloro-6-methylpyridin-3-yl)-12-fluoro-7a,13dihydro-7H-[l,2,4]triazoIo[4',3': 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ l,4]oxazonine-14(8H)~ carboxylate (120 mg, crude) was obtained as yellow solid.
Step 3: (S)-4-(5-chloro-6-meihylpyridin-3-yl)-l2-fluoro-7a,8,13,14-tetrahydro-7H[1,2,4]triazolo[4', 3 1,6]pyrido[3,2-b] benzqfuro[4,3-fg][1,4] oxazonine
To tert-butyl (S)-4-(5-chloro-6-methylpyridin-3-yl)-12-fIuoro-7a,13~dihydro-7H[l,2,4]triazolo[4f,3': l,6]pyrido[3,2-b]benzofuiO[4,3-fg][ 1,4]oxazonine-14(8H)-carboxylate (120 mg, 223 umol, 1.00 eq) was added HFIP (2.00 mL) at 20°C. The mixture was stirred at 100°C for 12 h. LC-MS showed tert-butyl (S)-4-(5-chloro-6-methylpyridin-3-yl)-12-fluoro-7a,13~dihydro-7H[l,2,4]triazolo[4',3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate was consumed completely and one main peak with desired mass was detected. The réaction mixture was concentrated under reduced pressure. The crude product was purified by prep-HPLC (HCl conditions). (S)-4-(5-chloro-6-methyIpyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H[ 1,2,4]triazolo[4',3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine (30.4 mg, 68.8 umol, 30% yield, 99.1% purity) was obtained as yellow solid. *H NMR CD3OD 400 MHz δ = ppm 9.81 (s,
319
IH), 9,09 (s, IH), 8,97 (s, IH), 8.33 (s, IH), 6.90 (t, J= 9,4 Hz, IH), 6.66 (dd,7=8.5, 3.6 Hz, IH), 5,19 (d, 7= 14.8 Hz, IH), 5.09 -4.93 (m, IH), 4.89 - 4.76 (m, IH), 4.62 (t, 7= 9.2 Hz, IH), 4.42 4.28 (m, IH), 4.19 - 3.90 (m, 2H), 2.93 (s, 3H). LCMS (ESI+): m/z 438.1/440,0 (M+H)/(M+3).
Example 108: (S)-12-fluoro-4-(2-methylpyridm-4-yl)-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3':l,6|pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
A mixture of (S)-4-bromo- 12-fluoro-7a,8,13,14-tetrahydro-7H-[ 1,2,4]triazolo[4',3': 1,6]pyrido[3,2b]benzofuro[4,3-fg][l,4]oxazonine (90.0 mg, 230 umol, 1.00 eq), (2-methyl-4-pyridyl)boronic acid (47.3 mg, 345 umol, 1.50 eq), 4-diterLbutylphosphanyl-N,N-dimethyl-aniline dichl oropalladium (16.3 mg, 23.0 umol, 16.3 uL, 0.100 eq), KOAc (45.0 mg, 459 umol, 1.99 eq) in EtOH (5,00 mL) and water (0.500 mL) was degassed and purged with nitrogen 3 times and the mixture was stirred at 80°C for 8 hr under nitrogen atmosphère. The residue was dissolved in MeOH (5.00 mL) and silica-thiol (200 mg, modified Silicon gel for eliminating Pd, irregular silica gel, 100-200 mesh, Chlorides (Cl), %<0.004, particle size distribution 45-75 um) was added at 20°C and stirred at 20°C for 3 h. The suspension was filtered, the filtrate was concentrated and purified by acidic prepHPLC (column: Phcnomenex Luna C18 150*30 mm*5 um; mobile phase: [water (0.04% HC1)ACN]; B%: 15%-40%, 10 min), The product-containing fraction was concentrated under reduced pressure to remove most of MeCN at 30°C and the aqueous phase was lyophilized. (S)-12-fluoro-4(2-methylpyridîn-4-yl)-7a,8,13,14-tetrahydro-7H-[ 1 ,2,4]ϊπηζο1ο[4',3': 1,6]pyrido[3,2b]benzofuro[4,3-fg][l,4]oxazonine (54.3 mg, 123 umol, 53% yield, 99.4% purity, HCl sait) was obtained as an orange solid. ’H NMR CD3OD 400 MHz δ = ppm 9.61 (s, IH), 8.68 (d, 7= 6.4 Hz, IH), 8.49 (s, IH), 8.44 (br d, 7= 6.2 Hz, IH), 8.40 (s, IH), 6.90 (t, 7 = 9.4 Hz, IH), 6.66 (dd, 7 = 8.7, 3.9 Hz, IH), 5.21 (brd,7= 14.8 Hz, 1H),4.98 (brd,7= 14.6 Hz, IH), 4.80 (br s, IH), 4.62 (br t,7=9,2 Hz, IH), 4.32 (brd,7=7.7 Hz, IH), 4.14 - 3,91 (m, 2H), 2.83 (s, 3H). LCMS (ESI+): m/z 404.2 (M+H).
Example 109: (S)-12-fluoro-4-(3-methoxypyridm-2-yI)-7a,8,13,14-tetrahydro-7H[1,2,4] triazolo|4’,3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4Joxazonine
Step 1: 3-merhoxy-2-(irimethylsictnnyl)pyridine
Me3Sn
320
To a solution of 2-biOmo-3-methoxypyridine (400 mg, 2.13 mmol, 1.00 eq) in dioxane (6.00 mL) was added Pd(PPha)4 (246 mg, 213 umol, 0.100 eq) and trimethyl(triinethylstannyl)stannane (1.39 g, 4.25 mmol, 882 uL, 2.00 eq) at 20°C under N2. The mixture was stirred at 100°C for 2 h. LC-MS showed no 2-bromo-3-methoxypyridine was remained. Several new peaks were shown on 5 LC-MS and desired m/s was detected. The réaction mixture was filtered and the filtrate was collected. 3-methoxy-2-(trimethylstannyl)pyridine (578 mg, crude) was dîssolved in dioxane (6.00 mL) and used into next step directly.
Step 2; tert-butyl (S)-12-fluoro-4-(3-methoxypyridin-2-yl)-7a,13-dihydro-7H[1,2,4]triazolo[4', 3 6]pyrido[3,2-b] benzofuro[4,3-fg] [1,4] oxazonine-14(8H)-carboxylate
To a solution of tert-butyl (S)-4-bromo-12-fluoro-7a,13-dihydiO-7H[l,2,4]triazolo[4',3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (200 mg, 407 umol, 1.00 eq) in dioxane (2.00 mL) was added 3-niethoxy-2-(trimethylstannyl)pyridme (578 mg, 2.13 mmol, 5.22 eq) in dioxane (6.00 mL), Pd(PPh3)4 (47.0 mg, 40.7 umol, 0.100 eq), Cul (38.8 15 mg, 204 umol, 0.500 eq) and LiCl (34.5 mg, 814 umol, 16.7 uL, 2.00 eq) at 20°C under N2. The mixture was stirred at 100°Cfor 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Petroleum ether/Ethyl acetate = 0/1). tertbutyl (S)- 12-fluoro-4-(3-methoxypyridin-2-yl)-7a, 13-dîhydro-7H[l^^triazolo^'p1: l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (85.0 20 mg, crude) was obtained as a yellow solid,
Step 3: (S)-l2-fluoro-4-(3-methoxypyridin-2-yl)-7a,8,l3,14-tetrahydro-7H[ 1,2,4]triazolo[4!,3 ': 1,6]pyrido[3,2-b] benzqfuro [4,3-fg] [1,4] oxazonine
A mixture of tert-butyl (S)-12-fluoro-4-(3-methoxypyridin-2-yl)-7a,13-dihydro-7H25 [1,2,4]triazolo[4',3': 1,6]pyrido[3,2-b]benzofuro(4,3-fg][ l,4]oxazonine- 14(8H)-carboxylate (85.0 mg, 164 umol, 1.00 eq) in HFIP (2.00 mL) was stirred at 100°C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Luna CI8 150 * 30 mm * 5 um; mobile phase: (water (0.04% HCl) - ACN]; B%: 20%
321
50%, 10 min). (S)-12-fluoro-4-(3-methoxypyridin-2-yl)-7a,8,13,14-tetrahydro-7H[ l,2,4]triazoJo[4',3’: 1,6]pyrido[ 3,2-b] benzofuro [4,3-fg] [1,4] oxazonine (23.0 mg, 48.9 umol, 29% yield, 97.0% purity, HCl sait) was obtained as a yellow solid. ’H NMR DMSO-rfi 400 MHz δ = ppm 10.13 (s, IH), 9.18 (br t, 7= 6.0 Hz, IH), 8.66 (s, IH), 8.42 - 8.34 (ni, IH), 7.80 - 7.71 (m, IH), 7.50 (dd, 7 = 8.4, 4.8 Hz, IH), 7.02 (t,7= 9.6 Hz, IH), 6.75 (dd,7= 8.4, 4.0 Hz, IH), 5.06 - 4.92 (m, 2H), 4.54 (br t, 7= 9.2 Hz, 2H), 4.29 - 4.22 (m, IH), 4.16 (br s, IH), 4.00 (br s, IH), 3.99 (s, 3H). LCMS (ESI+): m/z 420.0 (M+H).
Example 110: (S)-12-fluoro-4-(pyrimidin-4-yl)-7a,8,l3,14-tetrahydro-7H[l,2,4]triazolo[4’,3’:l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
Step 1: tert-butyl (S)-12-fluoro-4-(pyrimidin-4-yl)-7a, 13-dihydro-7H[1,2,4]triazolo[4!,3 1,6]pyrido[3,2-b] benzofuro]4,3-fg] [ 1,4] oxazonine-14(8H)-carboxylate
To a solution of tert-butyl (S)-4-bromo-12-fluoro-7a,13-dihydro-7H[l,2,4]triazolo[4',3': 1,6] pyrido[3,2-b]benzofuro [4,3-fg][ 1,4] oxazonine-14(8 H)-carboxylate (140 mg, 285 umol, 1.00 eq) in dioxane (6.00 mL) was added 4-(tributylstannyl)pyrimidine (210 mg, 569 umol, 2.00 eq), Pd(PPh3)4 (32.9 mg, 28.5 umol, 0.100 eq), LiCl (24.2 mg, 571 umol, 11.7 uL, 2.00 eq) and Cul (21.7 mg, 114 umol, 0.400 eq) at 20°C. The mixture was stirred at 100°C for 12 h under nitrogen atmosphère. The reaction was concentrated. The residue was purified by prep-TLC (SiO2, Petroleum ether/Ethyl acetate = 0/1). tert-butyl (S)-12-fluoro-4-(pyrimidin-4-yl)-7a,13dihydro-7H-[l,2,4]triazolo[4',3,:l,6]pyi-ido[3,2-b]benzofuro[4,3-fg][i,4]oxazonine-14(8H)carboxyiate (140 mg, crude) was obtained as a green solid.
Step 2: Example 151: (S)-12-fluoro-4-(pyrimidin-4-yl)-7a,8,13,14-tetrahydro-7H[1,2,4]triazolo[4',3 ':1,6]pyrido[3,2-b] benzofuro[4,3-fg] [1,4] oxazonine
A mixture of tert-butyl (S)-12-fluoro-4-(pyrimidin-4-yl)~7a,13-dihydro-7H[ 1,2,4] triazolof 4', 3': I,6]pyrîdo[ 3,2-b] benzofuro [4,3-fg] [1,4] oxazonine-14(8H)-carboxylate (140 mg, 285 umol, 1.00 eq) in HFIP (5.00 mL) was stirred at 100°C for 12 hThe réaction was concentrated. The residue was dîssolved in DMSO (4.00 mL), the mixture was purified by acidic prep-HPLC
322 (column: Phenomenex Luna Cl8 150 * 30 mm * 5 um; mobile phase: [water (0.04% HC1)-ACN]; B%: 25%-40%, 10 min). The product-containing fraction was concentrated under reduced pressure to remove most of MeCN at 30°C and the aqueous phase was lyophilized. (S)-12-fluoro-4(pyrimidin-4-yl)-7a,8,13,14-tetrahydro-7H-[ 1,2,4]triazolo[4',3': 1 ,6]pyrido[3,2-b]benzofuro| 4,3fg][ 1,4] oxazonine (36.2 mg, 84.8 umol, 29% yield, 100% purity, HCl sait) was obtained as an orange solid. 'H NMR DMSO-^ 400 MHz δ = ppm 9.95 (s, IH), 9.22 (s, IH), 9.01 (br s, IH), 8.88 (br d, J= 5.3 Hz, IH), 8.67 (s, 2H), 6.98 (br t, J= 9.5 Hz, IH), 6.71 (dd, J-8.6, 3.5 Hz, IH), 5.17 4.91 (m, 2H), 4.69 - 4.51 (m, 2H), 4.24 (dd, J-9.2, 4.1 Hz, IH), 4.17 - 4.09 (m, IH), 4.05 - 3.96 (m, IH). LCMS (ESI+): m/z 391.1 (M+H).
Example 111: (S)-12-fluoro-4-(6-methylpyrirnidin-4-yl)-7a,8,13,14-tetrahydro-7H[l,2,4]tnazolo[4',3':l,6|pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
Step 1: 4-methyl-6-(trimethylstannyl)pyrimidine
To 4-bromo-6-methylpyrimidine (200 mg, 1.16 mmol, 1.00 eq) in dioxane (4.00 mL) was added trimethyl(trimethylstannyl)stannane (757 mg, 2.31 mmol, 479 uL, 2.00 eq) and Pd(PPh3)4 (134 mg, 116 umol, 0.100 eq) al 20°C. The mixture was stirred at 100°C for 12 h under nitrogen atmosphère. LC-MS showed 4-biOmo-6-methylpyrimidine was consumed completely and one main peak with desired mass was detected. The obtained solution of 4-methyl-6-(trimethyl stannyl)pyrimidine (297 mg, crude) was used in next step directly.
Step 2: tert-butyl (S)-i 2-fluoro-4-(6-methylpyrimidin-4-yl)-7a, i 3-dihydro-7H[1,2,4]triazolo[4', 3 1,6]pyrido[3,2-b] benzofuro]4,3-fg] [ 1,4] oxazonine-14(8H)-carboxylate
To 4-methyl-6-(trimethylstannyl)pyrimidine (297 mg, 1.16 mmol, 2.84 eq) in dioxane (4.00 mL) was added tert-butyl (S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[l,2,4]triazolo[4',3':l,6]pyrido[3,2b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (200 mg, 407 umol, 1.00 eq), Cul (31.0 mg, 163 umol, 0.400 eq), LiCl (34.5 mg, 814 umol, 16.7 uL, 2.00 eq) and Pd(PPh3)4 (47.0 mg, 40.7 umol, 0.100 eq) at 20°C. The mixture was stirred at 80°C for 2 h under nitrogen atmosphère. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue
323 was purified by /^rep-TLC (SiO2, PE:EtOAc = 1:1). tert-butyl (S)-12-fluoro-4-(6-methylpyrimidin4-yl)-7a,13-dihydro-7H-[l,2,4]triazolo[4,,3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine14(8H)-carboxylate (180 mg, crude) was obtained as brown oil.
Step 3: (S)-12-fluoro-4-(6-methylpyrimidin-4-yl)-7a,8J3.14-tetrahydro-7H[1,2,4]triazolo [4’,3':1,6]pyrido[3,2-b] benzofiirof4,3-fg][l, 4/ oxazonine
To tert-butyl (S)-12-fluoro-4-(6-methylpyrimidin-4-yl)-7a, 13-dihydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (180 mg, 357 umol, 1.00 eq) was added HFIP (2.00 mL) at 20°C. The mixture was stirred at 100°C for 12 h. The reaction mixture was concentrated under reduced pressure. The crude product was purified by T?rep-HPLC (HCl conditions). (S)-12-fluoro-4-(6-methylpyrimidin-4-yl)-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine (24.9 mg, 55.9 umol, 15% yield, 98.9% purity, HCl sait) was obtained as yellow solid. ]H NMR CD3OD 400 MHz. δ = ppm 9.60 (s, 1H), 9.26 (s, 1H), 8.89 (s, IH), 8.41 (s, 1H), 6.94 (t, J = 9.2 Hz, 1H), 6.76 - 6.66 (m, 1H), 5.35 - 5.27 (m, 1H), 5.03 (br s, 2H), 4.70 - 4.60 (m, 1H), 4.42 - 4.28 (m, 1H), 4.19 - 3.95 (m, 2H), 2.74 (s, 3H). LCMS (ESI+): m/z 405.1 (M+H).
Example 112: (S)-4-(3-ethyM-methyl-lH-pyrazol-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo|4’,3’:l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,41oxazonine
Step 1: 3-ethyl-l-methyl-lH-pyrazol-5-ol /^N \\ I / Nx
HO
A mixture of methyl 3-oxopentanoate (5.00 g, 38.4 mmol, 4.76 mL, 1.00 eq), methylhydrazîne (1.86 g, 16.2 mmol, 2.13 mL, 0.420 eq), HCl (12.0 Μ, 160 uL, 0.0500 eq) in EtOH (100 mL) was degassed and purged with nitrogen 3 times at 20°C, and the mixture was stiired at 80°C for 10 h under nitrogen atmosphère. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-20% Ethylacetate/Petroleum ethergradient @ 50 mL/min). 3-Ethyl-l-methyllH-pyrazol-5-ol (1.90 g, 15.1 mmol, 39% yield) was obtained as a light red solid. lH NMR
324
DMSO-î/640Ü MHz J = ppm 10.67 (br s, 1 H), 5.1 1 (s, IH), 3.37 (br s, 3H), 2.34 (q, J= 7.6 Hz, 2H), 1.06 (t, J=7.6Hz, 3H).
Step 2: 3-ethyl-I -methyl-1 H-pyrazol-5-yl trifluoromethanesulfonate £ Λ NX TfO
To a solution of 3-eîhyI-l-methyl-lH-pyrazol-5-ol (500 mg, 3.96 mmol, 1.00 eq), 1,1,1-trifîuoro-Nphenyl-N-(trifluoiOmethylsulfonyl)methanesulfonamide (1.70 g, 4.76 mmol, 1.20 eq) in DCM (10.0 mL) was added DIPEA (1.02 g, 7.93 mmol, 1.38 mL, 2.00 eq) at 0°C. The mixture was stirred at 20°C for 10 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-20% Ethyl acetate/Petroleum ethergradient @ 30 mL/min). 3-ethyl-l-methyl-lH-pyrazol-5-yl trifluoromethanesulfonate (700 mg, 2.71 mmol, 68% yield) was obtained as a coiourless oil.
Step 3: 3-ethyl-l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole / N
O-B X / \
A mixture of 3-ethyl-l-methyl-lH-pyrazol-5-yl trifluoromethanesulfonate (500 mg, 1.94 mmol, 1.00 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (740 mg, 2.91 mmol, 1.50 eq), KOAc (570 mg, 5.81 mmol, 3.00 eq), Pd(dppf)Cl2 (142 mg, 194 umol, 0.100 eq) in dioxane (15.0 mL) was degassed and purged with nitrogen 3 times at 20°C, and the mixture was stirred at 90°C for 10 h under nitrogen atmosphère. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Petroleum ether/Ethyl acetate = 1/1). 3-ethyl- l-methyL5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-lHpyrazole (260 mg. 1.10 mmol, 56% yield) was obtained as a light yellow solid.
Step 4: tert-butyl (S)-4-(3-ethyl-l-methyl-lH-pyrazol-5-yl)-12-fluoro-7a,î3-dihydro-7H[1,2,4]triazolo[4',3 1,6]pyrido[3,2-b] benzofurof4,3-fg][I,4] oxazonine-14(8H)-carboxylate
325
A mixture of 3-ethyl-l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (127 mg, 538 umol, 1.20 eq), tert-butyl (S)-4-bromo-12-fluoro-7a,13-dihydro-7H[ 1,2,4]triazolo[4',3’: 1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate (220 mg, 448 umol, 1.00 eq), Na2CO3 (94.9 mg, 895 umol, 2.00 eq), Pd(dppf)C12 (32.8 mg, 44.8 umol, 0.100 eq) in dioxane (5.00 mL) and water (0.500 mL) was degassed and purged with nitrogen 3 times at 20°C, and the mixture was stirred at 80°C for 10 h under nitrogen atmosphère. The reaction mixture was coneentrated under reduced pressure. The residue was purified by prcp-TLC (SiO2, Petroleum ether/Ethyl acetate = 0/1). tert-butyl (S)-4-(3-ethyl-1 -methyl- lH-pyrazol-5-yl)-12-fluoro-7a, 13dihydro-7H-[ 1,2,4]triazolo[4',3': 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4] oxazonine-14(8 H)carboxylate (110 mg, 211 umol, 47% yield) was obtained as a brown solid.
Step 5.· (S)-4-(3-elhyl-l-methyl-lH-pyrazol-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H[1,2,4] triazolo [4 3 ’:1,6]pyrido[3,2-b]benzofuro[4,3-fg] [ 1,4] oxazonine
To a solution of tert-butyl (S)-4-(3-ethyl-l-methyl-IH-pyrazol-5-yl)-l 2-fluoro-7a,13-dihydro-7H[ l,2,4]triazolo[4',3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (110 mg, 211 umol, 1.00 eq) in DCM (2.50 mL) was added TFA (1.00 mL) at 20°C. The mixture was stirred at 20°C for 1 hr. The reaction mixture coneentrated under reduced pressure. The residue was purified by prep-HPLC (HCl condition). The product-containing fraction was coneentrated under reduced pressure to remove most of MeCN at 30°C and the aqueous phase was lyophilized. (S)-4(3-ethyl-l-methyl-lH-pyrazol-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofiiiO[4,3-fg][l,4]oxazonine (36.6 mg, 79.9 umol, 37% yield, 99.8% purity, HCl) was obtained as a yellow solid. 'H NMR CD3OD 400 MHz δ = ppm 9.56 (s, IH), 8.07 (s, IH), 6.93 (dd, 7= 10.0, 8.8 Hz, IH), 6.69 (dd, 7= 8.7, 3.9 Hz, IH), 6.54 (s, IH), 5.22 (d,7= 14.8 Hz, 1 H), 4.97 (brd,7= 14.7 Hz, IH), 4.83 - 4.72 (m, IH), 4.63 (t,7=9.5 Hz, IH), 4.32 (dd,7=9.7, 3.4 Hz, IH), 4.12 - 4.00 (m, IH), 3.97 - 3.86 (m, IH), 3.81 (s, 3H), 2.76 (q, 7= 7.6 Hz, 2H), 1.33 (t, 7= 7.6 Hz, 3H). LCMS (ESI+): m/z 421.1 (M+H).
326
Example 113: (S)-4-(5-ehloropyriinidin-4-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H[ 1,2,4] tri azolo[4',3':1,6 J pyrido[3,2-b]benzofuro[4,3-fg) [1,4] oxazonine
Step 1: 5-chloro-4-iodopyrimidine
To a solution of 5-chloropyrimidin-4-amine (760 mg, 5.87 mmol, 1.00 eq) and CH2I2 (3.14 g, 11.7 mmol, 946 uL, 2.00 eq) in MeCN (15.0 mL) was added isopentyl nitrite (1.51 g, 12.9 mmol, 1.74 mL, 2.20 eq) in MeCN (3.00 mL) under nitrogen atmosphère at 0°C. The mixture was stirred at 0°C for 3 h. Then the mixture was stirred at 60°C for 36 h under nitrogen atmosphère. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO?, Petroleum ether/Ethyl acetate = 9/1). 5-Chloro-4-iodopyrimidine (570 mg, 2.37 mmol, 40% yield) was obtained as a light yellow solid.
Step 2: tert-butyl (S)-4-(5-chloropyrimidin-4-yl)-12-fluoro-7 a, 13-dihydro-7H[1,2,4] triazolo[4',3 6]pyrido[3,2-b]benzo]ùro[4,3-fg][1,4] oxazonine-14(8H)-carboxylate
A mixture of tert-butyl (S)-12-fIuoro-4-(tributylstannyl)-7a,13-dihydro-7H[l,2,4]triazolo[4’,3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (200 mg, 285 umol, 1.00 eq), 5-chloiO-4-iodopyrimidine (137 mg, 570 umol, 2.00 eq), Pd(r-Bu3P)2 (14.6 mg, 28.6 umol, 0.100 eq) in dioxane (5.00 mL) was degassed and purged with nitrogen 3 times, and the mixture was stirred atl00°Cforl6 h under nitrogen atmosphère. The reaction mixture was concentrated under reduced pressure. The residue was purified by/vep-TLC (SiO2, Petroleum ether/Ethyl acetate = 1/3). tert-butyl (S)-4-(5-chloropyrimidin-4-yl)-12-fluoro-7a,13-dihydro-7H[ l,2,4]triazolo[4',3': l,6]pyrido[3,2-b]benzoharo[4,3-fg][1,4]oxazonine-14(8H)-carboxylate (125 mg, crude) was obtained as a yellow oil.
Step 3: (S)-4-(5-chloropyrimidin-4-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H[1,2,4]triazolo[4’, 3 ’:l,6]pyrido[3,2-b] benzofuro[4,3-fg][ 1,4] oxazonine
327
A mixture of tert-butyl (S)-4-(5-chloropyrimidin-4-yl)-12-fluoro-7a,13-dihydro-7H[l,2,4]triazolo[4’,3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (125 mg, 238 umol, 1.00 eq) in HFIP (5.00 mL) was stirred at 100°C for 12 hr under nitrogen atmosphère. LC-MS indicated low conversion. The mixture was concentrated under reduced pressure. The residue was dissolved in DCM (5.00 mL) and TFA (2.00 mL) at 25°C under nitrogen atmosphère, and the mixture was stirred at 25°C for 1 hr. LC-MS showed that the reaction was complété. The mixture was concentrated under reduced pressure. The residue was purified by /irep-HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water (0.04% HCl)-ACN]; B%: 10%-30%, 10 min). The product-containing fraction was concentrated under reduced pressure to remove most of MeCN at 30°C and the aqueous phase was lyophilized. (S)-4-(5-chloropyriinidin-4yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4’,3':l,6]pyrido[3,2-b]benzofuiO[4,3fg][ 1,4] oxazonine (22.0 mg, 46.9 umol, 19% yield, 98.3% purity, HCl) was obtained as a yellow solid. lH NMR CD3OD 400 MHz δ = ppm 9.65 (s, 1H), 9.20 (s, 1H), 8.98 (s, 1H), 8.95 (s, 1H), 6.95 (br t, J = 9.5 Hz, 1H), 6.71 (dd, J= 8.6, 3.8 Hz, 1H), 5.28 (br d, J = 14.7 Hz, 1H), 5.05 (br d, J = 14.7 Hz, 2H), 4.65 (br t, J= 9.4 Hz, IH), 4.35 (br d, 7.2 Hz, 1H), 4.12 (br s, 1H), 3.98 (br s, 1H). LCMS (ES1+): m/z 425.0/427.0 (M+H)/(M+3).
Example 114: (S)-12-fluoro-4-(5-fluoropyrimidin-4-yl)-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4, ;3':l,6]pyrido[3,2-b]benzofuiOl4,3-fg|[l,4]oxazonine
Step 1: 5-fluoro-4-iodopyrimidine
To a solution of 5-fluoropyrimidin-4-amine (250 mg, 2.21 mmol, 1.00 eq) and CH2I2 (1.18 g, 4.42 mmol, 357 uL, 2.00 eq) in MeCN (2.00 mL) was added isopentyl nitrite (570 mg, 4.87 mmol, 655 uL, 2.20 eq) in MeCN (0.500 mL) at 0°C. The mixture was stirred at 0°C for 1 hr. Then the mixture was warmed to 60°C. The mixture was stirred at 60°C for 1 hr. The residue was purified by />rep-TLC (SiO2, Petroleum ether/Ethyl acetate = 10/1). 5-fluoro-4-iodopyrimidine (80.0 mg, 357 umol, 16% yield) was obtained as a yellow solid.
Step 2: 5-fluoro-4-(trimethylstannyl)pyrimidine
Me3Sn
A mixture of 5-fluoro-4-iodopyriimdine (80.0 mg, 357 umol, 1.00 eq), trimethyl(trimethylstannyl)starmane (234 mg, 715 umol, 148 uL, 2.00 eq) and Pd(PPh3)4 (41.3 mg, 35.7 umol, 0.100 eq) in dioxane (3.00 mL) was degassed and purged with nitrogen 3 times at 20°C,
328 and the mixture was stirred at 100°C for 1 hr under nitrogen atmosphère. LC-MS showed 5-fluoro4-iodopyrimidine was consumed completely and one main peak with desired mass was detected. 5fluoro-4-(trimethylstannyl)pyrimidine (93.2 mg, crude) in 3.00 mL of dioxane was used in the next step directly.
Step 3; tert-butyl (S)-12-fluoro-4-(5-fluoropyrimidin-4-yl)-7a,I3-dihydro-7H[1,2,4]triazolo[4’, 3 ':1,6]pyrido[3,2-b]benzofuro[4,3-f$[l,4]oxazonine-l 4(8H)-carboxylale
A mixture of 5-fluoro-4-(trimethylstannyl)pyrimidine (93.2 mg, 357 umol, 1.00 eq) in dioxane (3.00 mL), tert-butyl (S)-4-bromo-12-fluoro-7a,13-dihydiO-7H-[l,2,4]triazolo[4’,3’:l56]pyrido[3,2b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (176 mg, 358 umol, 1.00 eq), LiCl (22.7 mg, 535 umol, 11.0 uL, 1.50 eq), Cul (34.0 mg, 179 umol, 0.500 eq) and Pd(PPh3)4 (41.3 mg, 35.7 umol, 0.100 eq) in dioxane ( 1.00 mL) was degassed and purged with nitrogen for 3 times at 20°C, and the mixture was stirred at 100°C for 12 h under nitrogen atmosphère. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Ethyl acetate/Methanol = 10/1). tert-butyl (S)-12-fluoiO-4-(5-fluoropyrimidin-4-yl)-7a,13-dihydro-7H[l,2,4]triazolo[4',3’:l,6]pyrido[3,2-b]benzofuiO[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (80.0 mg, crude) was obtained as a yellow solid.
Step 4: (S)-12-ftuoro-4-(5-fluoropyrimidin-4-yl)-7a,8,13,14-tetrahydro-7H[1,2,4]triazolo[4',3 6]pyrido[3,2-b]benzofuro[4,3-fg] [ l,4]oxazonine
A mixture of tert-butyl (S)-12-fluoro-4-(5-fluoropyrimidin-4-yl)-7a,13-dihydiO-7H[l,2,4]triazolo[4',3,:i,6]pyrido[3,2-b]benzofutO[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (75.0 mg, 148 umol, 1.00 eq) in HFIP (2.00 mL) was stirred at 80°C for 10 h under nitrogen atmosphère. The reaction mixture was concentrated under reduced pressure. The residue was purified by prepHPLC (HCl condition). The product-containing fraction was concentrated under reduced pressure to remove most of MeCN at 3Û°C and the aqueous phase was lyophilized. (S)-12-fluoro-4-(5fluoropyrimidin-4-yl)-7a,8,13,14-tetrahydro-7H-[ l,2,4]triazolo[4',3':l,6]pyrido[3,2
329
b]benzofLiro[4,3-fg][l,4]oxazonine (19.6 mg, 43,7 umol, 29% yield, 99.2% purity, HCl) was obtained as a yellow solid. JH NMR CD3OD 400 MHz δ = ppm 9.62 (s, IH), 9.14 (d, J = 2.9 Hz, IH), 8.88 (d, J=4.4Hz, IH), 8.68 (d, J = 1.5 Hz, 1 H), 6.95 (dd, 10.3, 8.8 Hz, IH), 6.71 (dd,./ = 8.8, 3.9 Hz, IH), 5.36 - 5.24 (m, IH), 5.13 - 4.94 (m, 2H), 4.70 - 4.58 (m, IH), 4.43 - 4.30 (m, IH), 4.17 - 4.09 (m, IH), 4.06 - 3.89 (m, IH). LCMS (ESI+): m/z 409.0 (M+H).
Exainple 115: (S)-4-(l,4-dimethyl-lH-imidazol-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H[l,2,4]trÎazolo[4',3':l,6]pyridoi3,2-b]benzofuro[4,3-fg][l,4]oxazonine
Step 1: 5-bromo-1,4-dimethyl-l H-imidazole
To a solution ofNaH (745 mg, 18.6 mmol, 60% purity, 1.20 eq) in THF (12.5 mL) was added 5bromo-4-methyl-l H-imidazole (2.50 g, 15.5 mmol, 1.00 eq) in THF (12.5 mL) at 0°C, and the mixture was stirred at 20°C for 0.5 hr. To the réaction mixture was added Mel (3.31 g, 23.3 mmol, 1.45 mL, 1.50 eq) dropwise at 20°C. The mixture was stirred at 20°C for 16 hr. The reaction mixture was quenched by addition of water (10.0 mL) and extracted with EtOAc (20.0 mL * 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Petroleum ether:Ethyl acetate = 0:1). 5Bromo-l,4-dimethyl-l H-imidazole (540 mg, 3.09 mmol, 19% yield) was obtained as a light-yellow oil. ‘H NMR CDC13 400 MHz δ = ppm 7.47 (s, 1 H), 3.57 (s, 3H), 2.19 (s, 3H).
Step 2: tert-butyl (5)-4-(1,4-dimethyl-lH-imidazol-5-yl)-12-]luoro-7a,13-dihydro-7H[1,2,4]triazolo[4', 3 1,6]pyrido[3,2-b]benzofuro[4,3-fg] [1,4] oxazonine-14(8H)-carboxylate
The reaction was set up in two batches. A mixture of tert-butyl (S)-12-fluoro-4-(tributylstannyl)7a,13-dihydiO-7H-[l,2,4]triazolo[4',3': l,6]pyrido[3,2-b]benzofuiO[4,3-fg][l,4]oxazonine-14(SH)carboxylate (100 mg, 143 umol, L10 eq), 5-bromo-l,4-dimethyl-lH-imidazoie (68.0 mg, 389 umol, 3.00 eq), Pd(t-Bu3P)2 (13.3 mg, 26.0 umol, 0.201 eq) in dioxane (5.00 mL) was degassed and purged with nitrogen 3 times, and the mixture was stirred at 100°C for 16 hunder nitrogen atmosphère. The batches we combined and concentrated under reduced pressure. The residue was dissolved in MeOH (5.00 mL) and silica-thiol (300 mg, modified Silicon gel for eliminating Pd, irregular silica gel, 100-200 mesh, Chlorides (Cl), %<0.004, particle size distribution 45-75 um) was added at 20°C
330 and stirred at 20°C for 3 h. The suspension was filtered, the filtrate was concentrated and purified by prep-HPLC (column: Welch Xtimate CI8 150*25 mm*5 um; mobile phase: [water (10 mM NH4HCOj)-ACN]; B%: 40%-65%, 10 min). The product-containing fraction was concentrated under reduced pressure to remove most of MeCN at 30°C and the aqueous phase was iyophilized.
tert-butyl (S)-4-(l,4-dimethyl-lH-imidazol-5-yl)-12-fluoro-7a, 13-dihydro-7H[ 1,2,4]triazolo[4',3': 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ l,4]oxazonine- 14(8H)-carboxylate ( 13 mg, 25.7 umol, 9% yield) was obtained as a colorless oil.
Step 3: (5)-4-(1,4-dimethyl-IH-imidazol-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H[1,2,4] triazolo [4 3':1,6]pyrido[3,2-b] benzqfuro[4,3 -fg] [1,4] oxazonine
F
A mixture of tert-butyl (S)-4-(l,4-dimethyl-lH-imidazol-5-yl)-12-fluoiO-7a,13-dihydro-7H[ 1,2,4]triazolo[4',3': 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4]oxazonine- 14(8H)-carboxylate (13.0 mg, 25.7 umol, 1.00 eq) in l,l,l,3,3,3-hexafluoropropan-2-ol (1.00 mL) was degassed and purged with nitrogen 3 times, and the mixture was stirred at l00°C for 36 hr under nitrogen atmosphère.
The mixture was concentrated under reduced pressure. The residue was dissolved in DCM (2.00 mL) and TFA (1.54 g, 13.5 mmol, 1.00 mL, 526 eq) was added dropwise at 20°C. The mixture was stirred at 20°C for 1 hr. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water (0.04% HC1)-ACN]; B%: l%-20%, 10 min). The product-containing fraction was concentrated under reduced pressure to remove most of MeCN at 30°C and the aqueous phase was Iyophilized. The obtained product was combined with another batch of 5 mg. !H NMR indicated insufficient purity. The product was purified by prep-HPLC (column: Phenomenex Luna Cl8 150*30 mm*5 um; mobile phase: [water (0.04% HC1)-ACN]; B%: 15%-45%, 10 min). The product-containing fraction was concentrated under reduced pressure to remove most of MeCN at
30°C and the aqueous phase was Iyophilized. (S)-4-(l,4-dimethyl-lH-imidazol-5-yl)-12-fluoro7a,8,13,14-tetrahydro-7H-[l ,2,4]triazolo[4',3': 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4]oxazonine (10.1 mg, 22.7 umol, 88% yield, 99.6% purity, HCl sait) was obtained as a white solid. ’H NMR CD3OD 400 MHz δ = ppm 9.57 (s, IH), 9.05 (s, IH), 8.10 (s, IH), 6.93 (t, J-9.4 Hz, IH), 6.69 (dd, 7 = 8.4, 3.7 Hz, IH), 5.23 (br d, 7= 14.6 Hz, IH), 4.97 (br d, 7= 15.0 Hz, IH), 4.79 (br s, IH), 4.63
331 (br t, J= 9,3 Hz, IH), 4.31 (br d, J= 6,8 Hz, IH), 4.07 (br s, IH), 3,92 (br d, J= 10.6 Hz, IH), 3.70 (br s, 3H), 2.24 (br s, 3H). LCMS (ESI+): m/z 407.0 (M+H).
Example 116: (S)-4-(l,5-dimethyl-lH-imidazol-2-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo|4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
Step 1: 2-bromo-J,5-dimethyl-lH-imidazole
Br
Two parallel reactions were set up. To a solution of 2-bromo-5-methyl-lH-imidazole (600 mg, 3.73 mmol, 1.00 eq) in THF (8.00 mL) was added NaH (298 mg, 7.45 mmol, 60% purity, 2.00 eq) at 0°C. The mixture was stirred at 0°C for 0.5 hr under nitrogen atmosphère. Mel (1.06 g, 7.45 mmol, 464 uL, 2.00 eq) was added to the mixture at 0°C and the mixture was stirred at 20°C for 12 h under nitrogen atmosphère, LCMS showed 2-bromo-5-methyl-lH-imidazole was consumed completely and the desired mass was detected, TLC (SiO2, Petroleum ether/Ethyl acetate = 1/1) showed two new spots formed. The batches were combined, water (10.0 mL) was added, and the mixture was extracted with ethyl acetate (10.0 mL * 3). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 1/0 to 0/1). 2-Bromo-l,5-dimethyl-IH-imidazole (450 mg, 2.57 mmol, 34% yield) was obtained as a yellow oil.
Step 2: tert-butyl (S)-4-(l,5-dimethyl-lH-imidazol-2-yl)-12-fluoro-7a,13-dihydro-7H[1,2,4]triazolo[4\3 1,6]pyrido[3,2-b]benzofiiro[4,3-fg] [1,4] oxazonine- 14(8H)~carboxylate
To a mixture of tert-butyl (S)-12-fluoro-4-(tributylstannyI)-7a,13-dihydro-7H[l,2,4]triazolo[4’,3':L6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (200 mg, 285 umol, 1.00 eq) in dioxane (8.00 mL) was added 2-bromo-l,5-dimethyl-lH-imidazole (99.8 mg, 570 umol, 2.00 eq), Cul (21.7 mg, 114 umol, 0.400 eq), LiCl (24.2 mg, 570 umol, 11.7 uL, 2.00^) and Pd(PPh3)4 (33.0 mg, 28,5 umol, 0.100 eq) at 20°C, The mixture was stirred at 100oC for 12 h under nitrogen atmosphère. The reaction mixture was concentrated. The residue was dissolved in DMSO (7.00 mL) and purified by prep-HPLC (column: Phenomenex Luna C18 200*40 mm* 10 um; mobile phase: [water (0.2% FA)-ACN]; B%: 25%-45%, 10 min). The product-containing
332 fraction was concentrated under reduced pressure to remove most of MeCN at 30°C and the aqueous phase was lyophilized. tert-Butyl (S)-4-(l,5-dimethyl-lH-imidazol-2-yl)-12-fluoro-7a, 13-dihydro7H-[ l,2,4]triazolo[4)3': 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4]oxazonine- 14(8H)-carboxylate (140 mg, 253 umol, 88% yield, formate sait) was obtained as a green solid.
Step3: (S)-4-(l,5-dimethyl-lH-imidazol-2-yl)-12-fluoro- 7a, 8,13,14-tetrahydro- 7H[ 1,2,4]triazolo[4', 3r: 1,6]pyrido[3,2-b]benzofuro[4,3-fg] [1,4] oxazonine
F
A mixture of tert-butyl (S)-4-(l,5-dimethyl-1H-imidazol-2-yl)-l2-fluoro-7a,l3-dihydro-7H[l,2,4]triazolo[4)3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxyIate (140 mg, 253 umol, 1.00 eq, FA) in HFÏP (8.00 mL) was stirred at 100°C for 6 h. . The reaction was concentrated. The residue was dissolved in DMSO (5.00 mL). The suspension was filtered, the filtrate was concentrated and purified by acidic prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40 mm* 10 um; mobile phase: [water (0.04% NH3H2O+I0 mM NHqHCOjj-ACN]; B%: 15%-55%, 10 min). The product-containing fraction was concentrated under reduced pressure to remove most of MeCN at 30°C and the aqueous phase was lyophilized. The obtained product was dissolved in water (2.00 mL), then HCl (12.0 M, 0.0100 mL) was added to the mixture, and the solution was re-lyophilized. (S)-4-(l,5-dimethyi-lH-imidazol-2-yl)-12-fluoro-7a,8,13,14tetrahydro-7H-[ 1,2,4]triazolo[4)3':l,6]pyrido[3,2-b]benzofuiO[4,3-fg] [l,4]oxazonine (17.1 mg, 38.4 umol, 15% yield, 99.4% purity, HCl sait) was obtained as a green solid. lH NMR CD3OD + 1 drop HCl in D2O 400 MHz δ = ppm 9.80 (s, IH), 8.36 (s, IH), 7.57 (s, IH), 7.05 - 6.86 (m, IH), 6.71 (dd, 7= 8.7, 3.9 Hz, IH), 5.27 (br d, 7= 14.8 Hz, IH), 5.09 (br s, IH), 4.81 (br s, IH), 4.65 (t, 7= 9.5 Hz, IH), 4.33 (br d, 7 = 6.7 Hz, IH), 4.15 (br s, IH), 3.99 (br s, IH), 3.74 (s, 3H), 2.49 (s, 3H). LCMS (ESI+): m/z 407.1 (M+H).
Example 117: (S)-12-fluoro-4-(2-methylpyrimidin-4-yl)-7a,8,13,14-tetrahydro-7H[ 1,2,4]triazolo [4)3':1,6] pyrido[3,2-b |benzofuro[4,3-fg] [1,4] oxazonine
Step 1: 2-methyl-4-(trimethylslannyl)pyrimidine
Me3:
333
To a solution of 4-bromo-2-methylpyrimidine (250 mg, 1.44 mmol, 1.00 eq) in dioxane (8.00 mL) was added trimethyl(trimethylstannyl)stannane (946 mg, 2.89 mmol, 599 uL, 2.00 eq) and Pd(PPh3)4 (167 mg, 145 umol, 0.100 eq) at 20°C under N2. The mixture was stirred at 100°C for 3 h. LC-MS showed the 4-bromo-2-methylpyrimidine was consumed complétély and the desired mass was 5 detected. The obtained solution of 2-methyl-4-(trimethylstannyl)pyrimidine was used in the next step directly.
Step 2: tert-butyl (S)-l2-fluoro-4-(2-methylpyrimidin-4-yl)-7a,l3-dihydro-7H[1,2,4]triazolo[4 3’:1,6]pyrido[3,2-b] benzofuro[4,3-fg] [1,4] oxazonine-14(8H)-carboxylate
To a solution of 2-methyl-4-(trimethylstannyl)pyrimidine (157 mg, 611 umol, 2.00 eq) in dioxane (8.00 mL) was added tert-butyl (S)-4-bromo-12-fluoro-7a,13-dihydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][I,4]oxazonine-14(8H)-carboxylate (150 mg, 305 umol, 1.00 eq), Pd(PPh3)4 (35.3 mg, 30.6 umol, 0.100 eq), Cul (23.3 mg, 122 umol, 0.400 eq) and LiCl (25.9 mg, 611 umol, 12.5 uL, 2.00 eq) at 20°C under N2. The mixture was stirred at 100°C ] 5 for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Petroleum ether:Ethyl acetate = 0:1). tert-Butyl (S)-I2-fluoro-4-(2methylpyrimidin-4-yl)-7a,13-dihydro-7H-[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3fg][l,4]oxazonine-14(8H)-carboxylate (154 mg, crude) was obtained as a brown oil.
Step 3 : (S)-12-fluoro-4-(2-methylpyrimidin-4-yl)-7a, 8,13,14-tetrahydro-7H20 [1,2,4] triazolo[4',3': 1,6]pyrido[3,2-b] benzojùro[4,3-fg] [1,4] oxazonine
F N V N N
To the HFIP (2.00 mL) was added tert-butyl (S)-12-fluoro-4-(2-methylpyrimidin-4-yl)-7a,13dihydro-7H-[l,2,4]triazolo[4',3’: l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)carboxylate (154 mg, 305 umol, 1.00 eq) at 20°C. The mixture was stirred at 100°C for 12 h. The 25 reaction mixture was concentrated under reduced pressure. The residue was dissolved in DMSO (5.00 mL). The suspension was purified by neutral prep-HPLC (column: Waters Xbridge BEH Cl8
334
100*25 mm*5 um; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 20%-50%, 8 min). The product was isolated by lyophilization. The product (30.0 mg) was obtained as a yellow solid with insufficient purity. The material was dissolved in DMSO (5.00 mL). The suspension was purified twice by acidic prep-HPLC (column; Phenomenex Luna C18 150*30 mm*5 um; mobile phase: [water (0.04% HC1)-ACN]; B%: 25%-37%, 10 min). The product-containing fraction was lyophilized. (S)-12-fluoro-4-(2-methylpyrimidin-4-yl)-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine (21.1 mg, 46.9 umol, 15% yield, 97.9% purity, HCl ait) was obtained as a yellow solid. ’H NMR CD3OD 400 MHz δ = ppm 9.63 (s, IH), 8.92 (s, JH), 8.87 (d, 6.6 Hz, IH), 8.45 (d, J = 6.6 Hz, IH), 6.94 (t, J =9.5 Hz, IH),
6.71 (dd, J = 8.7, 3.8 Hz, IH), 5.33 (br d, J = 14.4 Hz, IH), 5.04 (br s, 2H), 4.66 (br t, J = 9.2 Hz, IH), 4.36 (br s, IH), 4.1 i (br s, IH), 4.06 - 3.91 (m, IH), 2.99 (s, 3H). LCMS (ESI+): m/z 405.0 (M+H).
Exaniple 118: (S)-4-(3-chloropyridin-2-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo|4,,3':l,6]pyrido[3,2-blbenzofuro[4,3-fg]|l,4]oxazonîne
Step 1: 3-chloro-2-(tributylstannyl)pyridine ci-O (mBu)3Sn
To a solution of 2-biOmo-3-chîoropyridine (6.00 g, 31.2 mmol, 1.00 eq) in THF (50.0 mL) was added «-BuLi (2.50 M, 13.7 mL, 1.10 eq) at -78°C under nitrogen and the mixture was stirred at 78°C for 0.5 hr. Tributyl(chloro)stannane (20.3 g, 62.4 mmol, 16.8 mL, 2.00 eq) was added to the mixture under nitrogen atmosphère at -78°C and the resulting mixture was stirred at -78°C for 1.5 h under N2. The mixture was quenched with saturated aqueous NH4CI solution (30.0 mL) and the mixture was extracted with EtOAc (30.0 mL * 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The mixture was purified by MPLC (SiO2, ΡΕ/EtOAc = 1/0 to 3/1) to give the crude product. The crude product was purified by neutral prepHPLC. 3-Chloro-2-(tributylstannyl)pyridine (80.0 mg, 199 umol, 6.37e-1% yield) was obtained as yellow oil.
Step 2: tert-butyl (S)-4-(3-chloropyrîdin-2-yl)-l 2-fluoro-7a, 13-dihydro-7H[1,2,4] triazolo[4', 3 1,6]pyrido[3,2-b] benzofuro[4,3-fg] [1,4] oxazonine-14(8H)-carboxylate
335
To a stirred solution of 3-chloro-2-(tributylstannyl)pyridine (73.8 mg, 183 umol, 1.00 eq) in dioxane (2.00 mL) was added tert-butyl (S)-4-bromo-12-fluoro-7a,13-dihydro-7H[l,2,4]triazolo[4',3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (90.0 mg, 183 umol, 1.00 eq), Cul (14.0 mg, 73.3 umol, 0.400 eq), LiCl (15.5 mg, 366 umol, 7.50 uL, 2.00 eq) and Pd(PPh3)4 (21.2 mg, 18.3 umol, 0.100 eq) at 25°C under N2. The resulting mixture was stirred at 80°C for 12 h. The mixture was concentrated under reduced pressure. The mixture was purified by prep-TLC (SiO2, ΡΕ/EtOAc = 0/1). tert-butyl (S)-4-(3-chloropyridin-2-yl)~12-fluoro7a,13-dihydro-7H-[l,2,4]triazolo[4',3,:l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)carboxylate (90.0 mg, 172 umol, 93% yield) was obtained as yellow oil.
Step 3: (S)-4-(3-chloropyridin-2-yl)-l 2-fluoro-7a,8,13,14-tetrahydro-7H[ 1,2,4] triazolo[4', 3 1,6]pyrido[3,2-b] benzofuro]4,3-fg] [1,4] oxazonine HCl
To tert-butyl (S)-4-(3-chloropyridin-2-yl)-12-0uoro-7a,l 3-dihydro-7H[ l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][ l,4]oxazonine-14(8H)-carboxylate (90.0 mg, 172 umol, 1.00 eq) was added HFIP (2.00 mL) at 25°C and the mixture was stirred at 80°C for 12 h. The mixture was concentrated under reduced pressure. The mixture was purified by acidic prep-HP LC (HCl). (S)-4-(3-Chloropyridin-2-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3': 1,6] pyrido[3,2-b]benzofuro[4,3-fg][ 1,4] oxazonine (25.3 mg, 53.7 umol, 31% yield, 97.7% purity, HCl sait) was obtained as an orange solid. ’H NMR CD3OD 400 MHz δ = ppm 9.57 (s, IH), 8.53 (d,7=5.3 Hz, IH), 8.21 (s, JH), 7.83 (s, IH), 7.68 (d,7=5.3 Hz, IH), 6.98-6.86 (m, IH), 6.69 (dd.7=8.6, 3.9 Hz, IH), 5.21 (d,7= 14.8 Hz, IH), 4.97 (brd,7= 14.3 Hz, IH), 4.84 -4.78 (m, IH), 4.64 (t, 7 = 9.3 Hz, IH), 4.34 (dd,7= 9.8, 3.1 Hz, IH), 4.13 - 3.91 (m, 2H). LCMS (ESI+): m/z 424.0 (M+H).
Exaniple 119: (S)-4-(5-chloro-3-methylpyridin-2-yl)-12-fliiotO-7a,8,13,14-tetrahydro-7H[1,2,4] triazolo|4',3':l,6]pyrido[3,2-b]bcnzofuro[4,3-fg] [1,4] oxazonine
Step 1: 5-chloro-3-methyl-2-(trimethylstannyl)pyri.dine
Cl
336
A mixture of 2-bromo-5-chloiO-3-methylpyridine (150 mg, 727 umol, 1.00 eq'), trîmethyl(trimethylstannyl)stannane (476 mg, 1.45 mmol, 301 uL, 2.00 eq), Pd(PPh3)4 (84.0 mg, 72.7 umol, 0.100 eq) in dioxane (5.00 mL) was degassed and purged with nitrogen 3 times, and the mixture was stirred at 100°C for 12 hr under nitrogen atmosphère. The obtained solution of 5chloro-3-methyl-2-(trimethylstannyl)pyridine was used in the next step without further purification.
Step 2: tert-butyl (S)-4-(5-chloro-3-methylpyridin-2-yl)-12-fluoro-7a,l3-dihydro-7H[1,2,4]triazolo[4’, 3 1,6]pyrido[3,2-b]benzofuro[4,3-fg] [1,4] oxazonine-14(8H)-carboxylate
A mixture of 5-chloro-3-methyl-2-(trimethylstannyl)pyridine (211 mg, 727 umol, 2.38 eq) in dioxane (5.00 mL), tert-butyl (S)-4-bromo-12-fluoiO-7a,13-dihydiO-7H[ 1,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine- 14(8H)-carboxylate (150 mg, 305 umol, 1.00 eq), Pd(PPh3)4 (35.3 mg, 30.5 umol, 0.100 eq), LiCl (19.4 mg, 458 umol, 9.37 uL, 1.50 eq) and Cul (29.1 mg, 153 umol, 0.500 eq) was degassed and purged with nitrogen 3 times, and then the mixture was stirred at 100°C for 16 h under nitrogen atmosphère. The reaction mixture was concentrated under reduced pressure. The residue was purified byprep-TLC (SÎCh, Petroleum ether/Ethyl acetate = 1/1). tert-butyl (S)-4-(5-chloro-3-methylpyridin-2-yl)-12-fluoro-7a,13dihydro-7H-[L2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)carboxylate (127 mg, crude) was obtained as a yellow oil.
Step 3: (S)-4-(5-chloro-3-methylpyridin-2-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H[ 1,2,4]triazolo[4’, 3 6]pyrido[3,2-b]benzofuro[4,3-fg][1,4] oxazonine
A mixture of tert-butyl (S)-4-(5-chloro-3-methylpyridin-2-yl)-l2-fluoro-7a,13-dihydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (120 mg, 223 umol, 1.00 eq) in TFA (2.00 mL) and DCM (4.00 mL) was stirred at 25°C for 1 hr under nitrogen atmosphère. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 150*30 mm*5 um; mobile phase: [water (0.04%HCl)-ACN]; B%: 20%-45%, 10 min). The product-contaîning fraction was concentrated under reduced pressure to remove most of MeCN at 30°C and the aqueous phase was lyophilized.
337 (S)-4-(5-chloro-3-methylpyridin-2-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H[ l,2,4]triazolo[4’,3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine (17.1 mg, 36.0 umol, 16% yield, 99.9% purity, HCl sait) was obtained as a light yellow solid. !H NMR CD3OD 400 MHz δ = ppm 9.54 (s, IH), 8.58 (d, 7= 1.8 Hz, IH), 8.21 (s, IH), 7.96 (d,7= 1.7 Hz, 1 H), 6.94 (t, 7= 9.5 Hz, IH), 6.70 (dd, 7= 8.7, 3.9 Hz, IH), 5.21 (d,7= 14.8 Hz, IH), 5.00 (br d, 7 = 14.8 Hz, IH), 4.77 (br d, 7=5.0 Hz, IH), 4.63 (t, 7= 9.4 Hz, IH), 4.33 (dd, 7= 9.7, 3.3 Hz, IH), 4.17-4.03 (m, IH), 4.02 - 3.89 (m, IH), 2.50 (s, 3H). LCMS (ESI+): m/z 438.0 (M+H).
Example 120: (S)-4-(3-cldoro-5-fluoropyridm-2-yl)-12-fiuoro-7a,8,13,14-tetrahydro-7H[ 1,2,4]triazolo[4’,3':l,6]pyrido[3,2-b]benzofuro[4,3-fg] [l,4]oxazonine
Step 1: 3-chloro-5-fluoro-2-iodopyridine
F
To a solution of 3-chloro-5-fluoropyridin-2-amine (450 mg, 3.07 mmol, 1.00 eq) and Cul (1.17 g, 6.14 mmol, 2.00 eq) in MeCN (8.00 mL) was added isopentyl nitrite (791 mg, 6.76 mmol, 910 uL, 2.20 eq) in MeCN (2.00 mL) at 0°C under nitrogen atmosphère. The mixture was stirred at 0°C for 1 hr and then the mixture was stirred at 60°C for 12 h under nitrogen atmosphère. The reaction was filtered, water (10.0 mL) was added to the filtrate. The obtained solution was extracted with ethyl acetate (10.0 mL * 3), the combined organic layers were dried over MgSO4, and coneentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Petroleum ether/Ethyl acetate = 10/1). 3-ChIoro-5-f]uoro-2-iodopyridine (230 mg, 893 umol, 29% yield) was obtained as a white solid.
Step 2: tert-butyl (S)-4-(3-chloro-5-fluoropyridin-2-yl)-12-fluoro-7a,l3-dihydro-7H[1,2,4] triazolo] 4 3 ’:1,6]pyrido[3,2-b]benzofuro[4,3-fgJ [1,4] oxazonine-14(8H)-carboxylate
To a mixture of tert-butyl (S)-12-fluoro-4-(tributylstannyl)-7a,13-dihydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuiO[4)3-fg][l,4]oxazonine-14(8H)-carboxylate (200 mg, 285 umol, 1.00 eq) in dioxane (6.00 mL) were added 3-chloro-5-fluoro-2-iodopyridme (147 mg, 570 umol, 2.00 eq), Pd(PPh3)4 (33.0 mg, 28.5 umol, 0.100 eq), Cul (21.7 mg, 114 umol, 0.400 eq) and LiCl (24.2 mg, 570 umol, 11.7 uL, 2.00 eq) at 20°C. The mixture was stirred at 100°C for 12 h under nitrogen atmosphère. The reaction mixture was filtered, the filtrate was coneentrated. The 338 residue was purified by prep-TLC (SÎO2, Petroleum ether/Ethyl acetate = 0/1), tert-butyl (8)-4-(3chloro-5-fluoropyridin-2-yl)-12-lluoro-7a, 13-dihydro-7H-[ 1,2,4]triazolo[4',3': 1,6]pyrido[3,2b]benzofuro[4,3-fg] [1,4] oxazonine-14(8H)-carboxylate (80.0 mg, crude) was obtained as a yellow oil.
Step 3: (S)-4-(3-chlom-5-fluoropyridin-2-yl)-12-fliioro-7a,8,13,14-tetrahydro-7H[1,2,4] triazolo[4\3':l, 6]pyrido[3,2-b]benzofuro[4,3-fg] [1,4] oxazonine
A mixture of tert-butyl (S)-4-(3-chloro-5-fluoropyridin-2-yl)-12-fluoiO-7a,13-dihydro-7H[ 1,2,4]triazolo[4',3': 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4] oxazonine-14(8H)-carboxylate (80.0 mg, 148 umol, 1.00 eq) in HFIP (5.00 mL) was stirred at 100°C for 3 h. The reaction was concentrated. The residue was dissol ved in DMSO (4.00 mL). The suspension was purified b y acidic prep-HPLC (column: Phenomenex Luna C18 150*30 mm*5 um; mobile phase: [water (0.04% HC1)-ACN]; B%: 20%-45%, 10 min). The product-containing fraction was concentrated under reduced pressure to remove most of MeCN at 30°C and the aqueous phase was lyophilized.
(S)-4-(3-chloro-5-fluoropyridin-2-yl)- 12-fluoro-7a,8,13,l4-tetrahydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazomne (12.5 mg, 26.1 umol, 17% yield, 99.8% purity, HCl) was obtained as a green solid. 'H NMR CD3OD 400 MHz Ô = ppm 9.52 (s, IH), 8.63 (d, 7=2.4 Hz, IH), 8.51 (s, IH), 8.05 (dd,7=8.0, 2.3Hz, IH), 6.92 (1,7=9.6 Hz, IH), 6.68 (dd, 7 = 8.7, 3.6 Hz, IH), 5.20 (d, 7 = 15.0 Hz, IH), 4.98 (br d, 7= 15.0 Hz, IH), 4.76 (br s, 20 IH), 4.61 (t, 7= 9.5 Hz, 1H),4.31 (dd, 7=9.7, 3.1 Hz, IH), 4.06 (brd,7= 9.7 Hz, IH), 3.97-3.89 (m, IH). LCMS (ESI+): m/z 442.0 (M+H).
Example 121: (S)-12-fluoro-4-(l,4,5-trimethyl-lH-imidazol-2-yl)-7a,8,13,14-tetrahydro-7H[ 1.2.4|triazolo|4',3':1.6]pyrido[3.2-b|benzofïiro|4,3-fg|| l,4|oxazonine
Step 1: 1,4,5-trimethyl-1 H-imidazole
N
To a solution of 4,5-dimethyi-lH-îmidazole (500 mg, 3.77 mmol, 1.00 eq, HCl) in THF (8.00 mL) was added NaH (377 mg, 9.43 mmol, 60% purity, 2.50 eq) at 20°C under N2. The mixture was stin’ed at 20°C for 0.5 hr. Mel (500 mg, 3.52 mmol, 219 uL, 0.934 eq) was added to the mixture at 20°C. The mixture was stirred at 20°C for 1 hr. The reaction mixture was quenched by addition of MeOH (2.00 mL) at 0°C and the mixture was concentrated under reduced pressure. The residue was 339 purified byjPrep-HPLC (column: Waters Xbridge Prep OBD Cl8 150 * 40 mm * 10 um; mobile phase: [water (0.04% NH3water + 10 mM NH4HCO3) - ACN]; B%: 1% - 15%, 10 min). 1,4,5Trimethyl-lH-imidazole (300 mg, crude) was obtained as a yellow liquid.
Step 2: tert-butyl (S)-12-fluoro-4-(l,4,5-trimethyl-lH-imidazol-2-yl)-7a, 13-dihydro-7H[1,2,4] triazolo]4 3': 1,6]pyrido[3,2-b] benzofuro]4,3-fg]]l ,4] oxazonine-14(8H)-carboxylate
To a solution of tert-butyl (S)-4-bromo-12-fluoro-7a,13-dihydro-7H
[ 1,2,4]tri azolo[4',3':l,6]pyrido[ 3,2-b]benzofuro[4,3-fg] [1,4] oxazonine-l4(8H)-carboxylate (200 mg, 407 umol, 1.00 eq) in dioxane (2.00 mL) and EtOH (1.00 mL) in a microwave tube with a stir bar were added 1,4,5-trimethyl-lH-imidazole (100 mg, 908 umol, 2.23 eq), Pd(OAc)2 (24.0 mg, 107 umol, 0.263 eq), PPh3 (56.0 mg, 214 umol, 0.524 eq) andNa2CO3 (129 mg, 1.22 mmol, 3.00 eq) under argon. The tube was sealed with a Silicon septum and subjected to microwave irradiation at 15Ü°C with stirring for 2 h The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-TCC (SiO2, Petroleum ether/Ethyl acetate = 0/1). tert-butyl (S)-12fluoro-4-(l,4,5-trimethyl-lH-imidazol-2-yl)-7a,13-dihydro-7H-[l,2,4]triazoIo[4',3': l,6]pyrido[3,2b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (100 mg, crude) was obtained as a yellow solid.
Step 3: (S)-12-fhioro-4-(l,4,5-trimethyl-lH-imidazol-2-yl)~7a,8,13,14-tetrahydro-7H]1,2,4]triazolo]4', 3 1,6]pyrido]3,2-b] benzofuro [4,3-fg] ]1,4] oxazonine
To a solution of tert-butyl (S)-12-fluoro-4-(l,4,5-trimethyl-lH-imidazoi-2-yl)-7a,13-dihydro-7H[l,2,4]triazolo[4',3':l,6]pyrîdo[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (100 mg, 192 umol, 1.00 eq) in DCM (1.00 mL) was added TFA (1.00 mL) at 20°C. The mixture was stirred at 20°C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Luna Cl8 150 * 30 mm * 5 um; mobile phase: [water (0.04% HCl) -ACN]; B%: 20% - 40%, 10 min). (S)-12-fluoro-4-(l,4,5-trimethyl-lHimidazol-2-yl)-7a,8,13,14-tetrahydro-7H-[ 1,2,4]triazolo[4',3': 1,6]pyrido[3,2-b]benzofuro[4,3340 fg][ 1,4] oxazonine (65.0 mg, 141 umol, 73% yield, 99.4% purity, HCl sait) was obtained as a yellow solid. 'H NMR CD3OD 400 MHz δ = ppm 9.58 (s, 1H), 8.08 (s, 1H), 7.00 - 6.89 (m, 1H), 6.70 (dd, 7=8.7, 4.8 Hz, 1H), 5.23 (d,7= 14.8 Hz, 1H), 5.00 (brd, 7= 14.8 Hz, 1H), 4.78 (br s, 1 H), 4.65 (t, 7= 9.6 Hz, 1H), 4.33 (dd, 7= 9.8, 3.2 Hz, IH), 4.14 - 4.04 (m, 1H), 4.01 - 3.90 (m, 1H), 3.71 (s, 3H), 2.39 (s, 6H). LCMS (ESI+); m/z 421.0 (M+H).
Exaniple 122: (S)-12-fluoro-4-(5-methylpyrimidin-4-yl)-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4’,3’:l,6]pyrido(3,2-b]benzofuro[4,3-fg][ 1,4] oxazonine
Step 1: 5-methylpyrimidin-4-yl trifluoromethanesulfonate
An
TfO
To a stirred solution of 5-methylpyrimidin-4-ol (300 mg, 2.72 mmol, 1.00 eq) and DIPEA (704 mg, 5.45 mmol, 949 uL, 2.00 eq) in DCM (5.00 mL) was added 1,1,1-trifluoro-N-phenyl-N(trifluoromethylsulfonyl)methanesulfonamide (1.17 g, 3.27 mmol, 1.20 eq) at 25°C. The resultîng mixture was stirred at 25°C for 12 h. To the mixture was added water (10.0 mL) and the mixture was extracted with EtOAc (10.0 mL * 3). The combined organic layers were dried over Na2SÛ4 and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, ΡΕ/EtOAc = 10/1). 5-Methylpyrimidin-4-yl trifluoromethanesulfonate (240 mg, 991 umol, 36% yield) was obtained as yellow oil.
Step 2: tert-butyl (S)-12-fluoro-4-(5-methylpyrimidm-4-yl)-7a,13-dihydro-7H[1,2,4] trîazolo[4', 3 6]pyrido[3,2-b] benzofuro[4,3-fg] [ 1,4] oxazonine-14(8H)-carboxylate
F
To 5-methylpyrimidin-4-yl trifluoromethanesulfonate (240 mg, 992 umol, 3.48 eq) and tert-butyl (S)-12-fluoro-4-(tributylstannyl)-7a,13-dihydro-7H-[l,2,4]triazolo[4',3':l,6]pyrido[3,2b]benzofuiO[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (200 mg, 285 umol, 1.00 eq) in dioxane (5.00 mL) were added Cul (21.7 mg, 114 umol, 0.400 eq), LiCl (24.2 mg, 570 umol, 11.7 uL, 2.00 eq) and Pd(PPh3)4 (33.0 mg, 28.5 umol, 0.100 eq) at 25°C under N2. The resulting mixture was stirred at 80°C for 12 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, PE/EtOAc = 0/1). tert-butyl (S)-12-fluoro-4-(5-methylpyrimidin-4-yl)
341
7a,13-dihydiO-7H-[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)carboxylate (120 mg, 238 umol, 83% yield) was obtained as a yellow solid.
Step 3: (S)-12-flitoro-4-(5-methylpyrimidin-4-yl)-7a,8,13,14-tetrahydro-7H[ 1, 2,4] triazolo[4', 3 1,6]pyrido[3,2-b] benzofu.ro]4,3-fg] [ 1,4] oxazonine
To tert-butyl (S)-12-fluoro~4-(5-methylpyrimîdin-4-yl)-7a,13-dihydro-7H[l,2;4]triazolo[4,,3’:l,6]pyrido[3,2-b]benzofuiO[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (120 mg, 238 umol, 1.00 eq) was added HFIP (4.00 mL) at 25°C. The mixture was stirred at 80°C for 12 h. The mixture was concentrated under reduced pressure. The mixture was purified by acidic prepHPLC (HCl conditions). (S)~12-fluoro-4-(5-methy]pyrimidin-4-yl)-7a,8,13,14-tetrahydro-7H“ [i,2,4]triazoJo[4,,3':],6]pyrido[3,2-b]benzofuro[4,3-fg][i,4]oxazonine (34.4 mg, 76.2 umol, 32% yield, 97.6% purity, HCl sait) was obtained as an orange solid. *H NMR CD3OD 400 MHz Ô = ppm 9.57 (s, IH), 9.18 (s, IH), 8.84 (s, IH), 8.45 (s, IH), 7.03 - 6.89 (m, IH), 6.72 (dd, 7= 8.6, 4.0 Hz, IH), 5.27 (d, J= 15.0 Hz, IH), 5.04 (brd, 7 = 15.6 Hz, 1 H), 4.85 - 4.78 (m, IH), 4.65 (t. 7= 9.4 Hz, IH), 4.35 (dd, 7= 9.7, 3.5 Hz, IH), 4.17 ~ 4.06 (m, IH), 4.05 - 3.95 (m, IH), 2.65 (s, 3H). LCMS (ESI+): m/z 405.0 (M+H).
Example 123: (S)-2-(5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4’,3':l,6Jpyrido[3,2b]bcnzofuro[4,3-fg][ l,4Joxazonin-4-yl)-l-niethyl-l H-pyrazol-3-yl)ethan-l-ol
Step 1: methyl 2-(5-hydroxy-l-methyl-1 H-pyrazol-3-yl)acetate
1, OMe if 7 O
Methylhydrazine (6.61 g, 57.4 mmol, 7.56 mL, 40.0% in water, 1.00 eq) were added to dimethyl 3oxopentanedioate (10.0 g, 57.4 mmol, 8.26 mL, 1.00 eq) in MeOH (100 mL) at 20°C, during which the reaction température rose to 65°C. After completion of the addition, the mixture was stirred for a further 2 h andNaOMe (10.3 g, 57.4 mmol, 30.0% in MeOH, 1.00 eq) was then added at 65°C. The reaction was slightly exothermic. The reaction mixture was stirred for a further 4 h TLC (Petroleum ether:Ethyl acetate = 0:1) indicated no dimethyl 3-oxopentanedioate was remained, and one major new spot with larger polarity was detected. The reaction mixture was concentrated under reduced pressure to remove solvent, and the residue was dissolved in water (40.0 mL). After acidification with glacial acetic acid to pH = 5 the mixture was extracted with EtOAc (50.0 mL * 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced
342 pressure. The residue was suspended in EtOAc (30.0 mL) and filtered, the filter cake was dried and collected. Methyl 2-(5-hydroxy-I-methyl-lH-pyrazol-3-yl)acetate (4.50 g, crude) was obtained as a white solid.
Step 2: methyl 2-(5-bromo-l-methyl-lH-pyrazol-3-yl)acetate \ // zn-n
OMe
Twenty parallel reactions were set up. To a solution of methyl 2-(5-hydroxy-l-methyl-lH-pyrazol3-yl)acetate (100 mg, 588 umol, 1.00 eq) in MeCN (4.00 mL) was added POBr3 (842 mg, 2.94 mmol, 299 uL, 5.00 eq) at 20°C. The mixture was stirred at 80°C for 12 h. ΑΠ batches were combined and quenched by addition of sat. aq. NaHCO3 (50.0 mL) at 0°C. Then the mixture was extracted with EtOAc (70.0 mL * 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 1/0 to 0/1). Methyl 2-(5-bromo-l-methyllH-pyrazol-3-yl)acetate (1.20 g, crude) was obtained as a yellow liquid.
Step 3: 2-(5-bromo-l-methyl-lH-pyrazol-3-yl)ethan-l-ol
To a solution of methyl 2-(5-bromo-l-methyl-lH-pyrazol-3-yl)acetate (600 mg, 2.57 mmol, 1.00 eq) in DCM (10.0 mL) was added DIBAL-H (1.00 M, 9.01 mL, 3.50 eq) at 0°C under N2. The mixture was stirred at 25°C for 12 h The reaction mixture was quenched by addition of MeOH (5.00 mL) at 0°C, and the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOH = 1/0 to 20/1). 2-(5-bromo-l-methyl-lH-pyrazol-3yl)ethan-l-ol (200 mg, crude) was obtained as a yellow liquid.
Step 4: 2-( 1 -methyl-5-(tributylstannyl)-l H-pyrazol-3-yl)ethan-1 -ol (n-BuJaSm
To a solution of 2-(5-bromo-l-methyl-lH-pyrazol-3-yl)ethan-l-ol (200 mg, 975 umol, 1.00 eq) in THF (5.00 mL) was added n-BuLi (2.50 M, 819 uL, 2.10 eq) at -70°C under N2. The mixture was stirred al -70°C for 0.5 hr. Tributyl(chloro)stannane (476 mg, 1.46 mmol, 393 uL, 1.50 eq) was added to the mixture at -70°C which was then stirred at -70°C for 1 hr. The reaction mixture was quenched by addition of sat. aq. KF (1.00 mL) at 0°C. The mixture was extracted with MTBE (10.0 mL * 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under
343 reduced pressure. 2-(l-Methyl-5-(tributylstannyl)-lH-pyrazol-3-yl)ethan-I-ol (350 mg, crude) was obtained as a yellow liquid.
Step 5: tert-butyl (S)-l 2fluoro-4-(3-(2-hydroxyeihyl)-l-methyl-lH-pyrazol-5-yl)-7a, 13-dihydro-7H[ 1,2,4] triazolo[4',3 ':1,6]pyrido[3,2~b] benzofuro[4,3-fg] [1,4] oxazonine-14 (8H)-carboxylate
To a solution of tert-butyl (S)-4-bromo-12-fluoro-7a,13-dihydro-7H
[l,2,4]triazolo[4',3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-l4(8H)-carboxylate (200 mg, 407 umol, 1.00 eq) in dioxane (5.00 mL) were added 2-(l-methyl-5-(tributylstannyi)-IH-pyrazol-3yl)ethan-1-ol (338 mg, 814 umol, 2.00 eq), Pd(PPh3)4 (47.0 mg, 40.7 umol, 0.100 eq). Cul (31.0 mg, 162 umol, 0.400 eq) and LiCl (34.5 mg, 814 umol, 16.7 uL, 2.00 eq) at 20°C under N2. The mixture was stirred at 90°C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-ALC (SiO2, Petroleum ether/Ethyl acetate = 0/1). tert-butyl (S)-I2fluoro-4-(3-(2-hydroxyethyl)-l-methyl-lH-pyrazol-5-yl)-7a, 13-dihydro-7H[ l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofnro[4,3-fg][l,4]oxazonine~14(8H)-carboxylate (120 mg, crude) was obtained as a brown solid.
Step 6: (S)-2-(5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4',3': l,6]pyrido[3,2b]benzofuro[4,3-fg][ 1,4]oxazonin-4-yl)-l -methyl-lH-pyrazol-3-yl)ethan-1 -ol
A mixture of tert-butyl (S)-12-fluoro-4-(3-(2-hydroxyethyl)-l-methyl-lH-pyrazol-5-yI)-7a,13dihydrO’7H-[l,2,4]triazolo[4’,3,:L6]pyrido[3,2-b]benzofuro[4,3-fg][L4]oxazonine-14(8H)carboxylate (120 mg, 224 umol, 1.00 eq) in HFIP (2.00 mL) was stirred at 100°C for 2 h The reaction mixture was concentrated under reduced pressure. The residue was purified by prepHPLC (column: Waters Xbridge BEH C18 100 * 30 mm * 10 um; mobile phase: [water (10 mM NH4HCO3) - ACN]; B%: 20% - 45%, 10min). (S)-2-(5-(12-fluoro-7a,8,13,14-tetrahydro-7H[l)2,4]triazolo[4’,3':l,6]pyrido[3,2-b]benzofuro[4,3-fgj[l,4]oxazonin-4-yl)-l-methyLlH-pyrazol-3yl)ethan-l-ol (53.0 mg, 120 umol, 53% yield, 99.1% purity) was obtained as a whîte solid. *H NMR
344
DMSCM 400 MHz δ = ppm 9.44 (s, IH), 7.64 (br t, J = 6.4 Hz, IH), 7.39 (s, IH), 6.96 (dd, J = 10.1, 8.8 Hz, IH), 6.69 (dd, J= 8.6, 4.0 Hz, IH), 6.39 (s, IH), 4.96 - 4.87 (m, IH), 4.84 - 4.72 (m, IH), 4.66 (t, J= 5.2 Hz, IH), 4.59 - 4.45 (m, 2H), 4.21 (dd, J = 9.6, 3.6 Hz, IH), 4.09 - 3.98 (m, IH), 3.93 - 3.82 (m, IH), 3.74 (s, 3H), 3.65 (dt, J = 7.2, 5.4 Hz, 2H), 2.70 (t, J = 7.2 Hz, 2H). LCMS (ESI+): m/z 437.0 (M+H).
Example 124: (S)-4-(2,5-diinethylpyridin-4-yl)-l2-fluoro-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo|4’,3':l,6|pyrÎdo|3,2-b]benzofuro[4,3-fg]| 1,4] oxazonine
Step 1: 4~iodo-2,5-dimethylpyridine
To a solution of 2,5-dimethylpyridin-4-amine (500 mg, 4.09 mmol, 1.00 eq), Cul (1.01 g, 5.32 mmol, L30 eq) in MeCN (10.0 mL) was added isopentyl nitrite (719 mg, 6.14 mmol, 826 uL, 1.50 eq) in MeCN (5.00 mL) at 0°C. The mixture was stirred at 60°C for 12 hThe reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 1/0 to 10/1). 4-Iodo-2,5-dimethylpyridîne (320 mg, 1.37 mmol, 33% yield) was obtained as a yellow solid.
Step 2: tert-butyl (S)-4-(2,5-dimethylpyridin-4-yl)-12-]luoro-7a,l 3-dihydro-7H[1,2,4]triazolo[4 3 ’;1,6]pyrido[3,2-b] benzofuro[4,3-fg] [1,4] oxazomne-14(8H)-carboxylate F
To a solution of 4-iodo-2,5-dimethylpyridine (73.1 mg, 314 umol, 1.10 eq) and tert-butyl (S)-4bromo-12-fluoiO-7a,13-dihydro-7H-[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3fg][l,4]oxazonine-14(8H)-carboxylate ( Ex. 16; 200 mg, 285 umol, 1.00 eq) in dioxane (2.00 mL) were added Cul (21.7 mg, 114 umol, 0.400 eq), LiCl (24.2 mg, 571 umol, 11.7 uL, 2.00 eq) and Pd(PPh3)4 (33.0 mg, 28.6 umol, 0.100 eq) at 20°C, then the mixture stirred at 80°C for 12 h under N2. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, PE:EtOAc = 0:1). tert-butyl (S)-4-(2,5-dimethylpyridin-4-yi)-12-fluoiO-7a,13dihydro-7H-[l,2,4]triazoio[4',3,: l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazouine-14(8H)carboxylate (70.0 mg, 135 umol, 47% yield) was obtained as a yellow solid.
345
Step 3; (3)-4-(2,5-dimethylpyridin-4-yl)-l 2-fluoro-7a,S, 13,14-tetrahydro-7H[ 1,2,4]triazolo[4', 3 6]pyrido[3,2-b] benzofwo]4,3-fg] [1,4] oxazonine
To tert-butyl (S)-4-(2,5-dimethylpyridin-4-yl)-12-fluoiO-7a,13-dihydro-7H[ l,2,4]triazolo[4',3’: l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (70.0 mg, 135 umol, 1.00 eq) was added HFIP (2.00 mL) at 20°C, the mixture was stirred at 100°Cfor2h under N2. The reaction mixture was concentrated under reduced pressure. The residue was purified by jWe^-HPLC (HCl conditions). (S)-4-(2,5-dimethylpyridin-4-yl)-12-fluoro-7a,8,13,14-tetrahydro7H-[l,2,4]triazolo[4,,3’: 1,6]pyrido[3,2-b]benzofuro[4,3-fg][l ,4]oxazonine (24.7 mg, 54.3 umol, 40% yield, 99.7% purity, HCl sait) was obtained as a yellow solid. ’H NMR CD3OD 400 MHz S = ppm 9.59 (s, IH), 8.77 (s, IH), 8.09 (s, IH), 7.99 (s, IH), 6.95 (bi t, J=9.5 Hz, IH), 6.71 (br dd, J=8.6, 3.9 Hz, IH), 5.24 (br d, J= 14.8 Hz, IH), 5.04-4.94 (m, IH), 4.85 (br s, IH), 4.65 (bi t, J=9.5 Hz, IH), 4.33 (br dd, J-9.6, 3.2 Hz, IH), 4.08 (br d, J= 8.6 Hz, IH), 3.94 (br t, J = 10.8 Hz, IH), 2.82 (s, 3H), 2.43 (s, 3H). LCMS (ESI+): m/z 418.0 (M+H).
Exampic 125: (S)-4-(3-chloro-2-methylpyridin-4-yl)-12-fhioro-7a,8,13,14-tetrahydro-7H[l,2,41triazolo|4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
Step 1: 3-chloro-2-methylpyridin-4-amine
Cl—<
H2N
To a solution of 2-methylpyridin-4-amine (3.00 g, 27.7 mmol, 1.00 eq) in MeCN (20.0 mL) was added NC S (4.07 g, 30.5 mmol, L10 eq) in MeCN (10,0 mL) at 0°C. The mixture was stirred at 0°C for 2 h, The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 1/0 to 0/1). 3-chloro-2methylpyridin-4-amine (2.01 g, 14.1 mmol, 50% yield) was obtained as a gray solid.
Step 2: 3-chloro-4-iodo-2-methylpyridine Cl'\=y !
To a solution of 3-chloro-2-methylpyridin-4-amine (2.01 g, 14.1 mmol, 1.00 eq), Cul (3.49 g, 18.3 mmol, 1.30 eq) in MeCN (20.0 mL) was added isopentyl nitrite (2.48 g, 21.2 mmol, 2.85 mL, 1.50
346 eq) in MeCN (10.0 mL) al 0°C. The mixture was stirred at 60°C for 2 h under N2, The reaction mixture concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 1/0 to 10/1). 3-chloro-4-iodo-2-methylpyridine (350 mg, 1.38 mmol, 9% yield) was obtained as a yellow solid.
Step 3: (3-chloro-2-methylpyridin-4-yl)boronic acid
OH
To a solution of 3-chloro-4-iodo-2-methylpyridine (350 mg, 1.38 mmol, 1.00 eq) in THF (5.00 mL) at -78°C was added n-BuLi (2.50 M, 829 uL, 1.50 eq). The mixture was stirred at -78°C for 0.5 hr. And to the mixture was added triisopropyl borate (779 mg, 4.14 mmol, 952 uL, 3.00 eq) at 78°C. The mixture was stirred at -78°C for 1 hr under N2. The réaction mixture was quenched by addition of MeOH (2.00 mL) at -78°C, the reaction mixture was concentrated under reduced pressure. (3-Chloro-2-methylpyridin-4-yl)boiOnic acid (235 mg, crude) was obtained as a yellow solid.
Step 4: tert-butyl (S)-4-(3-chloro-2-methylpyrîdin-4-yi)-12-fluoro-7a, 13-dihydro-7H[1,2,4] triazolo[4 3 1,6]pyridof3,2-b] benzofuro [4,3-fg] [1,4] oxazonine-14(8H)-carboxylate
To a solution of (3-chloro-2-methylpyridin-4-yI)boronic acid (235 mg, 1.37 mmol, 1.00 eq) in dioxane (5.00 mL) and water (0.500 mL) were added tert-butyl (S)-4-bromo-12-fluoro-7a,13dihydro-7H-[l,2,4]triazolo[4',3': l,6]pyTido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)carboxylate (222 mg, 452 umol, 0.330 eq), Pd(dppf)Cl2 (10.0 mg, 13.7 umol, 0.0100 eq) and NaHCO;, (230 mg, 2.74 mmol, 2.00 eq) at 20°C. The mixture was stirred at 80°C for 12 h under N2. The reaction mixture was concentrated under reduced pressure. The residue was purified by prepTLC (SiO2, PE:EtOAc = 1:3). tert-butyl (S)-4-(3-chioro-2-methylpyridin-4-yl)-12-fluoro-7a,13dihydro-7H-[ 1,2,4]triazolo[4',3': 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4]oxazonine-14(8H)carboxylate (72.0 mg, 134 umol, 9% yield) was obtained as a yellow solid.
Step 5: (S)-4-(3-chloro-2-methylpyridin-4-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H[1,2,4]triazolo[4 3 1,6]pyrido[3,2-b] benzofuro]4,3-fg] f1,4] oxazonine
347
HCl
To tert-butyl (S)-4-(3-chloro-2-methylpyridin-4-yl)-12-fluoro-7a, 13-dihydro-7H[ l,2,4]triazolo[4',3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-l4(8H)-carboxyiate (70.0 mg, 130 umol, 1.00 eq) was added HFIP (2.00 mL) at 20°C, the mixture was stirred at 80°C for 12 h under N2. The reaction mixture concentrated under reduced pressure. The residue was purified by prep-HPLC (HCl conditions). (S)-4-(3-chloro-2-methylpyridin-4-yI)-12-fluoro-7a,8,13,14tetrahydro-7H-[ 1,2,4]triazolo[4’,3': 1 ,6]pyrido[3,2-b]benzofuiO[4,3-fg][ 1,4]oxazonine ( 15.9 mg, 32.9 umol, 25% yield, 98.0% purity, HCl sait) was obtained as a yellow solid. NMR CD3OD 400 MHz δ = ppm 9.56 (br s, IH), 8.67 (br d, /= 5.5 Hz, IH), 8.14 (br s, IH), 7.79 (br d, J = 5.5 Hz, IH), 6.95 (br t, J= 9.5 Hz, IH), 6.71 (br dd, J- 8.7, 3.9 Hz, IH), 5.24 (br d, J= 14.8 Hz, IH), 4.99 (brd,J= 14.5 Hz, IH), 4.80 (br s, IH), 4.65 (brt, J=9.5 Hz, IH), 4.34 (br dd, 9.8, 3.2 Hz, IH), 4.13-4.04 (m, IH), 4.01 - 3.90 (m, IH), 2.85 (br s, 3H). LCMS (ESI+): m/z 438.1 (M+H).
Example 126: (S)-4-(5-chloro-2-methylpyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3':l,6]pyrido|3,2-b]benzofuro[4,3-fg][l,4]oxazonine
Step 1: 3-bromo-5-chloro-2-methylpyridine
Cl O Br
To a solution of 5-brorno-6-rnethylpyridin-3-amine (2.00 g, 10.7 mmol, 1.00 eq) and CuCl (2.12 g, 21.4 mmol, 51 1 uL, 2.00 eq) in MeCN (20.0 mL) was added isopentyl nitrite (3.13 g, 26.7 mmol, 3.60 mL, 2.50 eq) at 0°C. The mixture was stirred at 0°C for 1 hr. The mixture was stirred at 80°C for 12 h under N2. LCMS showed the reaction was complété. The mixture was filtered, and the fdtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SÎO2, Petroleum ether/Ethyl acetate = 1/0 to 10/1) to give 3-bromo-5-chloro-2methylpyridine (850 mg, crude) as yellow oil.
Step 2: 5-chloro-2-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridme
348
Cl
Το a solution of 3-bromo-5-chloro-2-methylpyridine (600 mg, 2.91 mmol, 1.00 eq) and Pin2B2 (886 mg, 3.49 mmol, 1.20 eq) in dioxane (7.00 mL) were added Pd(dppf)CI2 (213 mg, 291 umol, 0.100 eq) and KOAc (570 mg, 5.81 mmol, 2.00 eq) at 25°C. The mixture was stirred at 80°C for 2 h under N2. The mixture was concentrated under reduced pressure to give 5-chloiO-2-methyl-3(4,4,5,5-tetramethyl-l,3,2-dioxaboroian-2-yl)pyridme (2.00 g, crude) as a black solid.
Step 3: tert-butyl (S)-4-(5-chloro-2-niethylpyridin-3-yl)-12-fluoro-7a, 13-dihydro-7H[1,2,4] triazolo[4', 3 1,6]pyrido[3,2-b] benzojùro[4,3-fg] [1,4] oxazonine-14(8H)-carboxylate
To a solution of tert-butyl (S)-4-bromo-12-fluoro-7a,13-dihydro-7H[ 1,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-l4(8H)-carboxylate (100 mg, 204 umol, 1.00 eq) and 5-chloro-2-methyI-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (310 mg, 1.22 mmol, 6.00 eq) in dioxane (4.00 mL) and water (0.800 mL) were added Na2CO3 (43.2 mg, 407 umol, 2.00 eq) and Pd(dppf)Cl2 (14.9 mg, 20.4 umol, 0.100 eq) at 25°C. The mixture was stirred at 80°C for 12 h under N2. The mixture was combined with the other batches (from 100 mg of tert-butyl (S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[l,2,4]triazolo[4',3': l,6]pyrido[3,2b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate). The mixture was fïltered and the fïltrate was concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Petroleum ether:Ethyl acetate = 1:1) to give tert-butyl (S)-4-(5-chloro-2-methylpyridin-3-yl)-12-fluoro-7a,13dihydro-7H-[ 1,2,4]trîazolo[4',3': 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ l,4]oxazonine- 14(8H)carboxylate (150 mg, cnide) was obtained as yellow oil.
Step 4: (S)-4-(5-chloro-2-methylpyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H[1,2,4]triazolo[4', 3 ’:1,6]pyrido[3,2-b] benzofuro[4,3-fg] [ 1,4] oxazonine
349
To a solution of tert-butyl (S)-4-(5-chloro-2-methylpyridin-3-yl)-I2-fluoro-7a,13-dihydro-7H[ l,2,4]triazolo[4',3': l,6]pyrido[3,2-b]benzofuro[4)3-fg][ l,4]oxazonine-14(8H)-carboxylate (150 mg, 279 umol, 1,00 eq) in DCM (2.00 mL) was added TFA (1.54 g, 13.5 mmol, 1.00 mL, 48.4 eq) at 25°C. The mixture was stirred at 25°C for 1 hr. LCMS showed that the reaction was complété. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (HCl condition). (S)-4-(5-chloro-2-methylpyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H[lf2,4]triazolo[4’,3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine (43.6 mg, 90.5 umol, 32% yield, 98.4% purity, HCl) was obtained as a yellow solid. 'H NMR DMSO-7, 400 MHz Ô = ppm 10.03 (s, IH), 8.85 (br s, IH), 8.65 (d, J =2.4 Hz, IH), 7.99 (d, 7= 2.4 Hz, IH), 7.94 (s, IH), 7.07 6.96 (m, IH), 6.74 (dd, 7= 8.6, 3.9 Hz, IH), 5.09 - 4.95 (m, IH), 4.89 - 4.85 (m, IH), 4.57 (br t, 7 = 9.4 Hz, 2H), 4.24 (dd, 7= 9.7, 3.6 Hz, IH), 4.07 - 4.03 (m, IH), 3.97 - 3.86 (m, IH), 2.38 (s, 3H). LCMS (ESI+): m/z 438.1 (M+H).
Example 127: (S)-2-(5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4’,3':l,6Jpyrido[3,2b]benzofuro[4,3-fg][l,4]oxazonin-4-yl)-l-methyl-lH-pyrazol-3-yl)-N,N-diinethyIethan-l-amine Step 1: (5-bromo-1-methyl-lH-pyrazol-3-yl)methyl methanesulfonate
JD Ms À Br
To a solution of (5-bromo-l-methyl-lH-pyrazol-3-yl)methanol (1.80 g, 9.42 mmoi, 1.00 eq) in DCM (20.0 mL) was added TEA (1.43 g, 14.1 mmol, 1.97 mL, 1.50 eq) and MsCl (2.16 g, 18.9 mmol, 1.46 mL, 2.00 eq) at 0°C. Then the mixture was stirred at 0°C for 30 mins. Saturated NaHCOi solution was added to the mixture to adjust pH to neutral. Then the mixture was extracted with EtOAc (10.0 mL * 4). The combined organic layers were washed with brine (5.00 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. 5Bromo-1-methyl-lH-pyrazol-3-yl)methyl methanesulfonate (2.20 g, crude) was obtained as yellow oil.
Step 2: 2-(5-bromo-l-methyl-lH-pyrazol-3-yl)acetonitrile
350
XN
V'N b/ N\
The reaction was set up in 10 parallel batches. To 5-bromo-l-methyl-lH-pyrazolXyl)methyl methanesulfonate (220 mg, 817 umol, 1.00 eq) in MeCN (2.00 mL) was added TMSCN (122 mg, 1.23 mmol, 154 uL, 1.51 eq) and TBAF (1.00 M, 1.23 mL, 1.50 eq) at 20°C. The mixture was stirred at 20°C for 12 h. The 10 batches were combined. The reaction mixture was concentrated under reduced pressure followe by addition of water (20.0 mL). The mixture was extracted with EtOAc (20.0 mL * 5). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, PE:EtOAc = 1:1). 2-(5-Bromo-l-methyl-lH-pyrazoL3-yl)acetonitrile (740 mg, crude) was obtained as yellow oil.
Step 3: 2-(5-bromo-l-methyl-lH-pyrazol-3-yl)ethan-l-amine
Bk
N ^nh2
To 2-(5-bromo-l-methyl-lH-pyrazoI-3-yl)acetonitrile (800 mg, 4.00 mmol, 1.00 eq) in THF (10.0 mL) was added BH3,THF (1.00 M, 24.0 mL, 6.00 eq) dropwise at 0°C. The mixture was stirred at 60°C for 12 h under nîtrogen atmosphère. MeOH (10.0 mL) was added to the mixture. The mixture was concentrated under reduced, 2-(5Bbromo-l-methyl-lH-pyrazol-3-yl)ethan-l-amine (800 mg, crude) was obtained as colourless oil.
Step 4: tert-butyl (2-(5-bromo-1 -methyl-1 H-pyrazol-3-yl)ethyl)carbamate
Br..
/N'N ^NHBoc
To 2-(5-bromo-l-methyl-lH-pyrazol-3-yl)ethan-l-amine (800 mg, 3.92 mmol, 1.00 eq) and Boc2O (1.71 g, 7.84 mmol, 1.80 mL, 2.00 eq) in DCM (5,00 mL) was added TE A (792 mg, 7.83 mmol, 1.09 mL, 2.00 eq) at 20°C. The mixture was stirred at 20°C for 3 hr. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prepTLC (SiO2, PE:EtOAc = 1:1). tert-Butyl (2-(5-bromo-l-methyl-lH-pyrazoL3-yl)ethyl)carbamate (430 mg, crude) was obtained as yellow oil.
Step 5: tert-butyl (S)-4-(3-(2-((tert-butoxycarbonyl)amino)ethyl)-l-methyl-lH-pyrazol-5-yl)-12fluoro-7 a, l3-dihydro-7H-[1,2,4] triazolo[4 3 f:l,6]pyrido[3,2-b] benzofuroj4,3-fg] [1,4] oxazonine14(8H)-carboxylate
351
To tert-butyl (2-(5-bromo-l -methyl-lH-pyrazol-3-yl)ethyl)carbamate (182 mg, 599 umol, 1.50 eq) and tert-butyl (S)-12-fluoro-4-(tributylstannyl)-7a,13-dihydro-7H[l,2,4]triazolo[4',3’: l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (280 mg, 399 umol, 1.00 eq) in dioxane (4.00 mL) was added palladium tritert-butyiphosphane (20.4 mg, 39.9 umol, 0.100 eq) al 20°C. The mixture was stirred at 80°C for 2 hr under nitrogen atmosphère. LCMS indicated partial conversion. The mixture stirred at 80°C for additîonal 2 h. LC-MS showed incompleted réaction. tert-Butyl (2-(5-bromo-l-methyl-lH-pyrazol-3-yl)ethyl)carbamate (50.0 mg, 164 umol, 4.12e-l eq) and palladium tritert-butyiphosphane (20.4 mg, 39.9 umol, 0.100 eq) were added to the mixture. The mixture was stirred at 100°C for 1 hr. LC-MS showed complété conversion. The réaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (SiCh, EtOAc). tert-ButyJ (S)-4-(3-(2-((tertbutoxycarbonyi)amino)ethyl)-l-methyl-lH-pyrazol-5-yl)-12-fluoro-7a,13-dihydiO~7H[ l,2,4]tnazolo[4',3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4]oxazonine-14(8H)-carboxylate ( 120 mg, crude) was obtained as yellow oil.
Step 6: (5)-2-(5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3': 1,6]pyrido[3,2b]benzofuro[4,3-Jg] [1,4] oxazonin-4-yl)-l-methyl-lH-pyrazol-3-yl)ethcm-l-amine
7a, 13-dihydro-7H-[ 1,2,4]triazolo[4',3’: 1,6]pyrido[3,2-b]benzofuro[4,3-fg][l ,4]oxazonine-14(8H)carboxylate (120 mg, 189 umol, 1.00 eq) in DCM (1.00 mL) was added TFA (462 mg, 4.05 mmol, 0.300 mL, 21.5 eq) at 20°C. The mixture was stirred at 20°C for 1 hr. DIPEA was added to the mixture to adjust pH to 7-8. The réaction mixture was concentrated under reduced pressure. The product (90.0 mg, crude) was obtained as yellow oil.
Step 7: (5)-2-(5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3': 1,6]pyrido[3,2b] benzofuro]4,3-fg] [1,4] oxazonin-4-yl)-l-methyl-lH-pyrazol-3-yl)-N,N-dimethylethan-l-amine
352
The reaction was set up in 7 parallel batches. To (S)-2-(5-(I2-fluoro-7a,8,13,14-tetrahydro-7H[ 1,2,4]triazolo[4',3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4]oxazonin-4-yl)-l-methyl-1 H-pyrazol-3yl)ethan-l-amine (20.0 mg, 45,9 umol, 1.00 eq) and formaldéhyde (18,6 mg, 230 umol, 17.1 uL, 5,00 eq) in MeOH (2.00 mL) was added AcOH (2.76 mg, 45.9 umol, 2.63 uL, 1.00 eq) at 20°C. NaBH3CN (5.77 mg, 91.9 umol, 2.00 eq) was added to each mixture and it was stirred at 20°C for 2 h. The batches were combinée!. The mixture was concentrated. The crude product was purified by prep-HPLC (basic conditions) to afford the product as a free base. To the product was added aqueous HCl (0.05 mL, 37%) and the obtained sait was lyophilized. ( S)-2-(5-( 12-fluoro7a,8,13,14-tetrahydro-7H-[ 1,2,4] tri azolo[4',3': 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4]oxazonin-4yl)-l-methyI-lH-pyrazol-3-yl)-N,N-dimethylethan-l-amine (13.6 mg, HCl sait) was obtained as yellow solid. !H NMR CD3OD 400 MHz δ = ppm 9.58 (s, IH), 8.04 (s, IH), 6.91 (dd, J = 10.0, 8.9 Hz, IH), 6.68 (dd, 7= 8.7, 3.9 Hz, IH), 6.52 (s, IH), 5.19 (d, 7= 14.8 Hz, IH), 5.01 - 5.00 (m, IH), 4.99 (br s, IH), 4.76 (br d, 7= 6.2 Hz, IH), 4.62 (t,7 = 9.5 Hz, IH), 4.31 (dd, 7= 9.7, 3.1 Hz, IH), 4.15-4.01 (m, IH), 3.97 - 3.87 (m, IH), 3.77 (s, 3H), 3.53 (t,7= 7.3 Hz, 2H), 3.16 (t, 7=7.2 Hz, 2H), 2.97 (s, 6H). LCMS (ES1+): m/z 464.3 (M+H),
Exainpïe 128: (S)-4-(l,3-dimethyl-lH-l,2,4-triazol-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4’,3’:l,6]pyrido[3,2-bjbenzofuro[4,3-fg][l,4]oxazonme
Step 1: 14-(tert-butyl) 4-methyl (S)-l2-fluoro-7a,l3-dihydro-7H[1,2,4]triazolo[4\3 1,6]pyrïdo[3,2-b] benzofuro[4,3-fg] [1,4] oxazonine-4,14(8H)-dicarboxylate
To a solution of tert-butyl (S)-4-bromo-12-fluoro-7a,13-dîhydro-7H[ l,2,4]triazolo[4',3': 1,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine- 14(8H)-carboxylate (4.50 g, 9.16 mmol, 1.00 eq) in MeOH (200 mL) was added TEA (9.27 g, 91.6 mmol, 12.8 mL, 10.0 eq) and Pd(dppf)Cl2 (670 mg, 916 umol, O.lOOeç) at 20°C, stirred at 60°C for 12 h under CO (50 psi). TLC (Petroleum ether/Ethyl acetate = 0/1) showed the reaction was complété. The mixture was concentrated and water (50.0 mL) and EtOAc (50.0 mL) were added to the solution. Brown
353 precîpitate was filtered off and dried to give 14-(tert-butyl) 4-methyl (S)-12-fluoro-7a,13-dihydro7H-[l,2,4]triazolo[4',3’:l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-4,14(8H)-dicarboxylate (3.8 g, crude) as a brown solid.
Step 2: (S)-14-(tert-butoxycarbonyl)-12-fluoro-7a,8,13,14-tetrahydro-7H[1,2,4]triazolo[4',3 41,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazomne-4-carboxylic acid
To a solution of 14-(tert-butyl)
4-methyl (S)-12-fluoro-7a, 13-dihydro-7H[ 1,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][i,4]oxazonine-4,14(8H)-dicarboxylate (4.10 g, 8.72 mmol, 1.00 eq) in MeOH (60.0 mL), water (20.0 mL) and THF (60.0 mL) was added NaOH (697 mg, 17.4 mmol, 2.00 eq) at 20°C and stirred at 20°C for 1 hr. The mixture was concentrated, water (50.0 mL) was added to the solution. The mixture was extracted with EtOAc (100 mL * 3), the aqueous phase was adjustedto pH of 2 with HCl (1 M), and extracted with EtOAc (50.0 mL * 3). Ail organic layers were combined, dried over Na2SO4, then concentrated. (S)-14-(tertbutoxycarbonyl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4',3':l,6]pyrido[3,2b]benzofuro[4,3-fg][l,4]oxazonine-4-carboxylic acid (3.20 g, 7.01 mmol, 80% yield) was obtained as a yellow solid.
Step 3: tert-butyl (S)-4-carbamoyl-12-fluoro-7a, 13-dihydro-7H-[l,2,4]triazolo[4’,341,6]pyrido[3,2b]benzofuro[4,3-fg] [1,4] oxazonine-14(8H)-carboxylate
To (S)-14-(tert-butoxycarbonyl)-12-fluoro-7a,8,13,14-tetrahydro-7H[l,2,4]trîazolo[4',3': L6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-4-carboxylic acid (2.00 g, 4.39 mmol, L00 eq) in DMF (20.0 mL) were added DIPEA (2.27 g, 17.6 mmol, 3.06 mL, 4.00 eq), HOBt (1.19 g, 8.78 mmol, 2.00 eq) and EDCI (1.68 g, 8.78 mmol, 2.00 eq) at 20°C. The mixture was stirred at 20°C for 5 min. NH4C1 (470 mg, 8.79 mmol, 2.00 eq) was added to the mixture at 20°C. The mixture was stirred at 20° C for 12 h. LC-MS showed (S)-14-(tert-butoxycarbonyl)-12fluoro-7a,8,13,14-tetrahydro-7H-[ 1,2,4]triazolo[4',3’: l,6]pyrido[3,2-b]benzofuro[4,3fg][l,4]oxazonine-4-carboxylic acid was consumed completely and one main peak with desired mass was detected. The mixture was combined with the pilot batch (same reaction, from 200 mg of
354 (S)-14-(tert-butoxycarbonyl)- 12-fluoro-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-4-carboxylic acid) for the workup. Water (10.0 mL) was added to the mixture and it was extracted with ethly acetate (20.0 mL * 5). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 1/0 to 1/1). tert-butyl (S)-4-carbamoyl-12-fluoro-7a, 13-dihydro-7H[l,2!4]triazolo[4,,3':l,6]pyrido[3,2-b]benzofiiro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (1.86 g, crude) was obtained as yellow oil.
Step 4: tert-butyl (S,Z)-4-((l-(dimethylantino)ethylidene)carbamoyl)-l2-fluoro-7a,13-dihydro-7H[l,2,4]triazolo[4 3 I, 6]pyrido[3,2-b] benzofuro[4,3-fgJ [I, 4] oxazonine-14(8H)-carboxylate
To tert-butyl (S)-4-carbamoyi-12-fluoro-7a,13-dihydiO-7H-[L2,4]triazolo[4',3':l,6]pyrido[3,2b]benzofuro[4,3-fg][i,4]oxazonine-14(8H)-carboxylate (1.86 g, 4.08 mmol, 1.00 eq) was added 1,1dimethoxy-N,N-dimethyl-ethanamine (21.2 g, 159 mmol, 23.3 mL, 39.0 eq) at 20°C. Then the mixture was stirred at 90°C for 2 h The reaction mixture was concentrated under reduced pressure. tert-Butyl (S,Z)-4-((l-(dimethylamino)ethylidene)carbamoyl)-I2-fluoro-7a,13-dihydro-7H[l,2,4]triazolo[4,,3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-l4(8EI)-carboxylate (2.00 g, crude) was obtained as brown oil.
Step 5: tert-butyl (S)-4-( 1,3-dimethyl-l H-l ,2,4-triazol-5-yl)-l 2-fluoro-7a, 13-dihydro-7H[1,2,4]triazolo[4’, 3 ':1, 6]pyrido[3,2-b] benzofuro[4,3-fg] [1,4] oxazonine-14(8H)-carboxyIate
To tert-butyl (S,Z)-4-((l-(dimethylamino)ethylidene)carbamoyl)-l 2-fluoro-7a, 13-dihydro-7H[l,2,4]triazoio[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (2.00 g, 3.81 mmol, 1.00 eq) in AcOH (21.0 g, 350 mmol, 20.0 mL, 91.7 eq) was added methylhydrazine (1.32 g, 11.4 mmol, 1.51 mL, 3.00 eq) at 20°C. The mixture was stirred at 60°C for 2 h. LC-MS showed tert-butyl (S,Z)-4-(( l-(dimethylamino)ethylidene)carbamoyl)- 12-fluoro-7a, 13-dihydro-7H[ l,2,4]triazolo[4’,3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate was
355 consumée! completely and one main peak with desired desired mass was detected. Water (10.0 mL) was added to the mixture which was then extracted with ethly acetate (50.0 mL * 4). The combined organic layers were dried over anhydrous NaiSCL, filtered, and coneentrated under reduced pressure. The residue was purified by column chromatography (SiO?, Petroleum ether/Ethyl acetate = 1/0 to 0/1). tert-butyl (S)-4-(I,3-dimethyl-lH-l,2,4-triazol-5-yI)-12-fluoro-7a,13-dihydiO-7H[l,2,4]triazolo[4',3’:l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonme-14(8H)-carboxylate (1.20 g, crude) was obtained as yellow oil.
Step 6: (S)-4-(l,3-dimethyl-lH-l,2,4-triazol-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4', 3 ':1,6]pyrido]3,2-b] benzofuro]4,3-fg][l, 4] oxazonine
To tert-butyl (S)-4-(l,3-dimethyl-lH-1,2,4-triazol-5-yl)-l 2-fluoro-7a,l 3-dihydro-7H[ 1,2,4]triazolo[4',3': 1,6]pyrido[ 3,2-b] benzofuro [4,3-fg] [ l,4]oxazonine-14(8H)-carboxylate (1.20 g, 2.36 mmol, 1.00 eq) in DCM (10.0 mL) was added TFA (5.10 g, 44.7 mmol, 3.31 mL, 18.9 eq) at 20°C. Then the mixture was stirred at 20°C for 1 hr. The reaction mixture was coneentrated under reduced pressure. The crude product was purified by /vty-HPLC (fbrmic acid conditions). (S)-4(l,3-dimethyl-lH-l,2,4-triazol5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4’,3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine (280 mg, 687 umol, 29% yield, N/A purity) was obtained as white solid. 'H NMR DMSO-rf^ 400 MHz δ = ppm 9.48 (s, IH), 7.87 (brt, 7=6.3 Hz, IH), 7.59 (s, IH), 6.96 (dd,7 = 10.1, 9.0 Hz, IH), 6.70 (dd,7 = 8.7, 3.8 Hz, IH), 4.99 - 4.88 (m, 1H), 4.88 - 4.76 (m, IH), 4.59 - 4.45 (m, 2H), 4.21 (dd, 7= 9.5, 3.7 Hz, IH), 4.10-3.98 (m, IH), 3.85 (brd,7 = 10.4 Hz, 1 H), 3.78 (s, 3H), 2.27 (s, 3H).
Step 7: (5)-4-(1,3-dimethyl-lH-l,2,4-triazol-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H[ 1,2,4]triazolo]4',3 6]pyrido]3,2-b]benzo]uro[4,3-fg][l,4]oxazonine mesylate
To free base (S)-4-(l,3-dimethyl-lH-l,2,4-triazol-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H
[l,2,4]triazolo[4',3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine (257 mg, 631 umol, 1.00 eq) în MeCN (1.84 mL) was added MsOH (61.2 mg, 637 umol, 45.4 uL, LOI eq) in MeCN (0.276 mL)
356 dropwise at 50°C. Then the mixture was stirred at 50°C for 1 hr, then the mixture was cooled to 30°C in the span of 1 hr, and the mixture was stirred at 30°C for 2 h. The mixture was cooled to 25°C and concentrated under reduced pressure to remove most of MeCN at 30°C. Water (10.Ü mL) was added to the mixture followed by lyophilization. (S)-4-(l,3-dimethyl-H-I-l,2,4-triazol-5-yl)-12fluoro-7a,8,13,14-tetrahydro-7H-[ J ,2,4]triazolo[4',3': l,6]pyrido[3,2-b]benzofuro[4,3fg][l,4]oxazonine (312 mg, 599 umol, 95% yield, 96.7% purity, CH3SO3H sait) was obtained as a yellow crystalline solid. lH NMR DMSO-^ 400 MHz δ = ppm 9.62 (s, IH), 8.57 - 8.30 (m, IH), 7.97 (brs, IH), 7.00 (t, 7= 9.5 Hz, 1H),6.73 (dd, 7=8.6, 3.7 Hz, IH), 5.09-4.78 (m, 2H),4.56(br t, 7= 9.5 Hz, 2H), 4.23 (br dd, 7= 9.5, 3.7 Hz, IH), 4.14 - 4.02 (m, IH), 3.95 (br s, IH), 3.88 (s, 3H), 2.34 (s, 3H), 2.32 (s, 3H). LCMS (ESI+): m/z 408.2 (M+H).
Example 129: (S)-4-(3-ethyl-l-methyl-lH-l,2,4-triazol-5-yl)-12-fluoro-7a,8,13,14-tetrahydro7H-[ 1,2,4] trîazolo[4’,3':1,6] pyrido[3,2-b] benzofuro[4,3-fg] |1,4| oxazonine
Step 1: tert-butyl (S)-l 2-fluoro-4-((l -iminopropyl)carbamoyl)-7a,l 3-dihydro-7H[1,2,4]triazolo[4', 3 1,6]pyrido[3,2-b] benzofuro]4,3-fg] [1,4] oxazomne-14(8H)-carboxylate
To (S)-14-(tert-butoxycarbonyl)-12-fluoro-7a,8,13,14-tetrahydro-7H[ l,2,4]triazolo[4',3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-4-carboxyIic acid (300 mg, 657 umol, 1.00 eq) in DMF (5.00 mL) was added DIPEA (340 mg, 2.63 mmol, 458 uL, 4.00 eq), the mixture was stirred at 20°C for 5 nains. Then EDCI (252 mg, 1.31 mmol, 2.00 eq) and HOBt (178 mg, 1.31 mmol, 2.00 eq) were added to the mixture at 20°C. The mixture was stirred at 20°C for 5 min followed by addition of propanamidine (143 mg, 1,31 mmol, 2.00 eq, HCl sait) at 20°C. The mixture was stirred at 2Ü°C for 12 hr. LC-MS showed that (S)-i4-(tert-butoxycarbonyl)-12-fluoro7a,8,13,14-tetrahydro-7H-[ 1,2,4]triazolo[4',3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4]oxazonine-4carboxylic acid was consumed completely and one main peak with the desired mass was detected. The obtained material was used directly in the next step.
Step 2: tert-butyl (S)-4-(3-ethyl-l -methyl-1 H-l ,2,4-triazol-5-yl)-l 2-fluoro-7a, 13-dihydro-7H[1,2,4] triazolo[4 3 1,6]pyrido[3,2-b] benzqfuro[4,3flg] [1,4] oxazomne-14(8H)-carboxylate
357
To tert-butyl (S)-12-fluoro-4-((l-iminopropyl)carbamoyl)“7a,13-dihydro-7H[l,2,4]triazolo[4',3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (656 umol theoretical yield, 1.00 eq) in DMF (5.00 mL) was added AcOH (315 mg, 5.25 mmol, 300 uL,
7.99 eq) and methylhydrazine (113 mg, 981 umol, 129 uL, 1.50 eq) at 20°C. The mixture was stirred at 60°C for 2 hr. LC-MS showed tert-butyl (S)-12-fluoro-4-((l-iminopropyl)carbamoyl)~ 7a, 13-dihydro-7H-[ 1,2,4]triazolo[4',3’: 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4] oxazonine- 14(8H)carboxylate was eonsumed completely and one main peak with the desired mass was detected. Water (5.00 mL) was added to the mixture. The reaction mixture was extracted with ethly acetate (5.00 mL * 5). The combined organic layers were dried over anhydrous NaiSCU, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (SiCh, ethly acetate). tert-Butyl (S)-4-(3-ethyl-1 -methyl-1 H-l,2,4-triazol-5-yl)-12-fluoro-7a,13-dihydro-7H-
[ 1,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine- 14(8H)-carboxylate ( 120 mg, crude) was obtained as yellow oil.
Step 3: (S)-4-(3-ethyl-l-methyl-lH-l,2,4-triazol-5-yl)-12-fluoro-7a,8,13,14-tetrahydro- 7H[ 1,2,4] triazolo[4',3 ':1,6]pyrido[3,2-b] benzqfwo[4,3-fg] [ 1,4] oxazonine
To tert-butyl (S)-4-(3-ethyl-1 -methyl -1 H-1,2,4-triazo 1-5-yl)-12-fluoro-7a, 13-dihydro-7H-
[l ,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate (120 mg, 20 230 umol, 1.00 eq) in DCM (1.00 mL) was added TFA (462 mg, 4.05 mmol, 0.300 mL, 17.6 eq) at
20°C. The mixture was stirred at 20°C for 1 hr. The reaction mixture was concentrated under reduced pressure. The crude product was purified by prep-HPLC (HCl conditions). (S)-4-(3-ethyll-methyl-lH-l,2,4-triazol-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4’,3':l,6]pyrido[3,2-b]benzofiiro[4,3-fg][l,4]oxazonine (13.7 mg, 29.2 umol, 12% 25 yield, 97.6% purity, HCl sait) was obtained as yellow solid. ’H NMR CD3OD 400 MHz δ = ppm
358
9.54 (s, ÏH), 8.18 (s, IH), 6.92 (dd,./ = 10.1, 8.8 Hz, IH), 6.68 (dd, 8.7, 3,9 Hz, IH), 5.21 (d, J = 14.8 Hz, IH), 5.01 - 4.95 (m, IH), 4.80 - 4.74 (m, IH), 4.68 - 4.58 (m, IH), 4.31 (dd, J = 9.7, 3.4 Hz, IH), 4.11 - 4.04 (m, 1 H), 4.01 (s, 3H), 3.99-3.91 (m, 1 H), 2.84 (q, J = 7.6 Hz, 2H), 1.36 (br t, J = 7.5 Hz, 3H). LCMS (ES1+): m/z 422.2 (M+H).
Example 130: (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[r,5’:l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazoninc
Step 1: tert-butyl (R)-9-chloro-5-fluoro-10-(2-methylpyridin-3-yl)-l3,13a-dihydro-lHbenzofuro[4,3-fg]pyrido[3,2-b] [1,4] oxazonine-7 (6H)-carboxylate
F /Γ~-χ Boc ; N Ll|
Two parallel reactions were set up. To a solution of tert-butyl (R)-10-bromo-9-chloiO-5-fluoro13,13a-dihydiO-lH-benzofuiO[4,3-fg]pyrido[3,2-b][l,4]oxazonine-7(6H)-carboxylate (Example 16; 500 mg, 1.03 mmol, 1.00 eq) in dioxane (8,00 mL) and water (0.800 mL) was added 2-methyl-3(4,4,5,5-tetramethyl-l,3,2-dioxaboiOlan-2-yl)pyridine (395 mg, 1.55 mmol, 1.50 eq, HCl), Pd(dppf)C12 (75.3 mg, 103 umol, 0.100 eq) and NaHCOj (432 mg, 5.14 mmol, 5.00 eq) at 20°C. The mixture was stirred at 80°C for 12 h under nitrogen atmosphère. The batches were combined, the mixture was fïltered, the filtrate was concentrated. The residue was purified b y column chromatography (SiO2, Petroleum ether/Ethyl acetate = 1/0 to 0/1). tert-butyl (R)-9-chloro-5-fluoro10-(2-metbylpyridin-3-yl)-13,13a-dihydro-lH-benzofuro[4,3-fg]pyrido[3,2-b] [l,4]oxazonine7(6H)-carboxylate (720 mg, 1.45 mmol, 70% yield) was obtained as a yellow solid.
Step 2: tert-butyl (R)-9-amino-5-fluoro-I0-(2-methylpyridin-3-yl)-13,13a-dihydro-lHbenzofuro[4,3-fg]pyrido[3,2-b] [1,4] oxazonine- 7(6H)-carboxylate F Z—/ Boc
To a mixture of tert-butyl (R)-9-chloiO-5-fluoro-10-(2-methylpyridin-3-yl)-13,13a-dihydiO-lHbenzofuro[4,3-fg]pyrido[3,2-b][l,4]oxazonine-7(6H)-carboxylate (450 mg, 904 umol, 1.00 eq), NaN3 (823 mg, 12.7 mmol, 14.0 eq) and sodium ascorbate (215 mg, 1.09 mmol, 1.20 eq) in dioxane (15.0 mL) and water (3.00 mL) were added Cul (241 mg, 1.27 mmol, 1.40 eq) and (1S,2S)-N1,N2dimethylcyclohexane-l,2-diamine (257 mg, 1.81 mmol, 2.00 eq) at 20°C. Tthe mixture was stirred
359 at 110°C for 16 h under nitrogen atmosphère, Water (15,0 mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (15.0 mL * 3), the combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Petroleum ether/Ethyl acetate = 0/1). tert-Butyl (R)-9-amino-5-fluoro-10-(2-methylpyridin3-yl)-13,I3a-dihydiO-lH-benzofuro[4,3-fg]pyrido[3,2-b][l,4]oxazonine-7(6H)-carboxylate (400 mg, 836 umol, 92% yield) was obtained as a yellow oil.
Step 3 : tert-butyl (R,Z)-5-fluorn-9- (((hydroxyamino)methylenejamino)-J0-(2-methylpyridin-3-yl)13,13a-dihydro-lH-benzofuro[4,3-fg]pyrido[3,2-b] [1,4] oxazomne-7 (6H)-carboxylate
OH i
To a solution of tert-butyl (R)-9-amino-5-tluoiO-10-(2-methylpyridin-3-yl)-13,13a-dihydro-lHbenzofuro[4,3-fg]pyrido[3,2-b][l,4]oxazonine-7(6H)-carboxylate (400 mg, 836 umol, 1.00 eq) in iPrOH (6.00 mL) was added DMF-DMA (249 mg, 2.09 mmol, 278 uL, 2.50 eq) at 20°C, the mixture was stirred at 90°C for 5 h under nitrogen atmosphère. Then NH2OH.HCl (145 mg, 2.09 mmol, 2.50 eq) was added to the mixture at 20°C, and the mixture was stirred at 50°C for 12 h. The réaction mixture was concentrated and the residue was purified by prep-TLC (SiO2, Petroleum ether/Ethyl acetate = 0/1). tert-Butyl (R,Z)-5-fluoiO-9-(((hydroxyamino)methylene)ainino)-10-(2meÎhylpyridin-3-yl)-13,13a-dihydro-lH-benzofuiO[4,3-fg]pyrido[3,2-b][],4]oxazonine-7(6H)~ carboxylate (390 mg, 748 umol, 89% yield) was obtained as a yellow oil.
Step 4: tert-butyl (S)-12-ftiioro-4-(2-methylpyridin-3-yl)-7a,13-dihydro-7H[ 1,2,4]triazolo[1 5 1,6]pyrido[3,2-b]benzqfùro[4,3-fg][ 1,4] oxazonine-14(8H)-carboxylate
F
To a solution of tert-butyl (R,Z)-5-fluoro-9-(((hydroxyamino)methylene)amino)-10-(2niethylpyridin-3-yl)-13,l 3a-dihydro-lH-benzofuro[4,3-fg]pyrido[3,2-b][l,4]oxazonine-7(6H)carboxylate (460 mg, 882 umol, 1.00 eq) in THF (10.0 mL) was added TFAA (926 mg, 4.41 mmol, 613 uL, 5.00 eq) at 0°C, the mixture was stirred at 50°C for 16 hr under nitrogen atmosphère. Water (10.0 mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (10.0 mL
360 * 3), the combined organic layers were dried over MgSO4 and concentrated under reduced pressure, tert-Butyl (S)-12-fluoro-4-(2-methyipyridin-3-yl)-7a, 13-dihydro-7H[ l,2,4]triazolo[ 1 ’,5’: 1,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8 H)-carboxylate ( 1.00 g, crude) was obtained as a yellow oil.
Step 5: (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H[1,2,4] triazolo]I',5':l, 6]pyrido[3,2-b] benzofuro]4,3-fg] [ 1,4]oxazomne
Two parallel réactions were set up. A mixture of tert-butyl (S)-12-fluoiO-4-(2-methylpyridin-3-yI)7a, 13-dihydro-7H-[l,2,4]triazolo[r,5': l,6]pyrido[3,2-b]benzofuro[4,3-fg][l ,4]oxazonine-14(8H)10 carboxylate (500 mg, 993 umol, 1.00 eq) in HFIP (10.0 mL) was stirred at 100°C for 12 h. The batches were combined and concentrated under reduced pressure. The residue was dissolved in MeOH (5.00 mL). The mixture was purified by acidicprep-HPLC (column: Phenomenex luna Cl8 250*50 mm*10 um; mobile phase: [water (0.05% HC1)-ACN]; B%: 10%-40%, 10 min). The product-contaînîng fraction was concentrated under reduced pressure to remove most of MeCN at
30°C and the aqueous phase was lyophilized. (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14tetrahydro-7H-[l,2,4]triazolo[Γ,5': 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4]oxazonine (100 mg, 227 umol, 11% yield, 100% purity, HCl sait) was obtained as a white solid. JH NMR CDjOD 400 MHz 5 = ppm 8.81 (dd, 7=6.0, L5 Hz, IH), 8.79 (s, IH), 8.57 (dd, 7= 8.2, 1.3 Hz, IH), 8.02 (dd, 7= 7.8, 6.1 Hz, IH), 7.91 (s, IH), 6.94 - 6.84 (m, IH), 6.66 (dd, 7= 8.7, 3.9 Hz, IH), 5.16 (d, 7= 14.8 Hz,
IH), 4.97 (brd, 7= 14.8 Hz, IH), 4.82 - 4.76 (m, 1H),4.61 (t, 7= 9.4 Hz, 1H),4.3I (dd, 7= 9.8, 3.0 Hz, IH), 4.10 - 3.88 (m, 2H), 2.66 (s, 3H). LCMS (ESI+): m/z 404.1 (M+H).
Example 131: (S)-2-(5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4',3’:l,6]pyrido[3,2b]benzofuro[4,3-fg][l,4]oxazonin-4-yl)-l-methyl-lH-pyrazol-3-yl)-2-inethylpropaneiHtrile
Step 1: (5-broma-l-methyl-lH-pyrazol-3-yl)methyl methcmesulfonate
JD Ms
VN /N
Br '
To (5-bromo-l-methyl-lH-pyrazol-3-yi)methanol (1.60 g, 8.38 mmol, 1.00 eq) in DCM (15.0 mL) was added TEA (1.70 g, 16.8 mmol, 2.33 mL, 2.00 eq) and MsCl (1.92 g, 16.8 mmol, 1.30 mL, 2.00
361 eq) at 0°C. The mixture was stirred at 0°C for 1 hr. Saturated NaHCOj was added to the mixture to adjust pH to 7.0. The mixture was extracted with EtOAc (10.0 mL * 4). The combined organic layers were washed with brine (5.00 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give (5-biOmo-l-rnethyl-lH-pyrazol-3-yI)methyl methanesulfonate (2.00 g, crude) as a yellow oil.
Step 2; 2-(5-broma-l-methyl-lH-pyrazol-3-yl)acetonitrile .CN
A eh
The reaction was set up in 20 parallel batches. To (5-bromo-I-methyLlH-pyrazoL3-yl)methyl methanesulfonate (100 mg, 372 umol, 1.00 eq) in MeCN (1.00 mL) was added TMSCN (55.3 mg, 557 umol, 69.7 uL, 1.50 eq) and TBAF (1.00 M, 557 uL, 1.50 eq) at 25°C. The mixture was stirred at 25°C for 12 h. LC-MS showed (5-bromo-1 -methyl-1 H-pyrazoL3-yl)m ethyl methanesulfonate was consumed completely and one main peak with desired mass was detected. The batches were combined and concentrated under reduced pressure. Water (30.0 mL) was added to the mixture. The mixture was extracted with EtOAc (50.0 mL * 4). The combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 1/0 to 1/1). 2-(5-bromo-l-methyl-lH-pyrazol-3-yl)acetonitrile (800 mg, crude) was obtained as a yellow solid.
Step 3: 2-(5-brome-1-methyl-lH-pyrazol-3-yl)-2-methylprüpanenitrile
CN ô
/—N
Br X
To NaH (390 mg, 9.75 mmol, 60% purity, 3.00 eq) was added THF (4.00 mL) at 25°C. The mixture was degassed and purged with nîtrogen 3 times, the mixture was stirred at 0°C for 10 mins. Then 2(5-bromo-l-methyl-lH-pyrazol-3-yl)acetonitrile (650 mg, 3.25 mmol, 1.00 eq) in THF (1.00 mL) was added to the mixture at 0°C. The mixture was stirred at 0°C for 0.5 hr under nîtrogen atmosphère. Mel (1.84 g, 13.0 mmol, 809 uL, 4.00 eq) was added at 0°C. The mixture was stirred at 0°C for 1 hr under nîtrogen atmosphère. Water (5,00 mL) was added to the mixture. The mixture was extracted with EtOAc (20.0 mL * 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-^C
362 (SiO2, PE:EtOAc = 2:1). 2-(5-bromo-l-methyl-lH-pyrazol-3-yl)-2-methylpropanenitrile (550 mg. crude) was obtained as a yellow oil.
Step 4: 2-methyl-2-( 1 -methyl-5-(tributylstannyl)-l H-pyrazol-3-yl)propanenitrile
CN
(n-Bu)3Sri
To 2-(5-bromo-l-methyl-lH-pyrazol-3-yl)-2-methylpropanenitrile (220 mg, 965 umol, 1.00 eq) in THF (3.00 mL) was added LPrMgCl-LiCl (1.30 M, 1.48 mL, 2.00^) at-78°C under N2. Then the mixture was stirred at 0°C for 0.5 lu* under N2. Then tributyl(chloro)stannane (628 mg, 1.93 mmol, 519 uL, 2.00 eq) was addednto the mixture at 0°C under N2. The mixture was stirred at 0°C for 1 hr under N2. Water (5.00 mL) was added to the mixture. Then the mixture was extracted with ethly acetate (10.0 mL * 3), the combined organic layers were dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. 2-methyl-2-(l-methyl-5-(tributylstannyl)-lHpyrazol-3-yl)propanenitrile (450 mg, crude) was obtained as a yellow oil.
Step 5: tert-butyl (S)-4-(3-(2-cyanopropan-2-yl)-l-methyl-lH-pyrazol-5-yl)-12jluoro-7a, 13dihydro-7H-[ 1,2,4] triazolo [4 ', 3’: 1,6]pyrido[3,2-b] benzofuro[4,3 -fg] [1,4] oxazonine-14(8H) 15 carboxylate
F
To 2-methyl-2-(l-methyl-5-(tributylstannyl)-lH-pyrazol-3-yl)propanenitrile (268 mg, 611 umol, 1.50 eq) and tert-butyl (S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[l,2,4]triazolo[4',3': l,6]pyrido[3,2b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (200 mg, 407 umol, 1.00 eq) in dioxane (3.00 mL) was added Pd(PPh3)4 (47.0 mg, 40.7 umol, 0.100 eq), LiCl (34.5 mg, 814 umol, 16.7 uL,
2.00 eq) and Cul (31.0 mg, 163 umol, 0.400 eq) at 25°C. The mixture was stirred at 80°C for 12 hr under N2. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Petroleum ether/Ethyl acetate = 0/1). tert-Butyl (S)-4-(3(2-cyanopropan-2-yl)- l-methyl-lH-pyrazol-5-yl)-12-fluoro-7a, 13-dihydro-7H25 [l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (200 mg, crude) was obtained as a yellow oil.
363
Step 6: (S)-2-(5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4',3’:l,6]pyrido]3,2b] benzofuro]4,3-fg] [l,4]oxazon in-4-yl)-l-methyl- lH-pyrazol-3-yl)-2-methylpropanemtrile
F
To tert-butyl (S)-4-(3-(2-cyanopropan-2-yl)-1 -methyl- lH-pyrazol-5-yl)-12-fluoro-7a, 13-dihydro7H-[ 1,2,4]triazolo[4',3': 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4]oxazonine-14(8H)-carboxylate (180 mg, 322 umol, 1.00 eq) was added HFIP (2.00 mL) at 25°C, the mixture was stirred at 100°C for 12 h. The mixture was combined with another batch from 20 mg of tert-butyl (S)-4-(3-(2-cyanopropan2-yl)-1-methyl-1 H-pyrazol-5-yl)-12-fluoro-7a, 13-dihydro-7H-[ 1,2,4]triazolo[4’,3': 1,6]pyrido[3,2b]benzofuro[4,3-fg][l,4]oxazonine-!4(8H)-carboxylate. The mixture was concentrated under reduced pressure. The crude product was purified by prep-HPLC (fonnic acid conditions). (S)-2(5-(12-fluoro-7a)8,13,14-tetrahydro-7H-[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3fg][l,4]oxazonin-4-yl)-l-methyl-lH-pyrazol-3-yl)-2-methylpropanenitrile (74.3 mg, 143 umol, 97.5% purity, formate sait) was obtained as a light-yellow solid. ’H NMR DMSO-7& 400 MHz δ = ppm 9.45 (s, IH), 7.70 (br t, J= 6.2 Hz, IH), 7.47 (s, IH), 6.96 (t, 7= 9.5 Hz, IH), 6.70 (dd, 7 = 8.6, 3.7 Hz, IH), 6.64 (s, IH), 4.97 - 4.87 (m, IH), 4.85 - 4.74 (m, IH), 4.60 - 4.45 (m, 2H), 4.20 (dd, 7=9.6, 3.4 Hz, IH), 4.10 - 3.96 (m, IH), 3.94- 3.84 (m, IH), 3.81 (s, 3H), 1.68 (s, 6H). LCMS (ES1+): m/z 460.1 (M+H).
Example 132: (S)-12-fluoro-4-(3-fluoro-l-methyl-lH-pyrazol-5-yl)-7a,8,13,14-tetrahydro-7H [l,2,4]triazolo[4',3': 1,6] pyrido[3,2-b] benzofuro[4,3-fg] [l,4]oxazonine
Step 1: 3-fluoro-l -methyl-1 H-pyrazole
To NaH (488 mg, 12.2 mmol, 60% purity, 3.00 eq) in THF (1.00 mL) was added 3-fluoro-lHpyrazole (350 mg, 4.07 mmol, 1.00 eq) at 0°C under nitrogen atmosphère. The mixture was stirred at 0°C for 0.5 hr under N2. Mel (2.31 g, 16.3 mmol, LOI mL, 4.00 eq) in THF (2.00 mL) was added to the mixture at 0°C, and the mixture was stirred at 0°C for 1 hr under nitrogen atmosphère. Water (5.00 mL) was added to the mixture, the mixture was extracted with EtOAc (5.00 mL * 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. 3-Fluoro-l-methyl-1 H-pyrazole (300 mg, crude) was obtained
364 as yellow oil. ’H NMR CDC13 400 MHz δ = ppm 7.15 (t, J = 2.2 Hz, 1H), 5.74 (dd, J= 6.0, 2.4 Hz, 1H), 3.77 (s,3H).
Step 2: 3-fluoro-i-methyl-5-(tributylstannyl)-lH-pyrazo
To 3-fluoro-1-methyl-IH-pyrazole (450 mg, 4.50 mmol, 1.00 eq) in THF (1.00 mL) was added nBuLi (2.50 M, 3.60 mL, 2.00 eq) at -78°C under N2. The mixture was stirred at -78°C for 30 min. Tributyl(chloro)stannane (2.93 g, 8.99 mmol, 2.42 mL, 2.00 eq) was added to the mixture at -78°C under N2. The mixture was stirred at -78°C for 1 hr under N2. The mixture was extracted with ethly acetate (5.00 mL * 3), the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Petroleum ether:ethyl acetate = 10:1). 3-Fluoro-l-methyl-5-(tributyIstannyl)-lH-pyrazole (350 mg, 899 umol, 20% yield) was obtained as a colorlesss oil.
Step 3: tert-butyl (S)-12-]luoro-4-(3-fluoro-l-methyl-lH-pyrazol-5-yl)-7a, 13-dihydro-7H[1,2,4]triazolo[4\3 1,6]pyrido[3,2-b]benzofuro[4,3-fg] [1,4] oxazonine-14(8H)-carboxylate
To 3-fluoro-l-methyl-5-(tributylstannyl)-lH-pyrazole (178 mg, 458 umol, 1.50 eq) and tert-butyl (S)-4-bromo-12-fluoiO-7a,13-dihydro-7H-[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3fg] [1,4] oxazonine-14(8H)-carboxyIate (150 mg, 305 umol, 1.00 eq) in dioxane (1.00 mL) was added Pd(PPh3)4 (35.3 mg, 30.5 umol, 0.100 eq), LiCl (25.9 mg, 611 umol, 12.5 uL, 2.00 eq) and Cul (23.3 mg, 122 umol, 0.400 eq) at 25°C. The mixture was stirred at 100°C for 12 h under N2. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Petroleum ether/Ethyl acetate = 1/2). tert-butyl (S)-12-fluoro-4-(3-fluoro-lmethyl-lH-pyrazol-5-yl)-7a,13-dihydro-7H-[l,2,4]triazolo[4’,3':l,6]pyrido[3,2-b]benzofuro[4,3fg][l,4]oxazonine-14(8H)-carboxylate (120 mg, crude) was obtained as a yellow oil.
Step 4: (S)-12-fluoro-4~(3-fluoro-1 -methyl-1 H-pyrazol-5-yl)-7a,8,l3,l4-tetrahydro-7H[1,2,4]triazolo[4',3 ’:1,6]pyrido[3,2-b]benzofùro[4,3-fg] [1,4] oxazonine
365
To tert-butyl (S)-12-fluoiO-4-(3-fluoro-l-methyl-lH-pyrazol-5-yl)-7a,13-dihydro-7H[l,2,4]triazolo[4',3’:I,6]pyrÎdo[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylaÎe (120 mg, 235 umol, 1.00 eq) was added HFIP (2.00 mL) at 25°C. The mixture was stirred at 100°C for 3 hThe mixture was concentrated under reduced pressure. The crude product was purified by prepHPLC (HCl conditions). (S)-12-fluoro-4-(3-fluoro-l-methyLlH-pyrazol-5-yl)-7a,8,I3,14tetrahydro-7H-[ 1,2,4]triazolo[4',3': 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4]oxazonine (39.6 mg, 88.62 umol, 37% yield, 100% purity, HCl sait) was obtained as a light-yellow solid. ’H NMR CD3OD 400 MHz δ = ppm 9.44 (s, IH), 7.85 (s, IH), 6.90 (dd, J = 10.0, 8.9 Hz, IH), 6.67 (dd, 7 = 8.6, 3.7 Hz, IH), 6.12 (d, 7= 5.7 Hz, IH), 5.16 (d, 7= 14.8 Hz, IH), 4.94 (s, IH), 4.76 - 4.67 (m, IH), 4.60 (t, J= 9.4 Hz, IH), 4.30 (dd, 7 = 9.6, 3.2 Hz, IH), 4.09 - 3.98 (m, IH), 3.93 - 3.84 (m, IH), 3.66 (s, 3H). LCMS (ESI+): m/z 411.0 (M+H).
Example 133: (S)-12-fluoro-4-(l,2,4-trimethyl-lH-imidazol-5-yl)-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3':l,6|pyrido[3,2-bjbenzofuro[4,3-fg][l,4|oxazonine
Step 1: tert-butyl (7aS)-12-fluoro-4-(l-hydroxypropyl)-7a,13-dihydro-7H[1,2,4]triazolo[4 , 3 ’:1,6]pyrldo[3,2-b]benzofùro[4,3-fg] [1,4] oxazonine-14(8H)-carboxylate
The reaction ws set up in two parallel batches. To a stirred solution of tert-butyl (S)-4-bromo-l2fluoro-7a,13-dihydro-7H-[l,2,4]triazoÎo[4',3,:l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine14(8H)-carboxylate (500 mg, 1.02 mmol, 1.00 eq) in THF (7.00 mL) was added LPrMgCl-LiCl (1.30 M, 1.57 mL, 2.00 eq) at -78°C under nitrogen, and the mixture was stirred at 0°C for 0.5 hr. To the mixture was added propanai (236 mg, 4.07 mmol, 296 uL, 4.00 eq) at -78°C under N2. The resulting mixture was stirred at 25°C for 12 h. The batches were combined. To the resulting mixture was added water (20.0 mL) and it was extracted with EtOAc (10.0 mL * 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The mixture was purified by MPLC (SiO2, ΡΕ/EtOAc = 10/1 to 1/2). tert-Butyl (7aS)-12-fluoro-4-(l-hydroxypropyi)-7a,13
366 dihydro-7H-[l,2,4]triazolo[4'3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazomne-14(8H)carboxylate (1.20 g, crude) was obtained as a brown solid.
Step 2: tert-butyl (S)-12-fluoro-4-propionyl-7a, 13-dihydro-7H-[1,2,4]triazolo[4',3’: 1,6]pyrido[3,2b] benzofuro[4,3-fg] [ 1,4] oxazonine-14(8H)-carboxylate
To a stirred solution of tert-butyl (7aS)-12-fluoro-4-(l-hydroxypropyl)-7a,13-dihydro-7H[l,2,4]triazolo[4',3': 1,6] pyrido[3,2-b] benzofuro[4,3-fg] [1,4] oxazonine-14(8H)-carboxylate (1.20 g, 2.55 mmol, 1.00 eq) in DCM (30.0 mL) was added DMP (2.16 g, 5.10 mmol, 1.58 mL, 2.00 eq) at 25°C. The mixture was stirred at 25°C for 12 h. The réaction mixture was diluted with water (30.0 mL) and extracted with EtOAc (30.0 mL * 3). The combined organic layers were dried over MgSOq, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, ΡΕ/EtOAc = 1/2). tert-butyl (S)-12-fluoro-4-propionyL7a,13-diliydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (240 mg, crude) was obtained as a yellow solid.
Step 3: tert-butyl (S,Z)-12-fluoro-4-(2-(hydroxyimino)propanoyl)-7a, 13-dihydro-7H[1,2,4]triazolo[4',3 1,6]pyrido[3,2-b]benzofiiro[4,3-fg][1,4] oxazonine-14(8H)-carboxylate and (S,Z)-1-(12-jluoro -7a,8,13,l 4-tetrahydro-7H-[1,2,4]triazolo[4’,3':1,6]pyrido[3,2-b] benzofuro[4,3fg][1,4]oxazonin-4-yl)-2-(hydroxyimino)propan-l-one
N-OH N—OH
To a solution of tert-butyl (S)-12-fluoro-4-propîonyl-7a,13-dihydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (240 mg, 512 umol, 1.00 eq) in DCM (3.00 mL) was added TMSC1 (55.7 mg, 512 umol, 65.0 uL, 1.00 eq) at 20°C. To the cooled solution was added dropwise isoamyl nitrite (60.0 mg, 512 umol, 68.9 uL, 1.00 eq). The mixture was stirred at 25°C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, EtOAc/MeOH = 20/1). tert-butyl
367 (S,Z)-12-iluoro-4-(2-(hydroxyimino)propanoyl)-7a,l 3-dihydro-7H[ 1,2,4]triazolo[4',3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4] oxazonine-14(8H)-carboxylate (30.0 mg, crude) was obtained as a yellow solid. (S,Z)-l-(12-fluoro-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3': I,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonin-4-yl)-2(hydroxyimino)propan-1-one (50.0 mg, crude) was obtained as a white solid.
Step 4: (5)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[ 1,2,4]lriazolo[43':1,6]pyrido[3,2b]benzofuro[4,3-fg][l,4]oxazonin-4-yl)-l,2,4-trimethyl-lH-imidazole 3-oxide
To a stirred solution of (S,Z)-l-(12-fluoro-7a,8,13,14-tetrahydiO-7H~ [l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuiO[4,3-fg][l,4]oxazonin-4-yl)-2(hydroxyimino)propan-l-one (50.0 mg, 126 umol, 1.00 eq) in AcOH (2.00 mL) was added MeCHO (5.54 mg, 126 umol, 7.06 uL, 1.00 eq) and MeNH2 (9.77 mg, 126 umol, 30.2 uL, 40% aqueous solution, 1.00 eq) at 25°C. The resulting mixture was stirred at 100°C for 12 h The mixture was concentrated under reduced pressure, (S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H[ l,2,4]triazolo[4',3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][I,4]oxazonin-4-yl)-l,2,4-Îrimethyl-lHimidazole 3-oxide (55.0 mg, crude) was obtained as yellow liquid, which was used to the next step directly.
Step 5: (S)-12-fluoro-4-(l,2,4-tnmethyl-lH-imidazol-5-yl)-7a,8,13,14-tetrahydro-7H[1,2,4] triazolo]4',3':1,6]pyrido[3,2-b] benzofuro[4,3-fg] [1,4] oxazonine
To a stirred solution of (S)-5-(12-fluoro-7a,8,13,l4-tetrahydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonin-4-yl)-l,2,4-trimethyLlHimidazole 3-oxide (55.0 mg, 126 umol, 1.00 eq) in MeOH (10.0 mL) was added Raney-Ni (30.0 mg) at 25°C under N2. The resulting mixture was stirred at 50°C for 12 h under H2 (15 psi). The mixture was concentrated under reduced pressure. The mixture was purified b y acidic prep-VWLC (HCl conditions) to give the crude product. The crude product was purified by acidic prep-HPLC (HCl) again. (S)-12-fluoro-4-(l,2,4-trimethyl-lH-imidazol-5-yl)-7a,8,13,14-tetrahydro-7H
368
[l,2,4]tnazolo[4\3,:L6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine (2.00 mg, 4.26 umol, 3% yield, 97.4% purity, HCl sait) was obtained as a yellow solid. ’H NMR CD3OD 400 MHz δ = ppm 9.53 (s, IH), 7.98 (s, IH), 6.93 (t, J= 9.4 Hz, IH), 6.69 (dd, 8.6, 3.9 Hz, IH), 5.22 (br d, J = 14.7 Hz, IH), 4.96 (br d, J= 14.9 Hz, IH), 4.84 - 4.69 (m, IH), 4.68 - 4.59 (m, IH), 4.31 (dd, J = 9.6, 3.1 Hz, IH), 4.14-4.00 (m, IH), 3.95 - 3.84 (m, IH), 3.35 (s, 3H), 2.69 (s, 3H), 2.20 (br s, 3 H). ‘H NMR DMSO-î4 400 MHz δ = ppm 14.47 (br s, IH), 9.63 (s, IH), 8.21 (br d, / = 6.2 Hz, IH), 7.59 (s, IH), 7.04 - 6.94 (m, IH), 6.71 (dd, J= 8.7, 3.9 Hz, IH), 5.01 - 4.92 (m, IH), 4.88 - 4.78 (m, IH), 4.59 - 4.51 (m, IH), 4.49 - 4.42 (m, IH), 4.20 (dd, 9.6, 3.6 Hz, IH), 4.12 - 4.01 (m, IH), 3.86 (br t, 11.1 Hz, IH), 3.50 (br s, 3H), 2.63 (s, 3H), 2.16 (s, 3H). LCMS (ESI+): m/z 421.2 (M+H).
Examplc 134: (S)-5-fluoro-12-(l-methyl-lH-pyrazol-5-yl)-6,7,15,15a-tctrahydro-lHbenzofu r o [4,3-fg] imidazo [ 1 *,2’ : 1,6] pyrîdo[3,2-b] [ 1,4]oxazonine- 10-carboxamide
To a solution of (S)-5-fluoro-12-( 1 -methyl-1 H-pyrazol-5-yl)-6,7,15,15a-tetrahydro-lHbenzofuro[4,3-fg]imidazo[T,2':l,6]pyrido[3,2-b][l,4]oxazonine-10-carboxyIic acid (55.0 mg, 126 umol, 1.00 eq) in DMF (3.00 mL) was added NH4C1 (20.3 mg, 379 umol, 3.00 eq), DI PEA (147 mg, 1.14 mmol, 198 uL, 9.00 eq) and HATU (72.1 mg, 190 umol, 1.50 eq) at 20°C. The mixture was stirred at 20°C for 12 hr. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Welch Xtimate Cl8 150*25 mm*5 um; mobile phase: [water (0.04% HC1)-ACN]; B%: 40%-60%, 10 min). The productcontaining fraction was concentrated under reduced pressure to remove most of MeCN at 30°C and the aqueous phase was lyophilized. (S)-5-fluoro-12-(1-methyl-IH-pyrazol-5-yl)-6,7,15,15atetrahydro- lH-benzofuro[4,3-fg]imidazo[ T, 2': l,6]pyrido[3,2-b] [ 1,4] oxazonine-10-carboxamîde (8.70 mg, 18.4 umol, 14% yield, 99.3% purity, HCI sait) was obtained as a yellow solid. 'H NMR CD3OD 400 MHz δ = ppm 8.58 (s, IH), 7.79 (s, IH), 7.63 (d, J = 2.1 Hz, IH), 6.80 (dd, J = 10.1, 8.9 Hz, IH), 6.57 (dd, J =8.7, 3.9 Hz, IH), 6.49 (d, J= 2.1 Hz, IH), 5.08 (d, J= 14.7 Hz, IH), 4.86 (brd, J = 14.8 Hz, IH), 4.66 -4.58 (m, IH), 4.50 (t,J=9.4Hz, IH), 4.19 (dd, J = 9.7, 3.2 Hz, IH), 4.02 - 3.90 (m, IH), 3.88 - 3.76 (m, IH), 3.69 (s, 3H). LCMS (ESI+): m/z 435.1 (M+H).
369
Example 135: (S)-5-fluoro-12-(l-methyl-lH-pyrazol-5-yl)-6,7,15,15a-tetrahydro-JHbenzofuro[4,3-fg]imidazo|r,2':l,6]pyrido[3,2-b][l,4]oxazonme-10-carboxylic acid Step 1: tert-butyl (R)-9-chloro-5-fluoro-iO-(l-methyl-lH-pyrazol-5-yl)-13,13 a-dihydro-IHbenzofuro[4,3-fg]pyrido[3,2-b][ I,4] oxazomne-7 (6H)-carboxylate
To a solution of tert-butyl (R)-10-bromo-9-chIoro-5-fluoro-13,13a-dihydro-lH-benzofuro[4,3fg]pyrido[3,2-b][l,4]oxazonine-7(6H)-carboxylate (2.00 g, 4.12 mmol, 1.00 eq) in dioxane (20.0 mL) and water (2.00 mL) was added (2-methylpyrazol-3-yl)boronic acid (780 mg 6.19 mmol, 1.50 eq), Cs2CO3 (4.02 g, 12.4 mmol, 3.00 eq) and Pd(dppf)Cl2 (302 mg 413 umol, 0.100 eq) at 20°C under nitrogen atmosphère. The mixture was stirred at 90°C for 12 h under nitrogen atmosphère. LC-MS showed tert-butyl (R)-10-bromo-9-chloro-5-fluoro-13,13a-dihydro-lH-benzofuro[4,3fg]pyrido[3,2-b][ 1,4]oxazonine-7(6H)-carboxylate was remained and one peak with the desîred mass was detected. Pd(dppf)CL (302 mg, 413 umol, 0.100 eq) and Cs2CO3 (2.68 g, 8.24 mmol, 2.00 eq) was added to the mixture at 20°C under nitrogen atmosphère. The mixture was stirred at 90°C for 18 h under nitrogen atmosphère. LC-MS showed tert-butyl (R)-10-bromo-9-chloro-5fluoro-13,13a-dihydro-1 H-benzofuro[4,3-fg]pyrido[3,2-b][ 1,4]oxazonine-7(6H)-carboxylate was consumed completely and one main peak with the desîred mass was detected. Water (15.0 mL) and ethyl acetate (15.0 mL) was added to the mixture and filtered, and the filtrate was extracted with ethyl acetate (10.0 mL * 3). The organic layers were combined, washed by brine (20.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 1/0 to 1/1). tert-Butyl (R)-9-chloro5-fluoiO-10-(I-methyl-lH-pyrazol-5-yl)-13,13a-dihydro-lH-benzofuro[4,3-fg]pyrido[3,2b][l,4]oxazonine-7(6H)-carboxylate (1.00 g, 2.05 mmol, 49% yield) was obtained as a yellow oil.
Step 2: tert-butyl (R)-9-amino-5-fluoro-10-(l-methyl-1 H-pyrazol-5-yl)-13,13a-dihydro-lHbenzofuro[4,3-fg]pyrido[3,2-b][1,4] oxazonme-7(6H)-carboxylate
To a solution of tert-butyl (R)-9-chloro-5-fluoro-10-(l-methyl-lH-pyrazol-5-y 1)-13,13a-dihydrolH-benzofuro[4,3-fg]pyrido[3,2-b][l,4]oxazonine-7(6H)-carboxylate (950 mg, 1.95 mmol, 1.00 eq),
370
NaN3 (2.66 g, 41.0 mmol, 21.0 eq), sodium ascorbate (696 mg, 3.51 mmol, 1.80 eq) in dioxane (12.0 mL) and water (4.00 mL) was added Cul (780 mg, 4.09 mmol, 2.10 eq) and (1S,2S)-N1,N2dimethylcyclohexane-l,2-diamine (832 mg, 5.85 mmol, 3.00 eq) at 20°C under nitrogen atmosphère. The mixture was stirred at 110°C for 12 h under nitrogen atmosphère. LC-MS indicated incomplète conversion. NaN3 (1.01 g, 15.6 mmol, 8.00 eq), sodium ascorbate (387 mg, 1.95 mmol, 1.00 eq), Cul (372 mg, 1.95 mmol, 1.00 eq) and (lS,2S)-Nl,N2-dimethylcyclohexane1,2-diamine (278 mg, 1.95 mmol, 1.00 eq) in dioxane (18.0 mL) and water (6.00 mL) were added to the mixture at 20üC under nitrogen atmosphère. The mixture was stirred at 110°C for 18 h under nitrogen atmosphère. Saturated aqueous NaHCO3 (20.0 mL) solution was added to mixture to adjust pH to -10, the mixture was extracted with ethyl acetate (20.0 mL * 3), the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. NaCIO (20.0 mL, 14%) was added dropwise to the aqueous phase to quench NaN3 with si irring, and NaOH (2 M) was added to mixture to adjust to pH = 10. The mixture was allowed to stand ovemight. The residue from the evaporated organic phase was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 1/0 to 0/1). tert-Butyl (R)-9-amino-5-fluoro-10-(l-methyl-lH-pyrazol-5-yl)13,13a-dihydro- lH-benzofuro[4,3-fg]pyrido[3,2-b][l,4]oxazonine-7(6H)-carboxylate (740 mg, 1.58 mmol, 81 % yield) was obtained as a brown oil.
Step 3: ethyl (S)-5-fluoro-12-(l-methyl-lH-pyrazol-5-yl)-6,7,15,15a-tetrahydro-lH-benzofiiro[4,3fg] imidazo]! 2':1,6]pyrido[3,2-b] [1,4] oxazonine-10-carboxylate COOEt
To a solution of tert-butyl (R)-9-amino-5-fluoro-10-(l-methyl-lH-pyrazol-5-yl)-13,13a-dihydro-lHbenzofuro[4,3-fg]pyrido[3,2-b][l,4]oxazonine-7(6H)-carboxylate (740 mg, 1.58 mmol, 1.00 eq) in AcOH (10.0 mL) was added ethyl 3-bromo-2-oxo-propanoate (772 mg, 3.96 mmol, 495 uL, 2.50 eq) at 20°C. The mixture was stirred at 120°C for 6 hr, The reaction mixture was concentrated, ethyl acetate (5.00 mL) and water (2.00 mL) were added to the mixture, followed b y saturated NaHCOj solution (20.0 mL) to adjust pH to 9. The mixture was extracted with ethyl acetate (10.0 mL * 3), the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HLC (SiO2, Ethyl acetate/MeOH = 20/1). ethyl (S)-5fluoro-12-(l-methyl~lH-pyrazol-5-yl)-6,7,15,15a-tetrahydro-lH-benzofuro[4,3
371 fg]imidazo[r,2':l,6]pyrido[3,2-b][l,4]oxazonine-10-carboxylate (220 mg, 475 umol, 30% yield) was obtained as a pink solid.
Step 4: (S)-5-fluoro-12-(l-methyl-lH-pyrazol-5-yl)-6,7,15,15a-tetrahydro-lH-benzofuro[4,3fg]imidazo[l ',2’:1,6]pyrido[3,2-b][ 1,4] oxazonine-10-carboxylic acid
COOH
To a solution of ethyl (S)-5-fluoro-12-(l-methyl-lH-pyrazol-5-yl)-6,7,15,15a-tetrahydro-lHbenzofuro^^-fglimidazon'^’T^pyridofS^-bHl^oxazomne-lO-carboxylate (220 mg, 475 umol, 1.00 eq) in MeOH (8.00 mL) and water (8.00 mL) was added NaOH (57.0 mg, 1.42 mmol, 3.00 eq) at 20°C. The mixture was stirred at 20°C for 5 h. 1 M HCl (5.00 mL) was added dropwîse to the reaction mixture to adjust pH to 3-4. The mixture was concentrated under reduced pressure to afford 470 mg of crude product. 20.0 mg of the crude product was purified byprcp-HPLC (column: Welch Xtimate C 18 150*25 mm*5 um; mobile phase: [water (0.04% HC1)-ACN]; B%: 25%-55%, 10 min). The product-containing fraction was concentrated under reduced pressure to remove most of MeCN at 30°C and the aqueous phase was lyophilized to gîve (S)-5-fluoro-12-(l-methyl-lHpyrazol-5-yl)-6,7,15,15a-tetrahydro-lH-benzofuro[4,3-fg]imidazo[r,2’:l,6]pyrido[3,2b][I,4]oxazonine-lO-carboxylic acid (12.0 mg, 25.4 umol, 99.8% purity, HCl) as a yellow gum. The remaining batch of the crude product was used in the next step directly. lH NMR CD3OD 400 MHz δ = ppm 8.95 (s, IH), 7.93 (s, IH), 7.78 (d, J= 2.0 Hz, IH), 6.92 (dd, J= 10.1, 8.8 Hz, IH), 6.68 (dd, 7 = 8.7, 3.9 Hz, IH), 6.61 (d, 7=2.0 Hz, IH), 5.20 (d, 7= 14.5 Hz, IH), 4.98 (br s, IH), 4.78 (brd, 7=6.1 Hz, IH), 4.63 (t,7=9.4 Hz, IH), 4.33 (dd, 7=9.7, 2.9 Hz, IH), 4.12-4.02 (m, IH), 3.97 - 3.88 (m, IH), 3.79 (s, 3H). LCMS (ESI+): m/z 436.1 (M+H).
Example 136: (S)-5-fluoro-12-(l-methyI-lH-pyrazol-5-yl)-6,7,15,15a-tetrahydro-lHbenzofuro[4,3-fg]imidazo[r,2':l,6Jpyrido[3,2-b][l,4]oxazonine-10-carbonitrile
CN
To a solution of (S)-5-fluoro-12-(l-methyl-lH-pyrazol-5-yl)-6,7,15,15a-tetrahydro-lHbenzofuro[4,3-fg]imidazo[T,2':l,6]pyrido[3,2-b][l,4]oxazonine-10-carboxamide (180 mg, 414
372 umol, 1.00 eq) and DIPEA (161 mg, 1.24 mmol, 217 uL, 3.00 eq) in DCM (5.00 mL) was added TF AA (174 mg, 829 umol, 115 uL, 2.00 eq) at 0°C. The mixture was stirred at 0°C for 1 hr under nitrogen atmosphère. The reaction mixture was concentrated. MeOH (2.00 mL) was added to the mixture and Na2CO3 (8.00 mg) was added to the mixture adjust pH to 8. LC-MS showed the intermediate was consumed completely and one peak with the desired mass was detected. The residue was dissolved in MeOH (3.00 mL). The suspension was filtered, the filtrate was concentrated and purified by prep-HPLC (column: Phenomenex Luna C18 200*40 mm* 10 um; mobile phase: [water (0.2% FA)-ACN]; B%: 30%-60%, 8 min). The product-containing fraction was concentrated under reduced pressure to remove most of MeCN at 30°C and tire aqueous phase was lyophilized. (S)-5-fluoro-12-(l-methyl-lH-pyrazol-5-yl)-6,7,15,15a-tetrahydro-lHbenzofuiO[4,3-fg]imidazo[ 1 ',2': 1,6]pyrido[3,2-b][ 1,4]oxazonine-l 0-carboxamide (13.1 mg, 28.16 umol, 6% yield, 99.4% purity, fonnate sait) was obtained as a yellow solid. 'H NMR DMSO-ùk 400 MHz δ = ppm 8.88 (s, IH), 7.52 (s, IH), 7.48 (d, 7= 1.6 Hz, IH), 6.97 (t, 7= 9.5 Hz, IH), 6.70 (dd,7= 8.6, 3.7 Hz, IH), 6.48 (d, 7= 1.7 Hz, IH), 4.99 - 4.90 (m, IH), 4.85 - 4.76 (m, IH), 4.59 4.49 (m, 2H), 4.22 (dd, 7 = 9.7, 3.2 Hz, IH), 4.04 (br s, IH), 3.95 - 3.84 (m, IH), 3.76 (s, 3H) . LCMS (ESN): m/z 417.1 (M+H).
Example 137: (S)-5-fluoro-12-(2-niethylpyridin-3-yl)-6,7,15,15a-tetrahydro-lH-benzofuro[4,3fgjiinidazû[r,2':l,6|pyrido[3,2-b||l,4|oxazonine-10-carboxylic acid
Step 1 : tert-butyl (R)-9-chloro-5-]luoro-10-(2-methylpyridiri-3-yl)-I3,13a-dihydro-lHbenzofuro]4,3-fg]pyrido[3,2-b] [1,4] oxazonine-7(6H)-carboxylate
F
To a solution of tert-butyl (R)-10-bromo-9-chloro-5-fluoro-13,13a-dihydro-lH-benzofuro[4,3fg]pyrido[3,2-b][l,4]oxazonine-7(6H)-carboxylate (1.00 g, 2.06 mmol, 1.00 eq) in dioxane (10.0 mL) and water (1.00 mL) were added 2-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)pyridine (586 mg, 2.68 mmol, 1.30 eq), Pd(dppf)Cl2 (151 mg, 206 umol, 0.100 eq) and NaHCO3 (865 mg, 10.3 mmol, 400 uL, 5.00 eq) at 20°C under nitrogen atmosphère, and the mixture was stirred at 80°C for 12 h under nitrogen atmosphère. Water (15.0 mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (15.0 mL * 3), the combined organic layers were dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 1/0 to 0/1). tert-Butyl (R)-9-chloro373
5-fluoro-10-(2-methyIpyr-idin-3-yl)-13,13a-dihydro-IH-benzofuro[4,3-fg]pyrido[3,2b][ l,4]oxazonine-7(6H)-carboxylate (830 mg, 1.67 mmol, 81% yield) was obtained as a yellow oil.
Step 2: tert-butyl (R)-9-amino-5-fluoro-l0-(2-methylpyridin-3-yl)-l3,13a-dihydro-lHbenzofuro[4,3-fg]pyrido[3,2-b][1,4] oxazonine-7 (6H)-carboxylate
To a mixture of tert-butyl (R)-9-chloro-5-fluoiO-10-(2-methylpyridir)-3-yl)-i3,13a-dihydiO-lHbenzofuro[4,3-fg]pyrido[3,2-b][l,4]oxazonine-7(6H)-carboxylate (415 mg, 833 umol, 1.00 eq), NaN3 (759 mg, 11.7 mmol, 14.0 eq) and sodium ascorbate (198 mg, 1.00 mmol, 1.20 eq) in dioxane (6.00 mL) and water (1.20 mL) were added Cul (222 mg, L17 mmol, 1.40 eq) and (1S,2S)-N1,N2dimethylcyclohexane-l,2-diamine (237 mg, 1.67 mmol, 2.00 eq) at 20°C, then the mixture was stirred at 11Ü°C for 12 h under nitrogen atmosphère. Saturated NaHCO3 (25.0 mL) was added to the mixture to adjust pl·! to -9, then the mixture was extracted with ethyl acetate (10.0 mL * 3), the combined organic layers were dried over MgSO4 and concentrated under reduced pressure. NaCIO (20 mL, 14%) was added dropwise to the aqueous phase to quenched NaN3 under stîning, and the mixture was allowed to stand ovemight. The organic residue was purified by prep-TLC (S1O2, Petroleum ether/Ethyl acetate = 0/1). tert-butyl (R)-9-amino-5-fluoro-10-(2-methylpyridin-3-yl)13,13a-dihydro- lH-benzofuro[4,3-fg]pyrido[3,2-b][ l,4]oxazonine-7(6H)-carboxylate (260 mg, 543 umol, 65% yield) was obtained as a yellow oil.
Step 3: ethyl (S)-5-flitoro-12-(2-methylpyridin-3-yl)-6,7,15,15a-tetrahydro-lH-benzofuro[4,3fg]imidazo[l’,2 ':l,6]pyrido[3,2-b] [1,4] oxazonine-10-carboxylate
To a solution of tert-butyl (R)-9-amino-5-fluoro-10-(2-methylpyridin-3-yl)-13,13a-dihydro-lHbenzofuro[4,3-fg]pyrido[3,2-b][l,4]oxazonine-7(6H)-carboxylate (100 mg, 209 umol, 1.00 eq) in AcOH (3.00 mL) was added ethyl 3-bromo-2-oxo-propanoate (102 mg, 522 umol, 65.3 uL, 2.50 eq) at 20°C. The mixture was stirred at 120°C for 2 h. NaHCO3 (5%, 8.00 mL) was added to the mixture to adjust pH to 7-8, then the mixture was extracted with ethyl acetate (5.00 mL * 3), the
374 combined organic layers were dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Ethyl acetate/Methanol = 20/1). ethyl (S)-5-fluoro-12-(2methylpyridin-3-yl)-6,7,15,15a-tetrahydro-1 H-benzofuro[4,3-fg]imidazo[ Γ,2': 1,6]pyrido[3,2b][l,4]oxazonine-10-carboxylate (40.0 mg, 84.3 umol, 40% yield) was obtained as a yellow oil.
Step 4: (S)-5-fluoro-12-(2-methylpyridin-3-yl)-6,7,15,15a-tetrahydro-lH-benzofuro[4,3fg]imidazo[ 1 ',2': 1,6]pyrido[3,2-b][l,4]oxazonine-10-carboxylic acid
To a solution of ethyl (S)-5-fluoro-12-(2-methylpyridin-3-yl)-6,7,15,15a-tetrahydro-lHbenzofuro[4,3-fg]imidazo[T,2':l,6]pyrido[3,2-b][!,4]oxazonine-10-carboxylate (40.0 mg, 84.3 umol, 1.00 eq) in water (2.00 mL) and MeOH (2.00 mL) was added NaOH (10.1 mg, 253 umol, 3.00 eq) at 20°C. The mixture was stirred at 20°C for 12 h. The reaction was concentrated. Aqueous HCl (LÛO M, 1.50 mL) was added to the mixture to adjust pH to 3-4, and the reaction was concentrated under reduced pressure to afford a crude product (40.0 mg). 20.0 mg of the crude product was purified by prep-HPLC (column: Luna Oméga 5u Polar Cl8 100A; mobile phase:
[water (0.04% HC1)-ACN]; B%: 16%-34%, 7 min). (S)-5-fluoro-12-(2-methylpyridin-3-yl)6,7,15,15a-tetrahydro-lH-benzofuiO[4,3-fg]imidazo[r,2t: l,6]pyrido[3,2-b][l,4]oxazonine-10carboxylic acid (7.00 mg, 14.3 umol, 98.4% purity, HCl sait) was obtained as a yellow solid. NMR DMSO-i/^ 400 MHz δ = ppm 9.03 (s, IH), 8.83 (d, J= 6.0 Hz, IH), 8.48 (br d, J = 7.7 Hz, IH), 8.18 (brs, IH), 8.01 - 7.91 (m, IH), 7.73 (s, 1 H), 6.97 (t, J = 9.5 Hz, IH), 6.70 (dd, J-8.7, 3.9
Hz, IH), 4.97 (br dd, J= 14.7, 5.2 Hz, IH), 4.80 (br dd, 14.0, 5.8 Hz, IH), 4.55 (brt, J= 9.4 Hz, 2H), 4.23 (brdd, J=9.8, 3.2 Hz, IH), 4.03 (br d, J=9.5 Hz, IH), 3.92 - 3.83 (m, IH), 2.59 (s, 3H). LCMS (ESI+): m/z 447.2 (M+H).
Example 138: (S)-5-fluoro-12-(2-methylpyridin-3-yl)-6,7,15,15a-tetrahydro-lH-benzofuro[4,3fg]Îmidazo[l',2':l,6]pyrido[3,2-b||l,4]oxazonine-10-carboxamide
375
To a solution of (S)-5-fluoro-12-(2-methylpyridin-3-yl)-6,7,15,15a-tetrahydro-lH-benzofuro[4,3fg]imidazo[l',2':l,6]pyrido[3,2-b][l,4]oxazonine-10-carboxylic acid (20.0 mg, 44.8 umol, 1.00 eq) in DMF (2.00 mL) was added NH4C1 (7.19 mg, 134 umol, 3.00 eq), DIPEA (52.1 mg, 403 umol, 70.2 uL, 9.00 eq) and HATU (25.6 mg, 67.2 umol, 1.50 eq) at 20°C. The mixture was stirred at 20°C for 12 h. The reaction was concentrated. The residue was purified by /we/i-HPLC (column: Luna Oméga 5u Polar C18 100A; mobile phase: [water (0.04% HC1)-ACN]; B%: 17%-35%, 7 min). (S)-5-fluoro-12-(2-methylpyridin-3-yl)-6,7,15,15a-tetrahydro-lH-benzofiiro[4,3fghmidazoDX'iLôjpyrido^Y-bTlYjoxazonine-lO-carboxamide (6.1 mg, 12.6 umol, 28% yield, 99.6% purity, HCl sait) was obtained as a yellow solid. NMR DMSO-dô 400 MHz S = ppm 8.82 (br d,7 = 6.0 Hz, IH), 8.68 (brs, IH), 8.56 (br d,7 = 7.7 Hz, IH), 8.02 (t,7=6.8 Hz, IH), 7.82 (s, IH), 6.89 (t, 7=9.5 Hz, IH), 6.65 (dd, 7=3.7, 8.6 Hz, IH), 5.17 (brd, 7= 14.8 Hz, 1 H), 4.95 (br d, 7= 14.8 Hz, IH), 4.72 (d, 7= 6.0 Hz, IH), 4.60 (t, 7 = 9.2 Hz, IH), 4.30 (br d, 7= 8.0 Hz, IH), 4.06 (br s, IH), 3.98 - 3.88 (m, IH), 2.65 (s, 3H). LCMS (ESI+): m/z 446.2 (M+H).
Example 139: General Procedure C for the préparation of (S)-12-fluoro-4-(l-methyl-lHpyrazol-5-yl)-7a,8,13,14-tetrahydro-7H-ll,2,41triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3fgH Ml oxazonine
Step 1: tert-butyl (S)-12-fluoro-4-(l-methyl-lH-pyrazol-5-yl)-7a,13-dihydro-7H[ 1,2,4]triazolo[4 3 1,6]pyrido[3,2-b] benzofuro[4,3-fg][1,4] oxazonine-14 (8H)-carboxylate
Two batches were set up. To tert-butyl (S)-4-bromo-12-fluoro-7a,13-dihydro-7H[ 1,2,4]triazolo[4’,3’: 1,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine- 14(8H)-carboxylate (21.5 g,
43.8 mmol, 1.00 eq) and (2-methylpyrazol-3-yl)boronic acid (7.16 g, 56.9 mmol, 1.30 eq) in
376 dioxane (50.0 mL) and H2O (5.00 mL) was added Pd(dppf)CI2 (3-20 g, 4.38 mmol, 0.100 eq) and Na2CO3 (9.28 g, 87.5 mmol, 2.00 eq) ai 25°C. The mixture was stirred at 80°C for 12 hrs under N2. LC-MS showed tert-butyl (S)-4-biOmo-I2-fluoro-7a,13-dihydro-7H[l,2,4]triazolo[4',3':I,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate was consumed completely and one main peak with desired mass was detected. Two batches were combined together to work up. The mixture was filtered and the filtrate was concentrated under reduce pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 1/0 to 0/1). tert-butyl (S)-12-fliioro-4-(l-methyl-lH-pyrazol-5-yl)7 a, 13-dihydro- 7H-[1,2,4]triazolo[4',3’:1,6]pyrido[3,2-b] benzofuro[4,3-fg] [1,4] oxazonine-14(8H) carboxylate (36.4 g, crude) was obtained as brown solid.
Step 2: (S)-12-fluoro-4-(l -methyl-1 H-pyrazol-5-yl)-7a,8,13,14-tetrahydro-7H[1,2,4] triazo lo[4',3 1,6]pyrido[3,2-b] benzofuro[4,3 -fg] [1,4] oxazonine
Three batches were set up. To tert-butyl (S)-12-iluoro-4-(l-methyl-lH-pyrazol-5-yl)-7a,13-dihydro7H-[l,2,4]triazolo[4,,3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (13.0 g, 26.4 mmol, 1.00 eq) in DCM (108 mL) was added TFA (60.1 g, 527 mmol, 39.0 mL, 20.0 eq) at 25°C. The mixture was stirred at 25°C for 12 hrs. LC-MS showed tert-butyl (S)-12-fluoro-4-(lmethy]-lH-pyrazol-5-yl)-7a,13-dihydro-7H-[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3fg][l,4]oxazonine-14(8H)-carboxylate was consumed completely and one main peak with desired mass was detected. Three batches were combined together to work up. The mixture was concentrated under reduce pressure to give a residue. Then the residue was dissolved with EtOAc/H2O (10.0 mL:10.0 mL). The NHj.H2O (25%) was added into the mixture to adjust pH = 7.00-8.00, the mixture was filtered and the filter cake was dried under reduce pressure. (S)-12fluoro-4-(l-methyl-lH-pyrazol-5-yl)-7a,8,13,14-tetrahydro-7H-[l,2)4]triazolo[4',3':l,6]pyrido[3î2b]benzofuro[4,3-fg][l,4]oxazonine (30.0 g, 76.5 mmol, 96.6% yield) was obtained as white solid.
Step 3: (S)-12-fluoro-4-(l-methyl-lH-pyrazol-5-yl)-7a,8,13,14-tetrahydro-7H[1,2,4] triazolo[4 ', 3': 1,6]pyrido[3,2-b] benzofuro[4,3 -fg][1,4] oxazonine
377
Το
(S)-12-fluoro-4-(l-methyl· lH-pyrazol-5-yl)-7a,8,13,14-tetrahydro-7H
[l,2,4]triazolo[4',3': 1,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine (27.0 g, 68.8 mmol, 1.00 eq) was added i-PrOH (80.0 mL) and H2O (10.0 mL) at 25°C, the mixture was stirred at 80°C for 1 hr. The mixture was cooled to 25°C slowly and stood at 25°C for 12 hrs. The mixture was filtered and the filter cake was dried by vacuum to afford 16.0 g of pure product. The filtrate was coneentrated under reduce pressure to give a residue. The residue was purified by reversed-MPLC (neutral condition). The fraction was coneentrated under reduced pressure to remove most of MeCN at 30°C and the precipitate was filtered and the filter cake was dried b y vacuum to give 2.00 g of the pure product. Totally 18.0 g of (S)-12-f]uolΌ-4-(l-meΐhyl·lH-pyrazol-5-yl)-7a,8,13,14-tetrahydlΌ-7H[ 1,2,4] triazolo[4',3l,6]pyrido[ 3,2-b]benzofuro [4,3-fg] [1,4] oxazonine was obtained as white solid.
Step 4: (S)-12-fluoro-4-(1 -methyl-lH-pyrazol-5-yl)-7a,8,!3,14-tetrahydro-7H[ 1,2,4J triazolo [4 ' 3 ’:l,6]pyrido[3,2-b]benzofuro[4,3-fg] [1,4] oxazonine
To (S)-12-fluoro-4-(l-methyl-lH-pyrazol-5-yl)-7a,8,13,14-tetrahydro-7H[ l,2,4]triazolo[4',3’: 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4]oxazonine (3.50 g, 8.92 mmol, 1.00 eq) in MeCN (60.0 mL) was added MsOH (857 mg, 8.92 mmol, 635 uL, 1.00 eq) in MeCN (3.00 mL) dropwise at 50°C, the mixture was stirred at 50°C for 1 hr. The mixture was cooled to 30°C ainong 1 hr, the mixture was stirred at 30°C for 2 hrs. The mixture was cooled to 25°C. The mixture was coneentrated under reduced pressure to remove most of MeCN at 30°C, the another batch product (25.0 g, 50.66 mmol, 69.02% yield, 99.1% purity, MsOH sait) was combined together and then H2O (600 mL) was added into the mixture, the aqueous phase was lyophilized. (S)-12378 fluoro-4-(l -methyl-1 H-pyrazol-5-yl)-7a, 8,13, !4-tetrahydro-7H-[ 1,2,4]triazolo[4’,3': 1,6]pyrido[3,2b]benzofuro[4,3-fg][I,4]oxazonine (29.1 g, 59.2 mmol, 99.4% purity, MsOH) was obtained as yellow crystal. 'H NMR ET20857-653-P1D CDjOD 400 MHz δ = ppm 9.51 (s, 1H), 8.03 (s, 1H), 7.68 (d, J = 1.8 Hz, 1H), 6.92 (t, 7=9.5 Hz, IH), 6.68 (dd, 7=8.8, 3.7 Hz, IH), 6.58 (d, J= 1.8 Hz, 5 IH), 5.20 (d, J = 14.8 Hz, IH), 4.96 (br d, J= 14.8 Hz, 1H), 4.76 (br dd, J= 9.8, 3.9 Hz, 1H), 4.62 (t, 7=9.5 Hz, IH), 4.31 (dd, 7= 9.7, 3.3 Hz, IH), 4.16 - 3.99 (m, IH), 3.98 - 3.87 (m, IH), 3.81 (s, 3H), 2.70 (s, 4H). LCMS (ESI+): m/z 393.1 (M+H).
Compounds 17, 75, 100, and 171 were prepared according to General Procedure C using the suitable starting materials, precursors, intermediates, and reagents.
Cmpd No. Compound Name Structure Spectral Data
75 (S)-12-fluoro-4- (] -isopropyl1 H-pyrazol-5-yl)-7a, 8,13,14tetrahydro-7H- [l,2,4]triazolo[4’,3':l,6]pyrido [3,2-b]benzofuro[4,3-fg][l,4] oxazonine n-n îQn Hn\ HCOOH νχΑ O' 1HNMR DMSO-d6 400 MHz δ = ppm 9.44 (s, IH), 7.65 (br t, J = 6.4 Hz, IH), 7.54 (d, J = 1.3 Hz, IH), 7.32 (s, IH), 7.03 - 6.93 (m, IH), 6.71 (dd, J = 8.6, 3.9 Hz, IH), 6.37 (d, J = 1.6 Hz, IH), 4.96 - 4.88 (m, IH), 4.83 - 4.75 (m, IH), 4.58 4.40 (m, 3H), 4.22 (dd, J = 9.5, 3.5 Hz, IH), 4.10 - 4.00 (m, IH), 3.91 3.81 (m, IH), 1.34 (dd, J = 8.9, 6.6 Hz, 6H). LCMS (ESI+): m/z 421.2 (M+H)
100 (S)-4-(3-ethyl-1 -methyl -1Hpyrazol-4-yl)-12-fluoro- 7a,8,13,14 -tetrahydro-7H- [l,2,4]triazolo [4',3': l,6]pyrido[3,2- b] benzofu ro [4,3 -fg] [l,4]oxazonine HCOOH\ N 'Ν' H /=7 ηνρύ Oô 'H NMR DMSO-<4 400 MHz δ = ppm 9.37 (s, IH), 8.33 (s, IH), 7.33 - 7.23 (m, IH), 7.19 (s, IH), 6.92 (dd, J = 10.1, 8.8 Hz, IH), 6.66 (dd, J= 8.5, 3.9 Hz, IH), 4.88 -4.81 (m, IH), 4.77 - 4.69 (m, IH), 4.53 4.42 (m, 2H), 4.21 (dd, J = 9.7, 3.3 Hz, IH), 4.06 - 3.96 (m, IH), 3.89 3.83 (m, IH), 3.82 (s, 3H), 2.77 (q, J= 7.5 Hz, 2H), 1.17 (t, J= 7.4 Hz, 3H). LCMS (ESI+): m/z 421.0 (M+H).
171 (S)-4-(5,6-dihydro- 4H- pyrrolo[l,2-b]pyrazol-3-yl)12-fluoro-7a,8,13,14tetrahydro-7H-[l,2,4]triazolo [4',3':l,6]pyrido[3,2-b] benzofuro[4,3-fg] [ 1,4] oxazonine Λ //N N\ /—z 03 !H NMR DMSO-74 400 MHz δ = ppm 9.37 (s, IH), 8.27 (s, IH), 7.27 - 7.23 (m, IH), 7.22 (s, IH), 6.93 (dd, J= 10.1, 8.8 Hz, IH), 6.66 (dd, 7= 8.6, 3.7 Hz, IH), 4.90 - 4.79 (m, IH), 4.78 - 4.67 (m, IH), 4.57 4.42 (m, 2H), 4.22 (dd, J = 9.6, 3.2 Hz, IH), 4.11 (t, J = 7.4 Hz, 2H), 4.01 (br dd, J = 8.7, 3.6 Hz, IH), 3.94 - 3.83 (m, IH), 3.17 (t, J = 7.3 Hz, 2H), 2.60 (quin, J = 7.2 Hz, 2H). LCMS (ESI+): m/z 419.1
379
Il I I (M+H).
Example 140: (S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4',3':l,6|pyrido[3,2 b]benzofuro[4,3-fg][l,4]oxazonin-4-yl)-l-methyl-lH-pyrazole-4-carbonitrile
Step 1: tert-butyl (S)-4-(4-cyano-l-methyl-lH-pyrazol-5-yl)-12-fluoro-7a,13-dihydro-7H5 [1,2,4]triazolo[4 ', 3 1,6]pyrido[3,2-b] benzofttro[4,3-fg][1,4] oxazomne-14(8H)-carboxylate
F
The reaction was set up as 10 parallel batches. The solution of tert-butyl (S)-12-fluoro-4(tributylstannyl)-7a, 13-dihydro-7H-[ 1,2,4]triazolo[4',3': l,6]pyrido[3,2-b]benzofuiO[4,3fg] [1,4] oxazonine-14(8H)-carboxyiate (20.0 mg, 28.5 umol, 1.00 eq) and 5-bromo-1 -methyl-1H10 pyrazoie-4-carbonitrile (5.30 mg, 28.5 umol, 1.00 eq) in dioxane (1.00 mL) was degassed with nitrogen three times. Xphos-Pd-G2 (3.00 mg, 3.81 umol, L34e-1 eq) was added at 25°C and the resulting solution was stiired at 110°C under nitrogen for 12 h. The batches were combined. The obtained mixture was concentrated under vacuum to give a crude product which was purified by prep-TLC (PE:EtOAc = l :2). tert-Butyl (S)-4-(4-cyano-1 -methyl-lH-pyrazol-5-yl)-12-fluoro15 7 a, 13-dihydro-7H-[ 1,2,4]triazolo[4',3': l,6]pyrido[3,2-b]benzolùro[4,3-fg][ 1,4]oxazonine-l 4(8H)carboxylate (40.0 mg, 77.3 umol) was obtained as a yellow oil.
Step 2: (5)-5-(12-fluoro-7a,S, 13,14-tetrahydro-7H-[1,2,4]triazolo[4!,3': 1,6]pyrido[3,2b]benzofuro[4,3-fg] [1,4] oxazonin-4-yl)-l-methyl-lH-pyrazole-4-carbonitrile
F
To a stirred solution of tert-butyl (S)-4-(4-cyano-l-methyl-lH-pyrazol-5-yl)-12-fluoro-7a,13dihydro-7H-[ 1,2,4]triazoio[4',3': 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ l,4]oxazonine-14(8H)carboxylate (20.0 mg, 38.7 umol, 1.00 eq) in MeOH (1.00 mL) was added HCl/MeOH (4.00 M, 1.00 mL) at 15°C. The resulting mixture was stirred at 15°C for 12 h. The mixture was concentrated under reduced pressure and purified by acidic prep-HPLC (FA conditions). (S)-5-(12-fluoro25 7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4',3,:l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonin“4yl)-l-methyl-lH-pyrazole-4-carbonitrile (1.10 mg, 2.25 umol, 5% yield, 94.9% purity, formate sait) was obtained as a yellow solid. lH NMR DMSO-76 400 MHz δ = ppm 9.49 (s, IH), 8.15 (s, IH),
380
8.06- 7.94 (m, IH), 7.67 (s, IH), 6.98 (t,7=9.5 Hz, IH), 6.71 (dd, 7= 8.8, 3.6 Hz, IH), 4.99-4.76 (m, 2H), 4.63 - 4.40 (m, 2H), 4.20 (br dd, 7= 9.8, 3.2 Hz, IH), 4.13 - 3.99 (m, IH), 3.91 - 3.73 (m, IH), 3.81 (s, 3H). LCMS (ESI+): m/z 418.1 (M+H).
Example 141: (S)-5-fluoro-12-(2-methylpyridin-3-yl)-6,7,15,I5a-tetrahydro-lH-benzofuro[4,3fg]imidazo[r,2':l,6]pyrido[3,2-bni,4]oxazonine-10-carbomtrile
Two parallel réactions were set up. To a mixture of (S)-5-fhioiO-12-(2-methylpyridin-3-yl)6,7,15,15 a-tetrahydro-1 H-benzofuro[4,3-fg] imidazofl’, 2': 1,6] pyrido[ 3,2-b] [1,4] oxazonine-10carboxamide (55.0 mg, 123 umol, 1.00 eq) in DCM (10.0 mL) was added methoxycarbonyl(triethylammonio)sulfonyl-azamde (44.1 mg, 185 umol, 1.50 eq) at 0°C, the mixture was stirred at 20°C for 2 h. LC-MS showed (S)-5-fluoro-12-(2-methylpyridin-3-yl)-6,7,15,15a-tetrahydro-lHbenzofuiO[4,3-fg]imidazo[r,2':l,6]pyrido[3,2-b][l,4]oxazoniiie-10-carboxamide was remained and the desired mass was detected. The mixture was stirred at 20°C for 12 h, LCMS showed (S)-5fluoiO-I2-(2-methylpyridm-3-yl)-6}7,15,I5a-tetrahydro-lH-benzofiiro[4,3fg]imidazo[l'J2':l)6]pyi’ido[3,2-b][l,4]oxazonine-10-carboxamide was remained and the desired mass was detected. Combined the two batches. Water (2.00 mL) was added to the mixture, then the reaction was concentrated. The residue was dîssolved in DMSO (3.00 mL). The solution was purified by acidic prep-HPLC (column: Phenomenex Luna C18 200*40 mm*10 um; mobile phase: [water (0.2% FA)-ACN]; B%: 20%-60%, 8 min). The product-containing fraction was concentrated under reduced pressure to remove most of MeCN at 30°C and the aqueous phase was lyophilized. lH NMR showed that the product was not pure, so the product was purified by prep-HPLC (column: Waters Xbridge BEH Cl8 100*25 mm*5 um; mobile phase: [water (10 mM NH4HCOs)-ACN]; B%: 25%-60%, 10 min)-ACN]; B%: 20%-60%, 8 min). The product-containing fraction was concentrated under reduced pressure to remove most of MeCN at 30°C and the aqueous phase was lyophilized. (S)-5-fluoro-12-(2-methylpyridin-3-yl)-6,7,15,15a-tetrahydro-1 H-benzofuro[4,3fg]iinidazo[l',2': 1,6]pyrido[3,2-b][1,4]oxazonine-10-carbonitrile (14.0 mg, 32.1 umol, 13% yield, 97.9% purity) was obtained as a yellow solid. 'H NMR CDCI3 400 MHz δ = ppm 8.57 (br d, J — 4.6 Hz, IH), 8.02 (s, IH), 7.66 (brd,7=7.7 Hz, IH), 7.22 (dd,7=7.4, 5.0 Hz, IH), 7.13 (s, IH), 6.90 (t, 7= 9.4 Hz, IH), 6.69 (dd, 7= 8.6, 3.9 Hz, IH), 5.22 - 5.06 (m, IH), 4.85 (br d, 7= 14.7 Hz, IH),
381
4.76 (br s, IH), 4.70 - 4.60 (m, 2H), 4.27 (dd, J = 9.7, 2.8 Hz, IH), 4.00 - 3.90 (m, IH), 3.88 - 3.80 (m, 1 H), 2.46 (s, 3H). LCMS (ESI+): m/z 428.1 (M+H).
Example 142: (S)-12-fluoro-4-(3-methylisoxazol-4-yl)-7a,8,13,14-tetrahydro-7H [ 1,2,4] triazolo[4',3’:l,6]pyrido[3,2-b]benzofuro|4,3-fg] [1,4] oxazonine
Step l: tert-butyl (S)-12-fluoro-4-(3-methylisoxazol-4-yl)-7a,13-dihydro-7H[1, 2,4]triazolo[4', 3 1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4] oxazonine- 14(8H)-carboxylate
F
To a stirred solution of tert-butyl (S)-4-biOmo-12-fluoro-7a,13-dihydiO-7H[L2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuiO[4,3-fg][L4]oxazonine-14(8H)-carboxylate (150 mg,
305 umol, L00 eq), 3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoxazole (95.7 mg,
457 umol, 1.50 eq) and Na2CO3 (64.7 mg, 610 umol, 2.00 eq) in dioxane (3.00 mL) and water (0.600 mL) was added Pd(dppf)Cl2 (22.3 mg, 30.5 umol, 0.100 eq) at 15°C under N2. The resulting mixture was stirred at 80°C for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, PE:EtOAc = 1:1) to give tert-butyl (S)-12-fluoro-4-(315 methyl isoxazoL4-yl)-7a,l 3-dihydro-7H-[ 1,2,4]triazolo[4',3': 1,6]pyrido[3,2-b]benzofuro[4,3fg][l,4]oxazonine-l4(8H)-carboxylate (80 mg, 162 umol, 53% yield) as a yellow solid.
Step 2: (S)-12-fluoro-4-(3-methylisoxazol-4-yl)-7a,8,13,14-tetrahydro-7H[ 1,2,4] triazolo[4’,3’ : 1,6]pyrido[3,2-b] benzofiiro[4,3-fg] [ 1,4] oxazonine
To tert-butyl (S)-12-fluoro-4-(3-methylisoxazol-4-yl)-7a,13-dihydro-7H[l,2,4]triazolo[4,,3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][i,4]oxazonine-14(8H)-carboxylate (70.0 mg, 141.8 umol, 1.00 eq) was added HFIP (2.00 mL) at I5°C. The solution was stirred at 80°C for 12 hr. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 200*40 mm* 10 um; mobile phase: [water (0.2% FA)25 ACN]; B%: 30%-70%, 8 min). (S)- 12-fluoro-4-(3-methylisoxazol-4-yl)-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuiO[4,3-fg][I,4]oxazonine (23.0 mg, 51.9 umol, 36% yield, 99.1% purity, formate sait) was obtained as a white solid. !H NMR DMSO-rL 400 MHz δ —
382 ppm 9.42 (d, 7=7.5 Hz, IH), 7.54 (br t, 7 = 6.2 Hz, IH), 7.46 (s, IH), 6.98 -6.89 (m, IH), 6.67 (dd, 7= 8.7, 3.9 Hz, IH), 4.93 - 4.84 (m, IH), 4.77 (br dd, 7 = 14.8, 6.4 Hz, IH), 4.57 - 4.44 (m, 2H), 4.21 (br dd, 7= 9.8, 3.2 Hz, IH), 4.02 - 3.97 (m, IH), 3.95 - 3.85 (m, IH), 2.50 (s, 3H). ’H NMR CD3OD + 1 drop HCl (12 M) 400 MHz δ = ppm 9.83 (s, IH), 8.98 (s, IH), 8.01 (s, IH), 6.96 - 6.86 (m, IH), 6.72 - 6.65 (m, IH), 5.15 (d, J = 14.9 Hz, IH), 4.98 (d, J = 14.9 Hz, IH), 4.82 - 4.70 (m, IH), 4.61 (t, J = 9.4 Hz, IH), 4.32 (dd, J = 9.6, 3.1 Hz, 1 H), 4.17 - 4.07 (m, lH), 3.99 - 3.86 (m, IH), 2.32 (s, 3H). LCMS (ESI+): m/z 394.1 (M+H).
Example 143: (S)-12-fluoro-4-(5-iluoro-6-methoxypyridin-3-yl)-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzoftiro[4,3-fg][l,4]oxazomne
Step 1: tert-butyl (S)-l 2-fluoro-4-(5-fluoro-6-methoxypyridin-3-yl)-7a, 13-dihydro-7H[1,2,4] triazolo[4', 3 1,6]pyrido[3,2-b]benzofuro[4,3-fg] [ 1,4] oxazonine-14(8H)-carboxylate
F
N OMe
To a stirred solution of tert-butyl (S)-4-bromo-i2-fluoiO-7a,13-dihydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (150 mg, 305 umol, 1.00 eq), (5-iluoiO-6-methoxy-3-pyridyl)boiOnic acid (78.3 mg, 457 umol, 1.50 eq) and KOAc (59.9 mg, 610 umol, 2.00 eq) in EtOH (2.10 mL) and water (0.300 mL) was added 4-ditertbutylphosphanyl-N,N-dimethyl-aniline dichloropalladium (21.6 mg, 30.5 umol, 21.6 uL, 0.100 eq) at 15°C under N2. The resulting mixture was stirred at 80°C for 2 hr. The mixture was concentrated under reduced pressure. The mixture was purified by prep-TLC (SiO2, PE:EtOAc = 1:2). tert-Butyl (S)-12-fiuoro-4-(5-fluoro-6-methoxypyridin-3-yl)-7a,13-dihydro-7H[ 1,2,4]triazolo[4'53’: l,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4]oxazonine-14(8H)-carboxylate ( 100 mg, 186 umol, 61% yield) was obtained as a yellow solid.
Step 2: (S)-12-fluoro-4-(5-fluoro-6-methoxypyridin-3-yl)-7a,8,I3,14-tetrahydro-7H[ 1,2,4]triazolo[ 4',3 ' : 1,6]pyrido [ 3,2-b]benzofuro[4,3-fg] [ 1,4]oxazonine
F
383
To tert-butyl (S)-12-fhioro-4-(5-fluoro-6-methoxypyridin-3-yl)-7a,13-dihydiO-7H[l,2,4]triazolo[4',3': l,6]pyrido[3,2-b]benzofÎiro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (90.0 mg, 167 umol, 1.00 eq) was added HFIP (2.00 mL) at 25°C. The solution was stirred at 80°C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 200*40 mm*10 um; mobile phase: [water (0.2% FA)ACN]; B%: 45%-65%, 8 min). (S)-12-fluoro-4-(5-fluoiO-6-methoxypyridin-3-yl)-7a,8,13,14tetrahydro-7H-[l,2,4]triazolo[4',3’:l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine (36.1 mg, 72.4 umol, 43% yield, 97.0% purity, formate sait) was obtained as a yellow solid. ’H NMR DMSO-i4 400 MHz δ = ppm 9.44 (s, IH), 8.90 (d, J = 2.0 Hz, IH), 8.51 (dd, J = 12.6, 2.0 Hz, IH), 7.79 (s, IH), 7.59 (brt, J = 6.4 Hz, 1H),6.93 (dd, J = 10.1, 9.0 Hz, IH), 6.67 (dd, J = 8.7, 3.9 Hz, 1H),4.934.84 (m, IH), 4.83 - 4.73 (m, IH), 4.58 - 4.46 (m, 2H), 4.20 (dd, J = 9.5, 3.1 Hz, IH), 4.07 - 3.99 (m, IH), 3.98 (s, 3H), 3.97 - 3.88 (m, IH). LCMS (ESI+): m/z 438.1 (M+H).
Example 144: (S)-4-(2-cyclopropyl-4-methylpyrimidin-5-yl)-12-fluoro-7a,8,13,14-tetrahydro7H-|l)2,4Jtriazolo[4’,3':l,61pyrido[3,2-b]benzofuro[4,3-fgl[l,41oxazonine
Step 1: 2-cyclopropyl-6-methylpyrimidin-4-ol
OH
The reaction was set up in two parallel batches. A mixture of methyl 3-oxobutanoate (4.81 g, 41.5 mmol, 4.46 mL, 1.00 eq), cyclopiOpanecarboximidamide hydrochloride (5.00 g, 41.5 mmol, 1.00 eq) and MeONa (14.9 g, 82.9 mmol, 54.4 mL, 30% purity, 2.00 eq) in MeOH (250 mL) was stirred at 25°C for 18 h. The batches were combined. The mixture was diluted with saturated aqueous Na2SO3 (250 mL), then concentrated under reduced pressure. The residue was dissolved in water (50.0 mL) and adjusted to pH = 4 with HCl (2.00 M). The precipitate was fïltered off and dried under reduced pressure. 2-CyciopropyL6-methyIpyrimidin-4-ol (11.4 g, crude) was obtained as white solid.
Step 2: 5-bromo-2-cyclopropyl-6-methylpyrimidin-4-ol
The reaction was set up in two parallel batches. To a solution of 2-cyciopropyl-6-methylpyrimidin4-ol (5.20 g, 34.6 mmol, 1.00 eq) and KOH (1.94 g, 34.6 mmol, 1.00 eq) in water (60.0 mL) was
384 added Br2 (5.53 g, 34.6 mmol, 1.78 mL, 1.00 eq) at 0°C. The mixture was stirred at 30°C for 18 h. The batches were combined. The precipitate was filtered off and dried under reduced pressure. 5Bromo-2-cyclopropyl-6-methylpyrimidin-4-ol (11.2 g, 48.9 mmol, 70% yield) was obtained as a white solid.
Step 3: 5-bromo-4-Moro-2-cyclopropyl-6-methylpyrimidme
P __7 N bPci
The reaction was set up in two parallel batches. To a mixture of 5-bromo-2-cyclopropyl-6methylpyrimidin-4-ol (2.50 g, 10.9 mmol, 1.00 eq) and DMF (1.99 g, 27.3 mmol, 2.10 mL, 2.50 eq) in toluene (100 mL) was added dropwise POC13 (2.51 g, 16.4 mmol, 1.52 mL, 1.50 eq) in toluene (25.0 mL) at 0ûC, and the mixture was stirred at 30°C for 3 h The batches were combined. The mixture was added to aqueous Na2COj (1.00 M, 150 mL) which was then extracted with EtOAc (50.0 mL *3). The combined organic phases were concentrated under reduced pressure. 5-Bromo4-chloro-2-cyclopiOpyl-6-methylpyrimidine (5.60 g ciude) was obtained as a yellow oil.
Step 4: N'-(5-bromo-2-cyclopropyl-6-methylpyrimidin-4-yl)-4-methylbenzenesulfonohydrazide
NHNHTs
The reaction was set up in two parallel batches. A mixture of 5-bromo-4-chloro-2-cyclopropyl-6methylpyrimîdine (3.40 g, 13.7 mmol, 1.00 eq) and 4-mcthylbenzenesulfonohydrazide (7.67 g, 41.2 mmol, 3.00 eq) in CHC13 (300 mL) was stirred at 90°C for 10 h. The batches were combined. The precipitate was filtered off, washed with DCM (50.0 mL), and dried under reduced pressure. N'-(5bromo-2-cyclopropyl-6-methylpyrimidin-4-yl)-4-methylbenzenesulfonohydrazide (6.61 g, crude) was obtained as a white solid.
Step 5: 5-bromo-2-cyclopropyl-4-methylpyrimidine ___// N
385
A mixture of N'-(5-bromo-2-cyclopropyl-6-methylpyrimidin-4-yl)-4methylbenzenesulfonohydrazide (6.61 g, 16.6 mmol, 1.00 eq) in aq, Na2CO3 (0.56 M, 89.1 mL, 3.00 eq) was stirred at 90°C for 2 hr. The mixture was extracted with ethyl acetate (50.0 mL * 3), the combined organic layers were dried over NaiSCQ and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 1/0 to 0/1). 5-bromo-2-cyclopropyI-4-methylpyrimidine (2.47 g, 11.6 mmol, 69% yield) was obtained as a brown oil.
Step 6: (2-cyclopropyl-4-methylpyrimidin-5-yl)boronic acid
ho-bx
OH
To a solution of 5-bromo-2-cyclopropyl-4-methylpyrimidine (500 mg, 2.35 mmol, 1.00 eq) in THF (5.00 mL) was added n-BuLÎ (2.50 M, 1.03 mL, 1.10 eq) at -78°C under N2, and the mixture was stirred at -78°C for 30 min. B(OMe)3 (732 mg, 7.04 mmol, 795 uL, 3.00 eq) was added to the mixture at -78°C, and the mixture was stirred at 25°C under nitrogen for 5 hr. MeOH (5.00 mL) was added and the mixture was concentrated under reduced pressure. The residue was purified by reversed phase MPLC (TFA conditions). (2-cyclopiOpyL4-meihylpyrimidin-5-yl)boronic acid (300 mg, 1.69 mmol, 71% yield) was obtained as a yellow oil.
Step 7: (S)-4-(2-cyclopropyl-4-methylpyrimidin-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H[1,2,4] triazolo[4 3':1,6]pyrido[3,2-b] benzo]ùro[4,3 -fg] [1,4/ oxazonine
To a mixture of (2-cyclopropyl-4~methylpyrirnidin-5-yl)boronic acid (150 mg, 843 umol, 2.00 eq) and (S)-4-bromo-12-fluoiO-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4’,3':l,6]pyrido[3,2b]benzofuro[4,3-fg][ 1,4]oxazonine (165 mg, 421 umol, 1.00 eq) in dioxane (3.00 mL) and water (0.300 mL) were added Pd(dppf)Cl2 (30.8 mg, 42.1 umol, 0.100 eq) and Na2CO3 (89.3 mg, 843 umol, 2.00 eq) at 25°C, the mixture was stirred at 90°C under nitrogen for 12 hr. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in MeOH (30.0 mL) and silica-thiol (3.00 g, modified silicone gel for eliminating Pd, imegular silica
386 gel, 100-200 mesh, Chlorides (Cl), %<0.004, particle size distribution 45-75 um) was added at 20°C and stirred at 20°C for 6 h. The suspension was fïltered and the filtrate was concentrated under reduced pressure. The residue was purified by acidic ^rep-HPLC (FA conditions), the fraction was concentrated under reduced pressure to remove most of MeCN at 30°C and the aqueous phase was lyophilized. (S)-4-(2-cyclopropyl-4-methylpyrimidin-5-yl)-12-iluoro-7a,8,13,14-tetrahydro-7H[l,2,4]Îriazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine (12.4 mg, 25.3 umol, 6% yield, 100% purity, formate sait) was obtained as white solid. lH NMR CD3OD 400 MHz ô = ppm 9.31 (s, IH), 8.46 (s, IH), 7.38 (s, IH), 6.90 - 6.S3 (m, IH), 6.63 (dd, J = 8.5, 3.9 Hz, IH), 5.06 (d, J = 15.7 Hz, IH), 4.87 (d, J= 15.7 Hz, IH), 4.57 (t, 9.3 Hz, 2H), 4.30 - 4.22 (m, IH), 4.00 (br s,
IH), 3.92 - 3.83 (m, IH), 2.34 (s, 3H), 2.25 - 2.18 (m, 1 H), 1.15 - 1.08 (m, 4H). LCMS (ESI+): m/z 445,1 (M+H).
Example 145: (S)-12-fiuoro-4-(3-inethylpyridazin-4-yl)-7a,8,13,14-tctrahydro-7H[1,2,4] triazolo[4’,3’:l,6]pyrÎdo[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
Step 1: 6-methylpyridazine 1-oxide and 3-methylpyridazine 1-oxide
To a solution of 3-methylpyridazine (5.00 g, 53,1 mmol, 4.85 mL, 1.00 eq) in DCM (100 mL) was added m-CPBA (11.5 g, 53.1 mmol, 80.0% purity, 1.00 eq) at 0°C. The mixture was stiiTed at 20°C for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 5-18% EtOH/Petroleum ether gradient @ 40 mL/min). 3-Methylpyridazine 1oxide (1.50 g, 13.6 mmol, 25% yield) with Rf = 0.38 was obtained as a light yellow gum. 6Methylpyridazine l-oxide (2.00 g, 18.2 mmol, 34% yield) with Rf = 0.43 was obtained as a light yellow solid. A mixture of 3-methylpyridazine 1-oxideand 6-methylpyridazine 1-oxide (2.50 g crude) was obtained as a brown gum.
Step 2: 3-methyl-4-mtropyridazine 1-oxide
To a solution of 3-methylpyridazine 1-oxide (4.00 g, 36.3 mmol, 1.00 eq) in H2SO4 (45.0 mL) was added HNO3 (15.9 g, 242 mmol, 11,4 mL, 96.0% purity, 6.67 eq) at 20°C. The mixture was stirred ai 90°C for 5 h. The reaction mixture was poured into ice water (150 mL) at 0°C and extracted with DCM (50.0 mL * 5), The combined organic layers were dried over anhydrous sodium sulfate,
387 filtered, and the filtrate was concentrated under reduced pressure. The residue (-2.50 g) was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 50-80% Dichloromethane/Petroleum ethergradient @ 40 mL/min). 3-Methyl-4-nitropyridazine 1-oxide (900 mg, 5.80 mmol, 16% yield) was obtained as a yellow gum.
Step 3: 3-methylpyridazin-4-amine
N il AzN
To a solution of 3-methyl-4-nitropyridazine 1-oxide (900 mg, 5.80 mmol, 1.00 eq) in MeOH (20.0 mL) was added Raney-Ni (1.00 g) and AcOH (3.15 g, 52.5 mmol, 3.00 mL, 9.04 eq) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15 psi) at 20°C for 12 h. The réaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a crude product. 3-methylpyridazin-4-amine (1.00 g, crude, HOAc) was obtained as a green solid.
Step 4: 4-iodo-3-methylpyridazine
I!
To a solution of 3-methylpyridazin-4-amme (1.00 g, 5.91 mmol, 1.00 eq, HOAc) and CH2I2 (7.92 g, 29.6 mmol, 2.38 mL, 5.00 eq) in MeCN (30.0 mL) was added isopentyl nitrite (1.52 g, 13.0 mmol, 1.75 mL, 2.20 eq) in MeCN (20.0 mL) at 0°C under N2. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-50% Ethyl acetate/Petroleum ethergradient @ 40 mL/min). 10.0 mL of dioxane was added to the fraction contining the product. Then the mixture was concentrated under reduced pressure until the residual volume of -3 mL (mostly dioxane). 3methylpyridazin-4-amine (200 mg, 1.83 mmol, 31% yield) was recovered as a brown solid. Note: After chromatography on silica gel, if the fraction was concentrated completely, the product decomposed. The yield was estimated, and the material was used a solution in dioxane.
Step 5: tert-butyl (S)-12-fluoro-4-(3-methylpyridazin-4-yl)-7a,13-dihydro-7H[ 1,2,4] triazolo [4',3 6]pyrido[3,2-b] benzofuro]4,3-fg] [1,4] oxazonine-14 (8H)-carboxylate
388
F
The reaction was set up in 7 parallel batches. A mixture of tert-butyl (S)-12-fluoro-4(tributylstannyl)-7a,13-dίhydro-7H-[l,2,4]triazolo[4',3,: l,6]pyrido[3,2-b]beiizofuro[4,3fg][l,4]oxazonine-14(8H)-carboxylate (30.0 mg, 42.S umol, 1.00 eq), 4-iodo-3-methylpyridazine (18.8 mg, S5.5 umol, 2.00 eq), LiCI (2.72 mg, 64.2 umol, 1.31 uL, 1.50 eq), Pd(PPh3)4 (4.94 mg, 4.28 umol, 0.100 eq) and Cul (4.07 mg, 21.4 umol, 0.500 eq) in dioxane (1.50 mL) was degassed and purged with nitrogen 3 times at 25°C, and the mixture was stirred at 80°C for 2 h under nitrogen atmosphère. The batches were combined. LC-MS showed that tert-butyl (S)-12-fluoro-4(tributylstannyl)-7a,13-dihydro-7H-[l,2,4]triazolo[4,,3r:l,6]pyrido[3,2-b]benzofuiO[4,3fg][ 1,4] oxazonine-14(8 H)-carboxylate was consumed completely and one main peak with desired mass was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Ethyl acetate/MeOH = 6/1). tert-butyl (S)-12-fluoro-4-(3melhylpyridazin-4-yl)-7a,13-dihydro-7H-[l,2,4]triazolo[4,,3':l,6]pyrido[3,2-b]benzofuro[4,3fg][l,4]oxazonine-14(8H)-carboxylate (100 mg, crude) was obtained as a brown solid.
Step 6: (S)-l2-fluoro-4-(3-methylpyridazin-4-yl)-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3 6]pyrido[3,2-b]benzofuro[4,3-fg] [1,4] oxazonine
A mixture of tert-butyl (S)-12-ftuoro-4-(3-methylpyridazin-4-yl)-7a,13-dihydiO-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (100 mg, 198 umol, 1.00 eq) in HFIP (3.00 mL) was stirred at 80°C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-PIPLC (formic acid conditions). (S)-12-fluoro-4-(3-methylpyridazin-4-yl)-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine (21.1 mg, 51.6 umol, 26% yield, 98.9% purity) was obtained as a brown solid. ’H NMR DM S 0-7^400 MHz S = ppm 9.47 (s, IH), 9.15 (d, J = 5.2 Hz, IH), 7.81 - 7.71 (m, 2H), 7.55 (s, IH), 7.02 - 6.93 (m, IH), 6.72 (dd, 7 = 8.6, 3.8 Hz, IH), 4.99 - 4.89 (m, IH), 4.87 - 4.75 (m, IH), 4.54 (q, 7 = 9.7 Hz, 2H), 4.22 (dd, J =
389
9. 6, 3.5 Hz, IH), 4.05 (br s, IH), 3.94 - 3.82 (m, IH), 2.60 (s, 3H). LCMS (ESI+): m/z 405.1 (M+H).
Example 146: (S)-12-lluoro-4-(oxazol-5-yI)-7a,8,13,14-tetrahydro-7H[l,2,4)triazolo|4',3':l,6|pyrido[3,2-b]benzofuro[4,3-fg]|l,4]oxazonine
Step 1: 2-(triisopropylsilyl)oxazole z N<x^TIPS ^-0
The reaction was set up in two parallel batches. To a stirred solution of oxazole (1.00 g, 14.5 mmol, 926 uL, 1.00 eq) in THF (10.0 mL) was added >i-BuLi (2.50 M, 6.37 mL, 1.10 eq) at -30°C under N2. The resultîng mixture was stirred at -30°C for 0.5 hr. To the mixture was added TIPS-OTf (4.8S g, 15.9 mmol, 4.28 mL, 1.10 eq) at -1Ü°C under N2. The resulting mixture was stirred at 15°C for 12 h. The batches were combined. The resulting mixture was quenched by addition of saturated aqueous NH4C1 solution (10.0 mL) and extracted with EtOAc (10.0 mL * 3). The combined organic layers were dried over Na2SO4 and coneentrated under reduced pressure. The mixture was purified by MPLC (SiO2, ΡΕ/EtOAc = 1/0 to l/ï) to give 2-(triisopropylsilyl)oxazole (3.00 g, 13.3 mmol, 46% yield) as a yellow oil.
Step 2: (2-(triisopropylsilyl)oxazol-5-yl)boronic acid x° (HO)2B
To the solution of 2-(triisopropylsilyl)oxazole (400 mg, 1.77 mmol, 1.00 eq) in THF (10.0 mL) was added n-BuLi (2.50 M, 781 uL, 1.10 eq) dropwise at -78°C under N2. The reaction mixture was stirred at -78°C for 1 hr. Triisopropyl borate (668 mg, 3.55 mmol, 816 uL, 2.00 eq) was added at 78°C. The mixture was stirred at -78°C for 1 hr then at 15°C for 0.5 hr. LCMS indicated complété conversion. MeOH (2.00 mL) was added, and the mixture was coneentrated under vacuum to give (2-(triisopiOpylsilyl)oxazol-5-yl)boronic acid (477 mg, crude) as a yellow oil which was used directly in the next step without further purification.
Step 3: tert-butyl (Sf 12-fluoro-4-(2-(lriisopropylsilyl)oxazol-5-yl)-7a, 13-dihydro-7H[1,2,4] triazolo [4 ', 3 1,6]pyrido[3,2-b] benzofuro]4,3-fg] [1,4] oxazonine-14(8H)-carboxylate
390
To the solution of tert-butyl (S)-4-bromo-12-fluoro-7a,13-dihydro-7H[ l,2,4]triazolo[4',3': l,6]pyi-ido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (150 mg, 305 umol, 1.00 eq) and (2-triisopiOpylsilyIoxazol-5-yi)boronic acid (205 mg, 763 umol, 2.50 eq) in dioxane (6.00 mL) and water (1.00 mL) were added KOAc (59.9 mg, 611 umol, 2.00 eq) and Pd(dppf)Cl2 (22.3 mg, 30.5 umol, 0.100 eq). The resulting solution was stiiTed at 90°C under nitrogen for 12 h. The mixture was concentrated under vacuum. The crude product was purified b y prep-TLC (SiO2, PE:EtOAc = 3:2) to obtain tert-butyl (S)-12-fluoiO-4-(2-(triisopropylsilyl)oxazoi5-yl)-7a, 13-dihydro-7H-[ 1,2,4]ίπ3ζο1ο[4’,3': 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4]oxazonine14(8H)-carboxylate (110 mg, 173 umol, 56% yield) as a yellow oil.
Step 4: (S)-12-fluoM-4-(oxazol-5-yl)-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4',3':l,6]pyrido[3,2-
To a solution of tert-butyl (S)-12-fluoro-4-(2-(triisopropylsilyl)oxazol-5-yl)-7a,13-dihydro-7H[l,2,4]triazolo[4',3':l,6]pyTÎdo[3,2-b]benzofuiO[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (110 mg, 173 umol, 1.00 eq) in DCM (2.00 mL) was added TFA (2.00 mL) at 15°C, and the resulting solution was stirred at 15°C for 2 h. LCMS indicated incomplète conversion. Additional TFA (2.00 mL) was added and the resulting solution was stirred at 15°C for 3 h. LCMS showed that the reaction was complété. The mixture was concentrated under a nitrogen stream to dryness. The crude product was purified byprep-HPLC (FA) to obtain (S)-12-fluoro-4-(oxazol-5-yl)-7a,8,13,14tetrahydiO-7H-[l,2,4]triazolo[4',3’:l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine (28.5 mg, 67.0 umol, 38% yield, 100% purity, formate sait) as light yellow solid. NMR CDCl3400 MHz δ = ppm 8.92 (s, IH), 8.12 (s, IH), 7.93 (s, IH), 7.51 (s, IH), 6.83 (t, J = 9.2 Hz, IH), 6.65 - 6.62 (m, IH), 5.24 - 5.22 (m, IH), 5.12 - 5.08 (m, IH), 4.90 - 4.85 (m, IH), 4.67 - 4.60 (m, 2H), 4.28 - 4.25 (m, 1 H), 3.91 - 3.87 (m, 2H). LCMS (ESI+): m/z 380.1 (M+H).
Example 147: (S)-12-fluoro-4-(4-methyloxazol-5-yl)-7a,8,13,14-tetrahydro-7H[l,2,41tnazolo[4',3':l,6]pyndo[3,2-b]benzoiuro[4,3-fg|[M]oxazonÎne Step 1: 4-methyl-2-(triisopropylsilyl)oxazole
To a solution of 4-methyloxazole (L50 g, 18.1 mmol, 1.00 eq) in THF (20.0 mL) was added n-BuLi (2.50 M, 7.94 mL, 1.10 eq) at -30°C under N2. The resulting solution was stirred at -30°C for 0.5 hr.
391
TIPS-OTf (6.08 g, 19.9 mmol, 5.34 mL, 1.10 eq) was added at -10°C under N2 and the resulting solution was stirred at 25°C for 12 h. Saturated aqueous NH4C1 solution (15.0 mL) was added, the mixture was extracted with EtOAc (10.0 mL * 3), the combined organic layers were washed with brine (10.0 mL), dried over Na2SO4, filtered, and under vacuum. The crude product was purified by column chromatography on basic ALOj (PE:EtOAc = 1:0 to 10:1). 4-methyl-2(triisopropylsilyl)oxazole (3.50 g, 14.6 mmol, 81% yield) was obtained as a yellow oil. 'H NMR CDCl3400 MHz δ = ppm 7.49 (s, 1 H), 2.21 (s, 3H), 1.44- 1.36 (m, 3H), 1.12 (d, J = 7.6 Hz, 18H).
Step 2: 4-methyl-5-(tributylstannyl)-2-(triisopropylsiîyl)oxazole ^z^MIPS y— o (n-Bu^Sn
To the solution of 4-methyl-2-(triÎsopropylsÎlyl)oxazole (0.200 g, 835 umol, 1.00 eq) in THF (4.00 mL) was added n-BuLi (2.50 M, 368 uL, 1.10 eq) dropwise at -78°C under N2 and the resulting solution was stirred at -78°C for 0.5 hr. Trîbutyl(chloro)stannane (299 mg, 919 umol, 247 uL, 1.10 eq) was added at -78°C and the resulting solution was stirred at -78°C for 1 hr, then at 15°C for 2 hr. MeOH (2.00 mL) was added and the mixture was concentrated under vacuum. The residue was purified by prep-TLC (PE : EtOAc = 10:1). 4-methyl-5-(tributylstannyl)-2-(triisopropylsilyl)oxazole (320 mg, 606 umol, 72% yield) was obtained as a colorless oil.
Step 3: tert-butyl (S)-12-fluoro-4-(4-methyl-2-(triisopropylsilyl)oxazol-5-yl)-7a,13-dihydro-7H[1,2,4]triazolo[4', 3 1,6]pyrido[3,2-b]benzqfuro[4,3-fg] [1,4] oxazonine-14(8H)-carboxylate
To the solution of 4-methyl-5-(tributylstanny 1)-2-(triisopropylsilyl)oxazole (194 mg, 366 umol, 1.20 eq) in dioxane (5.00 mL) were added tert-butyl (S)-4-bromo-12-fluoro-7a,13-dihydro-7H[1,2,4]triazolo[4’,3':l,6]pyrido[3,2-b]benzofuro[4,3-fg] [1,4] oxazonine-14(8H)-carboxylate (150 mg, 305 umol, 1.00 eq), Pd(PPh3)4 (35.3 mg, 30.5 umol, 0.100 eq), LiCl (25.9 mg, 611 umol, 12.5 uL, 2.00 eq) and Cul (23.3 mg, 122 umol, 0.400 eq) under N2. The resulting solution was stirred at 80°C for 12 hr. The mixture was concentrated under vacuum. The résiduel was purified by prepTLC (PE:EtOAc = 1:1). tert-butyl (S)-12-fluoro-4-(4-methyL2-(triisopropylsilyl)oxazol-5-yl)
392
7a,i3-dihydro-7H-[l,2,4]triazolo[4',3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][l)4]oxazonine-14(8H)carboxylate (180 mg, 277 umol, 90% yield) was obtained as a yellow oil.
Step 4: (S)-I2-fiuorü-4-(4-methyloxazol-5-yl)-7a,8,13,l4-teirahydro-7H[1,2,4]triazolo[4', 3 1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4] oxazonine
F
To the solution of tert-butyl (S)- 12-fluoro-4-(4-methyl-2-(triisopiOpylsilyl)oxazol-5-yl)-7a, 13dihydro-7H-[ 1,2,4]triazolo[4',3': 1,6]pyrîdo[3,2-b]benzofuro[4,3-fg][ l,4]oxazonine- 14(8H)carboxylate (180 mg, 277 umol, 1.00 eq) in DCM (1.50 mL) was added TFA ( l .50 mL) at 15°C and the resulting solution was stirred at 15°C for 4 hr. The mixture was concentrated under vacuum. The residue was purified by prep-HPLC (FA) to obtain (S)-12-fluoro-4-(4-methyloxazol-5-yl)7 a, 8,13,14-tetrahydro-7H-[ 1,2,4]triazolo[4’,3': 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4] oxazonine (29.1 mg, 64.7 umol, 23% yield, 97.7% purity, formate sait) as a yellow solid. lH NMR CDCh 400 MHz δ = ppm 8.95 (br s, IH), 7.93 (s, IH), 7.32 (s, IH), 6.87 (t, J = 9.2 Hz, IH), 6.69 -6.66 (m, IH), 5.30 (br s, IH), 5.15 - 5.09 (m, IH), 4.90 - 4.86 (m, IH), 4.68 - 4.63 (m, 2H), 4.29 - 4.26 (m, IH), 3.94 - 3.87 (ιη, 2H), 2.52 (s, 3H). LCMS (ESI+): m/z 394.1 (M+H).
Example 148: (S)-4-(2-cyclopropylpyrimîdin-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H[l,2,4|triazolo[4’,3’:l,6]pyrido[3,2-b]benzofuro|4,3-fg][l,4]oxazonine
Step I: tert-butyl (S)-4-(2-cyclopropylpyrimidin-5-yl)-l 2-fluoro-7a, 13-dihydro-7H[1,2,4] triazolo[4', 3 1,6]pyrido[3,2-b] benzofuro[4,3-fg] [1,4] oxazonine-14(8H)-carboxylate
To a solution of tert-butyl (S)-4-bromo-12-fluoro-7a,I3-dihydro-7H[l,2,4]triazolo[4’,3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (150 mg, 305 umol, 1.00 eq) in dioxane (5.00 mL) and water (0.500 mL) were added 2-cyclopropyL5(4,4,5,5-tetramethyl-lf3,2-dioxaborolan-2-yl)pyrimidine (150 mg, 609 umol, 2.00 eq), Na2CO3 (64.7 mg, 611 umol, 2.00 eq) and Pd(dppf)CL (22.3 mg, 30.5 umol, 0.100 eq) at 20°C under nîtrogen atmosphère. The mixture was stirred at 80°C for 12 h under nîtrogen atmosphère. The reaction mixture was concentrated. The residue was purified by prcp-TLC (SiO2, Petroleum ether/Ethyl acetate = 0/1). tert-butyl (S)-4-(2-cyclopropylpyrimîdin-5-yl)-12-fiuoro-7a,13-dihydiO-7H
393
[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]bcnzofuro[4,3-fg][l,4]oxazonine-I4(8H)-carboxylate (260 mg, crude) was obtained as a yellow oil.
Step 2: (S)-4-(2-cyclopropylpyrimidin-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
F yN rOv/
LV0 1
N ^7
A solution of tert-butyl (S)-4-(2-cyclopropylpyrimidin-5-yl)-12-fluoro-7a,I3-dîhydro-7H[ l,2,4]triazolo[4',3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4]oxazonine-14(8H)-carboxylate ( 160 mg, 302 umol, 1,00 eq) in HFIP (5.00 mL) was stirred at 100°C for 2 h. LC-MS indicated incomplète conversion. The mixture was stirred at 100°C for additional 6 h. LC-MS showed that the reaction was complété. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DMSO (3.00 mL). The mixture was purified by prep-HPLC (column: Welch Xtimate C18 150*25 mm*5 um; mobile phase: [water (0.2% FA)-ACN]; B%: 30%-60%, 10 min). The product-containing fraction was concentrated under reduced pressure to remove most of MeCN at 30°C and the aqueous phase was lyophilized. (S)-4-(2-cyclopropylpyrimidin-5-yl)-12-fluoro7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine (67.6 mg, 142 umol, 46% yield, 99.5% purity, formate sait) was obtained as a yellow solid, lH NMR DMSO-îL 400 MHz δ = ppm 9.47 (s, IH), 9.39 (s, 2H), 7.87 (s, IH), 7.70 (br t, J = 6.1 Hz, IH), 6,95 (t, J = 9.5 Hz, IH), 6.69 (dd, J = 8.6, 3.7 Hz, IH), 4.95 - 4.75 (m, 2H), 4.58 - 4.49 (m, 2H), 4.22 (br dd, 7 = 9.5, 2.8 Hz, IH), 4.03 (br d, 7= 9.2 Hz, IH), 3.99 - 3.90 (m, IH), 2.29 - 2.20 (m, 1 H), 1.10 - 1.02 (m, 4H), LCMS (ESI+): m/z 431,1 (M+H).
Example 149: (S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo|4’,3':l,6]pyrido[3,2b)benzofuro[4,3-fg][l,4]oxazonin-4-yl)-2-methylpyridin-3-aniine
Step 1 ; 2-methyÎ-3-nitro-5-(4,4,5,5-teiramethyl-l,3,2-dioxaborolan-2-y')pyridine O2N /
O-B
-A,0
To a solution of 5-bromo-2-methyl-3-nitropyridine (1.00 g, 4.61 mmol, 1.00 eq) in dioxane (15.0 mL) were added 4,4,5,5-tetramethyi-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2dioxaborolane (1.75 g, 6.91 mmol, 1.50 eq), KOAc (905 mg, 9.22 mmol, 2.00 eq) and Pd(dppf)Cl2
394 (337 mg, 461 umol, 0.100 eq) at 20°C under nitrogen atmosphère. The mixture was stirred at 80°C for 12 h under nitrogen atmosphère. Water (10.0 mL) was added to the mixture, the mixture was extracted with ethyl acetate (8.00 mL * 3), the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 1/0 to l/l). 2-Methyl-3-nitro-5-(4,4,5,5tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (1.15 g, 4.35 mmol, 94% yield) was obtained as a white solid.
Step 2: 2-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-3-amine H2N / —Jo
To a solution of 2-methyl-3-nitiO-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyiidÎne (1.15 g, 4.35 mmol, 1.00 eq) in MeOH (25.0 mL) was added 10% Pd/C (2.32 g, 50.0% purity) under nitrogen atmosphère. The suspension was degassed and purged with H2 5 times. The mixture was stirred under EI2 (15 Psi ) at 20°C for 4 h. LC-MS showed 2-methyl-3-nitro-5-(4,4,5,5-tetramethyll,3,2-dioxaborolan-2-yl)pyridine was consumed completely and one main peak with the desîred mass was detected. The reaction mixture was filtered and the filtare was concentrated under reduced pressure to give 2-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-3-amine (850 mg, crude) as a yellow oil.
Step 3: tert-butyl (S)-4-(5-amino-6-methylpyridin-3-yl)-12-fluoro-7a, 13-dihydro-7H]l,2,4]triazolo[4',3 1.6]pyrido[3,2-b] benzofuro]4,3-fg] [1,4] oxazonine-14(8H)-carboxylate / BOC
To a solution of 2-methy 1-5-(4,4,5,5-tetramethyI-1,3,2-dioxaborolan-2-yl)pyridin-3-amine (143 mg, 611 umol, 2.00 eq) in water (0.700 mL) and EtOH (4.90 mL) were added tert-butyl (S)-4-bromo-12fluoro-7a, 13-dihydro-7H-[l,2,4]triazolo[4',3’:l,6]pyrido[3,2-b] benzofuro [4,3-fg] [1,4] oxazonine14(8H)-carboxylate (150 mg, 305 umol, 1.00 eq), KOAc (59.9 mg, 610 umol, 2.00 eq) and 4-ditertbutylphosphanyl-N,N-dimethyl-aniline;dichloropaliadium (21.6 mg, 30.5 umol, 21.6 uL, 0.100 eq) at 20°C under nitrogen atmosphère. The mixture was stirred at 80°C for 12 hr under nitrogen
395 atmosphère. The reaction mixture was concentrated. The residue was purified by prep-TLC (SiO2, Ethyl acetate/MeOH = 10/1). tert-Butyl (S)-4-(5-ammo-6-methylpyridin-3-yl)-I2-fluoiO-7a,13dihydro-7H-[l,2,4]triazolo[4,,3':l,6]pyrido[3,2-b]benzofuro[4)3-fg][l,4]oxazonine-14(8H)carboxylate (138 mg, 266 umol, 87% yield) was obtained as a yellow solid.
Step 4: (S)-5-(l2-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4] triazolo[4',3 1,6]pyrido[3,2b] benzofuro[4,3-fg] [ 1,4] oxazomn-4-yl)-2-methylpyridin-3-amine
A solution of tert-butyl (S)-4-(5-amino-6-inethylpyridin-3-yl)-12-fluoro-7a,13-dihydiO-7H[ l,2,4]triazolo[4',3’: 1,6]pyrido[3,2~b]benzofuro[4,3-fg][ 1,4]oxazonine- 14(8H)-carboxylate (110 mg, 212 umol, 1.00 eq) in HFIP (5.00 mL) was stirred at 100°C for 15 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DMSO (3.00 mL). The mixture was purified by />rep-HPLC (column: Phenomenex Gemini-NX 80*40 mm*3 um; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 10%-40%, 8 min). The product-containing fraction was concentrated under reduced pressure to remove most of MeCN at 30°C and the aqueous phase was lyophilized. (S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[ 1,2,4]triazolo[4',3': 1,6]pyrido[3,2b]benzofuro[4,3-fg][ l,4]oxazonin-4-yl)-2-methylpyridin-3-amine (37.3 mg, 89.1 umol, 42% yield, 99.9% purity) was obtained as a yellow solid. !H NMR DMSO-t^ 400 MHz ô = ppm 9.43 (s, IH), 8.35 (s, IH), 7.78 (s, IH), 7.56 (s, IH), 7.50 (br t, J-6.2 Hz, IH), 6.95 (t, J = 9.5 Hz, IH), 6.68 (dd, 7=8.6, 3.7 Hz, IH), 5.10 (s, 2H), 4.95 - 4.72 (m, 2H), 4.59 -4.47 (m, 2H), 4.22 (br dd, 7=9.6, 3.0 Hz, IH), 4.02 (br d, 7= 8.9 Hz, IH), 3.95 - 3.87 (m, IH), 2.31 (s, 3H). LCMS (ESI+): m/z 419.1 (M+H).
Example 150: (S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[l,2,4]triazoIo[4',3':l,6|pyrido[3,2b]benzofuro[4,3-fg][l,4]oxazonin-4-yl)-6-methylpyridin-2-ol
Step 1: 6-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-ol
To a solution of 5-bromo-6-methylpyridin-2-oi (1.00 g, 5.32 mmol, 1.00 eq) in dioxane (12.0 mL) were added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane 396 (2.02 g, 7.95 mmol, 1.50 eq), KOAc (1.04 g, 10.6 mmol, 2.00 eq) and Pd(dppf)Cl2 (390 mg, 533 umol, 0.100 eq) at 20°C under nitrogen atmosphère. The mixture was stirred at 80°C for 12 hr under nitrogen atmosphère. Water (15.0 mL) was added to the mixture, the mixture was extracted with ethyl acetate (10.0 mL * 3), the combined organic layers were dried overNa2SO4, filtered, and concentrated under reduced pressure. The residue was purified by MPLC (SiO2, Petroleum ether/Ethyl acetate = 1/0 to 1/1). 6-MethyL5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin2-ol (690 mg, ciude) was obtained as a yellow solid.
Step 2: tert-butyl (S)-l2-fluoro-4-(6-hydroxy-2-methylpyridin-3-yl)-7a, 13-dihydro-7H[1,2,4] triazolo[4', 3 91,6]pyrido[3,2-b] benzofuro[4,3-fg] [1,4] oxazonine-14(8H)-carboxylate
F
To a solution of tert-butyl (S)-4-bromo-12-fluoro-7a,13-dihydro-7H[l,2,4]triazolo[4',3':i,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (120 mg, 244 umol, 1.00 eq) in dioxane (5.00 mL) and water (0.500 mL) were added 6-methyi-5-(4,4,5,5tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-ol (230 mg, 977 umol, 4.00 eq), Na2CO3 (5L8 mg, 489 umol, 2.00 eq) and Pd(dppf)Cl2 (17.9 mg, 24,4 umol, 0.100 eq) at 20°C under nitrogen atmosphère. The mixture was stirred at 80°C for 12 h under nitrogen atmosphère. LC-MS showed tert-butyl (S)-4-bIΌlΏO-12-fluolΌ-7a,13-dihydro-7H-[l,2,4]triazolo[4',3,: 1,6]pyrido[3,2b]benzofuro[4,3-fg][l,4]oxazonine-I4(8H)-carboxylate was remained and one main peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified byprep-TLC (SiO2, Ethyl acetate/MeOH = 5/1). tert-Butyl (S)-12-fluoro-4-(6hydroxy-2-methylpyridin-3-yl)-7a, 13-dihydro-7H-[l,2,4]triazolo[4',3': 1,6]pyrido[3,2b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (95.0 mg, 183 umol, 74% yield) was obtained as a yellow solid.
Step 3: (S)-5-(12-fliioro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',391,6]pyrido[3,2b]benzofuro[4,3-fg] [1,4] oxazonin-4-yl)-6-methylpyridin-2-ol
397
F
To a solution of tert-butyl (S)-12-fluoro-4-(6-hydroxy-2-methylpyridîn-3-yl)-7a,13-dihydro-7H[l,2,4]triazolo[4',3’: l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (200 mg, 385 umol, 1.00 eq) in DCM (2.00 mL) was added TFA (3.08 g, 27.0 mmol, 2.00 mL, 70.2 eq) at 20°C. The mixture was stirred at 20°C for 1 hr. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DMSO (2.00 mL). The mixture was purified by acidîc prep-HPLC (column: Luna Oméga 5u Polar C18 100A; mobile phase: [water (0.04% HC1)ACN]; B%: 15%-40%, 7 min). The product-containing fraction was concentrated under reduced pressure to remove most of MeCN at 30°C and the aqueous phase was lyophilized. (S)-5-(12-fhioro7a,8,l3,l4-tetrahydiO-7H-[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][1s4]oxazonin-4yl)-6-methylpyridin-2-ol (104 mg, 228 umol, 59% yield, 100% purity, HCl sait) was obtained as a yellow solid. ‘H NMR CD3OD 400 MHz δ = ppm 9.53 (s, IH), 7.94 (s, 1H), 7.70 (d, J = 9.2 Hz, 1H), 6.98 - 6.88 (m, 1H), 6.72 - 6.64 (m, 2H), 5.19 (d, J= 14.7 Hz, 1H), 4.95 (br d, J = 14.8 Hz, IH), 4.76 (brdd, 7 = 10.0,4.3 Hz, 1H), 4.63 (t,7=9.5 Hz, 1 H), 4.32 (dd, 7= 9.7, 3.2 Hz, 1H), 4.13 - 4.05 (m, IH), 3.953 - 3.85 (m, IH), 2.25 (s, 3H). LCMS (ESI+): m/z 420.1 (M+H).
Example 151: (S)-12-fluoro-4-(3-methyMH-pyrazol-l-yl)-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4’,3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
3-Methyl-lH-pyrazole (0.0492 mL, 0.611 mmol) was added to a mixture of tert-butyl (S)-4-bromo12-fluoro-7a,13-dihydiO-7H-[l,2,4]triazolo[4,,3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine14(8H)-carboxylate (Example 17; 150 mg, 0.305 mmol), K3PO4 (130 mg, 0.611 mmol), Cul (5.81 mg, 0.0305 mmol), and trans-N,N-dimethylcyclohexane-l,2-diamine (0.0193 mL, 0.122 mmol) in toluene (0.600 mL) under N2. The mixture was heated at 115 °C for 18 h. The mixture was
398 concentrated under reduced pressure. The residue was purified by silica ge] chromatography (12.0 g cartridge) eluting with EtOAc in hexanes (0-100%) to afford tert-butyl (S)-12-fluoro-4-(3-methyl1 H-pyrazol-1 -yl)-7a, 13-dihydro-7H-[ ! ,2,4]triazolo[4',3': 1,6]pyrido[3,2-b]benzofuro[4,3fg][ I,4]oxazonine-14(8H)-carboxylate as a solid (60 mg, 31%). m/z (ES+) [M+H]+ : 493.16. HPLC (A05) tr< = 2.78 min.
The solid was diluted with HFIP (3.00 mL) and stirred at 80 °C for 16 h. The solution was concentrated under reduced pressure, and the residue was purified by reverse phase chromatography (BEH C18 30x150 ACN/AmBicarb 19 min, 35-55%) to provide the title compound as a solid (5.77 mg). lH NMR (500 MHz, DMSO-d6) δ 9.50 (s, IH), 8.96 (d, J = 2.1 Hz, 1 H), 7.72 (s, 1 H), 7.42 (t, J = 6.0 Hz, IH), 6.93 (dd, J = 10.3, 8.7 Hz, IH), 6.67 (dd, J = 8.7, 3.8 Hz, IH), 6.35 (d, J = 2.4 Hz, IH), 4.86 (dd, J = 14.9, 5.7 Hz, IH), 4.75 (dd, J= 15.3, 6.4 Hz, IH), 4.58 - 4.47 (m, 2H), 4.24 (dd, J = 9.6, 3.5 Hz, IH), 4.09-3.98 (m, IH), 3.86 (t, J = 11.5 Hz, IH), 2.29 (s, 3H). m/z (ES+) [M+Hf : 393.2. HPLC (BEH C18 5-100% ACN/AmForm lOmM pH4) tR = 1.46 min.
Example 152: (S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo|4',3':l,6]pyrido[3,2bj benzofuro[4,3-fg] [1,4] oxazonin-4-yl)-N,N-dimethylpicolinamide
Step 1: 5-bromo~N,N-dimethylpicolinamide
To a solution of 5-bromopicolinic acid (1.00 g, 4.95 mmol, 1.00 eq), N-methylmethanamine (484 mg, 5.94 mmol, 1.20 eq, HCl sait) in DMF (10 mL) was added DIPEA (1.28 g, 9.90 mmol, 1.72 mL, 2.00 eq) and HATU (2.26 g, 5.94 mmol, 1.2 eq) at 25°C. The mixture was stirred at 25°C for 10 h. LCMS showed 5-bromopicolinic acid was consumed completely and the product was detected. To the mixture was added water (20 mL), the mixture was extracted with EtOAc (20 mL * 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by MPLC (SÎO2, PE:EtOAc = 1:0 to PE:EtOAc =1:1). 5Bromo-N,N-dimethylpicolinamide (560 mg, 2.44 mmol, 49% yield) was obtained as a yellow oil.
Step 2: N,N-dimethyl-5-(4,4,5,5-tetramethyl-I,3,2-dioxaborolan-2-yl)picolinamide
399
To a solution of 5-bromo-N,N-dimethylpicolinamide (500 mg, 2.18 mmol, 1.00 eq) and 4,4,4',4',5,5,5,,5’-octamethyL2,2’-bi(l,3,2-dioxaboiOlane) (831 mg, 3.27 mmol, 1.50 eq) in dioxane (5.00 mL) was added KOAc (643 mg, 6.55 mmol, 3.00 eq) and Pd(dppf)C12.DCM (89.1 mg, 109 umol, 0.0500 eq) under nitrogen atmosphère at 25°C. The mixture was stirred at 80°C for 10 h under nitrogen atmosphère. LCMS showed that the reaction was complété. The mixture was concentrated under reduced pressure. The residue was purified by MPLC (SiO2, PE:EtOAc = L0 to EtOAc:MeOH = 5:1) to give N,N-dimethyl-5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2yl)picolînamide (100 mg, crude) as a yellow oil.
Step 3: (S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2b] benzqfuro[4,3-fg] [1,4]bxazomn-4-yl)-NN-dimethylpicolinamide
To a solution of N,N-dimethyl-5-(4,4,5,5-tctramethyl-i ,3,2-dioxaborolan-2-yl)pico!inamide (74.1 mg, 268 umol, 1.50 eq), (S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuiO[4,3-fg][l,4]oxazonine (70.0 mg, 179 umol, 1.00 eq) and NaHCO3 (75.2 mg, 895 umol, 34.8 uL, 5.00 eq) in dioxane (1.00 mL) and water (0.100 mL) was added Pd(dppf)C12 (13.1 mg, 17.9 umol, 0.100 eq) under nitrogen at 25°C. The resulting mixture was stirred at 80°C under nitrogen for 3 hr. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in MeOH (2 mL) and silica-thiol (180 mg, modified Silicon gel for elîminating Pd, irregular silica gel, 100-200 mesh, Chlorides (Cl), %<0.004, particle size distribution 45-75 um) was added at 20°C and the mixture was stirred at 20°C for 3 h. The suspension was filtered, the filtrate was concentrated, and obtained residue was purified by acidic prep-HPLC (column; Phenomenex Luna CI8 150 * 30 mm* 5 um; mobile phase: [water (0.04% HCl) -ACN]; B%: 20%-50%, 10 min). The product-containing fraction was concentrated under reduced pressure to remove most of MeCN at 30°C and the aqueous phase was lyophilized. (S)-5
400 (12-fluoro-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4’,3':l,6]pyrido[3,2-b]benzofuro[4,3fg][l,4]oxazonin-4-yl)-N,N-dimethylpicohnamide (40.6 mg, 80.56 umol, 45% yield, 98.6% purity, HCl sait) was obtained as a yellow solid. IH NMR CD3OD 400 MHz δ = ppm 9.62 (s, IH), 9.00 (br s, IH), 8.41 (br d, J = 7.9 Hz, IH), 8.21 (s, IH), 7.93 (br d, J = 7.8 Hz, IH), 6.90 (t, .1 =9.5 Hz, IH), 6.67 (dd, .T = 8.6, 3.7 Hz, IH), 5.19 (d, J = 14.7 Hz, IH), 5.03 - 4.94 (m, IH), 4.85 - 4.74 (m, IH), 4.62 (brt, J = 9.2 Hz, 1H),4.33 (br d, J = 8.6 Hz, IH), 4.11 -4.03 (m, 1 H), 4.02 - 3.94 (m, IH), 3.18 (s, 3H), 3.13 (s, 3H). LCMS (ESI+): m/z 461.2 (M+H).
Example 153: (S)-3-(5-(12-fIuoro-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3’:l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonHi-4-yl)-6-niethylpyridin-2yl)-N-inethylpropanamîde
Step 1: tert-butyl (S,E)-4-(6-(3-ethoxy-3-oxoprop-l-en-l-yl)-2-methylpyridin-3-yl)-12-]luoro-7a,13dihydro- 7H-[l,2,4]triazolo[4 31,6]pyrido]3,2-b] benzofuro[4,3-fg] [1,4] oxazonine-/ 4(8H)~ carboxylate
To a stiiTed solution of ethyl (E)-3-(6-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)pyridin-2-yl)acrylate (678 mg, 2.14 mmol, 3.50 eq) and tert-buty] (S)-4-bromo-12-tluoro-7a,13dihydro-7H-[l,2,4]triazolo[4',3’:l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazomne-14(8H)carboxylate (300 mg, 611 umol, 1.00 eq) in dioxane (8.00 mL) and H2O (1.60 mL) were added Na2CO3 (129 mg, 1.22 mmol, 2.00 eq) and Pd(dppf)Cl2 (44.7 mg, 61.1 umol, 0.100 eq) at 15 °C. The resulting mixture was stirred at 80 °C for 2 h under N2. LCMS indicated incomplète conversion. The mixture was stirred at 80 °C for 12 h. LCMS showed that the reaction was complété. The mixture was coneentrated in vacuo. The mixture was purified by MPLC (SiO2, ΡΕ/EtOAc = 1/0 to 0/1) to give tert-butyl (S,E)-4-(6-(3-ethoxy-3-oxoprop-l-en-l-yl)-2methylpyridin-3-yl)-i2-fluoro-7a,13-dihydro-7H-[l,2,4]triazolo[4',3': 1,6]pyrido[3,2b]benzofiiro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (200 mg, 332 umol, 54% yield) as a yellow oil.
Step 2: tert-butyl (S)-4-(6-(3-ethoxy-3-oxopropyl)-2-methylpyridin-3-yl)-l 2-fluoro-7a, 13-dihydro7H-[1,2,4] triazolo]4',3':1,6]pyrido[3,2-b] benzofuro [4,3-fg] [1,4] oxazonine-14(8H)-carboxylate
401
To a stirred solution of tert-butyl (S,E)-4-(6-(3-ethoxy-3-oxoprop-l-en-l-yl)-2-methylpyridin-3-yl)12-fIuoro-7a,13-dihydro-7H-[ 1,2,4]triazolo[4',3': 1,6 ]pyrido[3,2-b] benzofuro[4,3-fg] [1,4] oxazonine14(SH)-carboxylate (180 mg, 299 umol, 1.00 eq) in MeOH (10.0 mL) was added 10% Pd/C (50.0 mg, 50% purity) at 15 °C under N2. The resulting mixture was stirred at 15 °C under H2 (15 psi) for 12 h. The mixture was fïltered and the filtrate was concentrated in vacuo. tert-Butyl (S)-4-(6-(3ethoxy-3-oxopropyl)-2-methylpyridin-3-yl)-12-fluoro-7a,13-dihydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuiO[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (150 mg, crude) was obtained as a yellow oil.
Step 3: (S)-3-(5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[ 1,2,4]triazolo[4’,3’:l,6]pyrido[3,2b]benzofuro[4,3-fg][ 1,4] oxazonin-4-yl)-6-methylpyridin-2-yl)propanoic acid
To a stirred solution of tert-butyl (S)-4-(6-(3-ethoxy-3-oxopropyl)-2-methylpyridm-3-yl)-12-fluoiO7a,13-dihydro-7H-[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)carboxylate (150 mg, 248 umol, 1.00 eq) in water (1.00 mL) and MeOH (2.00 mL) was added NaOH (19.9 mg, 497 umol, 2.00 eq) at 15 °C. The resulting mixture was stirred at 15 °C for 12 h. The mixture was concentrated in vacuo to remove MeOH. The aqueous phase was acidified with aqueous HCl soltion (2.00 M) to pH = 2~3 and the aqueous layer was concentrated in vacuo. (S)-3(5-( 14-(tert-butoxycarbonyl)-12-fluoro-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4’,3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonin-4-yl)-6-methylpyridin-2yl)propanoic acid (130 mg, crude, HCl sait) was obtained as a yellow solid.
Step 4: (S)-3-(5-(12-fluoro-7a,8,13,14-tetrahydra-7H-[1,2,4]triazolof4',3':1,6]pyrido[3,2b] benzofuro[4,3-fg] [1,4] oxazonm-4-yl)-6-melhylpyridin-2-yl)-N-methylpropanamide
402
To a stirred solution of (S)-3-(5-(12-fluoro-7a,8,13,14-tetrahydro~7H[l,2,4]triazolo[4,,3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonin-4-yl)-6-methylpyridin-2yl)propanoic acid (120 mg, 252 umol, 1,00 eq, HCl sait), methanamine hydrochloride (34,1 mg, 505 umol, 2.00 eq) and DIPEA (196 mg, 1.51 mmol, 264 uL, 6.00 eq) in DMF (3.00 mL) was added HATU (192 mg, 505 umol, 2.00 eq) at 15 °C. The resulting mixture was stirred at 30 °C for 12 h. The mixture was purified by neutral prep-HPLC (column: Waters Xbridge Prep OBD Cl8 150*40 mm* 10 um; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 10%-40%, 8 min). (S)3-(5-( 12-fluoro-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4',3': 1,6]pyrido[3,2-b]benzofuro[4,3fg][l,4]oxazonin-4-yl)-6-methylpyridin-2-yl)-N-methylpropanamide (37.7 mg, 75.9 umol, 30% yield, 98.3% purity) was obtained as a yellow solid. !H NMR CDC13 400 MHz δ = ppm 8.88 (s, 1 H), 7.63 (d, J = 7.9 Hz, IH), 7.11 (d, J = 8.0 Hz, IH), 7.06 (s, 1H),6.9O (t, J = 9.4 Hz, IH), 6.76 (br s, IH), 6.69 (dd, J = 8.7, 3.9 Hz, IH), 5.18 - 5.03 (m, 2H), 4.85 (br dd, J = 12.7, 4.0 Hz, IH), 4.71 4.58 (m, 2H), 4.27 (dd, J = 9.7, 3.2 Hz, IH), 4.02 - 3.91 (m, IH), 3.88 - 3.80 (m, IH), 3.14 (t, J = 7.0 Hz, 2H), 2.81 (d, J = 4.8 Hz, 3H), 2.68 (t, J = 7,0 Hz, 2H), 2.47 (s, 3H). LCMS (ESI+): m/z 489.2 (M+H).
Example 154:
Step I: 3-bromo-2-methylpyridin-4-amine
A solution of 2-methylpyridin-4-amine (3.00 g, 27.7 mmol, 1.00 eq) in 40.0% HBr (30.0 mL) aqueous solution was stirred at 70 °C and a solution of H2O2 (12.6 g, 55.5 mmol, 10.7 mL, 15.0% purity, 2.00 eq) was added dropwise over 1 hr period at such a rate that the température of the reaction mixture remained at 70 °C. The mixture was stirred for another 1 h at 70 °C. The mixture was poured on to crushed ice (40.0 g). The pH was adjusted to 7 with solid NaHCO3. The mixture
403 was extracted with EtOAc (50.0 mL * 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate - 1/0 to 0/1). 3-Bromo-2-methylpyridin-4amine (3.00 g, crude) was obtained as a yellow solid. IH NMR CD3OD 400 MHz 5 = ppm 7.76 (d, J=5.8 Hz, IH), 6.52 (d, J=5.8 Hz, IH), 2.48 (s, 3H).
Step 2: 3-hromo-2-methylpyridin-4-ol
H2SO4 (2.10 g, 21.4 mmol, 1.14 mL, 4.00 eq) (98% purity) and 3-bromo-2-methylpyridin-4-amine (1.00 g, 5.35 mmol, 1.00 eq) were added successively to H2O (8.00 mL) at 0 °C, and then NaNO? (553 mg, 8.02 mmol, 1.50 eq) in H2O (8.00 mL) was added dropwîse to maintain the température between 0-5 °C. After stirring at 15 °C for 1 hr, the reaction mixture was heated at 95 °C for additional 2 h. The mixture was poured on to ciushed ice (20.0 g) and the pH was adjusted to 8 with solid NaHCO3. The mixture was concentrated under reduced pressure to give a residue. The residue was purified b y column chromatography (SiO2, Petroleum ether/Ethyl acetate = 1/0 to 0/1 and then Ethyl acetate/MethanoI = 1/0 to 10/1). 3-BiOmo-2-methylpyridin-4-ol (1.80 g, crude) was obtained as a yellow solid.
Step 3: tert-butyl (S)-l2-fluoro-4-(4-hydroxy-2-methylpyridin-3-yl)-7a,i3-dihydro-7H[1,2,4]triazolo[4', 3 1,6]pyrido[3,2-b] benzofuro[4,3-fg][l, 4] oxazonine-14(8H)-carboxylate
N Boc
The reaction was set up in two parallel batches. To a solution of tert-butyl (S)-12-fluoro-4(tributylstannyl)-7a,l3-dihydro-7H-[ 1,2,4]triazolo[4',3': 1,6]pyrido[3,2-b]benzofuro[4,3fg][l,4]oxazonine-14(8H)-carboxylate (50.0 mg, 71.3 umol, L00 eq) in DMF (3.00 mL) were added 4-ditert-butylphosphanyl-N,N-dimethyl-aniline dichloropalladium (5.05 mg, 7.13 umol, 5.05 uL,
404
0.100 eq) and 3-bromo-2-methylpyridin-4-ol (26.8 mg, 143 umol, 2.00 eq) at 20 °C. The mixture was stirred at 110 °C for 12 h under N2. The batches were combined and concentrated under reduced pressure to remove solvent. The residue was purified by prep-TLC (SiO2, Ethyl acetate/MeOH = 5/1). tert-butyl (S)-12-fluoro-4-(4-hydroxy-2-methyIpyridia-3-yl)-7a,13-dihydro7H-[l,2,4]triazolo[4',3’:l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (100 mg, crude) was obtained as a yellow solid.
Step 4: (S)-3-(12-fluoro-7a,8,i3,l4-tetrahydro-7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2b]benzo]uro[4,3-fg] [1,4] oxazonin-4-yl)-2-methylpyridin-4-ol
To a solution of tert-butyl (S)-12-fluoiO-4-(4-hydroxy-2-methylpyridin-3-yl)-7a,13-dihydro-7H[ l,2,4]triazolo[4',3': I,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonÎne-I4(8H)-carboxylate (80.0 mg, 154 umol, 1.00 eq) in DCM (2.00 mL) was added TFA (0.750 mL) at 20 °C. The mixture was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified byprep-HPLC (column: Welch Xtimate C18 150*25 mm*5 um; mobile phase: [water (0.04% HC1)-ACN]; B%: 20%-40%, 8 min). (S)-3-(12-nuoro-7a,8,13,14tetrahydro-7H-[l,2,4]triazolo[4,,3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonin-4-yl)-2methylpyridin-4-ol (28.0 mg, 61.4 umol, 40% yield, 100% purity, HCl sait) was obtained as an offwhite solid. IH NMR CD3OD 400 MHz δ = ppm 9.53 (s, IH), 8.44 (br s, IH), 8.01 (s, IH), 7.23 (br dd, J = 18.5, 6.6 Hz, IH), 6.93 (t, J = 9.4 Hz, IH), 6.68 (dd, J = 8.7, 3.9 Hz, IH), 5.20 (br dd, J = 14.6, 6.4 Hz, IH), 4.98 - 4.92 (m, IH), 4.73 (br s, IH), 4.62 (brt, J = 9.5 Hz, JH), 4.3Ü (dd, J = 9.7, 3.1 Hz, IH), 4.07 (br s, IH), 3.89 (br s, IH), 2.63 (s, I.5H), 2.53 (s, L5H). IH NMR DMSO-06 400 MFIz δ = ppm 14.77 (br s, IH), 9.77 (s, IH), 8.49 (br s, IH), 8.44 (d, J = 7.2 Hz, IH), 7.78 (br s, IH), 7.31 (br s, IH), 6.99 (t, J = 9.6 Hz, IH), 6.72 (dd, J = 8.6, 3.7 Hz, IH), 5.01 - 4.91 (m, IH), 4.85 (brs, IH), 4.59 - 4.42 (m, 2H), 4.30 - 4.16 (m, IH), 4.08 (br s, IH), 3.83 (br s, IH), 2.38 (brs, 3H). LCMS (ESI+): m/z 420.2 (M+H).
Example 200:
Step 1: 5-bromo-6-methylpyridin-3-amine
405
To a solution of 3-bromo-2-methyl-5-nitropyridine (5.00 g, 23.0 mmol, 1.00 eq) and NH4CI (6.25 g, 117 mmol, 5.07 eq) in MeOH (100 mL) and H2O (100 mL) was added Fe (5.15 g, 92.2 mmol, 4.00 eq) at 25 °C, and the mixture was stirred at 90 °C for 2 h. LCMS showed that 3-bromo-2-methyl-5nitiOpyridine was consumed completely and the desired mass was detected. The mixture was fdtered, and the filtrate was concentrated under reduced pressure to remove MeOH and then extracted with EtOAc (50.0 mL * 3). The combined organic layers were dried over Na2SÛ4 and concentrated under reduced pressure to give 5-biOmo-6-methylpyridin-3-amine (3.91 g, crude) as a yellow solid.
Step 2: 5-bromo-6-methylpyridin-3-ol
To a mixture of 5-bromo-6-methylpyridin-3-amine (3.40 g, 18.2 mmol, 1.00 eq), trifluoiOborane hydrolluoride (21.6 g, 98.3 mmol, 15.3 mL, 40.0% purity, 5.41 eq) and H2O (15.0 mL) was added drop-wise a solution of NaNO2 (1.38 g, 20.0 mmol, 1.10 eq) in H2O (15.0 mL) at 0 °C. The mixture was stirred at 0 °C for 1 h. Water (15.0 mL) was added to the mixture which was then stirred at 100 °C for 12 h. The pH of the mixture was adjusted with NaHCO3 to 8. The precipitate was filtered off and dried under reduced pressure. 5-BiOmo-6-methylpyridin-3-ol (3.34 g, crude) was obtained as a brown solid.
Step 3: 6-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-3-ol
406
To a solution of 5-bromo-6-methylpyridin-3-ol (3.34 g, 17.8 mmol, 1.00 eq) in dioxane (100 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (6.77 g, 26.7 mmol, 1.50 eq), KOAc (3.49 g, 35.5 mmol, 2.00 eq) and Pd(dppf)C12 (1.30 g, 1.78 mmol, 0.100 eq) at 25 °C. The mixture was stirred at 100 °C for 12 h under nitrogen. The mixture was concentrated under reduced pressure to afford a crude product which was used in the next step directiy. 6-Methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaboiOlan-2-yl)pyridin-3-ol (4.20 g, crude) was obtained as brown solid.
Step 4: tert-butyl (S)-l2-flitoro-4-(5-hydroxy-2-mcthylpyridin-3-yl)-7a>13-dihydro-7H[1,2,4]triazolo[4 3 ’:1,6]pyrido[3,2-b]benzofuro[4,3-fg] [ 1,4] oxazonine-1 4(8Hfcarboxylate
The reaction was set up in 5 parallel batches. To a solution of 6-methyl-5-(4,4,5,S-tétraméthylia,2-dioxaborolan-2-yl)pyridin-3-ol (120 mg, 509 umol, 5.00 eq) in H2O (0.300 mL) and dioxane (2.00 mL) were added KOAc (20.0 mg, 204 umol, 2.00 eq), tert-butyl (S)-4-bromo-l2-fluoiO-7a,13dihydiO-7H-[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)carboxylate (50.0 mg, 102 umol, 1.00 eq) and 4-ditert-butylphosphanyl-N,N-dimethyl-aniline dichloropalladium (10.8 mg, 15.3 umol, 10.8 uL, 0.150 eq) at 25 °C, and the mixture was stirred at 90 °C under nitrogen for 12 h. The batches were combined. The obtained mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Ethyl acetate:Methanol — 10:1 ). tert-Butyl (S)-l2-fluoiO-4-(5-hydroxy-2-methylpyridin-3-yl)-7a,13-dihydro-7H[ 1,2,4]triazolo[4',3': 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4]oxazonine-14(8H)-carboxylate (200 mg, 385 umol, 76% yield) was obtained as a brown solid.
Step 5: (5)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4’,3':1,6]pyrido[3,2b]benzqfuro[4,3-fg] ] 1,4] oxazonin-4-yl)-6-methylpyrîdin-3-ol
407
A solution of tert-butyl (S)-12-fluoro-4-(5-hydroxy-2-methylpyridin-3-yl)-7a,13-dihydro-7H[ 1,2,4]triazolo[4’,3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4]oxazonine-14(8H)-carboxylate (200 mg, 385 umol, 1.00 eq) in HFIP (2.00 mL) was stirred at 100 °C for 2 h. The mixture was concentrated under reduced pressure. The residue was dissolved in MeCN (4.00 mL) and the mixture was purified by prep-HPLC (column: Phenomenex Luna Cl8 200*40 mm* 10 um; mobile phase: [water (0.2% FA)-ACN]; B%: l%-50%, 8 min). The product-containing fraction was concentrated under reduced pressure to remove most of MeCN at 30 °C and the aqueous phase was lyophilized. (S)-5(12-Fluoro-7a,8,13,14-tetrahydro-7H-[l,2,4]triazo!o[4',3': l,6]pyrido[3,2-b]benzofuro[4,3fg][l,4]oxazonin-4-yl)-6-methylpyridin-3-ol (65.0 mg, 140 umol, 36.3% yield, 100% purity, formate sait) was obtained as a yellow solid. IH NMR DMSO-d6 400 MHz δ = ppm 9.42 (s, IH), 8.15 (s, IH), 8.05 (d, J = 2.8 Hz, IH), 7.49 (br t, J = 6.4 Hz, IH), 7.30 (s, IH), 7.19 (d, J = 2.8 Hz, IH), 7.00 - 6.94 (m, IH), 6.70 (dd, J = 8.6, 3.9 Hz, IH), 4.97 - 4.87 (m, IH), 4.84 - 4.73 (m, IH), 4.54 (t, J = 9.5 Hz, IH), 4.47 (br d, J = 7.3 Hz, IH), 4.21 (dd, J = 9.7, 3.4 Hz, IH), 4.09 - 3.98 (m, IH), 3.91 - 3.80 (m, IH), 2.25 (s, 3H). LCMS (ESI+): m/z 420.2 (M+H).
Example 155: (S)-(3-(12-nuoro-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4,,3':l,6]pyrido[3,2b]benzofuro[4,3-fg] [1,4] oxazonin-4-yI)pyridin-2-yl)methanol
Step 1: 3-(tributylstannyl)picolinaldehyde
The reaction was set up in 2 parallel batches. To the solution of Ν,Ν',Ν'-trimethylethane-1,2diamine (572 mg, 5.60 mmol, 728 uL, 1.20 eq) in THF (10.0 mL) was added n-BuLi (2.50 M, 1.87 mL, 1.00 eq) at -20 °C under nitrogen, The resulting solution was stirred at -20 °C for 15 min folîowed by addition of pyridine-2-carbaldehyde (0.500 g, 4.67 mmol, 1.00 eq) was added at -20 °C. and the solution was stirred at -20 °C for 15 min. Another portion of n-BuLi (2.50 M, 2.80 mL, l .50
408 eq) was added at -20 °C, the resulting solution was stirred at -20 °C for 0.5 hr, and tributyl(chloro)stannane (4.56 g, 14.0 mmol, 3.77 mL, 3.00 eq) was added at -40 °C. The reaction mixture was stirred at -40 °C for 1 h. The reaction batches were combined, the obtained mixture was poured into cold (0 °C) HCl (1.00 M; 10.0 mL), and the mixture was extracted with EtOAc (20.0 mL * 3). The combined organic layers were washed with brine (10.0 mL), dried overNa2S04, and concentrated under vacuum. The crude product was purified by MPLC (PE:EtOAc = 1:0 to 10:1). 3-(Tributylstannyl)picolinaldehyde (2.20 g, 5.55 mmol, 59.5% yield) was obtained as a yellow oil which was used directly in the next step.
Step 2: tert-butyl (S)-l 2-fluoro-4-(2-formylpyridin-3-yl)-7a,l 3-dihydro-7H[1,2,4] triazolo[4 ', 3 91, 6]pyrido[3,2-b/ benzofuro[4,3 -fg] [1,4]oxazon in e-14(8H)-carboxylate
The reaction was set up in 9 parallel batches. To the solution of tert-butyl (S)-12-fluoro-4-(2(hydroxymethyl)pyridin-3-yl)-7a, 13-dihydro-7H-[ l,2,4]triazolo[4',3': 1,6]pyrido[3,2b]benzofuro[4,3-fg] [1,4] oxazonine-14(8 H)-carboxylate (100 mg, 204 umol, 1.00 eq) and crude 3(tributylstannyl)picolinaldehyde (242 mg, 611 umol, 3.00 eq) in dioxane (5.00 mL) was added Pd(tBu3P)2 (15.6 mg, 30.5 umol, 0.150 eq) and the resulting solution was stirred at 120 °C for 12 h under nitrogen. LCMS showed tert-butyl (S)-12-fluoro-4-(2-(hydroxymethyl)pyridin-3-yl)-7a,13dihydro-7H-[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)carboxylate was remained, and the desired ms was detected on LCMS. The parallel reactions were combined and the obtained mixture was concentrated under vacuum. The crude product was purified by prep-TLC (SiO2, EtOAc:MeOH = 10:1). Crude tert-Butyl (S)42-fhioro-4-(2formylpyridm-3-yl)-7a,13-dihydro-7H-[],2,4]triazolo[4',3,:l,6]pyrido[3,2-b]benzofuro[4,3fg][l,4]oxazonine-14(8H)-carboxylate was obtained as a brown oil which was used directly in the next step.
Step 3: tert-butyl (S)-12-fluoro-4-(2-(hydroxymethyl)pyridin-3-yl)-7a,13-dihydro-7H[1,2,4[triazolo [4',3 1,6]pyrido]3,2-b]benzofuro[4,3 -fg] [1,4] oxazonine-14(8H)-carboxylate
409
To the solution of tert-butyl (S)-l 2-fluoiO-4-(2-formylpyridin-3-yl)-7a, 13-dihydro-7H[ l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofÎiro[4,3-fg][i,4]oxazonine-14(8H)-carboxylate (110 mg, 213 umol, 1.00 eq) in MeOH (2.00 mL) was added NaBH4 (9.65 mg, 255 umol, 1.20 eq) at 10 °C, and the resulting solution was stirred at 10 °C for 0.5 h. The mixture solution was concentrated under vacuum to give tert-butyl (S)-I2-fluoro-4-(2-(hydroxymethyl)pyridin-3-yl)-7a,13-dihydro7H-[ 1,2,4]triazolo[4',3': 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4]oxazonine- 14(8H)-carboxylate (110 mg, crude) asa brown oil which was used dîrectly in the next step.
Step 4: (S)-(3-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4',31,6]pyrido[3,2b]benzofuro[4,3-fg] [1,4] oxazomn-4-yî)pyridin-2-yl)methanol
The solution of tert-butyl (S)-l2-fluoro-4-(2-(hydroxymethyl)pyridin-3-yl)-7a,13-dihydro-7H[l,2,4]triazolo[4',3': l,6]pyrido[3,2-b]benzofuiO[4,3-fg][l,4]oxazonine-l4(8H)-carboxylate (140 mg, 269 umol, 1.00 eq) in HCl/MeOH (3.00 mL; 4.00 M) was stirred at 10 °C for l h. The mixture was concentrated under vacuum to give a crude product which was purified by prep-HPLC (column: Phenomenex luna CI8 80*40 mm*3 um; mobile phase: [water (0.04% HC1)-ACN]; B%: 13%27%). QC indicated insufficient purity and the material was purified by prep-HPLC again (column: Phenomenex luna Cl 8 80*40 mm*3 um; mobile phase: [water (0.04% HC1)-ACN]; B%: I0%-25%) to obtain (S)-(3-( 12-fluoro-7a,8,13,14-tetrahydro-7H-[ 1,2,4]triazolo[4',3': 1,6]pyrido[3,2b]benzofuro[4,3-fg][l,4]oxazonin-4-yl)pyridin-2-yl)methanol (21.4 mg, 45.9 umol, 17% yield, 97.7% purity, HCl sait) as a yellow solid. IH NMR CD3OD 400 MHz 8 = ppm 9.58 (s, IH), 8.90 (d, J = 6.0 Hz, IH), 8.61 (d, J = 7.6 Hz, IH), 8.16 - 8.13 (m, IH), 8.08 (s, IH), 6.95 - 6.90 (m, IH), 6.68 (dd, J = 8.4, 3.6 Hz, IH), 5.23 - 5.19 (m, IH), 4.98 - 4.87 (m, IH), 4.87 (s, 2H), 4.77- 4.76 (m, IH),
410
4.62 (t, J = 9.6 Hz, IH), 4.33 - 4.29 (m, IH), 4.13 - 4.10 (m, IH), 3.95 - 3.92 (m, IH). LCMS (ESI+): m/z 420.1 (M+H).
Example 156: (S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[l,2,4Jtriazolo[4',3':l,6|pyrido|3,2b]benzofuro[4,3-fg][l,4] oxazonin-4-yI)-l-methyi-lH-pyrazol-3-ol
Step 1: 1 -methyl-1 H-pyrazol-4-ol
HO
To a solution of l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaboiOlan-2-yl)-lH-pyrazole (5.00 g, 24.0 mmol, 1.00 eq) in THF (120 mL) were added NaOH (3.00 M, 16.0 mL, 2.00 eq) and H2O2 (5.45 g, 48.1 mmol, 4.62 mL, 30% purity, 2.00 eq) at 0°C, and the mixture was stirred at 0°C for 3 h. To the 10 mixture was added HCl (12.0 M, 3.72 mL) and the mixture was extracted wirh a mixture of DCM and MeOH (9:1, 40.0 mL * 4). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. l-Methyl-lH-pyrazol-4-ol (5.10 g, crude) was obtained as a yellow oil.
Step 2: 4-(benzyloxy)-l-methyl-IH-pyrazole
BnO
To a solution of 1 -methyl-1 H-pyrazol-4-ol (2.00 g, 20.4 mmol, 1.00 eq) in DMF (20.0 mL) was added NaH (815 mg, 20.4 mmol, 60% purity, 1.00 eq) at 0°C, the mixture was stirred at 25°C for 30 mins. BnBr (5.23 g, 30.6 mmol, 3.63 mL, 1.50 eq) was added to the mixture at 25°C and the mixture was stirred at 25°C for 2 h. Water (20.0 mL) was added, the mixture was extracted with 20 EtOAc (30.0 mL * 3), the combined organic layers were dried overNa2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (SÎO2, Petroleum ether/Ethyl acetate = 1/0 to 0/1). 4-(Benzyloxy)-1 -methyl-IH-pyrazole (800 mg, 4.25 mmol, 21% yield) was obtained as a yellow oil.
Step 3: (4-(benzyloxy)-l-methyl-IH-pyrazol-5-yl)boi-omc acid
411
To the solution of 4-(benzyloxy)-l-methyl-1 H-pyrazole (750 mg, 3.98 mmol, 1.00 eq) in THF (10.0 mL) was added n-BuLi (2.50 M, 1.59 mL, 1.00 eq) drop-wise at -78 °C under nitrogen. The reaction mixture was stirred at -78 °C for 1 hr. Tri-isopropyl borate (749 mg, 3.98 mmol, 916 uL, 1.00 eq) was added at -78 °C, and the resulting solution was stirred at -78 °C under nitrogen for 1 hr, and then at 15 °C for 12 h. LCMS indicated incomplète conversion. To the mixture was added n-BuLi (2.50 M, 1.59 mL, 1.00 eq) drop-wise at -78 °C under nitrogen, and the resulting solution was stirred at -78 °C under N2 for 1 hr followed by addition of tri-isopropyl borate (749 mg, 3.98 mmol, 91.0 uL, 1.00 eq) at -78 °C. The reaction mixture was stirred at -78 °C under nitrogen for 1 hr, then at 15 °C for 12 h. LCMS showed showed that the conversion was complété. MeOH (5.00 mL) was added. The mixture was concentrated under reduced pressure to give (4-(benzyloxy)-l-methyl-1Hpyrazol-5-yl)boronîc acid (1.24 g, crade) as a white solid, which was used to the next step directly.
Step 4: tert-butyl (S)-4-(3-(benzyloxy)-l-metlryl-lH-pyrazol-5-yl)-12-fluoro-7a, 13-dihydro-7H[l, 2,4] triazolo[4', 3 1,6]pyrido[3,2-b] benzofùro]4,3-fg] [l, 4] oxazonine-14(8H)-carboxylate
Two parallel reactions were set up. To a solution of (4-(benzyloxy)-l-methyl-ÎH-pyrazol-5yl)boronic acid (354 mg, 1.53 mmol, 5.00 eq) in dioxane (5.00 mL) and H2O (1.00 mL) were added tert-butyl (S)-4-bromo-12-fluoiO-7a,13-dihydro-7H-[l,2,4]triazolo[4',3,:l,6]pyrido[3,2b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (150 mg, 305 umol, 1.00 eq), 4-ditertbutylphosphanyl-N,N-dimethyLaniline dîchloropalladium (32.4 mg, 45.8 umol, 32.4 uL, 0.150 eq) and KOAc (59.9 mg, 611 umol, 2.00 eq) at 25 °C, and the reaction mixture was stirred at 90 °C under N2 for 12 h. The batches were combined. The mixture was concentrated under reduced pressure and the residue was purified by prep-TLC (SiO2, Ethyl acetate :Methanol = 20:1). tertButyl (S)-4-(3-(benzyloxy)-l-methyl-lH-pyrazol-5-yl)-12-fluoro-7a,13-dihydro-7H
412
[ 1,2,4]triazolo[4’,3’:l,6]pyrido[3,2-b]benzofuiO[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (280 mg, crude) was obtained as a yellow solid.
Step 5: tert-butyl (S)-l 2-fluoro-4-(3-hydroxy-l -methyl-1 H-pyrazol-5-yl)-7a,13-dihydro-7H[ 1,2,4] triazolo[4', 3 1,6]pyrido[3,2-b]benzofuro[4,3-fg] [1,4] oxazonine-14(8H)-carboxylate
To a solution of tert-butyl (S)-4-(3-(benzyloxy)-l -methyl-lH-pyrazol-5-yl)-12-fluoro-7a, 13dihydro-7H-[ 1,2,4]triazolo[4',3': 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ l,4]oxazonine- 14(8H)carboxylate (280 mg, 468 umol, 1.00 eq) in MeOH (3.00 mL) was added 10% Pd/C (300 mg, 50% purity) under N? atmosphère at 25 °C. The suspension was degassed and purged with hydrogen 3 times. The mixture was stirred under hydrogen (15 Psi) at 40 °C for 1 h. The mixture fïltered and the filtrate was concentrated under reduced pressure to give tert-butyl (S)-12-nuoro-4-(3-hydroxy-lmethyl-lH-pyrazol-5-yl)-7a,13-dihydro-7H-[l ,2,4]triazolo[4',3’: I,6]pyrido[3,2-b]benzofuro[4,3fg][l,4]oxazonine-14(8H)-carboxylate (220 mg, crude) as a yellow solid which was used to the next step directly.
Step 6: (5)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4fb 1,6]pyrido[3,2b] benzofurof4,3-fg] [1,4] oxazonin-4-yl)-l-methyl-lH-pyrazol-3-ol
A solution of tert-butyl (S)-12-fluoro-4-(3-hydroxy-l-methyl-lH-pyrazol-5-yl)-7a,13-dihydro-7H[ l,2,4]triazolo[4',3’: 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4]oxazonine-14(8H)-carboxylate (220 mg, 432 umol, 1.00 eq) in DCM (1.00 mL) and TFA (1.00 mL) was stirred at 25 °C for 1.5 h. The mixture was concentrated under reduced pressure. The residue was dissolved in MeCN (4.00 mL) and the mixture was purified by prep-HPLC (column: Phenomenex Luna C18 200*40 mm* 10 um;
413 mobile phase: [water (0.2% FA)-ACN]; B%: 10%-50%, 8 min). The product-containing fraction was concentrated under reduced pressure to remove most of MeCN at 30 °C and the aqueous phase was lyophilized. (S)-5-( 12-Fluoro-7a,8,13,14-tetrahydro-7H-[ l ,2,4]triazolo[4',3': 1,6]pyrido[3,2b]benzofuro[4,3-fg][l,4]oxazonin-4-yl)-l-methyl-1 H-pyrazol-3-oI (50.0 mg, 110 umol, 25.4% yield, 100% purity, formate) was obtained as a white solid. IH NMR CD3OD 400 MFIz δ = ppm 9.31 (s, IH), 7.45 (s, IH), 7.18 (s, IH), 6.87 (t, J = 9.6 Hz, IH), 6.63 (dd, J = 8.6, 3.7 Hz, IH), 5.07 (d, J = 14.8 Hz, IH), 4.84 (d, J = 14.8 Hz, IH), 4.62 - 4.53 (m, 2H), 4.27 (dd, J = 9.7, 3.1 Hz, IH), 4.05 3.95 (m, IH), 3.92- 3.84 (m, 1H),3.71 (s, 3H). LCMS (ESÏ+): m/z 409.1 (M+H).
Example 157: (S)-l-(4-(12-fluoro-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4Joxazonin-4-yl)-3,6-dihydropyridinl(2H)-yl)ethan-l-one
Step l: 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l ,2,3,6-tetrahydropyridine
To a solution of tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridinel(2H)-carboxylate (1.00 g, 3.23 mmol, 1.00 eq) in EtOAc (5.00 mL) was added HCl/EtOAc (4.00 M, 10.0 mL, 12.4 eq) at 0 °C, the mixture was stirred at 25 °C for 2 h. The reaction was concentrated to afford 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (820 mg, crude, HCl sait) as a white solid.
Step 2: 1-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridin-l(2H)-yl)ethan-l-one
To a solution of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (820 mg, 3.34 mmol, 1.00 eq, HCl) in DCM (12.0 mL) was added DIPEA (1.73 g, 13.4 mmol, 2.33 mL, 4.00 eq) and acetyl chloride (393 mg, 5.01 mmol, 357 uL, 1.50 eq) at 0 °C, and the mixture was stirred at 20 °C for 12 h. The reaction was concentrated. The residue was diluted with H3O (100 mL) and extracted with EtOAc (50.0 mL * 3). The combined organic layers were washed with brine (10.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. 1-(4-(4,4,5,5
414 tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridin-l(2H)-yl)ethan-l-one (850 mg, crude) was obtained as a brown solid.
Step 3; (S)-1-(4-(12-fhioro-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[43’:1,6]pyrido[3,2b]benzofuro[4,3-fg] [1.4]oxazonin-4-yl)-3,6-dihydropyridin-l (2H)-yl)ethan-l -one
To a solution of (S)-4-bromo-12-fluoro-7a,8,I3,I4-tetrahydro-7H[l,2,4]triazolo[4’,3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonme (100 mg, 256 umol, 1.00 eq) in dioxane (2.00 mL) and H2O (0.200 mL) were added l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan2-yl)-3,6-dihydropyridin-i(2H)-yl)ethan-l-one (128 mg, 511 umol, 2.00 eq), Na2CO3 (54.2 mg, 511 umol, 2.00 eq) and Pd(dppf)Cl2 (18.7 mg, 25.6 umol, 0.100 eq) at 20 °C under N2, and the mixture was stirred at 80 °C for 2 h under N2 atmosphère. The reaction was filtered and the filtrate concentrated. The residue was dissolved in MeOH (3.00 mL) and silîca-thiol ( 300 mg, modified Silicon gel for eliminating Pd, irregular silica gel, 100-200 mesh, Chlorides (Cl), %<0.004, particle size distribution 45-75 um) was added at 20 °C and stirred at 20 °C for 12 h. The suspension was filtered and the filtrate was concentrated and purified by acidic prep-HPLC (column: Phenomenex Luna C18 200*40 mm*10 um; mobile phase: [water (0.2% FA)-ACN]; B%: 20%-60%, 8 min). The product-containing fraction was concentrated under reduced pressure to remove most of MeCN at 30 °C and the aqueous phase was lyophilized. (S)-l-(4-(12-Fluoro-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3’:L6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonin-4-yl)-3,6-dihydropyridinl(2H)-yl)ethan-l-one (66.4 mg, 138 umol, 54% yield, 100% purity, formate) was obtained as a yellow solid. IH NMR DMSO-d6 400 MHz δ = ppm 9.29 (s, IH), 7.29 (br s, IH), 7.21 - 7.10 (m, 2H), 6.91 - 6.84 (m, IH), 6.62 (dd, J = 8.8, 3.9 Hz, IH), 4.91 - 4.81 (m, IH), 4.79 - 4.70 (m, IH), 4.50 (t, J = 9.2 Hz, IH), 4.43 (dd, J = 10.5, 4.4 Hz, IH), 4.23 - 4.09 (m, 3H), 3.97 (br d, J = 8.8 Hz, IH), 3.89 - 3.80 (m, IH), 3.63 (br s, 2H), 2.63 (br s, 2H), 2.02 (s, 3H). LCMS (ESI+): m/z 436.2 (M+H).
Ëxample 158: (S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[l,2,4Jtriazolo[4',3’:l,6]pyridol3,2 b]benzofuro[4,3-fg][l,4]oxazonin-4-yl)-l-methyl-lH-pyrazol-4-ol
Step 1: 1 -methyl-3-((triisopropylsilyl)oxy)-l H-pyrazole
415
Το l-methyl-lH-pyrazol-3-ol (500 mg, 5.10 mmol, 1.00 eq) and imidazole (694 mg, 10.2 mmol, 2.00 eq) in DCM (10.0 mL) was added triisopropylsilyl trifluoromethanesulfonate (2.34 g, 7.65 mmol, 2.05 mL, 1.50 eq) at 0°C. The mixture was stirred at 10 °C for 4 h under N2. The mixture was concentrated under reduce pressure to remove most of DCM and H2O (3.00 mL) was added. The mixture was extracted with ethyl acetate (10.0 mL * 3). The combined organic layers were dried with anhydrous Na2SO4, filtered, and concentrated under reduce pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 1/0 to 2/1). l-Methyl-3((triisopropylsilyl)oxy)-lH-pyrazole (L 10 g, 4.32 mmol, 85% yield) was obtained as a colorless oil.
Step 2: l-methyl-5-(tribiitylstannyl)-l H-pyrazol-3-ol
To l-methyL3-((triisopiOpylsilyï)oxy)-lH-pyrazole (900 mg, 3.54 mmol, 1.00 eq) in THF (3.00 mL) was added t-BuLi (1.30 M, 8.16 mL, 3.00 eq) at -78 °C under N2. The mixture was stirred at 78 °C for 0.5 hr under N2. Then tributyl(chloro)stannane (3.45 g, 10.6 mmol, 2.85 mL, 3.00 eq) was added into the mixture which was then stirred at -78 °C for 1 hr under N2. MeOH (5.00 mL) was added to the mixture and it was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 1/0 to 0/1). l-Methyl-5(tributylstannyl)-lH-pyrazol-3-ol (600 mg, 1.55 mmol, 43.8% yield) was obtained as a colorless oil.
Step 3: l-methyl-5-(tributylstannyl)-3-((triisopropylsilyl)oxy)-1 H-pyrazole
416
To l-methyI-5-(tributylstannyl)-lH-pyrazol-3-ol (600 mg, 1.55 mmol, 1.00 eq) and imidazole (211 mg, 3.10 mmol, 2.00 eq) in DCM (10.0 mL) was added triisopropylsilyl trifluoromethanesulfonate (712 mg, 2.32 mmol, 625 uL, 1.50 eq) at 0 °C. The mixture was stirred at 10 °C for 12 h under N2. LC-MS showed minimal conversion. Additional triisopropylsilyl trifluoromethanesulfonate (712 mg, 2.32 mmol, 625 uL, l .50 eq) was added to the mixture under N2, and it was stirred at 10 °C for 12 h. TLC (SiO2, petroleum ether: ethyl acetate = 1:1) indicated complété conversion. The mixture was concentrated under reduce pressure to remove most of DCM, H2O (10,0 mL) was added înto the mixture which was then extracted with ehyl acetate (10.0 mL * 3). The combined organic layers were dried wtih anhydrous Na2SO4, filtered, concentrated under reduce pressure. 1Methyl-5-(tributylstannyI)-3-((triisopiOpylsilyl)oxy)-IH-pyrazole (300 mg, crude) was obtained as colorless oil.
Step 4: tert-butyl (S)-l 2-fluoro-4-( 1 -methyl-4-((triisopropylsilyl)oxy)-1 H-pyrazol-5-yl)-7a, 13dihydro-7H-[1,2.4]triazolo[4',3’: 1,6]pyrido]3,2-b] benzofuro]4,3-fg] [ 1,4] oxazonine-14(8H)carboxylate
The reaction was set up in two parallel batches. To tert-butyl (S)-4-bromo-12-fluoro-7a,13-dihydro7H-[l,2,4]triazolo[4',3’: l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxyiate (40.0 mg, 81.4 umol, 1.00 eq) and l-methyl-5-(tributylstannyl)-3-((triisopropylsilyl)oxy)- IH-pyrazole (66.4 mg, 122 umol, 1.50 eq) in dioxane (1.00 mL) were added Pd(PPh3)4 (9.41 mg, 8.14 umol, 0.100 eq), LiCl (6.90 mg, 163 umol, 3.33 uL, 2.00 eq) and Cul (6.20 mg, 32.6 umol, 0.400 eq) at 10 °C. The mixture was stirred at 100 °C for 12 h under N2. The batches were combined. The obtained mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Petroleum ether/Ethyl acetate = 1/3). tert-Butyl (S)-12-fluoro-4( l-methyl-4-((triisopropylsilyl)oxy)-lH-pyrazol-5-yl)-7a, 13-dihydro-7H[ 1,2,4] triazolo[4',3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (90.0 mg, 135 umol, 83% yield) was obtained as a yellow oil.
Step 5 : (5)-5-(12-fluoro-7a,8,13,l 4-tetrahydro- 7H-]1,2,4] triazolo]4)381,6]pyrido]3,2b] benzofuro]4,3-fg] ]1,4]oxazonin-4-yl)-l-methyl-lH-pyrazol-4-ol
417
To tert-butyl (S)-l 2-lluoro-4-(l -methyl-4-((triisopropylsilyl)oxy)-1 H-pyrazoI-5-yl)-7a, 13-dihydro7H-[i,2,4]triazolo[4',3,:l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine-14(8H)-carboxylate (155 mg, 233 umol, 1.00 eq) in DCM (3.00 mL) was added TFA (1.54 g, 13.5 mmol, 1.00 mL, 57.9 eq) at 10 °C. The mixture was stirred at 10 °C for 2 h. The mixture was concentrated under reduce pressure to give a residue. The crude product was purified by prep-HPLC (HCl conditions). (S)-5(12-Fluoro-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4’,3': l,6]pyrido[3,2-b]benzofuro[4,3fg][l,4]oxazonin-4-yl)-l-methyl-IH-pyrazol-4-ol (40.3 mg, 90.2 umol, 39% yield, 99.6% purity, HCl sait) was obtained as a yellow solid. IH NMR CD3OD 400 MHz δ = ppm 9.51 (s, IH), 8.02 (s, IH), 6.92 (dd, J = 10.1, 8.8 Hz, 1 H), 6.68 (dd, J = 8.7, 3.9 Hz, IH), 5.90 (s, IH), 5.20 (d, J = 14.8 Hz, IH), 4.95 (brd, J = 14.8 Hz, IH), 4.76 (br dd, J = 9.6, 3.9 Hz, IH), 4.62 (t, J = 9.4 Hz, 1H),4.31 (dd, J = 9.8, 3.4 Hz, IH), 4.11 - 4.00 (m, IH), 3.97 - 3.85 (m, IH), 3.61 (s, 3H) LCMS (ESI+): m/z 409.1 (M+H)
Example 159: Histone methyltransferase assay
Effect of compounds of the présent disclosure on EZH2/PRC2 complex methyltransferase functional activity was measured using the radioisotope-based HotSpot assay described by Horiuchi, K.Y., et al. Assay Dnig Dev TechnoL 11(4):227-36 (2013). Briefly, compounds were prepared in a 10-point 3-fold serial dilution in DMSO from a 10 mM stock in ECHO qualified plate using Assist Plus (Integra Biosciences) liquîd handler. Four microiiters of EZH2/PRC2 complex (12.5 nM) and core histone substrate (0.0625 mg/mL) mix in assay buffer (50 mM Tris-HCl (pH 8.0), 0.01% Brij35, 1 mM EDTA, 1 mM DTT, 1% DMSO) were transferred into a 384-well assay plate by hand.
Nanoliter quantities of each compound’s concentration sériés were transferred into the enzyme/substrate mix using (Echo 550, LabCyte Inc. Sunnyvale, CA) acoustic dispenser and preincubated for 20 min at room température. The méthylation reaction was initiated by the addition of 1 μΐ of 5 μΜ S-AdenosyLL-[methyl-3H] méthionine (ÎH-SAM) and incubated at 30°C for 1 h. The final concentration of the EZH2/PRC2 complex, core histone substrate and 3H-SAM were 10 nM, 0.05 mg/ml. and 1 μΜ respectively, The % activity of test samples were calculated with reference to positive (no compound) and négative (no EZH2/PRC2) Controls on the plate using Excel
418 (Microsoft). The resulting values were exporter! to Prism (GraphPad software) to generate concentration response curves and IC50 values usîng the four-parameter logistic équation.
Exampie 160: EED binding SPR assay
Biotinylated EED Protein Production
Biotinylated AVI-tagged EED was produced using standard molecular biology techniques. A pGEX plasmid with a GST-preScissîon-cleavage-site-AVI-EED(76-441) sequence was placed into E. coli BL21(DE3) cells and co-expressed with pGro7. The E. coli were grown in shaker flasks in LB with ampicillin at 37° C at 110 rpm to an OD6oq = 0.7. At this time the température was lowered to 15° C and IPTG was added to 0.3 mM. The cells were allowed to express ovemight. Cells were then harvested.
For purification, the E. coli cell pellet was lysed into a buffer of 50 mM Tris pH 8.0, 500 mM NaCl, 5% glycerol and 5 mM DTT. The lysate was loaded onto a GSTrap FF column from GE Healthcare. After washing, the bound protein was eiuted with 50 mM Tris pH 8.0, 500 mM NaCl, 5% glycerol, 5 mM DTT and 15 mM GSH. The collected fractions were combined and incubated with PreScission enzyme ovemight at 4° C. The cleaved protein was then passed through a GSTrap FF column in a buffer of 50 mM Tris pH 8.0, 500 mM NaCl, 5% glycerol and 5 mM DTT. The cleaved protein was confinned through mass spectrometry. The AVI-EED(76-441) was then buffer exchanged into 50 mM Bicine pH 8.3, 10 mM ATP, 10 mM magnésium acetate and 50 pM DBiotin. 3 mg of BirA enzyme was added to the System and incubated at 4° C for 2 hours to biotinylate the AVI-EED(76-441). The biotinylated-AVI-EED(76-441) was then buffer exchanged into 20 mM Tris pH 8.0 and 400 mM NaCl and passed through a size exclusion column of Superdex 200 16/60 Increase. The purified monomeric biotinylated-AVI-EED(76-441) was confinned through S DS-PAGE, LC-MS and analytical size exclusion chromatography.
Surface Plasmon Résonance Assay
Ail surface plasmon résonance (SPR) assays were perfonned using a GE Biacore S200 utilizing GE Biotîn CAPture chips. Capturing of CAP reagents was perfonned with a flow rate of 2 pL/min for 90 seconds. For protein capturing, a solution of 50 pg/mL of biotinylated AVI-tagged EED (76441) in 10 mM HEPES pH 7.4, 150 mM NaCl, 0.05% Tween 20 and 2% DMSO (Running Buffer) was flowed over the chip with a flow rate of 5 pL/min for a contact time of 30 seconds. Final readings were 2200-2400 RU. For compounds, 7 concentrations were made with 3-diIutions using the Running Buffer for a total of 300 pL of each concentration in a 96-well microplate. During the binding experiments, a flow rate of 50 pL was used for an association time of 90 seconds followed 419 by a disassociation time of 180 seconds. The compartment température was set at 10° C with the chip at 25 °C. During régénération the flow rate was set to 30 pL/min for 30 seconds. Ail fittings were done using a 1:1 binding mode!.
Example 161: H3K27me3 and HbF immunocytochemistry Assay and Hemoglobin ELISA assay
Génération of a P-gp expressing HEK293T cell line
A plasmid encoding the human ABCB1 gene under the control of a CMV promoter was purchased from Origene (Cat# RC216080). The HEK293T cells were purchased from ATCC (Cat# CRL-3216) and were cultured for expansion in the recommended conditions. The HEK293T cells were transfected with 2 ug of the pCMV-ABCBl plasmid using Lipofectamine 3000 following recommendations from the manufacturer (ThermoFisher Scientific, Cat# L30Û0008). After 24h, cells were dissociated, and 5000 cells were seeded on a 10 cm tissue culture dish. On the next day, fresh media containing 5 nM Vinblastine (Sigma, Cat#V1377) was added, and media containing compound was replenished every 72h. After surviving cells reached confluency, cells were passaged, and Unes were maintained in the presence of 2.5 nM Vinblastine until further characterization.
Tissue culture
P-gp expressing HEK293T, HUDEP2, and Human Mobilized Peripheral Blood Primary CD34+ cells were cultured for use in an H3K27me3 immunocytochemistry assay. HUDEP2 and Human Mobilized Peripheral Blood Primary CD34+ cells were cultured for use in an HbF immunocytochemistry assay. P-gp expressing HEK293T cells were maintained and passaged every 3-4 days by plating 300,000 viable cells in a T-25 culture flask containing 6 mLs of 293 Passaging Media comprised of DMEM (ThermoFisher #10566016), 10% fêtai bovine sérum (ThermoFisher #A3160502), 1% penicillin-streptomycin (ThermoFisher #15140122), and 2.5 nM Vinblastine (Sigma #V1377). To evaluate the inhibitory effect of the compounds of the présent disclosure and their brain pénétrant properties via P-gp mediated efflux, the H3K27me3 immunocytochemistry assay was conducted in the presence or absence of 250 nM of the P-gp inhibitor, elacridar. Poor brain pénétrant compounds were expected to show higher potencies in the presence of Elacridar. However, brain pénétrant compounds would show similar potencies irrespective of whether Elacridar is présent or not. In these experiments plates without elacridar were seeded with P-gp expressing HEK293T cells at 1000 viable cells per well in a poly-d-lysîne coated 384-well plate (Corning Cat# 356697) in 45 μΕ of 293 Assay Media comprised of DMEM (ThermoFisher
420 #10566016), 10% fêtai bovine sérum (ThermoFisher #A3160502), 1% penicillin-streptomycin (ThermoFisher #15140122). A replicate set of plates were seeded under the same conditions with 45 pL of 293 Assay Media supplemented with 250 nM of Elacridar to inhibit P-gp activity. Compounds were serially diluted at 10X concentration in 293 Media, and 5 pL transferred to their respective wells on both sets of plates for a total volume of 50 pL per well. The compound treated HEK293T cells were allowed to incubate for 4 days at 37°C, 85% relative humidîty, and 5% CO2 before proceeding to ICC Fix and Stain protocol.
HUDEP2 cells were maintained and passaged every 2-3 days by seeding 300,000 viable cells/mL in a culture flask containing HUDEP2 Growth Media comprised of StemSpan SFEM (Stemcell Technologies #09650), 50 ng/mL human stem cell factor (Stemcell Technologies #78062.2), 3 lU/mL erythropoietin (ThermoFisher #PHC2054), 1 pM dexamethasone (Sigma #D2915), and 1 pg/mL doxycycline (Sigma #D3072). HUDEP2 cells were différent!ated towards erythroid lineage by seeding at 25,000 viable cells/well in 96-well V-Bottom plates (Corning #3894) containing 135 pL FIUDEP2 Différentiation Media comprised of Iscove's Modified Dulbecco's Medium (Stemcell Technologies #36150), 1% L-glutamine (ThermoFisher #25030081), 2% penicillin-streptomycin (ThermoFisher #15140122), 330 pg/mL holo-human transfemn (Sigma #T0665), 2 lU/mL heparin (Stemcell Technologies #07980), 10 pg/mL recombinant human insulin (Sigma #91077C), 3 lU/mL erythropoietin (ThermoFisher #PHC2054), 100 ng/mL human stem cell factor (Stemcell Technologies #78062.2), and 4% fêtai bovine sérum (ThermoFisher #A3160502). Chemical probes for treatment were resuspended in 100 pL of Iscove's Modified Dulbecco's Medium (Stemcell Technologies #36150) to a lOx concentration, and 15 pL of 10X concentrated Chemical probes were added to each well for a total well volume of 150 pL. HUDEP2 cells were left to incubate at 37□, 85% relative humidity, and 5% CO2 for 3 days. On Day 3, assay plates containing HUDEP2 cells were centrifuged at 500xg for 5 minutes. After centrifugation cells were pelleted to the bottom of the well, and 100 pL of media aspirated from the well without disturbing the cells. Then 90 pL of fresh HUDEP2 Différentiation Media and 10 pL of lOx concentrated Chemical probes were added back each well. For the H3K27me3 assay, cells were harvested on Day 4 of treatment. The HUDEP2 cells were centrifuged at 500xg for 5 minutes and ail media was aspirated from the well. Then 150 pL of phosphate buffered saline (ThermoFisher #10010023) was added to each well to resuspend the cells. Finally, 50 pL of the HUDEP2 cell suspension from each well was transferred to a poly-d-lysîne coated 3 84-well plate (Corning Cat# 356697) and centrifuged at lOOOxg for 5 minutes before proceeding to ICC Fix and Stain Protocol. Assay plates for the HbF assay were retumed to the incubator until Day 5, where the media was exchanged and Chemical probes added 421 exactly as on Day 3. On Day 7 of the HbF assay, the HUDEP2 cells were harvested in the saine manner as described for the H3K27me3 assay before proceeding to ICC Fix and Stain Protocol. Human Mobilized Peripheral Blood Primary CD34+ cells were expanded from thaw by seeding 100,000 viable cells/mL in a culture flask contaîning CD34+ Expansion Media comprised of StemSpan SFEMII (Stemcell Technologies #09655), 1% erythroid expansion supplément (Stemcell Technologies #02692), and 1 μΜ dexamethasone (Sigma #D2915). The cells were supplemented by adding an additional IX culture volume of CD34+ Expansion Media on Day 3 after thaw. After 7 days of expansion, Primary CD34+ cells were differentiated towards erythroid lineage by seeding at 15,000 viable cells/well in 96-welI V-Bottom plates (Corning #3894) containmg 135 pL CD34+ Différentiation Media comprised of StemSpan SFEMII (Stemcell Technologies #09655), 3% normal human sérum (Sigma #H4522), 3 ILJ/mL erythropoietin (ThermFisher #PHC2054). Chemical probes for treatment were resuspended in 100 pL of Iscove's Modified Dulbecco's Medium (Stemcell Technologies #36150) to a 1 Ox concentration, and 15 pL of 10X concentrated Chemical probe was added to each well for a total well volume of 150 pE. Primary CD34+ cells were left to incubate at 37°C, 85% relative humidity, and 5% CO2 for 3 days. On Day 3, assay plates contaîning Primary CD34+ cells were centrifuged at 500xg for 5 minutes. After centrifugation cells were pelleted to tire bottom of the well, and 100 pL of media aspirated from the well without disturbing the cells. Then 90 pL of fresh CD34+ Différentiation Media and 10 pL of lOx concentrated Chemical probes were added back each well. For the H3K27me3 assay, cells were harvested on Day 4 of treatment. The Primary CD 34+ cells were centrifuged at 500xg for 5 minutes and ail media was aspirated from the well. Then 150 pL of phosphate buffered saline (ThennoFisher #10010023) was added to each well to resuspend the cells. Finally, 50 pL of the Primary CD34+ cell suspension from each well was transferred to a poly-d-lysine coated 384-well plate (Corning Cat# 356697) and centrifuged at lOOOxg for 5 minutes before proceeding to ICC Fix and Stain Protocol. Assay plates for the HbF assay were retumed to the incubator until Day 5, where the media was exchanged and Chemical probes added exactly as on Day 3. On Day 7 of the HbF assay, the Primary CD34+ cells were harversted in the saine manner as described for the H3K27me3 assay before proceeding to ICC Fix and Stain Protocol.
The Fix and Stain Protocol was the saine for HEK293T, HUDEP2, and Primary CD34+ cell assays except the spécifie primary and secondary antibodies used for détection. Followîng 4 days of compound treatment, the respective plates were washed once with 25 pL of PBS (ThennoFisher #10010023) and fîxed with 25 pL of 4% parafonnaldehyde (ThennoFisher #28908) for 10 minutes at room température. The plates were then washed three times with 25 pL of PBS. Subséquent to 422 that, the cells were penneabilized and blocked for 1 hour at room température in 25 pL of Perm/Block buffer comprised of IX PBS, 1% bovine sérum albumin (ThermoFisher #A3294), 10% fêtai bovine sérum (ThermoFisher #A3160502), 0.3M glycine (Sigma #G7126), and 0.1% tween-20 (Sigma #P7949)., This was followed by additional washing (three times) of the plates with 25 pL of 0.1% tween in PBS.
For the H3K27me3 assay, the cells were incubated ovemight at 4°C with 25 pL of H3K27me3 Primary Antibody (Cell Signaling #9733) diluted 1 ;200 in 0.1% tween-20 in PBS. On the next day, the cells were washed again three times with 25 pL of 0.1% tween-20 in PBS and incubated at room température in the dark for 1 hour with 25 pL Secondary Antibody Solution comprised of Donkey Anti-Rabbit 488 (ThermoFisher #A21206) and Hoechst (ThermoFisher #H3570) diluted 1:2000 in 0.1% tween in PBS. Final ly, the cells were washed three times with 25 pL of PBS and sealed with a foil (BîoRad #MSBI001) for imagîng on the ThermoFisher Celllnsight CX7.
Plates for the HbF assay were treated similarly as described above except that HbF Primary Antibody (ThermoFisher #MHFH01-4) diluted 1:40 in 0.1% tween-20 in PBS and Hoescht (ThermoFisher #H3570) diluted 1:2000 in 0.1% tween-20 in PBS were used for détection.
H3K27me3 andHbF immunocytochemistiy assay
The plates were then scaimed on the CX7 at lOx magnification, and 9 images were acquired per well. The software algorithm then identified nuclei and calculated a total nuclei count using the Hoechst staining on channel 1. After nuclei were identified, the algorithm calculated the average nuclear intensity of the H3K27me3 or HbF staining on channel 2. Data for total nuclei count was reported as a percentage of négative control (%DMSO). Data for average nuclear intensity of H3K27me3 or HbF was reported as a Controls normalized percent inhibition ((opos-Samplei/aposüNeg)* 100). A threshold for HbF positîvity was set and HbF data was also reported at %HbF+ out of total number of cells.
Hemoglobin ELIS A assay
HUDEP2 cells were cultured as described above. Briefly, 100,000 cells were grown in différentiation media and treated with compound for 7 days with media and compound changed on Day 3 and Day 5. Cells were pelleted by centrifugation (900 x g for 5 minutes), resuspended in lOOuL of lysis buffer (50mM Tris buffered saline, pH8.0; 0.05% Tween 20 (Sigma Chemical #T9039) to generate cell lysâtes and frozen at -80C. The cell lysâtes were analyzed for protein content per well using bicinchoninic acid (BCA) assay (Pierce BCA kit #23225), total hemoglobin content per well using enzyme-lînked immunosorbent (ELISA) assays (Bethyl Laboratories #E80423
134) and fêtai hemoglobin (HbF) content per well using ELISA assays (Bethyl Laboratories #E80136).
BCA assays were run to calculate the total protein content and détermine the amount of lysate to load onto the total hemoglobin and HbF assays. In general, lOOuL of BCA buffer was added to a well of a clear 96-well plate. 2uL of cell lysate was loaded to the well. Sample was incubated at 37 degrees Celsius for 30 minutes and analyzed on an Envisîon plate reader (PerkinElmer). Protein content was calculated using bovine sérum albumin as a standard.
Total hemoglobin and HbF ELISA assays were perfonned following the protocol recommended by the manufacturer. In general, each sample was analyzed for total hemoglobin and HbF content. 1 μΐ of affmity purified antibody (Total hemoglobin: A80-134A, HbF: A80-136A) to 100 pl Coating Buffer (0.05M carbonate-bicarbonate in water) for each well to be coated (example: for 100 wells dilute 100 μΐ to 10 ml) m the ELISA plates. Plates were incubated at room température for 60 minutes. The well was then washed 5 times with lOOuL of wash buffer (50mM Tris buffered saline, pH8.0; 0.05% Tween 20). 200uL of blocking buffer (50mM Tris buffered saline, pH8.0; 1% bovine sérum albumin) was added to each well and incubated for 1 hour at room température. The well was then washed 5 times with lOOuL of wash buffer. Cell lysâtes were diluted in 50mM Tris buffered saline, pH8.0; 0.05% Tween 20; 1% bovine sérum albumin and the appropriate amount of material was added to be within the linear range of the total hemoglobin or HbF standard curve (Total hemoglobin calibrator: Bethyl RC8O-135-5; Fêtai hemoglobin calibrator; Bethyl RC80-135-5).
Samples were incubated at room température for 1 hour with shaking (300 rpm). The well was then washed 5 times with lOOuL of wash buffer. Détection antibody (Total hemoglobin: A80-134P and HbF: A80-136P) was diluted 1:100,000 in 50mM Tris buffered saline, pH8.0; 0.05% Tween 20; 1% bovine sérum albumin and lOOuL was added per corresponding well. Samples were incubated for 1 hour at room température with shaking (300 rpm). The well was then washed 5 times with lOOuL of wash buffer. 1 OOuL of TMB One Component HRP reagent was added to the well and incubated for 15 minutes in the dark at room température. 1 OOuL of stop solution (Bethyl Laboratories #E 115) was then added to each well, directly into the TMB solution. The absorbance was measured on an Envision plate reader at 450 nm.
Table 2 below describes înhibitory effects of compounds of Formula I on the HMT enzyme where “+++++” indicates a measured IC50 value < 0.025 μΜ; “++++” indicates a measured IC50 value from 0.025 μΜ to 0.050 μΜ of the disclosed compound; “+++” indicates a measured IC50 value from 0.050 μΜ to 0.10 μΜ ofthe disclosed compound; “++” indicates a measured IC50 value from
424
0.10 μΜ to 0.50 μΜ of the disclosed compound; and “+” indicates a measured IC50 value > 0.50 μΜ of the disclosed compound.
Table 2
Compounds with an 1C5I) value < 0.025 μΜ Compounds with an IC50 value from 0.025 μΜ to 0.050 μΜ Compounds with an IC50 value from 0.050 μΜ to 0.10 μΜ Compounds with an IC5o value from 0.10 μΜ to 0.50 μΜ Compounds with an TC5o value > 0.50 μΜ
1,3,4, 7, 8, 9,10, 12, 13, 15, 16, 17, 18, 19, 20,21,22, 23,24,25, 27, 28, 29, 30, 31,32, 33, 34, 35, 36, 38, 39, 40,41,42, 43, 44, 48, 49, 51, 53, 57, 59, 60, 62, 63, 68, 69, 70,71, 72, 85, 86, 89,94, 102, 115, 121, 125, 126, 130, 131, 132, 133, 145, 146, 157, 164, 165, 167, 168, 169, 172, 175, 186, 189 5, 26, 176 14 11 6, 185, 198
Table 3 below desribes the equilibrium dissociation constant (XD) as measured by surface plasmon résonance (SPR) of compounds of Formula I where“+++++” indicates a measured KO concentration < 0.0025 μΜ; “+H ++” indicates a measured Ko concentration from 0.0025 μΜ to 0.0050 μΜ of the disclosed compound; “+++” indicates a measured Ko concentration from 0.0050 μΜ to 0.010 μΜ of the disclosed compound; “++” indicates a measured concentration from 0.010 μΜ to 0.050 μΜ of the disclosed compound; and “+” indicates a measured concentration > 0.050 μΜ of the disclosed compound.
Table 3
Compounds with an Aq value < 0.0025 μΜ Compounds with an value from 0.0025 μΜ to 0.0050 μΜ Compounds with an Aq value from 0.0050 μΜ to 0.010 μΜ Compounds with an Aq value from 0.010 μΜ to 0.050 μΜ Compounds with an KD value> 0.050 μΜ
1, 3, 8, 9, 13, 15, 16, 17, 18, 19, 20, 22, 23, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 40,41,42, 43, 44, 45,47, 49, 50, 51,52,53, 54, 57, 58, 59, 60, 61,62, 63, 66, 67, 68, 69, 70,71,72, 73,75, 76, 77, 80, 84, 85, 12,21,24, 37,38, 46, 48, 55, 56, 64, 74,81, 82, 110, 111, 112, 136, 142, 144, 150, 153, 154, 162, 166 5, 10,25,78,79, 83, 105, 122, 143, 161, 174 4, 7,14, 26, 39,65, 98, 101, 107, 113, 120, 121, 138, 141, 149, 159, 165, 176, 177, 192, 197 6, 11, 140
425
86, 87, 88, 89, 90, 91,92, 93,94, 95, 96, 97,99, 100, 102, 103, 104, 106, 108, 109, 114, 115, 116, 117, 118, 119, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 137, 139, 145, 146, 147, 148, 151, 152, 155, 156, 157, 158, 160, 163, 164, 167, 168, 169, 170, 171, 172, 175, 178, 179, 186, 187, 188, 189, 190, 191, 193, 194, 195, 196, 197
Table 4 below describes inhibitory activity of compounds of Formula I on human P-glycoprotein HEK cells (HEK-P-gp) where “ I I l 1 l ” indicates a measured IC50 value < 0.025 μΜ; “++++” indicates a measured IC50 value from 0.025 μΜ to 0.050 μΜ of the disclosed compound; “+++” 5 indicates a measured IC50 value from 0.050 μΜ to 0.10 μΜ of the disclosed compound; “++” indicates a measured IC5Ü value from 0.10 μΜ to 0.50 μΜ of the disclosed compound; and “+” indicates a measured IC50 value > 0.50 μΜ of the disclosed compound.
Table 4
Compounds with an ICS0 value < 0.025 μΜ Compounds with an IC5o value from 0.025 μΜ to 0.050 μΜ Compounds with an ICjo value from 0.050 μΜ to 0.10 μΜ Compounds with an IC5o value from 0.10 μΜ to 0.50 μΜ Compounds with an IC5Ü value > 0.50 μΜ
8, 17, 18, 19, 23, 13,15,40, 49,50, 12, 20,21,27,28, 1, 16, 22, 39,41, 3, 4,5,6,7 ,9, 10,
29, 32, 33, 34,35, 53,62,66,80,86, 30,31,38,44,46, 45,47, 52,55,63, 11, 14, 24,25, 26,
36, 42, 43, 57, 69, 87,88,89, 90, 94, 48,51,59, 60,68, 74,77, 84,91,93, 37, 54,56, 58, 61,
70, 71, 85,102, 115, 124, 126, 72, 73, 75, 92, 96, 95, 99, 100, 104, 64, 65, 67, 76,78,
130, 131,145, 162,172,193, 196 106,125, 133, 105, 109, 110, 79, 81,82, 83, 97,
146, 152,157, 135,151,156, 111,112,114, 98, 101,107,108,
164, 167, 168, 186,191, 194 117,118,119, 113, 116, 121,
169, 189, 190, 120, 122, 129, 123, 127, 128,
195,197 137, 141, 142, 132,134, 136,
143,144,150, 138, 139, 140,
154,155, 160, 147, 148, 149,
163,170,178, 153,158,159,
184,188 161, 165, 166, 171, 175, 176, 177, 179, 181, 182,183,185, 187,192
426
Table 5 below describes inhibitory activity of compounds of Formula I on human P-glycoprotein HEK cells (HEK-P-gp) pretreated with elacridar where ”1111+” indicates a measured IC3q value < 0.025 μΜ; ”+++4·” indicates a measured IC50 value from 0.025 μΜ to 0.050 μΜ of the disclosed compound; “+++” indicates a measured IC50 value from 0.050 μΜ to 0.10 μΜ of the disclosed compound; “++” indicates a measured IC50 value from 0.10 μΜ to 0.50 μΜ of the disclosed compound; and “+” indicates a measured IC50 value > 0.50 μΜ of the disclosed compound.
Table 5
Compounds with an IC;o value < 0.025 μΜ Compounds with an ICjfl value from 0.025 μΜ to 0.050 μΜ Compounds with an IC5(i value from 0.050 μΜ to 0.10 μΜ_____ Compounds with an 1CSO value from 0.10 μΜ to 0.50 μΜ Compounds with an ICS0 value > 0.50 μΜ
1, 8, 13, 15, 17, 18, 19, 23, 29, 31, 32, 33, 34, 35, 36, 41, 42, 43,44, 49, 57, 59, 60, 62, 63, 69, 70, 71, 72, 85, 86, 89, 94, 102, 115, 126, 130, 131, 133, 145, 146, 152, 156, 157, 164, 167, 168, 169, 172, 189, 190 12, 20,21,22, 27, 28, 30, 40, 50, 53, 68, 80, 84, 87, 88, 90, 92,106, 125, 127, 129, 132, 163, 172,186 9, 16,47,48,51,52, 66, 73, 75, 77, 78, 91, 93,95, 96,110, 117, 118, 119, 124, 135, 151, 158, 162, 178, 186, 193, 194, 195, 196, 197 3,7,10, 24,38,39, 45, 46, 54, 55, 56, 74, 79, 97, 100, 104, 105, 109, 111, 112, 114, 116, 120, 122, 137, 138, 139, 142, 143, 144, 147, 148, 150, 154, 155, 160, 170, 175, 179, 184, 188, 191 4, 5,6, 11, 14, 25, 26, 37,58, 61,64, 65, 67, 76,81, 82, 83, 98, 99, 101, 107, 108, 113, 121, 123, 128, 134, 136, 140, 141, 149, 153, 159, 161, 165, 166, 171, 176, 177, 181, 182, 183, 185, 187, 192
Table 6 below describes half-maximal effective concentration (EC$q) of compounds of Formula I in the fêtai hemoglobîn (HbF) upregulation assay of HUDEP2 cells where “+++++” indicates a measured EC50 value < 0.025 μΜ; “++++” indicates a measured EC50 value from 0.025 μΜ to 0.050 μΜ of the disclosed compound; “+++” indicates a measured EC50 value from 0,050 μΜ to 0.10 μΜ of the disclosed compound; “++” indicates a measured EC50 value from 0.10 μΜ to 0.50 μΜ of the disclosed compound; and “+” indicates a measured EC50 value > 0.50 μΜ of the disclosed compound.
Table 6
Compounds with an EC5tl value < 0.025 μΜ Compounds with an ECS0 value from 0.025 μΜ to 0.050 μΜ Compounds with an EC5o value from 0.050 μΜ to 0.10 μΜ Compounds with an ECsfl value from 0.10 μΜ to 0.50 μΜ
17, 33,71, 115 8,28, 29,31,57, 69, 70, 72, 184 13, 18, 19, 36,49 23, 30, 62
Table 7 below describes half-maximal effective concentration (EC50) of compounds of Formula I in the fêtai hemoglobîn (HbF) upregulation assay of CD34+ cells where “+++++” indicates a measured EC50 value < 0.025 μΜ; ”++++” indicates a measured EC50 value from 0.025 μΜ to 0.050 μΜ of 427 the disclosed compound; “+++” indicates a measured ECjo value from 0,050 μΜ to 0.10 pM of the disclosed compound; “++” indicates a measured EC50 value from 0,10 pM to 0.50 pM of the disclosed compound; and “+” indicates a measured EC50 value > 0.50 pM of the disclosed compound.
Table 7
17, 131,164
Compounds with an ECS(i value < 0.025 pM Compounds with an EC^ value from 0.050 pM to 0.10 pM Compounds with an ECS0 value from 0.10 pM to 0.50 pM
8, 18, 33,57,69, 70, 71, 89, 115, 130, 146 15, 20, 28, 85, 94
Equivalents
Those skilled in the art will recognize, or be able to ascertain, using no more than routine expérimentation, numerous équivalents to the spécifie embodiments described specifically herein. Such équivalents are intended to be encompassed in the scope of the foliowing daims.

Claims (22)

1. A compound of Formula I:
or a pharmaceutically acceptable sait, prodrug, solvaté, hydrate, enantiomer, isomer, or tautomer thereof, wherein:
Xi, X2, and X3 are independently selected from N and C(R5), provided that X(, X2, and X3 are not ail N and at least one of Xb X2, or X3 is N;
Ai is selected from the group consisting of a bond, -C(R8)(R9)-, -O-, -NR8, -S-, -S(O)-, and -SO?-;
A2 and Y are independently, at each occurrence, selected from the group consisting ofC(R8)(R9)-, -O-, -NR8, -S-, -S(O)-, and -SO2-;
Ri is 6-membered heteroaryl optionally substituted with one or more R^;
R2 and R3 are independently, at each occurrence, selected from the group consisting of H, halogen, -OH, -NH2, -CN, Cj-C6 alkyl, Ci-C6 alkoxy, C2-C6 alkenyl, and C2-C6 alkynyl, wherein each of the alkyl, alkoxy, alkenyl, and alkynyl is optionally substituted with one or more R7;
R4 is selected from the group consisting of H, halogen, -OH, -NH2, -CN, Cj-Cô alkyl, Ci-C9 alkoxy, C2-C6 alkenyl, and C2-C6 alkynyl, wherein each of the alkyl, alkoxy, alkenyl, and alkynyl is optionally substituted with one or more R7, or R4 and R9 when taken together form a ring selected from the group consisting of C3-C10 cycloalkyl, C3-C8 cycloalkenyl, heterocyclyl, aryl, and heteroaryl, wherein each of the cycloalkyl, cycloalkenyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more Rio;
R5 îs selected from the group consisting of H, halogen, -CN, ORs, -NR8R9, -C(O)R8, C(O)ORg, -C(O)NR8R9, -NR8C(O)R9, -S(O)R8s -S(O)2R8, -NR8S(O)2R9, -S(O)2NR8R9, CrC6 alkyl, Cj-Cû haloalkyl, C2-Ce alkenyl, C2-Cé alkynyl, C3-C]q cycloalkyl, C3-C8 cycloalkenyl,
429 heterocyclyl, aryl, and heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycioalkyl, cycloalkenyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R7;
R6 is independently, at each occurrence, selected from the group consisting of oxo, halogen, -CN, OH, -NR8R9, -OR8, -C(O)R8, -C(O)OR8j - C(O)NR8R9, -NR8C(O)R9, -S(O)R8, -S(O)2R8, NR8S(O)2R9, -S(O)2NR8R9, CrC6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycioalkyl, heterocyclyl, aryl, or heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycioalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more Ri0; or two R6 combine to form a ring selected from the group consisting of C3-Ci0 cycioalkyl, C5C8 cycloalkenyl, heterocyclyl, aryl, and heteroaryl, wherein each of the cycioalkyl, cycloalkenyl, heterocyclyl, aryl, and heteroaryl îs optionally substituted with one or more Rio;
R7 is independently, at each occurrence, selected form the group consisting of oxo, halogen, -CN, -OR8, -C(O)R8, -C(O)OR8j - C(O)NR8R9, -NR8C(O)R9, -S(O)R8, -S(O)2R8, -NR8S(O)2R9, S(O)2NR8R9, C|-C6 alkyl, Ci-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycioalkyl, heterocyclyl, aryl, and heteroaryl;
R8 is independently, at each occurrence, selected from the group consisting H, OH, halogen, C|-C6 alkyl, C(-C6 alkoxy, C2-Cô alkenyl, C2-C0 alkynyl, C3-C8 cycioalkyl, heterocyclyl, aryl, and heteroaryl, wherein each ofthe alkyl, alkoxy, alkenyl, alkynyl, cycioalkyl, heterocyclyl, aryl, and heteroaryl îs optionally substituted with one or more R^;
R9 is independently, at each occurrence, selected from the group consisting of H, halogen, Cj-Cé alkyl, C|-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycioalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of the alkyl, alkoxy, alkenyl, alkynyl, cycioalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more Rio;
or R8 and R9 when taken together form a ring selected from the group consisting of C3-C& cycioalkyl and heterocyclyl, wherein each of the cycioalkyl and heterocyclyl is optionally substituted with Rjo; and
Rio is independently, at each occurrence, selected from the group consisting of oxo, halogen, -CN, -ORh, -C(O)Ru, -C(O)ORu, - C(O)NRuRi2, -NRuRi2,-NRnC(O)Ri2, -S(O)Ru, S(O)2Ru, -NRnS(O)2Ri2, -S(O)2NRhRi2, CrC6 alkyl, CrC6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycioalkyl, heterocyclyl, aryl, and heteroaryl; and
Ri । and Ri2 are independently selected from the group consisting of H, C|-Cô alkyl, Ci-Cù haloalkyl, C|-Cé alkoxy, C2-Co alkenyl, C2-Cé alkynyl, C3-C8 cycioalkyl, heterocyclyl, aryl, and heteroaryl.
430
2. The compound of daim 1, wherein X] is C(R3) and X2 and X3 are N.
The compound of any one of daims 1-3, wherein Rj is selected from the group consisting of:
4.
The compound of daim 3, wherein R| is selected from the group consisting of:
431
5. The compound of claim 1, wherein R2 is selected from the group consîsting of H, Ci-C6 alkyl, and halogen.
6. The compound of claim 1, wherein Ai is -O- or -C(R8)(R9)-.
7. The compound of claim 1, wherein A2 is -O- or -CiRsXRo)—.
8. The compound of claim 1, wherein Y is -C(R8)(R9)- or-NRsR9.
9. The compound of claim 1, wherein R4 and R y fonns a ring selected from the group consîsting of C3-C10 cycloalkyl, heterocyclyl, aryl, and heteroaryl.
10. The compound of daim 1, wherein R3 is selected from the group consîsting of H, OH, and halogen.
11. The compound of claim 1, wherein R4 is Cj-Cô alkyl optionally substituted with one or more
R7.
12. The compound of daim I having the formula (la), (Ib), (le), (Id), (If), (Ih), (Ih-a), (li), (li-a), or (Ij):
432
433
R’ (Ij), wherein the D ring represents a cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl, and the T ring represents 6-membered heteroaryl.
5
13. The compound of claim 12, wherein the D ring represents a heterocyclyl.
14. The compound of claim 1, wherein the compound is selected from the group consisting of:
14. The compound of claim 1 selected from the group consisting of:
Compound No. Compound Naine
1 (15R)-10-(2-methyl-3-pyridyl)-13,17-dioxa-3,5,7,8-tetrazapentacyclo [13.6.1.04,12.05,9.018,22] docosa-l(22),4(12),6,8,10,18,20-heptaene
5 12-fluoro-4-(2-methylpyridin-3-yl)-718,13,14-tetrahydro[l^^ltnazolofd'^'rtjôlpyndoD^-bjbenzoIfJILAjoxazonine
6 12-fluoro-4-(2-methylpyridin-3-yl)-6,8,13,14-tetrahydro- [l,2,4]triazolo[4',3':l,6]pyrido[3,2-c]benzo[g][l,5]oxazonine
8 (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H- [l,2,4]triazolo[4’,3':l,6]pyrido[3.2-b]benzofuro[4,3-fg][l,4]oxazonine
13 (S)-4-(2,4-dimethylpyrimidin-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H- [l,2,4]tnazolo[4\3': IjôlpyridoB.Z-blbenzofüraN^-fglIl^loxazorune
14 4-(2,4-dimethylpyrimidin-5-yi)-12-fluoro-7,8,13,14“tetrahydro[l,2,4]triazolo[4',3':l,6]pyndo[3,2-b]benzo[f|[l,4]oxazon!ne
434
19 (S)-12-fluoro-4-(4-methy!pyrimidin-5-yl)-7a,8,l3,14-tetraliydro-7H[ 1,2,4]triazol o[4',3 1,6] pyndo[3,2-b] benzofuro [4,3-fg] [ 1,4]oxazonine
20 (S)-12-fluoro-4-(2-methylpynmidin-5-yl)-7a,8,13J4-tetrahydro-7H- [l,2,4]tnazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
21 (S )-12-fluoro-4-(pyri<iin-2-yl)-7a,8,13,14-tetrahydro-7H- [l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
29 (S)-4-(2,3-dimethylpyridin-4-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H- [l,2,4]triazolo[4',3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
30 (S)-12-fluoro-4-(2-methoxypyrimidin-5-yl)-7a,8,13,14-tetrahydro-7H- [l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazorune
31 (S)-12-fluoro-4-(6-methoxypyndin-3-yl)-7a,8,13,14-tetrahydro-7H[1Ί2,4](ΐΊ3ζοΙο[4\3':1,6]ργΓίάο[3,2^^εηζοίίιΐΌ[4,3-Γ§][1,4]οχαζοηΐηε
32 (S)-4-(6’ethyl·4-methylpyridin-3-y])-l2-fluoro-7a,8,l3,14-tetrahydro-7H[l,2,4]triazolo[4',3';l,6]pyndo[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
33 (S)-4-(2-(dinuoromethyl)pyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H[ 1,2,4]tnazolo[4',3': 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4]oxazonine
34 (S)-4-( 2,6-dimethy 1 py ri din-3-y 1)-12-fluoro-7a, 8,13,14-tetiahydro-7H[ 1,2,4] triazolo[4',3 1,6] pyrido[3,2-b] benzofuro [4,3-fg][1,4]oxazonine
35 (S)-2-(5-(12-fluoro-7a,8,13,14-(etrahydro-7H-[l,2,4]triazolo[4,,3':l,6]pyrido[3,2b]benzofuro[4,3-fg] [ 1,4]oxazonin-4-yl)pyridin-2-yl)propan-2-ol
40 (S)-12- fluoro-4-(5-fl uoro-2-metliylpyridin-3 -yl)-7a,8,13,14-tetrahydro-7H[l^rtltriazoloNAILôlpyridofDjl-blbenzofuroH^-fgjtl^loxazonine
41 ( S )-12-fl uoro-4-(3 -fl uoropyridin-2-yl )-7a,8,13,14-tetrahydro-7H- [ 1,2,4] triazolo[4',3 1,6] pyrido [3,2-b] benzofuro [4,3 -fg] [ 1,4]oxazonine
42 (S)-12-fluoro-4-(5-fluoropyridin-2-yl)-7a,8,l 3,14-tetrahydro-7H- [l,2,4]triazolo[4',3,:l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
43 (S)-12-fluoro-4-(3-fluoro-5-methylpyndin-2-yl)-7a,8,13,14-tetrahydro-7H- [1,2,4)(032010(4^351,6] pyndo[3,2-b]benzofuro[4,3-fg][l,4]oxazorune
44 (S)-4-(3,5-difluoropyridin-2-y i)-12- fl uoro-7a,8,13,14-tetrahydro-7H- [l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
45 (S)-12-fluoro-4-(5-fluoro-3-methylpyridin-2-yl)-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3':l,6]pyndo[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
46 (S)-12-fluoro-4-(5-methylpyrazin-2-yl)-7a,8,13,14-tetrahydro-7H- [1,2,4] triazolo[4',3' : 1,6]pyrido[3,2-b] benzofuro [4,3 -fg] [ 1,4]oxazonine
47 (S)-12-fiuoro-4-(3-methylpyrazin-2-yl)-7a,8,13,14-tetrahydro-7H- [1 Ί2,4](π3ζο1ο[4τ,3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonjne
50 (S)-12-fluoro-4-(2-methoxypy ridin-4-y I )-7a, 8,13,14-tetrahydro-7H- [l,2,4]triazoio[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazoïiine
435
51 (5)-3-(12-fluoiO-7a,8,13,14-tetrahydiO-7H-[ 1,2,4]triazolo[4',3T: l,6]pyrido[3,2b]benzofuro[4,3-fg][l,4]oxazonin-4-yl)-2-methylpyridine 1-oxide
52 (S)-4-(3,5-dimethylpyraztn-2-y!)-12-fluoro-7a,8,13,14-tetrahydra-7H[l,2,4]triazolo[4',3':1,6]pyrido[3,2-b]benzofuiO[4,3-fg][l,4]c>xazonine
53 (S)-12-fluoro-4-(3-metliylpyridazin-4-y])-7a,8,13,14-tetrahydro-7H[l.ZjdJtriazoloUA1: l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
54 (S)- 12-fiuoro-4-(4-meÎhylpyridazin-3-yl)-7a,8,13,14-tetrahydro-7H- [l,2,4]triazolo[4',3':l ,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
55 (S)-12-fluoro-4-(6-methy]pyndin-2-yl)-7a,8,13,14-tetrahydra-7H- [l,2,4]tnazolo[4',3’:l,6]pyrido[3.2-b]benzofuro[4,3-fg][l,4]oxazonine
56 (S)-12-fluoro-4-(2-methylpyrimidin-4-yl)-7a,8,13,14-tetrahydro-7H- [1,2,4]triazolo[4,,3':l,6]pyrido[3,2-b]benzofuiO[4,3-fg][l,4]oxazonine
57 (S)-12-fluotO-4-(2-metlioxy-4-methylpyriniidin-5-yl)-7a,8,13,14-tetrahydro-7H[1,2,4}ΐπ3ζο1ο[4',3':1,6]ργιύ1ο[3,2-6^€ηζοίυΓο[4,3^][1,4]οχ3ζοηίιΐ6
58 (S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[l,2,4]tnazoio[4’,3':l,6]pyndo[3,2b ] benzo furo [4,3 - fg] [ 1,4 ] oxazon i n -4 -y ] ) -N, N,4 - tri m e t hy 1 py ri mid i ne -2 - c arb ox ami de
59 (S)-5-(12-fluoro-7a,8,13,l 4-te!rahydro-7H-[l,2,4]triazolo[4’,3': l,6]pyrido[3,2b] benzo furo [4,3 - fg] [ 1,4] o x azoni n-4 -y 1) -N,N - d i me t hy ] p ico 1 ina m i de
65 ( S)-12-fluoro-4-(5-methy Ipy ri midin-2-y l)-7a, 8,13,14-tetrahydro-7H- [l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
66 (S)-12-fluoro-4-(6-methylpyridazin-3-yl)-7a,8,13,14-tetrahydro-7H- [l,2,4]triazo!o[4’,3’:l ,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonme
67 (S)-4-(4,6-dimethylpyridazin-3-y1)-12-fluoro-7a,8,13,14-tetrahydiO-7H[1 J2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
68 ( S )-4- (4 - (di fl uoro methy 1 ) -2 - methy 1 py r i mi d in-5 -y 1 ) -12 - fl u o ro- 7 a, 8,13,14 - tetrahy dro- 7H[1,2,4] triazolo[4',3’ : 1,6]pyrido[3,2-b] benzofuro[4,3-fg] [ 1,4]oxazonine
69 (S)-4-(2-(dinuoromethyl)-4-metbylpyrimidin-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H- [l,2,4]triazolo[4',3,:l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
70 (S)-4-(4-(difluoromethyl)pyrimidin-5-y])-12-fluoiO-7a,8,13,14-tetrahydro-7H- [l,2,4]triazolo[4',3':l ,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
76 ( S )-4-( 2-( di fl uoro methoxy ) py r i mi d î n-5-y I ) -12 - fl uo ro - 7 a, $, 13,14- tetrahy d ro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuiO[4,3-fg][l,4]oxazonine
77 (S)-12-fluoro-4-(2-methoxypyridin-3-yl)-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
78 (S)-4-(2-(difluoiOmethoxy)pyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4’,3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
436
81 (S )-1 -(3-( 12-fluoro-7a,8,13,14-teüahydro-7H-[ 1,2,4]triazolo]4',3’: 1,6]pyrido[3,2b]benzofuro[4,3-fg][f,4]oxazonin-4-yl)pyridin-2-yl)-2-methy]propan-2-ol
82 (S)-4-(3-(12-fluoiO-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4'}3’;I,6]pyrido[3,2b]benzofuro[4,3-fg][l,4]oxazonin-4-yl)pyridin-2-yl)-2-methylbutan-2-ol
83 ( S ) -12 - fl uo ro-4-(2 - ( tri fl uo ro metli oxy )py ri d i n- 3 -y 1 )- 7a, 8,13,14 - tetrahy d ro - 7H[1,2,4]tnazolo[4',3’:l,6]pyrido[3,2-b]benzofuro[4,3-tg][l,4]oxazouine
84 (S)-4-(6-(difluoromethyI)-2-metliylpyndin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H- [l,2,4]tnazok>[4\3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazomne
85 ( S )-4-(2 - (d i fl uo ro methy 1 )-6-me thy 1 py ri d ί n-3-y 1 )-12-fl u oro-7 a. 8,13,14 - te trah y dr o-7 H - [l,2,4]triazolo[4',3’;l,6]pyrido[3,2-b]benzofiiro[4,3-fg][t,4]oxazonine
86 (S)-4-(4,6-dimethylpyridin-3-y])-12-fluûro-7a,8,13,14-tetrahydro-7H[t^rtJtriazoloH’jS'iLôlpyridoDJ-blbenzofuroU.S-fgKl^loxazomne
87 (S)-12-fluoro-4-(3-fluoro-2-methylpyridin-4-yl)-7a,8,13,14-tetrahydro-7H[1,2,4]^3Ζθ1ο[4',3':1,6]ρνιΗο[3,2-0]0εηζοίίπΌ[4,3-ί§][1,4]οχ3ζοηίη€
88 ( S) -4-(4 - ( di fl uo ro methy l ) -6- m ethy Ip y ri d i n - 3 - y 1 ) -12- fl uo ro -7 a, 8,13,14-ietrahy dro- 7H- [l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
89 (S)-12-fluoro-4-(5-fluoro-2-metbylpyridin-4-yl)-7a,8,13,14-tetrahydro-7H[l^ltriazoloH^’iLôJpyridoD^-blbenzofuroH^-fgHl/lJoxazotiine
90 (S)=l-(6-(difluoronietliyl)-4-methylpyridin-3-yi)-12-fluoiO-7a,8,13,14-tetrahydro-7H- [l,2,4]triazolo[4',3':t,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
91 (S)-12-fluoro-4-(pyrimidin-5-yl)-7a,8,13,14-tetrahydro-7H- [l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
94 (S)-Î2-fIuoro-4-(6-methylpyridin-3-yl)-7a,8,13,t4-tetrahydro-7H- [l,2,4]triazolo[4’,3':l:6]pyrido[3,2-b]benzüfuro(4,3-fg][l,4]oxazonme
95 (S)-12-fluoro-4-(3-methylpyridin-2-yl)-7a,8,13,14-tetrahydro-7H- [ 1,2,4] triazoio[4',3': 1,6]pyrido[3,2-b] benzofuro [4,3-fg][1,4] oxazonine
96 (S)-4-(2-ethylpyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydiO-7H- [l,2,4]triazo]o[4',3';l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
98 (S)-12-fluoro-4-(6-methoxypyridin-2-yl)-7a,8,13,14-tetrahydro-7H- [l,2,4]triazo]o[4',3':t,6]pyrido[3,2-b]benzofuiOf4,3-fg][l,4]oxazonine
101 (S)-4-(5-chioropyridm-2-yl)-t2-fluoΓo-7a,8,13,14-tetl·ahydΓO-7H- [l,2,4]triazolo[4’,3':l,6]pyrido[3,2-b]benzofura[4,3-fg][t,4]oxazonine
102 (S)-4-(4-cyclopropylpyrimidin-5-yl)-12-fluoro-7a,8,f3,i4-tetrahydro-7H[l,2,4]triazoloÎ4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
103 (S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4’,3':l,6]pyrido[3,2- b]benzofuro[4,3-fg][f,4]oxazonin-4-yl)-N,N-dimethylpyridin-2-amine
437
104 (S)-12-fluoro-4-(6-methoxy-4-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H- [1,2,4)^2010(4^: l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
105 ( S )-12 - fl uo ro -4 - ( 2 -metho x y-6-me thy Ip y ridi n - 3 -y 1 )- 7 a, 8,13,14 -tetrahy d ro-7 H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
106 ( S)-12 -fl uo ro-4- ( 6- me t ho x y -2 - methy 1 py ri d i n- 3 -y ] )-7a, 8,13,14- tetrahy dro -7H[I^AJtnazoloH'^^LôlpyridolSjZ-bJbenzoftiroH^-fgKLdJoxazonine
107 (S)-12-fluoro-4-(2-methoxy-4-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H- [l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
108 (S)-5-(12-fluoro-7a,8,l3,l4-tetrahydro-7H-[l,2,4]triazolo[4',3':l,6]pyrido[3,2b] benzo furo [4,3 - fg] [ 1,4 ] oxazo n i n-4-y 1 ) -N,N-d i me thy Ip y ri m i d i n- 2 -a m i ne
109 (S)-4-(2-ethoxypyrimidîn-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H[L2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazomne
110 ( S)-12 41 uo ro-4 - (5 - fl uo ro-6 - methoxy p y ri d i n-3 -y 1 )-7 a, 8,13,14-tetrahy dro-7H [ 1,2,4] triazolo[4',3' : 1,6]py rido[3,2-b] benzofuro[4,3 -fg] [ 1,4]oxazonine
111 (S)-12-fluoro-4-(5-fluoro-2-methoxypyridm-3-yl)-7a,8,l 3,14-tetrahydro-7H[ 1,2,4]triazolo[4',3': 1,6]pyrido[3,2-b]benzofuro[4,3-fg] [ l,4]oxazonine
112 (S)-12-fluoro-4-(6-(trifluoromethyl)pyridin-3-yl)-7a,8,13,14-tetrahydro-7H[L2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazomne
113 (S)-12-fluoro-4-(5-(trifluoromethyl)pyridin-2-yl)-7a,8,13,14-tetrahydiO-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
114 (S)-12-fluoro-4-(2-(trifluoromethy1)pyri mid in-5 -yl)-7a,8,13,14-tetrahydro-7H[l,2,4]triazo]o[4',3':I,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
116 (S)-12-fluoiO-4-(6-morpholinopyridin-3-yl)-7a,8,13,14-tetrahydro-7H[ 1,2,4]triazolo[4',3': 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4]oxazonine
117 (S)-12-fluoro-4-(6-(4-methy]piperazin-l-yl)pyridin-3-yl)-7a,8,13,144etrahydiO-7H- [l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
118 (S)-12-fluoro-4-(2-(4-methylpiperazm-l-yl)pyrimidin-5-yl)-7a,8,13,14-tetrahydro-7H[1,2,4]triazolo[4',3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
119 ( S )-12 -fl uo ro-4 - (2 -(tri fl uo ro m e thy 1) py ri d in- 3 -y 1)- 7a, 8,13,14 - te trahy dro -7 H[1,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazomne
120 (S)-12-fluoro4-(5-fluoro-6-methylpyridin-2-yl)-7a,8,13,14-tetrahydro-7H[ 1,2,4] tri azolo[4’,3' : 1,6]py rido[3,2-b] benzofuro [4,3 -fg] [ 1,4]oxazonine
121 ( S)-12 - fl uoro-4 - ( 2 - methy Ip y rid i n- 3 -y 1) - 7 a, 8,13,14 -tetrahy dro- 7 H [l,2,4]triazolo[r)5,:l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
123 (S)-12-fluoro-4-(6-methy lpyridazin-4-yl)-7a, 8,13,14-tetrahydro-7H- [ 1,2,4] triazolo[4’, 3' :l,6]pyrido[3,2-b] benzo furo [4,3-fg] [1,4] oxazonine
438
141 (S)-4-(5-(difluoromethy])-6-methylpyridiii-2-y!)-12-fluoro-7a,8,13,14-tetrahydro-7H- [l,2,4]triazolo[4’,3’:l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
144 (S)-4-(3-(difluoromethyl)-6-methylpyridin-2-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H- [l,2,4]triazo]o[4',3':l,6]pyrido[3,2-b]besizofuro[4,3-fg][l,4]oxazonine
149 (S)-12-fluoro-4-(4-methylpyridin-2-yl)-7a,8,13,14-tetrahydro-7H- [ 1,2,4] tri azolo[4',3': 1,6] pyrido[3,2-b] benzofuro[4,3 -fg] [ 1,4]oxazonine
150 (S)-12-fluoro-4-( 5 -methy Ipy ridin-2-yl)-7a, 8,13,14-tetrahydro-7H- [l,2,4]triazoio[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
151 (S)-4-(3-cHoropyridin-2-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H- [l,2,4]triazolo[4,,3,:l,6]pyrido[3,2-b]benzofura[4,3-fg][l,4]oxazonine
152 (S)-4-(5-chloro-2-methylpyridin-3-y])-12-fluoro-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuiO[4,3-fg][l,4]oxazonine
153 (S)-4-(5-chloro-6-methylpyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H[l^riJtriazoloH'^^LôJpyridolS^-blbenzofuraUT-fglll^joxazonine
154 (S)-12-fluoro-4-(5-fluoro-6-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofiiro[4,3-fg][l,4]oxazonine
155 (S)-12-flLioro-4-(2-methylpyridin-4-yl)-7a,8,13,14-tetrahydro-7H- [I,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
156 (S)-4-(2,5-di methy lpyridin-4-yl )-12 - fluoro-7a, 8,13,14-tetrahydio-7H- [l,2.4]triazolo[4',3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
157 (S )-4-(3-chloro-2-methy Ipy ridin-4-y 1 )-12-fl uoro-7a, 8,13,14-tetrahydro-7H[ 1.2,4] triazolo[4's3 1,6] pyrido [3,2-b] benzoftiro [4,3-fg] [ 1,4]oxazonine
158 (S)-4-(3-chloro-5-flLioropyridin-2-yl)-12-fluoro-7a,8,13,14-tetrabydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
159 (S)-12-fluoro-4-(3-methoxypyndin-2-yl)-7a,8,13,14-tetrahydro-7H- [l,2,4]triazolo[4',3':l ,6]pyrido[3;2-b]benzofuro[4,3-fg][l,4]oxazorune
160 (S)-12-fluoro-4-(pyrimidiii-4-yl)-7a,8,13,14-tetrahydro-7H- [l,2,4]triazolo[4’,3';l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
161 (S)-12-fluoro-4-(6-methylpyrimidin-4-yl)-7a,8,13,14-tetrahydiO-7H[ 1,2,4] triazolo[4',3 ’ : 1,6] pyrido[3,2-b]benzofuro[4,3 -fg] [ 1,4]oxazonine
162 (S)-12-fluoro-4-(5-methylpyrimidm-4-yj)-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonitie
163 (S)-4-(5-ch]oropyrimidin-4-y!)-12-fluoro-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3*:l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine
164 (S)-12-fluoro-4-(5-fluoropyrîmidîn-4-yl)-7a,8,13,14-tetrahydro-7H[ 1,2,4] triazolo[4',3': 1,6] pyrido [3,2-b]benzofuro [4,3-fg] [1,4] oxazonine
439
166 (S)-4-(5-chloro-3-methyl pyridin-2-y l)-l2-fluoro-7 a,8,13,14-tetrahydro-/H[l^priazoiotd'^’il.ôlpyridoD^-blbenzofuroH^-fgKl/lloxazonjne
176 (S)-5-f]uoro-12-(2-methylpyridin-3-yl)-6,7,15)l5a-tetrahydro-lH-benzofuro[4,3fg]imidazo[r,2’:l,6]pyrido[3,2-b][l,4]oxazonine-10-carbox3mide
177 (S)-5-fluoro-12-(2-methylpyridin-3-y])-6,7,15,15a-tetrahydro-lH-benzoftjro[4,3- fg]imidazo[r,2':l,6]pyrido[3,2-b][l,4]oxazonine-lÛ-carboxylic acid
178 (S)-4-(2-cyclopropy lpyrimidin-5 -y 1)-12-fluoro-7a,8,13,14-tetrahydro-7H[L2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazorune
179 (S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-(l,2,4]triazolo[4',3':l,6]pyndo[3,2- b]benzofuiO[4,3-fg][l,4]oxazonin-4-yl)-2-methylpyridin-3-annine
182 4-(2,4-dimethylpyrimîdiii-5-yl)-12-fluoro-6,8,13,l4-tetrahydro[l^^triazoloD'^'ikôJpyridotS^-clbenzotgKLSloxazonine
185 (R)-12-fiuoro-4-(2-methy]pyridin-3-yI)-7a,8,13,14-tetrahydro-7H- [l,2,4]triazolo[4’,3’:l,6]pyndo[3,2-b)benzofmO[4,3-fg][î,4]oxazonine
186 (S)-5-fluoiO-l2-(2-methylpyridin-3-y1)-6,7,l5,l5a-tetrahydro-lH-benzofuro(4,3- fgjiirudazotr^'iLeipyridcD^-bKlTjoxazonine-IO-carbonitrile
187 (S)-5-(l2-fluoro-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4’,3’:l,6]pyrido[3,2- b]benzofLiro[4,3-fg][l,4]oxazonin-4-yl)’6-methylpyridin-2-o1
190 (S)-4-(2-cyclopropyl-4-methylpynmidin-5-yl)-12-fluoro-7a,8,13,14-teaahydro-7H[l.Z^ltriazoloXA'J.ôJpyndoD^-bJbenzofuroD^-fgKlTJoxazonine
191 (S)-3-(5-(12-fluoro-7a,8,13,14-tetrahydro-7H41,2,4]tnazolo[4',3,:l,6]pyrido[3,2- b]benzofuiO[4,3-fg][l,4]oxazonin-4-yl)-6-inethylpyridin-2-yl)-N-methylpropanamide
192 (S)-3-(12-fi(joro-7a,8,13,14-tetrahydro-7H-[1.2,4]tria2o]o[4T,3':l,6]pyrido[3,2b]benzofuro[4,3-fg][l,4]oxazonin-4-yl)-2-methylpyndin-4-o!
194 (S)-5-(12-fluoro-7a.8,13,14-tetrahydro-7H-[l,2,4]tnazolo[4',3':l,6]pyndo[3,2b] benzofuro[4,3 -fg] [ 1,4]oxazonin-4-yl)-6- methylpyrid in-3 -ol
195 (Sl-Ddn-nuoro-Va&BJd-tetrahydro-TH-U^XJtriazolo^'iLeipyridop^- b]benzoiuro[4,3-fg][l,4]oxazonin-4-yl)pyridin-2-yl)methanol
15. The compound of claim 14, wherein the compound is selected from the group consîsting of: (15R)-10-(2-methyl-3-pyridyl)-13,17-dioxa-3,5,7,8-tetrazapentacyclo [13.6.1.04,12.05,9.018,22] docosa-1(22),4( 12),6,8,10,18,20-heptaene;
(S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,I3,14-tetrahydro-7H[ 1,2,4]triazolo[4)3’: l,6]pyrido[3,2-b]benzofuro[4,3-fg]( l,4]oxazonine; (S)-4-(2,4-dimethylpyrimidin-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4)3':I,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine;
440 (S)-12-fluoro-4-(4-inethylpyrimidin-5-yl)-7a,8,13,14-tetrahydro-7H-
[ 1,2,4]tr iazolo[4',3': 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4]oxazonine;
(S)-12-fluoro-4-(2-methylpyiimidin-5-yl)-7a,8,13,14-tetrahydro-7H-
[ 1,2,4]tr iazolo[4',3': 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4]oxazonine;
(S)-4-(2,3-dimethylpyridin-4-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4\3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine;
(S)- 12-tluoro-4-(2-methoxypyrimidin-5-yl)-7a,8,13,14-tetrahydro-7H-
[ 1,2,4]tr iazolo[4’,3': 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4]oxazonine;
(S)-12-fluoro-4-(6-methoxypyridin-3-yi)-7a,8,13,14-tetrahydro-7H-
[ 1,2,4]tn azolo[4',3': 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ l,4]oxazonine;
(S )-4-(6-ethyl -4-methylpyridin-3 -yl)-12 -fluoro-7a, 8,13,14-tetrahydro-7H-
[ 1,2,4]tr iazolo[4',3’: l,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4] oxazonine;
(S)-4-(2-(difluoiOmeihyl)pyridin-3-yl)~12-fluoiO-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine; (S)-4-(2,6-dimethylpyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H[ 1,2,4]triazolo[4',3’: 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4]oxazonine;
(S)-2-(5-( 12-fluoro-7a,8,13,14-tetrahydro-7H-[ 1,2,4]triazolo[4',3':l,6]pyrido[3,2b]benzofuro[4,3-fg][l,4]oxazonin-4-yI)pyridin-2-yl)propan-2-ol;
(S)- 12-fluoro-4-(5-fluoro-2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-
[ 1,2,4]tr iazolo[4',3': l,6]pyrido[3,2-b]benzofiiro[4,3-fg][ 1,4]oxazonine;
(S)-12-fluoro-4-(3-fluoropyridin-2-yl)-7a, 8,13,14-tetrahydro-7H-
[1,2,4]tri azolo[4’,3': 1,6]pyrido[ 3,2-b]benzofuro[4,3-fg] [1,4] oxazonine;
(S)-l 2-fluoro-4-(5-fluoropyridin-2-yl)-7a,8,13,14-tetrahydro-7H-
[ 1,2,4]tr iazolo[4',3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4]oxazonine;
( S)-l 2-fluoro-4-(3-fluoro-5-methylpyridin-2-yl)-7a,8,13,14-tetrahydro-7H-
[ 1,2,4]tr iazolo[4’,3': 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4]oxazonine;
(S)-4-(3,5-difluoropyridin-2-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-
[ 1,2,4]tr iazolo[4',3’: l,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4]oxazonine;
(S)-12-fluoro-4-(2-m ethoxy-4-methylp yrimidin-5-yl)-7 a,8,13,14-tetrahydro-7H-
[ 1,2,4]tr iazolo[4',3': 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ l,4]oxazonine;
(S)-5-(12-fluoiO-7a,8,13,14-tetrahydro-7H-[l,2,4]triazolo[4',3': l,6]pyrido[3,2-
b] benzofuro [4,3 -fg] [ 1,4] oxazonin-4-yl)-N,N-dimethylpicoli namide;
441 (S)-4-(4-(difluoromethyl)-2-methylpyrimidin-5-yl)- 12-fluoro-7a,8,l 3,14-tetrahydro-7 H[ 1,2,4]triazolo[4',3’: 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4]oxazonine;
(S)-4-(2-(difluoromethyl)-4-inethylpyrimidin-5-yl)-12-fluoro-7a,8,13,14-tetrahydiO-7H[l,2,4]triazolo[4’,3':l,6]pyrido[3,2-b]benzoiuro[4,3-fg][l,4]oxazonine;
(S)-4-(4-(difluoromethyl)pyrimidin-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-
[ l,2,4]tr iazolo[4',3': l,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4]oxazonine;
(S)-4-(2-(difluoromethyl)-6-methylpyridin-3-yl)-l 2-fluoro-7a, 8,13,14-tetrahydro-7H-
[ 1,2,4]tr iazolo[4',3’: 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4]oxazonine;
(S)-4-(4,6-dimethylpyridin-3-yl)- 12-fluoro-7a,8,13,14-tetrahydro-7H-
[ 1,2,4] triazolo[4',3': 1,6 ]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4] oxazonine;
(S)-12-fluoro-4-(5-fluoro-2-methylpyridin-4-yl)-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4',3':l,6]pyrido[3,2-b]benzofuiO[4,3-fg][l,4]oxazonine;
(S)-12-fluoro-4-(6-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-
[1,2,4]tri azolo[4',3’: 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4]oxazonine;
(S)-4-(4-cyclopropylpyrimidin-5-yl)-l 2-fluoro-7a,8,13,14-tetrahydro-7H[l,2,4]triazolo[4’,3':l,6]pyrido[3,2-b]benzofuro[4,3-fg][l,4]oxazonine;
(S)-4-(3-chloro-2-methylpyridin-4-yl)- 12-fluoro-7a,8,13,14-tetrahydro-7H-
[ 1,2,4]tr iazolo[4',3’: 1,6]pyrido[3,2-b]benzofuro[4,3-fg][ 1,4]oxazonine;
(S)- 12-fluoro-4-(5-fluoropyrimidm-4-yl)-7a,8,13,14-tetrahydro-7H[ 1,2,4]triazolo[4’,3':1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine; and (S)-4-(2-cyclopropyl-4-methylpyrimidin-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-
[ 1,2,4]tr iazolo[4’,3': 1,6]pyrido[3,2-b]benzofuiO[4,3-fg][ l,4]oxazonine.
16.
A compound represented by:
442 or a pharmaceutically acceptable sait thereoi, wherein
A| is -O- ;
A2 is -CH2-;
R? and R3 are each independently selected, for each occurrence, from the group consisting of: H, halogen, -OH, and Ci alkyl, wherein the Ci alkyl is optionally substituted with one or more halogens; and
Rj is selected from the group consisting of:
The compound of claim 16, wherein R| is
18. The compound of 17, wherein R2 is selected from the group consisting of H, CrC6 alkyl, and halogen.
19. A compound represented by:
or a pharmaceutically acceptable sait thereof.
20. A compound represented by:
443 or a pharmaceutically acceptable sait thereof.
21. A pharmaceutical composition comprising the compound of any one of daims 1-20, or pharmaceutically acceptable sait thereof, and a pharmaceutically acceptable carrier.
22. The pharmaceutical composition of claim 21, further comprising at least one additional therapeutic agent, wherein the additional therapeutic agent is selected from the group consisting of anti-cancer agents, immunomodulators, anti-allergie agents, anti-emetics, pain relievers, cytoprotective agents, anti-sickling agents, EZH2 inhibitors, anti-adhesion agents, détoxification agents, anti-inflammatory agents, anti-thrombiotic agents, N-((4,6-dimethyl-2-oxo-l,2dihydropyridin-3-yl)methyl)-5-( ethyl(tetrahydro-2H-pyran-4-y 1) amino)-4-methy 1-4’(morpholinomethyl)-[I,T-biphenyl]-3-carboxamide (tazemetostat), (2R)-7-chloro-2-[4(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-lH-pyridin-3-yl)methyl]-2,4-dimethyl-l,3benzodîoxole-5-carboxamide (valemetostat, DS-3201b), N-[(4-methoxy-6-methyl-2-oxo-lHpyridin-3-yl)methyl]-2-methyl-l-[(l R)-1-[ 1-(2,2,2-trifiuoroethyl)piperidin-4-yl]ethyl]indole-3carboxamide (CPI-1205), (S)-l-(sec-butyl)-N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3yl)methyl)-3-methyl-6-(6-(piperazin-l-yl)pyridin-3-yl)-lH-indole-4-carboxamide (GSK2816126), (R)-5,8-dichloro-7-(methoxy(oxetan-3-yl)methyl)-2-((4-methoxy-6-methyl-2-oxo-I,2dihydiOpyridin-3-yl)methyl)-3,4-dihydroisoquinolin-l(2H)-one (PF-06821497), SHR2554, hydroxyurea, 2-hydroxy-6-((2-(l-isopropyl-l H-pyrazol-5-yl)pyridin-3-yi)methoxy)benzaldehyde (voxelotor, GBT-440), P-Selectin antibodies, L-Glutamine, crizanlîzumab (SEG101), (2S)-2[(2R,3R,4S,5S,6R)-3-benzoyloxy-2-[(lR,2R,3S,5R)-3-[(2,4-dioxo-lH-pyrimidine-6carbonyl)amino]-5-[2-[[2-[2-[2-oxo-2-[(3,6,8-trisulfonaphthalen-l- yl)amino]ethoxy]ethoxy]acetyl]amino]ethylcarbamoyl]-2-[(2S,3S,4R,5S,6S)-3,4,5-trihydroxy-6methyloxan-2-yl]oxycyclohexyI]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3cyclohexylpropanoic acid (rivipansel, GMI-1070), sevuparin, 6-[(3S,4S)-4-methyl-l-(pyrimidin-2ylmethyl)pyrrolidin-3-yl]-l-(oxan-4-yl)-5H-pyrazolo[3,4-d]pyrimidin-4-one (PF-04447943), inclacumab (LC 1004-002), 3-[3-[4-(l-aminocyclobutyl)phenyl]-5-phenylimidazo[4,5-b]pyridin-2yl]pyridin-2-amine (miransertib, ARQ 092), 2-hydroxy-6-((2-(l-isopropyl-lH-pyrazol-5-yl)pyridin3-yl)methoxy)benzaldehyde (voxelotor, GBT-440), 6-[(3S,4S)-4-Methyl-l-(2-pyrimidinylmethyl)3-pyrroIidinyl]-3-(tetrahydro-2H-pyran-4-yl)imidazo[l,5-a]pyrazin-8(7H)-one (IMR-687), LJPC401, (lS,2S,3R,5S)-3-[7-{[(lR,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5(propylthio)-3H[l,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-l,2-diol (brilinta,
444 tricagrelor), (2R)-3,3,3-trifluoro-2-[[[5-fluoro-2-[ l-[(2-fluoiOphenyl)methyl]-5-(l ,2-oxazol-3yI)pyrazoL3-yl]pyrimidin-4-yl]amino]methyl]-2-hydroxypropanainîde (olinciguat), NKTT120, sanguinate, AZD9291, and combinations thereof..
23. A compound of any one of daims 1-20, or a pharmaceutically acceptable sait thereof, for use in treating a blood disorder.
24. The compound for use of claim 23, wherein the blood disorder is selected from the group consisting of Acute lymphoblastic leukemia (ALL), Acute myeloid leukemia (AML), Amyloidosîs, Anémia, Aplastic anémia, Bone marrow failure syndromes, Chronic lymphocytic leukemia (CLL), Chrome myeloid leukemia (CML), Deep vein thrombosis (DVT), Diamond-Blackfan anémia, Diffused large B cell lymphoma, Dyskeratosis congenita (DKC), Eosinophilie disorder, Essential thrombocythemia, Fanconi anémia, Follicular lymphoma. Gaucher disease, Hemochromatosis, Hemolytic anémia, Hemophilia, Hereditary spherocytosis, Hodgkin’s lymphoma, Idiopathic thrombocytopénie purpura (ITP), Inherited bone marrow failure syndromes, Iron-deficiency anémia, Langerhans cell histiocytesis, Large granular lymphocytic (LGL) leukemia, Leukemia, Leukopenia, Mastocytosis, Monoclonal gammopathy, Multiple myeloma, Myelodysplastic syndromes (MDS), Myelofibrosis, Myeloproliferative neoplasms (MPN), Non-Hodgkin’s lymphoma, Paroxysmal noctumal hemoglobinuria (PNH), Pernicious anémia (B 12 deficiency), Polycythemia vera, Porphyria, Post-transplant lymphoproliférative disorder (PTLD), Pulmonary embolism (PE), Shwachman-Diamond syndrome (SDS), sickle cell disease (SCD), β-thalassemia, Thrombocytopenia, Thrombotic thrombocytopénie purpura (TTP), Venous thromboembolism, Von Willebrand disease, and Waldenstrom’s macroglobulinemia (lymphoplasmacytic lymphoma).
25. The compound for use of claim 23 or 24, wherein the blood disorder is sickle cell disease (SCD).
26. The compound for use of claim 23 or 24, wherein the blood disorder is β-thalassemia.
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