Heterobicyclic metalloprotease inhibitors

FIELD OF THE INVENTION

The present invention relates generally to amide containing heterobicyclic metalloprotease inhibiting compounds, and more particularly to heterobicyclic MMP-13 inhibiting compounds.

BACKGROUND OF THE INVENTION

Matrix metalloproteinases (MMPs) and aggrecanases (ADAMTS=a disintegrin and metalloproteinase with thrombospondin motif) are a family of structurally related zinc-containing enzymes that have been reported to mediate the breakdown of connective tissue in normal physiological processes such as embryonic development, reproduction, and tissue remodelling. Over-expression of MMPs and aggrecanases or an imbalance between extracellular matrix synthesis and degradation has been suggested as factors in inflammatory, malignant and degenerative disease processes. MMPs and aggrecanases are, therefore, targets for therapeutic inhibitors in several inflammatory, malignant and degenerative diseases such as rheumatoid arthritis, osteoarthritis, osteoporosis, periodontitis, multiple sclerosis, gingivitis, corneal epidermal and gastric ulceration, atherosclerosis, neointimal proliferation (which leads to restenosis and ischemic heart failure) and tumor metastasis.

The ADAMTSs are a group of proteases that are encoded in 19 ADAMTS genes in humans. The ADAMTSs are extracellular, multidomain enzymes whose functions include collagen processing, cleavage of the matrix proteoglycans, inhibition of angiogenesis and blood coagulation homoeostasis (Biochem. J. 2005, 386, 15-27; Arthritis Res. Ther. 2005, 7, 160-169; Curr. Med. Chem. Anti-Inflammatory Anti-Allergy Agents 2005, 4, 251-264).

The mammalian MMP family has been reported to include at least 20 enzymes, (Chem. Rev. 1999, 99, 2735-2776). Collagenase-3 (MMP-13) is among three collagenases that have been identified. Based on identification of domain structures for individual members of the MMP family, it has been determined that the catalytic domain of the MMPs contains two zinc atoms; one of these zinc atoms performs a catalytic function and is coordinated with three histidines contained within the conserved amino acid sequence of the catalytic domain. MMP-13 is over-expressed in rheumatoid arthritis, osteoarthritis, abdominal aortic aneurysm, breast carcinoma, squamous cell carcinomas of the head and neck, and vulvar squamous cell carcinoma. The principal substrates of MMP-13 are fibrillar collagens (types I, II, III) and gelatins, proteoglycans, cytokines and other components of ECM (extracellular matrix).

The activation of the MMPs involves the removal of a propeptide, which features an unpaired cysteine residue complexes the catalytic zinc (II) ion. X-ray crystal structures of the complex between MMP-3 catalytic domain and TIMP-1 and MMP-14 catalytic domain and TIMP-2 also reveal ligation of the catalytic zinc (II) ion by the thiol of a cysteine residue. The difficulty in developing effective MMP inhibiting compounds comprises several factors, including choice of selective versus broad-spectrum MMP inhibitors and rendering such compounds bioavailable via an oral route of administration.

MMP-3 (stromelysin-1; transin-1) is another member of the MMP family (Woesner; FASEB J. 1991; 5:2145-2154). Human MMP-3 was initially isolated from cultured human synoviocytes. It is also expressed by chondrocytes and has been localized in OA cartilage and synovial tissues (Case; Am. J. Pathol. 1989 December; 135(6):1055-64).

MMP-3 is produced by basal keratinocytes in a variety of chronic ulcers. MMP-3 mRNA and Protein were detected in basal keratinocytes adjacent to but distal from the wound edge in what probably represents the sites of proliferating epidermis. MMP-3 may this prevent the epidermis from healing (Saarialho-Kere, J. Clin. Invest. 1994 July; 94(1):79-88)).

MMP-3 serum protein levels are significantly elevated in patients with early and long-term rheumatoid arthritis (Yamanaka; Arthritis Rheum. 2000 April; 43(4):852-8) and in osteoarthritis patients (Bramono; Clin Orthop Relat Res. 2004 November; (428):272-85) as well as in other inflammatory diseases like systemic lupus erythematosis and ankylosing spondylitis (Chen, Rheumatology 2006 April; 45(4):414-20.).

MMP-3 acts on components of the ECM as aggrecan, fibronectin, gelatine, laminin, elastin, fibrillin and others and on collagens of type III, IV, V, VII, KX, X (Bramono; Clin Orthop Relat Res. 2004 November; (428):272-85). On collagens of type II and IX, MMP-3 exhibits telopeptidase activity (Sandell, Arthritis Res. 2001 ;3(2): 107-13; Eyre, Clin Orthop Relat Res. 2004 October; (427 Suppl):S118-22.). MMP-3 can activate otherMMP family members as MMP-1; MMP-7; MMP-8; MMP-9 and MMP-13 (Close, Ann Rheum Dis 2001 November; 60 Suppl 3:iii62-7).

MMP-3 is involved in the regulation of cytokines and chemokines by releasing TGFβ1 from the ECM, activating TNFα, inactivation of IL-1β and release of IGF (Parks, Nat Rev Immunol. 2004 August; 4(8):617-29). A potential role for MMP-3 in the regulation of macrophate infiltration is based on the ability of the enzyme to converse active MCP species into antagonistic peptides (McQuibban, Blood. 2002 Aug. 15; 100(4):1160-7.).

SUMMARY OF THE INVENTION

The present invention relates to a new class of heterobicyclic amide containing pharmaceutical agents which inhibits metalloproteases. In particular, the present invention provides a new class of metalloprotease inhibiting compounds that exhibit potent MMP-13 inhibiting activity and/or activity towards MMP-3, MMP-8, MMP-12, ADAMTS-4, and ADAMTS-5.

The present invention provides several new classes of amide containing heterobicyclic metalloprotease compounds, of which some are represented by the following general formulas:
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wherein all variables in the preceding Formulas (I) to (VI) are as defined hereinbelow.

The heterobicyclic metalloprotease inhibiting compounds of the present invention may be used in the treatment of metalloprotease mediated diseases, such as rheumatoid arthritis, osteoarthritis, abdominal aortic aneurysm, cancer (e.g. but not limited to melanoma, gastric carcinoma or non-small cell lung carcinoma), inflammation, atherosclerosis, multiple sclerosis, chronic obstructive pulmonary disease, ocular diseases (e.g. but not limited to ocular inflammation, retinopathy of prematurity, macular degeneration with the wet type preferred and corneal neovascularization), neurologic diseases, psychiatric diseases, thrombosis, bacterial infection, Parkinson's disease, fatigue, tremor, diabetic retinopathy, vascular diseases of the retina, aging, dementia, cardiomyopathy, renal tubular impairment, diabetes, psychosis, dyskinesia, pigmentary abnormalities, deafness, inflammatory and fibrotic syndromes, intestinal bowel syndrome, allergies, Alzheimers disease, arterial plaque formation, oncology, periodontal, viral infection, stroke, atherosclerosis, cardiovascular disease, reperfusion injury, trauma, chemical exposure or oxidative damage to tissues, chronic wound healing, wound healing, hemorroid, skin beautifying, pain, inflammatory pain, bone pain and joint pain, acne, acute alcoholic hepatitis, acute inflammation, acute pancreatitis, acute respiratory distress syndrome, adult respiratory disease, airflow obstruction, airway hyperresponsiveness, alcoholic liver disease, allograft rejections, angiogenesis, angiogenic ocular disease, arthritis, asthma, atopic dermatitis, bronchiectasis, bronchiolitis, bronchiolitis obliterans, bum therapy, cardiac and renal reperfusion injury, celiac disease, cerebral and cardiac ischemia, CNS tumors, CNS vasculitis, colds, contusions, cor pulmonae, cough, Crohn's disease, chronic bronchitis, chronic inflammation, chronic pancreatitis, chronic sinusitis, crystal induced arthritis, cystic fibrosis, delayted type hypersensitivity reaction, duodenal ulcers, dyspnea, early transplantation rejection, emphysema, encephalitis, endotoxic shock, esophagitis, gastric ulcers, gingivitis, glomerulonephritis, glossitis, gout, graft vs. host reaction, gram negative sepsis, granulocytic ehrlichiosis, hepatitis viruses, herpes, herpes viruses, HIV, hypercapnea, hyperinflation, hyperoxia-induced inflammation, hypoxia, hypersensitivity, hypoxemia, inflammatory bowel disease, interstitial pneumonitis, ischemia reperfusion injury, kaposi's sarcoma associated virus, liver fibrosis, lupus, malaria, meningitis, multi-organ dysfunction, necrotizing enterocolitis, osteoporosis, periodontitis, chronic periodontitis, peritonitis associated with continous ambulatory peritoneal dialysis (CAPD), pre-term labor, polymyositis, post surgical trauma, pruritis, psoriasis, psoriatic arthritis, pulmatory fibrosis, pulmatory hypertension, renal reperfusion injury, respiratory viruses, restinosis, right ventricular hypertrophy, sarcoidosis, septic shock, small airway disease, sprains, strains, subarachnoid hemorrhage, surgical lung volume reduction, thrombosis, toxic shock syndrome, transplant reperfusion injury, traumatic brain injury, ulcerative colitis, vasculitis, ventilation-perfusion mismatching, and wheeze.

In particular, the heterobicyclic metalloprotease inhibiting compounds of the present invention may be used in the treatment of MMP-13 mediated osteoarthritis and may be used for other MMP-13 mediated symptoms, inflammatory, malignant and degenerative diseases characterized by excessive extracellular matrix degradation and/or remodelling, such as cancer, and chronic inflammatory diseases such as arthritis, rheumatoid arthritis, osteoarthritis atherosclerosis, abdominal aortic aneurysm, inflammation, multiple sclerosis, and chronic obstructive pulmonary disease, and pain, such as inflammatory pain, bone pain and joint pain.

The present invention also provides heterobicyclic metalloprotease inhibiting compounds that are useful as active ingredients in pharmaceutical compositions for treatment or prevention of metalloprotease—especially MMP-13—mediated diseases. The present invention also contemplates use of such compounds in pharmaceutical compositions for oral or parenteral administration, comprising one or more of the heterobicyclic metalloprotease inhibiting compounds disclosed herein.

The present invention further provides methods of inhibiting metalloproteases, by administering formulations, including, but not limited to, oral, rectal, topical, intravenous, parenteral (including, but not limited to, intramuscular, intravenous), ocular (ophthalmic), transdermal, inhalative (including, but not limited to, pulmonary, aerosol inhalation), nasal, sublingual, subcutaneous or intraarticular formulations, comprising the heterobicyclic metalloprotease inhibiting compounds by standard methods known in medical practice, for the treatment of diseases or symptoms arising from or associated with metalloprotease, especially MMP-13, including prophylactic and therapeutic treatment. Although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient. The compounds from this invention are conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.

The heterobicyclic metalloprotease inhibiting compounds of the present invention may be used in combination with a disease modifying antirheumatic drug, a nonsteroidal anti-inflammatory drug, a COX-2 selective inhibitor, a COX-1 inhibitor, an immunosuppressive, a steroid, a biological response modifier or other anti-inflammatory agents or therapeutics useful for the treatment of chemokines mediated diseases.

DETAILED DESCRIPTION OF THE INVENTION

The terms “alkyl” or “alk”, as used herein alone or as part of another group, denote optionally substituted, straight and branched chain saturated hydrocarbon groups, preferably having 1 to 10 carbons in the normal chain, most preferably lower alkyl groups. Exemplary unsubstituted such groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl and the like. Exemplary substituents may include, but are not limited to, one or more of the following groups: halo, alkoxy, alkylthio, alkenyl, alkynyl, aryl (e.g., to form a benzyl group), cycloalkyl, cycloalkenyl, hydroxy or protected hydroxy, carboxyl (—COOH), alkyloxycarbonyl, alkylcarbonyloxy, alkylcarbonyl, carbamoyl (NH₂—CO—), substituted carbamoyl ((R¹⁰)(R¹¹)N—CO— wherein R¹⁰or R¹¹are as defined below, except that at least one of R¹⁰or R¹¹is not hydrogen), amino, heterocyclo, mono- or dialkylamino, or thiol (—SH).

The terms “lower alk” or “lower alkyl” as used herein, denote such optionally substituted groups as described above for alkyl having 1 to 4 carbon atoms in the normal chain.

The term “alkoxy” denotes an alkyl group as described above bonded through an oxygen linkage (—O—).

The term “alkenyl”, as used herein alone or as part of another group, denotes optionally substituted, straight and branched chain hydrocarbon groups containing at least one carbon to carbon double bond in the chain, and preferably having 2 to 10 carbons in the normal chain. Exemplary unsubstituted such groups include ethenyl, propenyl, isobutenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, and the like. Exemplary substituents may include, but are not limited to, one or more of the following groups: halo, alkoxy, alkylthio, alkyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, hydroxy or protected hydroxy, carboxyl (—COOH), alkyloxycarbonyl, alkylcarbonyloxy, alkylcarbonyl, carbamoyl (NH₂—CO—), substituted carbamoyl ((R¹⁰)(R¹¹)N—CO— wherein R¹⁰or R¹¹are as defined below, except that at least one of R¹⁰or R¹¹is not hydrogen), amino, heterocyclo, mono- or dialkylamino, or thiol (—SH).

The term “alkynyl”, as used herein alone or as part of another group, denotes optionally substituted, straight and branched chain hydrocarbon groups containing at least one carbon to carbon triple bond in the chain, and preferably having 2 to 10 carbons in the normal chain. Exemplary unsubstituted such groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, and the like. Exemplary substituents may include, but are not limited to, one or more of the following groups: halo, alkoxy, alkylthio, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, hydroxy or protected hydroxy, carboxyl (—COOH), alkyloxycarbonyl, alkylcarbonyloxy, alkylcarbonyl, carbamoyl (NH₂—CO—), substituted carbamoyl ((R¹⁰)(R¹¹)N—CO— wherein R¹⁰or R¹¹are as defined below, except that at least one of R¹⁰or R¹¹is not hydrogen), amino, heterocyclo, mono- or dialkylamino, or thiol (—SH).

The term “cycloalkyl”, as used herein alone or as part of another group, denotes optionally substituted, saturated cyclic hydrocarbon ring systems, containing one ring with 3 to 9 carbons. Exemplary unsubstituted such groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, and cyclododecyl. Exemplary substituents include, but are not limited to, one or more alkyl groups as described above, or one or more groups described above as alkyl substituents.

The term “bicycloalkyl”, as used herein alone or as part of another group, denotes optionally substituted, saturated cyclic bridged hydrocarbon ring systems, desirably containing 2 or 3 rings and 3 to 9 carbons per ring. Exemplary unsubstituted such groups include, but are not limited to, adamantyl, bicyclo[2.2.2]octane, bicyclo[2.2.1]heptane and cubane. Exemplary substituents include, but are not limited to, one or more alkyl groups as described above, or one or more groups described above as alkyl substituents.

The term “spiroalkyl”, as used herein alone or as part of another group, denotes optionally substituted, saturated hydrocarbon ring systems, wherein two rings of 3 to 9 carbons per ring are bridged via one carbon atom. Exemplary unsubstituted such groups include, but are not limited to, spiro[3.5]nonane, spiro[4.5]decane or spiro[2.5]octane. Exemplary substituents include, but are not limited to, one or more alkyl groups as described above, or one or more groups described above as alkyl substituents.

The term “spiroheteroalkyl”, as used herein alone or as part of another group, denotes optionally substituted, saturated hydrocarbon ring systems, wherein two rings of 3 to 9 carbons per ring are bridged via one carbon atom and at least one carbon atom is replaced by a heteroatom independently selected from N, O and S. The nitrogen and sulfur heteroatoms may optionally be oxidized. Exemplary unsubstituted such groups include, but are not limited to, 1,3-diaza-spiro[4.5]decane-2,4-dione. Exemplary substituents include, but are not limited to, one or more alkyl groups as described above, or one or more groups described above as alkyl substituents.

The terms “ar” or “aryl”, as used herein alone or as part of another group, denote optionally substituted, homocyclic aromatic groups, preferably containing 1 or 2 rings and 6 to 12 ring carbons. Exemplary unsubstituted such groups include, but are not limited to, phenyl, biphenyl, and naphthyl. Exemplary substituents include, but are not limited to, one or more nitro groups, alkyl groups as described above or groups described above as alkyl substituents.

The term “heterocycle” or “heterocyclic system” denotes a heterocyclyl, heterocyclenyl, or heteroaryl group as described herein, which contains carbon atoms and from 1 to 4 heteroatoms independently selected from N, O and S and including any bicyclic or tricyclic group in which any of the above-defined heterocyclic rings is fused to one or more heterocycle, aryl or cycloalkyl groups. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom.

Examples of heterocycles include, but are not limited to, 1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolinyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, b-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl, oxindolyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl.

Further examples of heterocycles include, but not are not limited to, “heterobicycloalkyl” groups such as 7-oxa-bicyclo[2.2.1]heptane, 7-aza-bicyclo[2.2.1]heptane, and 1-aza-bicyclo[2.2.2]octane.

“Heterocyclenyl” denotes a non-aromatic monocyclic or multicyclic hydrocarbon ring system of about 3 to about 10 atoms, desirably about 4 to about 8 atoms, in which one or more of the carbon atoms in the ring system is/are hetero element(s) other than carbon, for example nitrogen, oxygen or sulfur atoms, and which contains at least one carbon-carbon double bond or carbon-nitrogen double bond. Ring sizes of rings of the ring system may include 5 to 6 ring atoms. The designation of the aza, oxa or thia as a prefix before heterocyclenyl define that at least a nitrogen, oxygen or sulfur atom is present respectively as a ring atom. The heterocyclenyl may be optionally substituted by one or more substituents as defined herein. The nitrogen or sulphur atom of the heterocyclenyl may also be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. “Heterocyclenyl” as used herein includes by way of example and not limitation those described in Paquette, Leo A.; “Principles of Modern Heterocyclic Chemistry” (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and “J. Am. Chem. Soc.”, 82:5566 (1960), the contents all of which are incorporated by reference herein. Exemplary monocyclic azaheterocyclenyl groups include, but are not limited to, 1,2,3,4-tetrahydrohydropyridine, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6-tetrahydropyridine, 1,4,5,6-tetrahydropyrimidine, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, and the like. Exemplary oxaheterocyclenyl groups include, but are not limited to, 3,4-dihydro-2H-pyran, dihydrofuranyl, and fluorodihydrofuranyl. An exemplary multicyclic oxaheterocyclenyl group is 7-oxabicyclo[2.2.1]heptenyl.

“Heterocyclyl,” or “heterocycloalkyl,” denotes a non-aromatic saturated monocyclic or multicyclic ring system of about 3 to about 10 carbon atoms, desirably 4 to 8 carbon atoms, in which one or more of the carbon atoms in the ring system is/are hetero element(s) other than carbon, for example nitrogen, oxygen or sulfur. Ring sizes of rings of the ring system may include 5 to 6 ring atoms. The designation of the aza, oxa or thia as a prefix before heterocyclyl define that at least a nitrogen, oxygen or sulfur atom is present respectively as a ring atom. The heterocyclyl may be optionally substituted by one or more substituents which may be the same or different, and are as defined herein. The nitrogen or sulphur atom of the heterocyclyl may also be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.

“Heterocyclyl” as used herein includes by way of example and not limitation those described in Paquette, Leo A.; “Principles of Modern Heterocyclic Chemistry” (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and “J. Am. Chem. Soc.”, 82:5566 (1960). Exemplary monocyclic heterocyclyl rings include, but are not limited to, piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.

“Heteroaryl” denotes an aromatic monocyclic or multicyclic ring system of about 5 to about 10 atoms, in which one or more of the atoms in the ring system is/are hetero element(s) other than carbon, for example nitrogen, oxygen or sulfur. Ring sizes of rings of the ring system include 5 to 6 ring atoms. The “heteroaryl” may also be substituted by one or more substituents which may be the same or different, and are as defined herein. The designation of the aza, oxa or thia as a prefix before heteroaryl define that at least a nitrogen, oxygen or sulfur atom is present respectively as a ring atom. A nitrogen atom of a heteroaryl may be optionally oxidized to the corresponding N-oxide. Heteroaryl as used herein includes by way of example and not limitation those described in Paquette, Leo A.; “Principles of Modern Heterocyclic Chemistry” (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and “J. Am. Chem. Soc.”, 82:5566 (1960). Exemplary heteroaryl and substituted heteroaryl groups include, but are not limited to, pyrazinyl, thienyl, isothiazolyl, oxazolyl, pyrazolyl, furazanyl, pyrrolyl, 1,2,4-thiadiazolyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[1,2-a]pyridine, imidazo[2,1-b]thiazolyl, benzofurazanyl, azaindolyl, benzimidazolyl, benzothienyl, thienopyridyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, benzoazaindole, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, benzthiazolyl, dioxolyl, furanyl, imidazolyl, indolyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, , oxadiazolyl, oxazinyl, oxiranyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, pyrrolidinyl, quinazolinyl, quinolinyl, tetrazinyl, tetrazolyl, 1,3,4-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, thiatriazolyl, thiazinyl, thiazolyl, thienyl, 5-thioxo-1,2,4-diazolyl, thiomorpholino, thiophenyl, thiopyranyl, triazolyl and triazolonyl.

The phrase “fused” means, that the group, mentioned before “fused” is connected via two adjacent atoms to the ring system mentioned after “fused” to form a bicyclic system. For example, “heterocycloalkyl fused aryl” includes, but is not limited to, 2,3-dihydro-benzo[1,4]dioxine, 4H-benzo[1,4]oxazin-3-one, 3H-Benzooxazol-2-one and 3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one.

The term “amino” denotes the radical —NH₂wherein one or both of the hydrogen atoms may be replaced by an optionally substituted hydrocarbon group. Exemplary amino groups include, but are not limited to, n-butylamino, tert-butylamino, methylpropylamino and ethyldimethylamino.

The term “cycloalkylalkyl” denotes a cycloalkyl-alkyl group wherein a cycloalkyl as described above is bonded through an alkyl, as defined above. Cycloalkylalkyl groups may contain a lower alkyl moiety. Exemplary cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclopentylethyl, cyclohexylpropyl, cyclopropylpropyl, cyclopentylpropyl, and cyclohexylpropyl.

The term “arylalkyl” denotes an aryl group as described above bonded through an alkyl, as defined above.

The term “heteroarylalkyl” denotes a heteroaryl group as described above bonded through an alkyl, as defined above.

The term “heterocyclylalkyl,” or “heterocycloalkylalkyl,” denotes a heterocyclyl group as described above bonded through an alkyl, as defined above.

The terms “halogen”, “halo”, or “hal”, as used herein alone or as part of another group, denote chlorine, bromine, fluorine, and iodine.

The term “haloalkyl” denotes a halo group as described above bonded though an alkyl, as defined above. Fluoroalkyl is an exemplary group.

The term “aminoalkyl” denotes an amino group as defined above bonded through an alkyl, as defined above.

The phrase “bicyclic fused ring system wherein at least one ring is partially saturated” denotes an 8- to 13-membered fused bicyclic ring group in which at least one of the rings is non-aromatic. The ring group has carbon atoms and optionally 1-4 heteroatoms independently selected from N, O and S. Illustrative examples include, but are not limited to, indanyl, tetrahydronaphthyl, tetrahydroquinolyl and benzocycloheptyl.

The phrase “tricyclic fused ring system wherein at least one ring is partially saturated” denotes a 9- to 18-membered fused tricyclic ring group in which at least one of the rings is non-aromatic. The ring group has carbon atoms and optionally 1-7 heteroatoms independently selected from N, O and S. Illustrative examples include, but are not limited to, fluorene, 10,11-dihydro-5H-dibenzo[a,d]cycloheptene and 2,2a,7,7a-tetrahydro-1H-cyclobuta[a]indene.

The term “pharmaceutically acceptable salts” refers to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. Examples therefore may be, but are not limited to, sodium, potassium, choline, lysine, arginine or N-methyl-glucamine salts, and the like.

The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as, but not limited to, hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as, but not limited to, acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two. Organic solvents include, but are not limited to, nonaqueous media like ethers, ethyl acetate, ethanol, isopropanol, or acetonitrile. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, Pa., 1990, p. 1445, the disclosure of which is hereby incorporated by reference.

The phrase “pharmaceutically acceptable” denotes those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.

The phrase “pharmaceutically acceptable carrier” denotes media generally accepted in the art for the delivery of biologically active agents to mammals, e.g., humans. Such carriers are generally formulated according to a number of factors well within the purview of those of ordinary skill in the art to determine and account for. These include, without limitation: the type and nature of the active agent being formulated; the subject to which the agent-containing composition is to be administered; the intended route of administration of the composition; and, the therapeutic indication being targeted. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers can include a number of different ingredients and additives in addition to the active agent, such additional ingredients being included in the formulation for a variety of reasons, e.g., stabilization of the active agent, well known to those of ordinary skill in the art. Non-limiting examples of a pharmaceutically acceptable carrier are hyaluronic acid and salts thereof, and microspheres (including, but not limited to poly(D,L)-lactide-co-glycolic acid copolymer (PLGA), poly(L-lactic acid) (PLA), poly(caprolactone (PCL) and bovine serum albumin (BSA)). Descriptions of suitable pharmaceutically acceptable carriers, and factors involved in their selection, are found in a variety of readily available sources, e.g., Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, the contents of which are incorporated herein by reference.

Pharmaceutically acceptable carriers particularly suitable for use in conjunction with tablets include, for example, inert diluents, such as celluloses, calcium or sodium carbonate, lactose, calcium or sodium phosphate; disintegrating agents, such as croscarmellose sodium, cross-linked povidone, maize starch, or alginic acid; binding agents, such as povidone, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.

Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example celluloses, lactose, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with non-aqueous or oil medium, such as glycerin, propylene glycol, polyethylene glycol, peanut oil, liquid paraffin or olive oil.

The compositions of the invention may also be formulated as suspensions including a compound of the present invention in admixture with at least one pharmaceutically acceptable excipient suitable for the manufacture of a suspension. In yet another embodiment, pharmaceutical compositions of the invention may be formulated as dispersible powders and granules suitable for preparation of a suspension by the addition of suitable excipients.

Carriers suitable for use in connection with suspensions include suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia, dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycethanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate); and thickening agents, such as carbomer, beeswax, hard paraffin or cetyl alcohol. The suspensions may also contain one or more preservatives such as acetic acid, methyl and/or n-propyl p-hydroxy-benzoate; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents such as sucrose or saccharin.

Cyclodextrins may be added as aqueous solubility enhancers. Preferred cyclodextrins include hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of α-, β-, and γ-cyclodextrin. The amount of solubility enhancer employed will depend on the amount of the compound of the present invention in the composition.

The term “formulation” denotes a product comprising the active ingredient(s) and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical formulations of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutical carrier.

The term “N-oxide” denotes compounds that can be obtained in a known manner by reacting a compound of the present invention including a nitrogen atom (such as in a pyridyl group) with hydrogen peroxide or a peracid, such as 3-chloroperoxy-benzoic acid, in an inert solvent, such as dichloromethane, at a temperature between about −10-80° C., desirably about 0° C.

The term “polymorph” denotes a form of a chemical compound in a particular crystalline arrangement. Certain polymorphs may exhibit enhanced thermodynamic stability and may be more suitable than other polymorphic forms for inclusion in pharmaceutical formulations.

The compounds of the invention can contain one or more chiral centers and/or double bonds and, therefore, exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers, or diastereomers. According to the invention, the chemical structures depicted herein, and therefore the compounds of the invention, encompass all of the corresponding enantiomers and stereoisomers, that is, both the stereomerically pure form (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) and enantiomeric and stereoisomeric mixtures.

The term “racemic mixture” denotes a mixture that is about 50% of one enantiomer and about 50% of the corresponding enantiomer relative to all chiral centers in the molecule. Thus, the invention encompasses all enantiomerically-pure, enantiomerically-enriched, and racemic mixtures of compounds of Formulas (I) through (VI).

Enantiomeric and stereoisomeric mixtures of compounds of the invention can be resolved into their component enantiomers or stereoisomers by well-known methods. Examples include, but are not limited to, the formation of chiral salts and the use of chiral or high performance liquid chromatography “HPLC” and the formation and crystallization of chiral salts. See, e.g., Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E. L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S. H., Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind., 1972); Stereochemistry of Organic Compounds, Ernest L. Eliel, Samuel H. Wilen and Lewis N. Manda (1994 John Wiley & Sons, Inc.), and Stereoselective Synthesis A Practical Approach, Mihaly Nogradi (1995 VCH Publishers, Inc., NY, N.Y.). Enantiomers and stereoisomers can also be obtained from stereomerically- or enantiomerically-pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.

“Substituted” is intended to indicate that one or more hydrogens on the atom indicated in the expression using “substituted” is replaced with a selection from the indicated group(s), provided that the indicated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., ═O) group, then 2 hydrogens on the atom are replaced.

Unless moieties of a compound of the present invention are defined as being unsubstituted, the moieties of the compound may be substituted. In addition to any substituents provided above, the moieties of the compounds of the present invention may be optionally substituted with one or more groups independently selected from:

C₁-C₄alkyl;

C₂-C₄alkenyl;

C₂-C₄alkynyl;

CF₃;

halo;

OH;

O—(C₁-C₄alkyl);

OCH₂F;

OCHF₂;

OCF₃;

ONO₂;

OC(O)—(C₁-C₄alkyl);

OC(O)NH—(C₁-C₄alkyl);

OC(O)N(C₁-C₄alkyl)₂;

OC(S)NH—(C₁-C₄alkyl);

OC(S)N(C₁-C₄alkyl)₂;

SH;

S—(C₁-C₄alkyl);

S(O)—(C₁-C₄alkyl);

S(O)₂—(C₁-C₄alkyl);

SC(O)—(C₁-C₄alkyl);

SC(O)O—(C₁-C₄alkyl);

NH₂;

N(H)—(C₁-C₄alkyl);

N(C₁-C₄alkyl)₂;

N(H)C(O)—(C₁-C₄alkyl);

N(CH₃)C(O)—(C₁-C₄alkyl);

N(H)C(O)-CF₃;

N(CH₃)C(O)—CF₃;

N(H)C(S)—(C₁-C₄alkyl);

N(CH₃)C(S)—(C₁-C₄alkyl);

N(H)S(O)₂—(C₁-C₄alkyl);

N(H)C(O)NH₂;

N(H)C(O)NH—(C₁-C₄alkyl);

N(CH₃)C(O)NH—(C₁-C₄alkyl);

N(H)C(O)N(C₁-C₄alkyl)₂;

N(CH₃)C(O)N(C₁-C₄alkyl)₂;

N(H)S(O)₂NH₂);

N(H)S(O)₂NH—(C₁-C₄alkyl);

N(CH₃)S(O)₂NH—(C₁-C₄alkyl);

N(H)S(O)₂N(C₁-C₄alkyl)₂;

N(CH₃)S(O)₂N(C₁-C₄alkyl)₂;

N(H)C(O)O—(C₁-C₄alkyl);

N(CH₃)C(O)O—(C₁-C₄alkyl);

N(H)S(O)₂O—(C₁-C₄alkyl);

N(CH₃)S(O)₂O—(C₁-C₄alkyl);

N(CH₃)C(S)NH—(C₁-C₄alkyl);

N(CH₃)C(S)N(C₁-C₄alkyl)₂;

N(CH₃)C(S)O—(C₁-C₄alkyl);

N(H)C(S)NH₂;

NO₂;

CO₂H;

CO₂—(C₁-C₄alkyl);

C(O)N(H)OH;

C(O)N(CH₃)OH:

C(O)N(CH₃)OH;

C(O)N(CH₃)O—(C₁-C₄alkyl);

C(O)N(H)—(C₁-C₄alkyl);

C(O)N(C₁-C₄alkyl)₂;

C(S)N(H)—(C₁-C₄alkyl);

C(S)N(C₁-C₄alkyl)₂;

C(NH)N(H)—(C₁-C₄alkyl);

C(NH)N(C₁-C₄alkyl)₂;

C(NCH₃)N(H)—(C₁-C₄alkyl);

C(NCH₃)N(C₁-C₄alkyl)₂;

C(O)—(C₁-C₄alkyl);

C(NH)—(C₁-C₄alkyl);

C(NCH₃)—(C₁-C₄alkyl);

C(NOH)—(C₁-C₄alkyl);

C(NOCH₃)—(C₁-C₄alkyl);

CN;

CHO;

CH₂OH;

CH₂O—(C₁-C₄alkyl);

CH₂NH₂;

CH₂N(H)—(C₁-C₄alkyl);

CH₂N(C₁-C₄alkyl)₂;

aryl;

heteroaryl;

cycloalkyl; and

heterocyclyl.

In some cases, a ring substituent may be shown as being connected to the ring by a bond extending from the center of the ring. The number of such substituents present on a ring is indicated in subscript by a number. Moreover, the substituent may be present on any available ring atom, the available ring atom being any ring atom which bears a hydrogen which the ring substituent may replace. For illustrative purposes, if variable R^Xwere defined as being:
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this would indicate a cyclohexyl ring bearing five R^Xsubstituents. The R^Xsubstituents may be bonded to any available ring atom. For example, among the configurations encompassed by this are configurations such as:

These configurations are illustrative and are not meant to limit the scope of the invention in any way.

In one embodiment of the present invention, the amide containing heterobicyclic metalloprotease compounds may be represented by the general Formula (I):
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wherein:

R¹is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, aryl, heteroaryl, cycloalkyl fused aryl, heterocycloalkyl fused aryl, cycloalkyl fused heteroaryl, heterocycloalkyl fused heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, bicycloalkylalkyl, heterobicycloalkylalkyl, spiroalkylalkyl, spiroheteroalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl fused arylalkyl, heterocycloalkyl fused arylalkyl, cycloalkyl fused heteroarylalkyl, and heterocycloalkyl fused heteroarylalkyl,

wherein R¹is optionally substituted one or more times, or

wherein R¹is optionally substituted by one R¹⁶group and optionally substituted by one or more R⁹groups;

R²is selected from the group consisting of hydrogen and alkyl, wherein alkyl is optionally substituted one or more times or R¹and R²when taken together with the nitrogen to which they are attached complete a 3- to 8-membered ring containing carbon atoms and optionally containing a heteroatom selected from O, S(O)_x, or NR⁵⁰and which is optionally substituted one or more times;

R³is NR²⁰R²¹;

R⁴in each occurrence is independently selected from the group consisting of R¹⁰, hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, haloalkyl, CF₃, (C₀-C₆)-alkyl-COR¹⁰, (C₀-C₆)-alkyl-OR¹⁰, (C₀-C₆)-alkyl-NR¹⁰R¹¹, (C₀-C₆)-alkyl-NO₂, (C₀-C₆)-alkyl-CN, (C₀-C₆)-alkyl-S(O)_yOR¹⁰, (C₀-C₆)-alkyl-S(O)_yNR¹⁰R¹¹, (C₀-C₆)-alkyl-NR¹⁰CONR¹¹SO₂R³⁰, (C₀-C₆)-alkyl-S(O)_xR¹⁰, (C₀-C₆)-alkyl-OC(O)R¹⁰, (C₀-C₆)-alkyl-OC(O)NR¹⁰R¹¹, (C₀-C₆)-alkyl-C(═NR¹⁰)NR¹⁰R¹¹, (C₀-C₆)-alkyl-NR¹⁰C(═NR¹¹)NR¹⁰R¹¹, (C₀-C₆)-alkyl-C(O)OR¹⁰, (C₀-C₆)-alkyl-C(O)NR¹⁰R¹¹, (C₀-C₆)-alkyl-C(O)NR¹⁰SO₂R¹¹, (C₀-C₆)-alkyl-C(O)—NR¹¹—CN, O—(C₀-C₆)-alkyl-C(O)NR¹⁰R¹¹, S(O)_x—(C₀-C₆)-alkyl-C(O)OR¹⁰, S(O)_x—(C₀-C₆)-alkyl-C(O)NR¹⁰R¹¹, (C₀-C₆)-alkyl-C(O)NR¹⁰—(C₀-C₆)-alkyl-NR¹⁰R¹¹, (C₀-C₆)-alkyl-NR¹⁰—C(O)R¹⁰, (C₀-C₆)-alkyl-NR¹⁰—C(O)OR¹⁰, (C₀-C₆)-alkyl-NR¹⁰—C(O)—NR¹⁰R¹¹, (C₀-C₆)-alkyl-NR¹⁰—S(O)_yNR¹⁰R¹¹, (C₀-C₆)-alkyl-NR¹⁰—S(O)_yR¹⁰, O—(C₀-C₆)-alkyl-aryl and O—(C₀-C₆)-alkyl-heteroaryl,

wherein each R⁴group is optionally substituted one or more times, or

wherein each R⁴group is optionally substituted by one or more R¹⁴groups;

R⁵in each occurrence is independently selected from the group consisting of hydrogen, alkyl, C(O)NR¹⁰R¹¹, aryl, arylalkyl, SO₂NR¹⁰R¹¹and C(O)OR¹⁰, wherein alkyl, aryl and arylalkyl are optionally substituted one or more times;

R⁹in each occurrence is independently selected from the group consisting of R¹⁰, hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, CHF₂, CF₃, OR¹⁰, SR¹⁰, COOR¹⁰, CH(CH₃)CO₂H, (C₀-C₆)-alkyl-COR¹⁰, (C₀-C₆)-alkyl-OR¹⁰, (C₀-C₆)-alkyl-NR¹⁰R¹¹, (C₀-C₆)-alkyl-NO₂, (C₀-C₆)-alkyl-CN, (C₀-C₆)-alkyl-S(O)_yOR¹⁰, (C₀-C₆)-alkyl-P(O)₂OH, (C₀-C₆)-alkyl-S(O)_yNR¹⁰R¹¹, (C₀-C₆)-alkyl-NR¹⁰CONR¹¹SO₂R³⁰, (C₀-C₆)-alkyl-S(O)_xR¹⁰, (C₀-C₆)-alkyl-OC(O)R¹⁰, (C₀-C₆)-alkyl-OC(O)NR¹⁰R¹¹, (C₀-C₆)-alkyl-C(═NR¹⁰)NR¹⁰R¹¹, (C₀-C₆)-alkyl-NR¹⁰C(═NR¹¹)NR¹⁰R¹¹, (C₀-C₆)-alkyl-NR¹⁰C(═N—CN)NR¹⁰R¹¹, (C₀-C₆)-alkyl-C(═N—CN)NR¹⁰R¹¹, (C₀-C₆)-alkyl-NR¹⁰C(═N—NO₂)NR¹⁰R¹¹, (C₀-C₆)-alkyl-C(═N—NO₂)NR¹⁰R¹¹, (C₀-C₆)-alkyl-C(O)OR¹⁰, (C₀-C₆)-alkyl-C(O)NR¹⁰R¹¹, (C₀-C₆)-alkyl-C(O)NR¹⁰SO₂R¹¹, C(O)NR¹⁰—(C₀-C₆)-alkyl-heteroaryl, C(O)NR¹⁰—(C₀-C₆)-alkyl-aryl, S(O)₂NR¹⁰—(C₀-C₆)-alkyl-aryl, S(O)₂NR¹⁰—(C₀-C₆)-alkyl-heteroaryl, S(O)2NR¹⁰-alkyl, S(O)₂-(C₀-C₆)-alkyl-aryl, S(O)₂—(C₀-C₆)-alkyl-heteroaryl, (C₀-C₆)-alkyl-C(O)—NR¹¹—CN, O—(C₀-C₆)-alkyl-C(O)NR¹⁰R¹¹, S(O)_x—(C₀-C₆)-alkyl-C(O)OR¹⁰, S(O)_x-(C₀-C₆)-alkyl-C(O)NR¹⁰R¹¹, (C₀-C₆)-alkyl-C(O)NR¹⁰—(C₀-C₆)-alkyl-NR¹⁰R¹¹, (C₀-C₆)-alkyl-NR¹⁰—C(O)R¹⁰, (C₀-C₆)-alkyl-NR¹⁰-C(O)OR¹⁰, (C₀-C₆)-alkyl-NR¹⁰—C(O)—NR¹⁰R¹¹, (C₀-C₆)-alkyl-NR¹⁰—S(O)_yNR¹⁰R¹¹, (C₀-C₆)-alkyl-NR¹⁰—S(O)_yR¹¹, O—(C₀-C₆)-alkyl-aryl and O—(C₀-C₆)-alkyl-heteroaryl,

wherein each R⁹group is optionally substituted, or

wherein each R⁹group is optionally substituted by one or more R¹⁴groups;

R¹⁰and R¹¹in each occurrence are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl are optionally substituted one or more times, or R¹⁰and R¹¹when taken together with the nitrogen to which they are attached complete a 3- to 8-membered ring containing carbon atoms and optionally containing a heteroatom selected from O, S(O)_x, or NR⁵⁰and which is optionally substituted one or more times;

R¹⁴is independently selected from the group consisting of hydrogen, alkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclylalkyl and halo, wherein alkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl and heterocyclylalkyl are optionally substituted one or more times;

R¹⁶is selected from the group consisting of cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, aryl, heteroaryl, cycloalkyl fused aryl, heterocycloalkyl fused aryl, cycloalkyl fused heteroaryl, heterocycloalkyl fused heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, bicycloalkylalkyl, heterobicycloalkylalkyl, spiroalkylalkyl, spiroheteroalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl fused arylalkyl, heterocycloalkyl fused arylalkyl, cycloalkyl fused heteroarylalkyl, heterocycloalkyl fused heteroarylalkyl, (i) and (ii):
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wherein cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, aryl, heteroaryl, cycloalkyl fused aryl, heterocycloalkyl fused aryl, cycloalkyl fused heteroaryl, heterocycloalkyl fused heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, bicycloalkylalkyl, heterobicycloalkylalkyl, spiroalkylalkyl, spiroheteroalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl fused arylalkyl, heterocycloalkyl fused arylalkyl, cycloalkyl fused heteroarylalkyl, and heterocycloalkyl fused heteroarylalkyl are optionally substituted one or more times;

R²⁰is selected from the group consisting of hydrogen and alkyl, wherein alkyl is optionally substituted one or more times;

R²¹is a bicyclic or tricyclic fused ring system, wherein at least one ring is partially saturated, and

wherein R²¹is optionally substituted one or more times, or

wherein R²¹is optionally substituted by one or more R⁹groups;

R²²is selected from the group consisting of hydrogen, hydroxy, halo, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, NO₂, NR¹⁰R¹¹, CN, SR¹⁰, SSR¹⁰, PO₃R¹⁰, NR¹⁰NR¹⁰R¹¹, NR¹⁰N═CR¹⁰R¹¹, NR¹⁰SO₂R¹¹, C(O)OR¹⁰, C(O)NR¹⁰R¹¹, SO₂R¹⁰, SO₂NR¹⁰R¹¹and fluoroalkyl, wherein alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, and fluoroalkyl are optionally substituted one or more times;

R³⁰is selected from the group consisting of alkyl and (C₀-C₆)-alkyl-aryl, wherein alkyl and aryl are optionally substituted;

R⁵⁰in each occurrence is independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, C(O)R⁸⁰, C(O)NR⁸⁰R⁸¹, SO₂R⁸⁰and SO₂NR⁸⁰R⁸¹, wherein alkyl, aryl, and heteroaryl are optionally substituted one or more times;

R⁸⁰and R⁸¹in each occurrence are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl are optionally substituted, or R⁸⁰and R⁸¹when taken together with the nitrogen to which they are attached complete a 3- to 8-membered ring containing carbon atoms and optionally a heteroatom selected from O, S(O)_x, —NH, and —N(alkyl) and which is optionally substituted one or more times;

E is selected from the group consisting of a bond, CR¹⁰R¹¹, O, NR⁵, S, S═O, S(═O)₂, C(═O), N(R¹⁰)(C═O), (C═O)N(R¹⁰), N(R¹⁰)S(═O)₂, S(═O)₂N(R¹⁰), C═N—OR¹¹, —C(R¹⁰R¹¹)C(R¹⁰OR¹¹)—, —CH₂—W¹— and
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Q is a 5- or 6-membered ring selected from the group consisting of aryl and heteroaryl, wherein aryl and heteroaryl are optionally substituted one or more times with R⁴;

D is a member selected from the group consisting of CR²²and N;

U is selected from the group consisting of C(R⁵R¹⁰), NR⁵, O, S, S═O and S(═O)₂;

W¹is selected from the group consisting of O, NR⁵, S, S═O, S(═O)₂, N(R¹⁰)(C═O), N(R¹⁰)S(═O)₂and S(═O)₂N(R¹⁰);

X is selected from the group consisting of a bond and (CR¹⁰R¹¹)_wE(CR¹⁰R¹¹)_w;

g and h are independently selected from 0-2;

w is independently selected from 0-4;

x is selected from 0 to 2;

y is selected from 1 and 2; and

N-oxides, pharmaceutically acceptable salts, prodrugs, formulation, polymorphs, racemic mixtures and stereoisomers thereof.

In another embodiment, compounds of Formula (I) may be selected from Group I(a):
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wherein:

R⁵¹is independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl and haloalkyl, wherein alkyl, aryl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl and haloalkyl are optionally substituted one or more times.

In still another embodiment, compounds of Formula (I) may be selected from:
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In yet another embodiment, compounds of Formula (I) may be selected from:
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In some embodiments, R³of the compounds of Formula (I) may be selected from Substituent Group 1:
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wherein:

R⁷is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, halo, R⁴and NR¹⁰R¹¹, wherein alkyl and cycloalkyl are optionally substituted one or more times, or optionally two R⁷groups together at the same carbon atom form ═O, ═S or ═NR¹⁰;

A and B are independently selected from the group consisting of CR⁹, CR⁹R¹⁰, NR¹⁰, N, O and S(O)_x;

G, L, M and T are independently selected from the group consisting of CR⁹and N;

m and n are independently selected from 0-3, provided that:

- (1) when E is present, m and n are not both 3;
- (2) when E is —CH₂—W¹—, m and n are not 3; and
- (3) when E is a bond, m and n are not 0; and

p is selected from 0-6;

wherein the dotted line represents a double bond between one of: carbon “a” and A, or carbon “a” and B.

For example, in some embodiments, R³of the compounds of Group I(a) may be selected from Substituent Group 1 as defined hereinabove.

In some embodiments, R³of Formula (I) may be selected from Substituent Group I(2):
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wherein:

R is selected from the group consisting of C(O)NR¹⁰R¹¹, COR¹⁰, SO₂NR¹⁰R¹¹, SO₂R¹⁰, CONHCH₃and CON(CH₃)₂, wherein C(O)NR¹⁰R¹¹, COR¹⁰, SO₂NR¹⁰R¹¹, SO₂R¹⁰, CONHCH₃and CON(CH₃)₂are optionally substituted one or more times; and

r is selected from 1-4.

For example, in some embodiments, R³of the compounds of Group I(a) may be selected from Substituent Group 2, as defined hereinabove.

In yet a further embodiment, R³of Formula (I) may be selected from Substituent Group 3:
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For example, in some embodiments, R³of the structures of Group I(a) may be selected from Substituent Group 3 as defined hereinabove.

In another embodiment, R⁹may be selected from Substituent Group 4:
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wherein:

R⁵²is selected from the group consisting of hydrogen, halo, CN, hydroxy, alkoxy, fluoroalkoxy, alkyl, aryl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, haloalkyl, C(O)NR¹⁰R¹¹and SO₂NR¹⁰R¹¹, wherein alkoxy, fluoroalkoxy, alkyl, aryl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, and haloalkyl are optionally substituted one or more times.

For example, in some embodiments, R⁹of Substituent Group 3 may be selected from Substituent Group 4 as defined hereinabove.

In yet a further embodiment, R³of the structures of Formula (I) may be Substituent Group 16:
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For example, in some embodiments, R³of the structures of Group I(a) may be selected from Substituent Group 16 as defined hereinabove.

In still a further embodiment, R³of Formula (I) may be selected from Substituent Group
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wherein:

R⁹is selected from the group consisting of hydrogen, fluoro, halo, CN, alkyl, CO₂H,
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For example, in some embodiments, R³of the structures of Group I(a) may be selected from Substituent Group 5 as defined hereinabove.

In another embodiment, R¹of Formula (I) may be selected from Substituent Group 6:
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wherein:

R¹⁸is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, heteroaryl, OH, halo, CN, C(O)NR¹⁰R¹¹, CO₂R¹⁰, OR¹⁰, OCF₃, OCHF₂, NR¹⁰CONR¹⁰R¹¹, NR¹⁰COR¹¹, NR¹⁰SO₂R¹¹, NR¹⁰SO₂NR¹⁰R¹¹, SO₂NR¹⁰R¹¹and NR¹⁰R¹¹, wherein alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, heteroaryl are optionally substituted one or more times;

R²⁵is selected from the group consisting of hydrogen, alkyl, cycloalkyl, CO₂R¹⁰, C(O)NR¹⁰R¹¹and haloalkyl, wherein alkyl, cycloalkyl, and haloalkyl are optionally substituted one or more times;

B₁is selected from the group consisting of NR¹⁰, O and S(O)_x;

D², G², L², M²and T²are independently selected from the group consisting of CR¹⁸and N; and

Z is a 5- to 8-membered ring selected from the group consisting of cycloalkyl, heterocycloalkyl, or a 5- to 6-membered ring selected from the group consisting of aryl and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted one or more times.

For example, in another embodiment, R¹of the structures of Group I(a) may be selected from Substituent Group 6 as defined hereinabove.

In yet another embodiment, R¹of the structures of Group I(a) may be selected from Substituent Group 7:
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For example, in some embodiments, R¹of the structures of Group I(a) may be selected from Substituent Group 7 as defined hereinabove.

In still another embodiment, R¹of Formula (I) may be selected from Substituent Group 8:
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wherein:

R¹²and R¹³are independently selected from the group consisting of hydrogen, alkyl and halo, wherein alkyl is optionally substituted one or more times, or optionally R¹²and R¹³together form ═O, ═S or ═NR¹⁰;

R¹⁸is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, heteroaryl, OH, halo, CN, C(O)NR¹⁰R¹¹, CO₂R¹⁰, OR¹⁰, OCF₃, OCHF₂, NR¹⁰CONR¹⁰R¹¹, NR¹⁰COR¹¹, NR¹⁰SO₂R¹¹, NR¹⁰SO₂NR¹⁰R¹¹, SO₂NR¹⁰R¹¹and NR¹⁰R¹¹, wherein alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, and heteroaryl are optionally substituted one or more times;

R¹⁹is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, heteroaryl, OH, halo, CN, C(O)NR¹⁰R¹¹, CO₂R¹⁰, OR¹⁰, OCF₃, OCHF₂, NR¹⁰CONR¹⁰R¹¹, NR¹⁰COR¹¹, NR¹⁰SO₂R¹¹, NR¹⁰SO₂NR¹⁰R¹¹, SO₂NR¹⁰R¹¹and NR¹⁰R¹¹, wherein alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, and heteroaryl are optionally substituted one or more times, or optionally two R¹⁹groups together at one carbon atom form ═O, ═S or ═NR¹⁰;

J and K are independently selected from the group consisting of CR¹⁰R¹⁸, NR¹⁰, O and S(O)_x;

A₁is selected from the group consisting of NR¹⁰, O and S(O)_x; and

D², G², J², L², M²and T²are independently selected from the group consisting of CR¹⁸and N.

For example, some embodiments, R¹of the structures of Group I(a) may be selected from Substituent Group 8 as defined hereinabove.

In a further embodiment, R¹of Formula (I) may be selected from Substituent Group 9:
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For example, in some embodiments, R¹of the structures of Group I(a) may be selected from Substituent Group 9 as defined hereinabove

In yet a further embodiment, R¹of Formula (I) may be selected from Substituent Group 10:
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wherein:

R¹⁸is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, heteroaryl, OH, halo, CN, C(O)NR¹⁰R¹¹, CO₂R¹⁰, OR¹⁰, OCF₃, OCHF₂, NR¹⁰CONR¹⁰R¹¹, NR¹⁰COR¹¹, NR¹⁰SO₂R¹¹, NR¹⁰SO₂NR¹⁰R¹¹, SO₂NR¹⁰R¹¹and NR¹⁰R¹¹, wherein alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, and heteroaryl are optionally substituted one or more times;

R²⁵is selected from the group consisting of hydrogen, alkyl, cycloalkyl, CONR¹⁰R¹¹and haloalkyl, wherein alkyl, cycloalkyl and haloalkyl are optionally substituted one or more times;

L², M², and T²are independently selected from the group consisting of CR¹⁸and N;

D³, G³, L³, M³, and T³are independently selected from N, CR¹⁸, (i), or (ii),
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with the proviso that one of L³, M³, T³, D³, and G³is (i) or (ii)

B₁is selected from the group consisting of NR¹⁰, O and S(O)_x; and

Q²is a 5- to 8-membered ring selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, which is optionally substituted one or more times with R¹⁹.

For example, in some embodiments, R¹of the structures of Group I(a) may be selected from Substituent Group 10 as defined herinabove.

In still a further embodiment, R¹of Formula (D) may be selected from Substituent Group 11:
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For example, in some embodiments, R¹of the structures of Group I(a) may be selected from Substituent Group 11 as defined hereinabove.

In another embodiment, R¹of Formula (I) may be selected from Substituent Group 12:
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For example, in some embodiments, R¹of the structures of Group I(a) may be selected from Substituent Group 12 as defined hereinabove.

In yet another embodiment, the amide containing heterobicyclic metalloprotease compounds may be represented by the general Formula (II):
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- and N-oxides, pharmaceutically acceptable salts, prodrugs, formulation, polymorphs, racemic mixtures and stereoisomers thereof,

wherein:

R¹in each occurrence may be the same or different and is as defined hereinabove;

R²in each occurrence may be the same or different and is as defined hereinabove; and

all remaining variables are as defined hereinabove.

In still another embodiment, the compound of Formula (II) may be selected from Group II(a):
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wherein all variables are as defined hereinabove.

In a further embodiment, the compound of Formula (II) may be selected from:
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In yet a further embodiment, the compound of Formula (II) may be selected from:
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In still a further embodiment, at least one R¹of Formula (II) may be selected from Substituent Group 13:
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wherein:

R⁶is independently selected from the group consisting of R⁹, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, aryl, heteroaryl, C(O)OR¹⁰, CH(CH₃)CO₂H, (C₀-C₆)-alkyl-COR¹⁰, (C₀-C₆)-alkyl-OR¹⁰, (C₀-C₆)-alkyl-NR¹⁰R¹¹, (C₀-C₆)-alkyl-NO₂, (C₀-C₆)-alkyl-CN, (C₀-C₆)-alkyl-S(O)_yOR¹⁰, (C₀-C₆)-alkyl-P(O)₂OH, (C₀-C₆)-alkyl-S(O)_yNR¹⁰R¹¹, (C₀-C₆)-alkyl-NR¹⁰CONR¹¹SO₂R³⁰, (C₀-C₆)-alkyl-S(O)_xR¹⁰, (C₀-C₆)-alkyl-OC(O)R¹⁰, (C₀-C₆)-alkyl-OC(O)NR¹⁰R¹¹, (C₀-C₆)-alkyl-C(═NR¹⁰)NR¹⁰R¹¹, (C₀-C₆)-alkyl-NR¹⁰C(═NR¹¹)NR¹⁰R¹¹, (C₀-C₆)-alkyl-NR¹⁰C(═N—CN)NR¹⁰R¹¹, (C₀-C₆)-alkyl-C(═N—CN)NR¹⁰R¹¹, (C₀-C₆)-alkyl-NR¹⁰C(═N—NO₂)NR¹⁰R¹¹, (C₀-C₆)-alkyl-C(═N—NO₂)NR¹⁰R¹¹, (C₀-C₆)-alkyl-C(O)OR¹⁰, (C₀-C₆)-alkyl-C(O)NR¹⁰R¹¹, (C₀-C₆)-alkyl-C(O)NR¹⁰SO²R¹¹, C(O)NR¹⁰—(C₀-C₆)-alkyl-heteroaryl, C(O)NR¹⁰—(C₀-C₆)-alkyl-aryl, S(O)₂NR¹⁰—(C₀-C₆)-alkyl-aryl, S(O)₂NR¹⁰—(C₀-C₆)-alkyl-heteroaryl, S(O)²NR¹⁰-alkyl, S(O)₂-(C₀-C₆)-alkyl-aryl, S(O)₂—(C₀-C₆)-alkyl-heteroaryl, (C₀-C₆)-alkyl-C(O)-NR¹¹—CN, O—(C₀-C₆)-alkyl-C(O)NR¹⁰R¹¹, S(O)^x—(C₀-C₆)-alkyl-C(O)OR¹⁰, S(O)_x—(C₀-C₆)-alkyl-C(O)NR¹⁰R¹¹, (C₀-C₆)-alkyl-C(O)NR¹⁰—(C₀-C₆)-alkyl-NR¹⁰R¹¹, (C₀-C₆)-alkyl-NR¹⁰—C(O)R¹⁰, (C₀-C₆)-alkyl-NR¹⁰—C(O)OR¹⁰, (C₀-C₆)-alkyl-NR¹⁰—C(O)—NR¹⁰R¹¹, (C₀-C₆)-alkyl-NR¹⁰—S(O)_yNR¹⁰R¹¹, (C₀-C₆)-alkyl-NR¹⁰—S(O)_yR¹¹, O—(C₀-C₆)-alkyl-aryl and O—(C₀-C₆)-alkyl-heteroaryl, wherein each R⁶group is optionally substituted by one or more R¹⁴groups;

R⁹is independently selected from the group consisting of hydrogen, alkyl, halo, CHF₂, CF₃, OR¹⁰, NR¹⁰R¹¹, NO₂, and CN, wherein alkyl is optionally substituted one or more times;

D⁴, G⁴, L⁴, M4, and T⁴are independently selected from CR⁶and N; and

all remaining variables are as defined hereinabove.

For example, in some embodiments, at least one R¹of the structures of Group II(a) may independently be selected from Substituent Group 13 as defined hereinabove.

In another embodiment, at least one R¹of Formula (II) may be selected from Substituent Group 14:
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For example, in some embodiments, at least one R¹of Group II(a) may independently be selected from Substituent Group 14 as defined hereinabove.

In yet another embodiment, R⁶of Substituent Group 14 may be selected from hydrogen, halo, CN, OH, CH₂OH, CF₃, CHF₂, OCF₃, OCHF₂, COCH₃, SO₂CH₃, SO₂CF₃, SO₂NH₂, SO₂NHCH₃, SO₂N(CH₃)₂, NH₂, NHCOCH₃, N(COCH₃)₂, NHCONH₂, NHSO₂CH₃, alkoxy, alkyl, cycloalkyl, heterocycloalkyl, bicycloalkyl, CO₂H,
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R⁹is independently selected from the group consisting of hydrogen, fluoro, chloro, CH₃, CF₃, CHF₂, OCF₃, and OCHF₂;

R²⁵is selected from the group consisting of hydrogen, CH₃, COOCH₃, COOH, and CONH₂.

In yet another embodiment, at least one R¹of Formula (II) may be selected from Substituent Group 15:
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For example, in some embodiments, at least one R¹of Group II(a) may be selected from Substituent Group 15 as defined hereinabove.

In still another embodiment, at least one R¹of Formula (II) may be selected from Substituent Group 8:
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wherein all variables are as defined hereinabove.

For example, in some embodiments, at least one R¹of Group II(a) may be selected from Substituent Group 8 as defined hereinabove.

In a further embodiment, at least one R¹of Formula (II) may be selected from Substituent Group 9:
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For example, in some embodiments, at least one R¹of Group II(a) may be selected from Substituent Group 9 as defined hereinabove.

In yet a further embodiment, one R¹of Formula (II) may be selected from Substituent Group 10:
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wherein all variables are as defined hereinabove.

For example, in some embodiments, one R¹of Group II(a) may be selected from Substituent Group 10 as defined hereinabove.

In still a further embodiment, one R¹of Formula (II) may independently be selected from Substituent Group 11:
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For example, in some embodiments, one R¹of Group II(a) may be selected from Substituent Group 11 as defined hereinabove.

In one embodiment, one R¹of Formula (II) may be selected from Substituent Group 12:
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For example, in some embodiments, one R¹of Group II(a) may be selected from Substituent Group 12 as defined hereinabove.

In some embodiments:

A) the first occurrence of R¹of Formula (II) is selected from Substituent Group 13:

B) the second occurrence R¹of Formula (II) is selected from Substituent Group 8 and Substituent Group 10:
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wherein all variables are as defined hereinabove.

For example in some embodiments, the first occurrence of R¹of the structures of Group II(a) may be selected from Substituent Group 13 as defined hereinabove, and the second occurrence of R¹may be selected from Substituent Group 10 as defined hereinabove.

In another embodiment of the present invention, the amide containing heterobicyclic metalloprotease compounds may be represented by the general Formula (III):
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and N-oxides, pharmaceutically acceptable salts, prodrugs, formulation, polymorphs, racemic mixtures and stereoisomers thereof,

wherein all variables are as defined hereinabove.

In yet another embodiment, the compounds of Formula (III) may be selected from Group III(a):
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wherein all variables are as defined hereinabove.

In still another embodiment, the compounds of Formula (III) may be selected from:
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In a further embodiment, the compounds of Formula (III) may be selected from:
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In yet a further embodiment, R³of Formula (III) may be selected from Substituent Group 1:
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wherein all variables are as defined hereinabove.

For example, in some embodiments, R³of the structures of Group III(a) may be selected from Substituent Group 1 as defined hereinabove.

In still a further embodiment, R³of Formula (III) may be selected from Substituent Group 2:
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wherein all variables are as defined hereinabove.

In still a further embodiment, R³of the structures of Group III(a) may be selected from Substituent Group 2 as defined hereinabove.

In one embodiment, R³of Formula (III) may be selected from Substituent Group 3:
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For example, in some embodiments, R³of the structures of Group III(a) may be selected from Substituent Group 3 as defined hereinabove.

In one embodiment, R⁹of the structures of Substituent Group 3 may be selected from:
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wherein all variables are as defined hereinabove.

In another embodiment, R³of Formula (III) may be Substituent Group 16:
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For example, in some embodiments, R³of the structures of Group III(a) may be Substituent Group 16 as defined hereinabove.

In yet another embodiment, R³of Formula (III) may be selected from Substituent Group 5:
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wherein:

R⁹is selected from hydrogen, fluoro, halo, CN, alkyl, CO₂H,
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For example, in some embodiments, R³of the structures of Group III(a) may be selected from Substituent Group 5 as defined hereinabove.

In still another embodiment, R¹of the structures of Formula (III) may be selected from Substituent Group 6:
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wherein all variables are as defined hereinabove.

For example, in some embodiments, R¹of the structures of Group III(a) may be selected from Substituent Group 6 as defined hereinabove.

In a further embodiment, R¹of Formula (III) may be selected from Substituent Group 7:
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For example, in some embodiments, R¹of the structures of Group III(a) may be selected from Substituent Group 7 as defined hereinabove.

In yet a further embodiment, R¹of Formula (III) may be selected from Substituent Group 8:
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wherein all variables are as defined hereinabove.

For example, in some embodiments, R¹of the structures of Group III(a) may be selected from Substituent Group 8 as defined hereinabove.

In still a further embodiment, R¹of Formula (III) may be selected from Substituent Group 9:
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For example, in some embodiments, R¹of the structures of Group III(a) may be selected from Substituent Group 9 as defined hereinabove.

In one embodiment, R¹of Group III(a) may be selected from Substituent Group 10.
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wherein all variables are as defined hereinabove.

For example, in some embodiments, R¹of the structures of Group III(a) may be selected from Substituent Group 10 as defined hereinabove.

In another embodiment, R¹of Formula (III) may be selected from Substituent Group 11:
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wherein all variables are as defined hereinabove.

For example, in some embodiments, R¹of the structures of Group III(a) may be selected from Substituent Group 11 as defined hereinabove.

In yet another embodiment, R¹of Formula (III) may be selected from Substituent Group 12:
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For example, in some embodiments, R¹of the structures of Group III(a) may be selected from Substituent Group 12 as defined hereinabove.

In one embodiment of the present invention, the amide containing heterobicyclic metalloprotease compounds may be represented by the general Formula (IV):
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and N-oxides, pharmaceutically acceptable salts, prodrugs, formulation, polymorphs, racemic mixtures and stereoisomers thereof,

wherein:

R²³is selected from the group consisting of hydrogen, hydroxy, halo, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, NO₂, NR¹⁰R¹¹, CN, SR¹⁰, SSR¹⁰, PO₃R¹⁰, NR¹⁰NR¹⁰R¹¹, NR¹⁰N═CR¹⁰R¹¹, NR¹⁰SO₂R¹¹, C(O)OR¹⁰, and fluoroalkyl, wherein alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, and fluoroalkyl are optionally substituted one or more times;

W is a 5- or 6-membered ring selected from the group consisting of aryl and heteroaryl, wherein aryl and heteroaryl are optionally substituted one or more times with R⁴; and

all remaining variables are as defined herein above.

In another embodiment, the compounds of Formula (IV) may be selected from Group IV(a):
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wherein:

K¹is O, S(O)_x, or NR⁵¹; and

all remaining variables are as defined hereinabove.

In yet another embodiment, the compounds of Formula (IV) may be selected from Group IV(b):
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In still another embodiment, R³of Formula (IV) may be selected from Substituent Group 1:
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wherein all variables are as defined hereinabove.

For example, in some embodiments, R³of the structures of Groups IV(a) and (b) may be selected from Substituent Group 1 as defined hereinabove.

In a further embodiment, R³of Formula (IV) may be selected from Substituent Group 2:
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wherein all variables are as defined hereinabove.

For example, in some embodiments, R³of the structures of Groups IV(a) and (b) may be selected from Substituent Group 2 as defined hereinabove.

In yet a further embodiment, R³of Formula (IV) may be selected from Substituent Group 3
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For example, in some embodiments, R³of the structures of Groups IV(a) and (b) may be selected from Substituent Group 3 as defined hereinabove.

In still a further embodiment, R⁹of Substituent Group 3 may be selected from:
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wherein all variables are as defined hereinabove.

In one embodiment, R³of Formula (IV) may be Substituent Group 16:
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For example, in some embodiments, R³of the structures of Groups IV(a) and (b) may be Substituent Group 16 as defined hereinabove.

In another embodiment, R³of Formula (IV) may be selected from Substituent Group 5:
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wherein R⁹is selected from hydrogen, fluoro, halo, CN, alkyl, CO₂H,
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For example, in some embodiments, R³of the structures of Groups IV(a) and (b) may be selected from Substituent Group 5 as defined hereinabove.

In yet another embodiment, R¹of Formula (IV) may be selected from Substituent Group 6:
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wherein all variables are as defined hereinabove.

For example, in some embodiments, R¹of the structures of Groups IV(a) and (b) may be selected from Substituent Group 6 as defined hereinabove.

In still another embodiment, R¹of Formula (IV) may be selected from Substituent Group 7:
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For example, in some embodiments, R¹of the structures of Groups IV(a) and (b) may be selected from Substituent Group 7 as defined hereinabove.

In a further embodiment, R¹of Formula (IV) may be selected from Substituent Group 8:
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wherein all variables are as defined hereinabove.

For example, in some embodiments, R¹of the structures of Groups IV(a) and (b) may be selected from Substituent Group 8 as defined hereinabove.

In yet a further embodiment, R¹of Formula (IV) may be selected from Substituent Group 9:
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For example, in some embodiments, R¹of the structures of Groups IV(a) and (b) may be selected from Substituent Group 9 as defined hereinabove.

In still a further embodiment, R¹of Formula (IV) may be selected from Substituent Group 10:
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wherein all variables are as defined hereinabove.

For example, in some embodiments, R¹of the structures of Groups IV(a) and (b) may be selected from Substituent Group 10 as defined hereinabove.

In one embodiment, R¹of Formula (IV) may be selected from Substituent Group 11:
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For example, in some embodiments, R¹of the structures of Groups IV(a) and (b) may be selected from Substituent Group 11 as defined hereinabove.

In another embodiment, R¹of Formula (IV) may be selected from Substituent Group 12:
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For example, in some embodiments, R¹of the structures of Groups IV(a) and (b) may be selected from Substituent Group 12 as defined hereinabove.

In still another embodiment of the present invention, the amide containing heterobicyclic metalloprotease compounds may be represented by the general Formula (V):
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and N-oxides, pharmaceutically acceptable salts, prodrugs, formulation, polymorphs, racemic mixtures and stereoisomers thereof,

wherein:

R¹in each occurrence may be the same or different and is as defined hereinabove;

R²in each occurrence may be the same or different and is as defined hereinabove; and

all remaining variables are as defined hereinabove.

In a further embodiment, compounds of Formula (V) may be selected from Group V(a):
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wherein all variables are as defined hereinabove.

In yet a further embodiment, the compounds of Formula (V) may be selected from Group V(b):
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In still a further embodiment, at least one R¹of Formula (V) may be selected from Substituent Group 13:
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wherein all variables are as defined hereinabove.

For example, in some embodiments, at least one R¹of the structures of Groups V(a) and (b) may be selected from Substituent Group 13 as defined hereinabove.

In one embodiment, at least one R¹of the compounds of Formula (V) may be selected from Substituent Group 14:
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For example, in some embodiments, at least one R¹of the structures of Groups V(a) and (b) may be selected from Substituent Group 14 as defined hereinabove.

In another embodiment, R⁶of Substituent Group 14 may be selected from hydrogen, halo, CN, OH, CH₂OH, CF₃, CHF₂, OCF₃, OCHF₂, COCH₃, SO₂CH₃, SO₂CF₃, SO₂NH₂, SO₂NHCH₃, SO₂N(CH₃)₂, NH₂, NHCOCH₃, N(COCH₃)₂, NHCONH₂, NHSO₂CH₃, alkoxy, alkyl, CO₂H,
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R⁹is independently selected from the group consisting of hydrogen, fluoro, chloro, CH₃, CF₃, CHF₂, OCF₃, and OCHF₂;

R²⁵is selected from the group consisting of hydrogen, CH₃, COOCH₃, COOH, and CONH₂.

In yet another embodiment, at least one R¹of Formula (V) may be selected from Substituent Group 15:
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For example, in some embodiments, at least one R¹of the structures of Groups V(a) and (b) may be selected from Substituent Group 15 as defined hereinabove.

In still another embodiment, at least one R¹of Formula (V) may be selected from Substituent Group 8:
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wherein all variables are as defined hereinabove.

For example, in some embodiments, at least one R¹of the structures of Groups V(a) and (b) may be selected from Substituent Group 8 as defined hereinabove.

In a further embodiment, at least one R¹of Formula (V) may be selected from Substituent Group 9:
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For example, in some embodiments, at least one R¹of the structures of Groups V(a) and (b) may be selected from Substituent Group 9 as defined hereinabove.

In yet a further embodiment, one R¹of Formula (V) may be selected from Substituent Group 10:
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wherein all variables are as defined hereinabove.

For example, in some embodiments, one R¹of the structures of Groups V(a) and (b) may be selected from Substituent Group 10 as defined hereinabove.

In still a further embodiment, each R¹of Formula (V) may be independently selected from Substituent Group 11:
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For example, in some embodiments, one R¹of the structures of Groups V(a) and (b) may be selected from Substituent Group 11 as defined hereinabove.

In one embodiment, one R¹of Formula (V) may be selected from Substituent Group 12:
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For example, in some embodiments, one R¹of the structures of Groups V(a) and (b) may be selected from Substituent Group 12 as defined hereinabove.

In some embodiments:

A) the first occurrence of R¹of Formula (V) is selected from Substituent Group 13:

and
B) the second occurrence of R¹of Formula (V) is selected from Substituent Group 10:

wherein all variables are as defined hereinabove.

For example in some embodiments, the first occurrence of R¹of the structures of Groups V(a) and (b) may be selected from Substituent Group 13 as defined hereinabove, and the second occurrence of R¹of the structures of Groups V(a) and (b) may be selected from Substituent Group 10 as defined hereinabove.

In another embodiment of the present invention, the amide containing heterobicyclic metalloprotease compounds may be represented by the general Formula (VI):
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and N-oxides, pharmaceutically acceptable salts, prodrugs, formulation, polymorphs, racemic mixtures and stereoisomers thereof,

wherein all variables are as defined hereinabove.

In yet another embodiment, the compounds of Formula (VI) may be selected from Group VI(a):
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wherein all variables are as defined hereinabove.

In still another embodiment, the compounds of Formula (VI) may be selected from Group VI(b):
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In a further embodiment, R³of Formula (VI) may be selected from Substituent Group 1:
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wherein all variables are as defined hereinabove.

For example, in some embodiments, R³of the structures of Groups VI(a) and (b) may be selected from Substituent Group 1 as defined hereinabove.

In yet a further embodiment, R³of Formula (VI) may be selected from Substituent Group 2:
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wherein all variables are as defined hereinabove.

For example, in some embodiments, in some embodiments, R³of the structures of Groups VI(a) and (b) may be selected from Substituent Group 2 as defined hereinabove.

In still a further embodiment, R³of Formula (VI) may be selected from Substituent Group 3:
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For example, in some embodiments, R³of the structures of Groups VI(a) and (b) may be selected from Substituent Group 3 as defined hereinabove.

In one embodiment, each R⁹of Substituent Group 3 may independently be selected from:
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wherein all variables are as defined hereinabove.

In another embodiment, R³of Formula (VI) may be Substituent Group 16:
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For example, in some embodiments, R³of the structures of Groups VI(a) and (b) may be selected from Substituent Group 16 as defined hereinabove.

In yet another embodiment, R³of Formula (VI) may be selected from Substituent Group 5:
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wherein:

R⁹is selected from the group consisting of hydrogen, fluoro, halo, CN, alkyl, CO₂H,
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For example, in some embodiments, R³of the structures of Groups VI(a) and (b) may be selected from Substituent Group 5 as defined hereinabove.

In still another embodiment, R¹of the compounds of Formula (VI) may be selected from Substituent Group 6:
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wherein all variables are as defined hereinabove.

For example, in some embodiments, R¹of the structures of Groups VI(a) and (b) may be selected from Substituent Group 6 as defined hereinabove.

In a further embodiment, R¹of Formula (VI) may be selected from Susbstituent Group 7:
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For example, in some embodiments, R¹of the structures of Groups VI(a) and (b) may be selected from Substituent Group 7 as defined hereinabove.

In yet a further embodiment, R¹of Formula (VI) may be selected from Substituent Group 8:
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wherein all variables are as defined hereinabove.

For example, For example, in some embodiments, R¹of the structures of Groups VI(a) and (b) may be selected from Substituent Group 8 as defined hereinabove.

In still a further embodiment, R¹of Formula (VI) may be selected from Substituent Group 9:
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For example, in some embodiments, R¹of the structures of Groups VI(a) and (b) may be selected from Substituent Group 9 as defined hereinabove.

In one embodiment, R¹of Formula (VI) may be selected from Substituent Group 10:
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wherein all variables are as defined hereinabove.

For example, in some embodiments, R¹of the structures of Groups VI(a) and (b) may be selected from Substituent Group 10 as defined hereinabove.

In another embodiment, R¹of Formula (VI) may be selected from Substituent Group 11:
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For example, in some embodiments, R¹of the structures of Groups VI(a) and (b)) may be selected from Substituent Group 11 as defined hereinabove.

In yet another embodiment, R¹of Formula (VI) may be selected from Substituent Group 12:
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For example, in some embodiments, R¹of the structures of Groups VI(a) and (b) may be selected from Substituent Group 12 as defined hereinabove.

In another embodiment, the present invention provides a compound selected from:
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wherein all variables are as hereinabove.

In still another embodiment, the present invention provides a compound selected from:
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wherein all variables are as defined hereinabove.

In still another embodiment, the present invention provides a compound selected from:
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or a pharmaceutically acceptable salt thereof.

In a further embodiment, the present invention provides a compound selected from:
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or a pharmaceutically acceptable salt thereof.

In yet a further embodiment, the present invention provides a compound selected from:
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or a pharmaceutically acceptable salt thereof.

In still a further embodiment, the present invention provides a compound selected from:
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or a pharmaceutically acceptable salt thereof.

In a further embodiment, the present invention provides a compound selected from:
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or a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention provides a compound having the structure:
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or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a compound having the structure:
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or a pharmaceutically acceptable salt thereof.

In yet another embodiment, the present invention provides a compound having the structure:
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or a pharmaceutically acceptable salt thereof.

In still another embodiment, the present invention provides a compound having the structure:
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or a pharmaceutically acceptable salt thereof.

In a further embodiment, the present invention provides a compound having the structure:
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or a pharmaceutically acceptable salt thereof.

In yet a further embodiment, the present invention provides a compound having the structure:
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or a pharmaceutically acceptable salt thereof.

In still a further embodiment, the present invention provides a compound having the structure:
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or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a compound having the structure:
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or a pharmaceutically acceptable salt thereof.

In yet another embodiment, the present invention provides a compound having the structure:
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or a pharmaceutically acceptable salt thereof.

In still another embodiment, the present invention provides a compound having the structure:
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or a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention provides a compound having the structure:
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or a pharmaceutically acceptable salt thereof:

In another embodiment, the present invention provides a compound having the structure:
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or a pharmaceutically acceptable salt thereof.

In yet another embodiment, the present invention provides a compound having the structure:
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or pharmaceutically acceptable salt thereof.

In still another embodiment, the present invention provides a compound having the structure:
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or a pharmaceutically acceptable salt thereof.

In a further embodiment, the present invention provides a compound having the structure:
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or a pharmaceutically acceptable salt thereof.

In yet a further embodiment, the present invention provides a compound having the structure:
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or a pharmaceutically acceptable salt thereof.

In still a further embodiment, the present invention provides a compound having the structure:
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or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a compound having the structure:
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or a pharmaceutically acceptable salt thereof.

In yet another embodiment, the present invention provides a compound having the structure:
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or a pharmaceutically acceptable salt thereof.

In still another embodiment, the present invention provides a compound having the structure:
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or a pharmaceutically acceptable salt thereof.

The present invention is also directed to pharmaceutical compositions which include any of the amide containing heterobicyclic metalloproteases of the invention described hereinabove. In accordance therewith, some embodiments of the present invention provide a pharmaceutical composition which may include an effective amount of an amide containing heterobicyclic metalloprotease compound of the present invention and a pharmaceutically acceptable carrier.

In one embodiment, the present invention provides a pharmaceutical composition including an effective amount of the compound of Formula (I) and N-oxides, pharmaceutically acceptable salts, prodrugs, formulation, polymorphs, racemic mixtures and stereoisomers thereof, and a pharmaceutically acceptable carrier.

In yet another embodiment, the present invention provides a pharmaceutical composition including an effective amount of the compound of Formula (II) and N-oxides, pharmaceutically acceptable salts, prodrugs, formulation, polymorphs, racemic mixtures and stereoisomers thereof, and a pharmaceutically acceptable carrier.

In another embodiment, the present invention provides a pharmaceutical composition including an effective amount of the compound of Formula (III) and N-oxides, pharmaceutically acceptable salts, prodrugs, formulation, polymorphs, racemic mixtures and stereoisomers thereof, and a pharmaceutically acceptable carrier.

In still another embodiment, the present invention provides a pharmaceutical composition including an effective amount of the compound of Formula (IV) and N-oxides, pharmaceutically acceptable salts, prodrugs, formulation, polymorphs, racemic mixtures and stereoisomers thereof, and a pharmaceutically acceptable carrier.

In a further embodiment, the present invention provides a pharmaceutical composition including an effective amount of the compound of Formula (V) and N-oxides, pharmaceutically acceptable salts, prodrugs, formulation, polymorphs, racemic mixtures and stereoisomers thereof, and a pharmaceutically acceptable carrier.

In yet a further embodiment, the present invention provides a pharmaceutical composition including an effective amount of the compound of Formula (VI) and N-oxides, pharmaceutically acceptable salts, prodrugs, formulation, polymorphs, racemic mixtures and stereoisomers thereof, and a pharmaceutically acceptable carrier.

The present invention is also directed to methods of inhibiting metalloproteases and methods of treating diseases or symptoms mediated by an metalloprotease enzyme, particularly an MMP-13, MMP-8, MMP-3, MMP-12 and/or an ADAMTS-4 enzyme, and more particulary an MMP-13 enzyme and/or an MMP-3 enzyme. Such methods include administering a bicyclic metalloprotease inhibiting compound of the present invention, or a pharmaceutically acceptable salt thereof. Examples of diseases or symptoms mediated by an metalloprotease mediated enzyme include, but are not limited to, rheumatoid arthritis, osteoarthritis, abdominal aortic aneurysm, cancer (e.g. but not limited to melanoma, gastric carcinoma or non-small cell lung carcinoma), inflammation, atherosclerosis, multiple sclerosis, chronic obstructive pulmonary disease, ocular diseases (e.g. but not limited to ocular inflammation, retinopathy of prematurity, macular degeneration with the wet type preferred and corneal neovascularization), neurologic diseases, psychiatric diseases, thrombosis, bacterial infection, Parkinson's disease, fatigue, tremor, diabetic retinopathy, vascular diseases of the retina, aging, dementia, cardiomyopathy, renal tubular impairment, diabetes, psychosis, dyskinesia, pigmentary abnormalities, deafness, inflammatory and fibrotic syndromes, intestinal bowel syndrome, allergies, Alzheimers disease, arterial plaque formation, oncology, periodontal, viral infection, stroke, atherosclerosis, cardiovascular disease, reperfusion injury, trauma, chemical exposure or oxidative damage to tissues, wound healing, hemorroid, skin beautifying, pain, inflammatory pain, bone pain and joint pain, acne, acute alcoholic hepatitis, acute inflammation, acute pancreatitis, acute respiratory distress syndrome, adult respiratory disease, airflow obstruction, airway hyperresponsiveness, alcoholic liver disease, allograft rejections, angiogenesis, angiogenic ocular disease, arthritis, asthma, atopic dermatitis, bronchiectasis, bronchiolitis, bronchiolitis obliterans, burn therapy, cardiac and renal reperfusion injury, celiac disease, cerebral and cardiac ischemia, CNS tumors, CNS vasculitis, colds, contusions, cor pulmonae, cough, Crohn's disease, chronic bronchitis, chronic inflammation, chronic pancreatitis, chronic sinusitis, crystal induced arthritis, cystic fibrosis, delayted type hypersensitivity reaction, duodenal ulcers, dyspnea, early transplantation rejection, emphysema, encephalitis, endotoxic shock, esophagitis, gastric ulcers, gingivitis, glomerulonephritis, glossitis, gout, graft vs. host reaction, gram negative sepsis, granulocytic ehrlichiosis, hepatitis viruses, herpes, herpes viruses, HIV, hypercapnea, hyperinflation, hyperoxia-induced inflammation, hypoxia, hypersensitivity, hypoxemia, inflammatory bowel disease, interstitial pneumonitis, ischemia reperfusion injury, kaposi's sarcoma associated virus, lupus, malaria, meningitis, multi-organ dysfunction, necrotizing enterocolitis, osteoporosis, periodontitis, peritonitis associated with continous ambulatory peritoneal dialysis (CAPD), pre-term labor, polymyositis, post surgical trauma, pruritis, psoriasis, psoriatic arthritis, pulmatory fibrosis, pulmatory hypertension, renal reperfusion injury, respiratory viruses, restinosis, right ventricular hypertrophy, sarcoidosis, septic shock, small airway disease, sprains, strains, subarachnoid hemorrhage, surgical lung volume reduction, thrombosis, toxic shock syndrome, transplant reperfusion injury, traumatic brain injury, ulcerative colitis, vasculitis, ventilation-perfusion mismatching, wheeze

In one embodiment, the present invention provides a method of inhibiting a metalloprotease, particularly MMP-13, MMP-8, MMP-3, MMP-12 and/or ADAMTS-4, and more particulary MMP-13, which includes administering to a subject in need of such treatment a compound of Formula (I) and N-oxides, pharmaceutically acceptable salts, prodrugs, formulation, polymorphs, racemic mixtures and stereoisomers thereof.

In one embodiment, the present invention provides a method of inhibiting a metalloprotease, particularly MMP-13, MMP-8, MMP-3, MMP-12 and/or ADAMTS-4, and more particulary MMP-13, which includes administering to a subject in need of such treatment a compound of Formula (II) and N-oxides, pharmaceutically acceptable salts, prodrugs, formulation, polymorphs, racemic mixtures and stereoisomers thereof.

In yet another embodiment, the present invention provides a method of inhibiting a metalloprotease, particularly MMP-13, MMP-8, MMP-3, MMP-12 and/or ADAMTS-4, and more particulary MMP-13, which includes administering to a subject in need of such treatment a compound of Formula (III) and N-oxides, pharmaceutically acceptable salts, prodrugs, formulation, polymorphs, racemic mixtures and stereoisomers thereof.

In still another embodiment, the present invention provides a method of inhibiting a metalloprotease, particularly MMP-13, MMP-8, MMP-3, MMP-12 and/or ADAMTS-4, and more particulary MMP-13 and/or MMP-3, which includes administering to a subject in need of such treatment a compound of Formula (IV) and N-oxides, pharmaceutically acceptable salts, prodrugs, formulation, polymorphs, racemic mixtures and stereoisomers thereof.

In a further embodiment, the present invention provides a method of inhibiting a metalloprotease, particularly MMP-13, MMP-8, MMP-3, MMP-12 and/or ADAMTS4, and more particulary MMP-13 and/or MMP-3, which includes administering to a subject in need of such treatment a compound of Formula (V) and N-oxides, pharmaceutically acceptable salts, prodrugs, formulation, polymorphs, racemic mixtures and stereoisomers thereof.

In yet a further embodiment, the present invention provides a method of inhibiting a metalloprotease, particularly MMP-13, MMP-8, MMP-3, MMP-12 and/or ADAMTS-4, and more particulary MMP-13 and/or MMP-3, which includes administering to a subject in need of such treatment a compound of Formula (VI) and N-oxides, pharmaceutically acceptable salts, prodrugs, formulation, polymorphs, racemic mixtures and stereoisomers thereof.

In still a further embodiment, the present invention provides a method of treating an metalloprotease mediated disease, particulary a MMP-13 mediated disease, a MMP-8 mediated disease, a MMP-3 mediated disease, a MMP-12 mediated disease and/or an ADAMTS-4 mediated disease and more particulary a MMP-13 mediated disease, which includes administering to a subject in need of such treatment an effective amount of a compound of Formula (I) and N-oxides, pharmaceutically acceptable salts, prodrugs, formulation, polymorphs, racemic mixtures and stereoisomers thereof.

In one embodiment, the present invention provides a method of treating an metalloprotease mediated disease, particulary a MMP-13 mediated disease, a MMP-8 mediated disease, a MMP-3 mediated disease, a MMP-12 mediated disease and/or an ADAMTS-4 mediated disease and more particulary a MMP-13 mediated disease, which includes administering to a subject in need of such treatment an effective amount of a compound of Formula (II) and N-oxides, pharmaceutically acceptable salts, prodrugs, formulation, polymorphs, racemic mixtures and stereoisomers thereof.

In another embodiment, the present invention provides a method of treating an metalloprotease mediated disease, particulary a MMP-13 mediated disease, a MMP-8 mediated disease, a MMP-3 mediated disease, a MMP-12 mediated disease and/or an ADAMTS-4 mediated disease and more particulary a MMP-13 mediated disease, which includes administering to a subject in need of such treatment an effective amount of a compound of Formula (III) and N-oxides, pharmaceutically acceptable salts, prodrugs, formulation, polymorphs, racemic mixtures and stereoisomers thereof.

In another embodiment, the present invention provides a method of treating an metalloprotease mediated disease, particulary a MMP-13 mediated disease, a MMP-8 mediated disease, a MMP-3 mediated disease, a MMP-12 mediated disease and/or an ADAMTS-4 mediated disease and more particulary MMP-13 mediated disease and/or MMP-3 mediated disease, which includes administering to a subject in need of such treatment an effective amount of a compound of Formula (IV) and N-oxides, pharmaceutically acceptable salts, prodrugs, formulation, polymorphs, racemic mixtures and stereoisomers thereof.

In another embodiment, the present invention provides a method of treating an metalloprotease mediated disease, particulary a MMP-13 mediated disease, a MMP-8 mediated disease, a MMP-3 mediated disease, a MMP-12 mediated disease and/or an ADAMTS-4 mediated disease and more particulary a MMP-13 mediated disease and/or MMP-3 mediated disease, which includes administering to a subject in need of such treatment an effective amount of a compound of Formula (V) and N-oxides, pharmaceutically acceptable salts, prodrugs, formulation, polymorphs, racemic mixtures and stereoisomers thereof.

In another embodiment, the present invention provides a method of treating an metalloprotease mediated disease, particulary a MMP-13 mediated disease, a MMP-8 mediated disease, a MMP-3 mediated disease, a MMP-12 mediated disease and/or an ADAMTS-4 mediated disease and more particulary a MMP-13 mediated disease and/or MMP-3 mediated disease, which includes administering to a subject in need of such treatment an effective amount of a compound of Formula (VI) and N-oxides, pharmaceutically acceptable salts, prodrugs, formulation, polymorphs, racemic mixtures and stereoisomers thereof.

Illustrative of the diseases which may be treated with such methods are: rheumatoid arthritis, osteoarthritis, abdominal aortic aneurysm, cancer, inflammation, atherosclerosis, multiple sclerosis, chronic obstructive pulmonary disease, ocular diseases, neurological diseases, psychiatric diseases, thrombosis, bacterial infection, Parkinson's disease, fatigue, tremor, diabetic retinopathy, vascular diseases of the retina, aging, dementia, cardiomyopathy, renal tubular impairment, diabetes, psychosis, dyskinesia, pigmentary abnormalities, deafness, inflammatory and fibrotic syndromes, intestinal bowel syndrome, allergies, Alzheimer's disease, arterial plaque formation, oncology, periodontal, viral infection, stroke, atherosclerosis, cardiovascular disease, reperfusion injury, trauma, chemical exposure or oxidative damage to tissues, wound healing, hemorroids, skin beautifying, pain, inflammatory pain, bone pain and joint pain.

In some embodiments, of the present invention, the amide containing heterobicyclic metalloprotease compounds defined above are used in the manufacture of a medicament for the treatment of a disease or symptom mediated by an MMP enzyme, particularly an MMP-13, MMP-8, MMP-3, MMP-12 and/or an ADAMTS-4 enzyme, and more particulary an MMP-13 enzyme and/or an MMP-3 enzyme.

In some embodiments, the amide containing heterobicyclic metalloprotease compounds defined above may be used in combination with a drug, active, or therapeutic agent such as, but not limited to: (a) a disease modifying antirheumatic drug, such as, but not limited to, methotrexate, azathioptrineluflunomide, penicillamine, gold salts, mycophenolate, mofetil, and cyclophosphamide; (b) a nonsteroidal anti-inflammatory drug, such as, but not limited to, piroxicam, ketoprofen, naproxen, indomethacin, and ibuprofen; (c) a COX-2 selective inhibitor, such as, but not limited to, rofecoxib, celecoxib, and valdecoxib; (d) a COX-1 inhibitor, such as, but not limited to, piroxicam; (e) an immunosuppressive, such as, but not limited to, methotrexate, cyclosporin, leflunimide, tacrolimus, rapamycin, and sulfasalazine; (f) a steroid, such as, but not limited to, p-methasone, prednisone, cortisone, prednisolone, and dexamethasone; (g) a biological response modifier, such as, but not limited to, anti-TNF antibodies, TNF-α antagonists, IL-1 antagonists, anti-CD40, anti-CD28, IL-10, and anti-adhesion molecules; and (h) other anti-inflammatory agents or therapeutics useful for the treatment of chemokine mediated diseases, such as, but not limited to, p38 kinase inhibitors, PDE4 inhibitors, TACE inhibitors, chemokine receptor antagonists, thalidomide, leukotriene inhibitors, and other small molecule inhibitors of pro-inflammatory cytokine production.

In one embodiment, the present invention provides a pharmaceutical composition which includes:

- A) an effective amount of a compound of Formula (I) and N-oxides, pharmaceutically acceptable salts, prodrugs, formulation, polymorphs, racemic mixtures and stereoisomers thereof;
- B) a pharmaceutically acceptable carrier; and
- C) a member selected from: (a) a disease modifying antirheumatic drug; (b) a nonsteroidal anti-inflammatory drug; (c) a COX-2 selective inhibitor; (d) a COX-1 inhibitor; (e) an immunosuppressive; (f) a steroid; (g) a biological response modifier; and (h) a small molecule inhibitor of pro-inflammatory cytokine production.

In another embodiment, the present invention provides a pharmaceutical composition which includes:

- A) an effective amount of a compound of Formula (II) and N-oxides, pharmaceutically acceptable salts, prodrugs, formulation, polymorphs, racemic mixtures and stereoisomers thereof;
- B) a pharmaceutically acceptable carrier; and
- C) a member selected from: (a) a disease modifying antirheumatic drug; (b) a nonsteroidal anti-inflammatory drug; (c) a COX-2 selective inhibitor; (d) a COX-1 inhibitor; (e) an immunosuppressive; (f) a steroid; (g) a biological response modifier; and (h) a small molecule inhibitor of pro-inflammatory cytokine production.

In still another embodiment, the present invention provides a pharmaceutical composition which includes:

- A) an effective amount of a compound of Formula (III) and N-oxides, pharmaceutically acceptable salts, prodrugs, formulation, polymorphs, racemic mixtures and stereoisomers thereof;
- B) a pharmaceutically acceptable carrier; and
- C) a member selected from: (a) a disease modifying antirheumatic drug; (b) a nonsteroidal anti-inflammatory drug; (c) a COX-2 selective inhibitor; (d) a COX-1 inhibitor; (e) an immunosuppressive; (f) a steroid; (g) a biological response modifier; and (h) a small molecule inhibitor of pro-inflammatory cytokine production.

In a further embodiment, the present invention provides a pharmaceutical composition which includes:

- A) an effective amount of a compound of Formula (IV) and N-oxides, pharmaceutically acceptable salts, prodrugs, formulation, polymorphs, racemic mixtures and stereoisomers thereof;
- B) a pharmaceutically acceptable carrier; and
- C) a member selected from: (a) a disease modifying antirheumatic drug; (b) a nonsteroidal anti-inflammatory drug; (c) a COX-2 selective inhibitor; (d) a COX-1 inhibitor; (e) an immunosuppressive; (f) a steroid; (g) a biological response modifier; and (h) a small molecule inhibitor of pro-inflammatory cytokine production.

In yet a further embodiment, the present invention provides a pharmaceutical composition which includes:

- A) an effective amount of a compound of Formula (V) and N-oxides, pharmaceutically acceptable salts, prodrugs, formulation, polymorphs, racemic mixtures and stereoisomers thereof;
- B) a pharmaceutically acceptable carrier; and
- C) a member selected from: (a) a disease modifying antirheumatic drug; (b) a nonsteroidal anti-inflammatory drug; (c) a COX-2 selective inhibitor; (d) a COX-1 inhibitor; (e) an immunosuppressive; (f) a steroid; (g) a biological response modifier; and (h) a small molecule inhibitor of pro-inflammatory cytokine production.

In yet a further embodiment, the present invention provides a pharmaceutical composition which includes:

- A) an effective amount of a compound of Formula (VI) and N-oxides, pharmaceutically acceptable salts, prodrugs, formulation, polymorphs, racemic mixtures and stereoisomers thereof;
- B) a pharmaceutically acceptable carrier; and
- C) a member selected from: (a) a disease modifying antirheumatic drug; (b) a nonsteroidal anti-inflammatory drug; (c) a COX-2 selective inhibitor; (d) a COX-1 inhibitor; (e) an immunosuppressive; (f) a steroid; (g) a biological response modifier; and (h) a small molecule inhibitor of pro-inflammatory cytokine production.
  
  Biological Activity

The inhibiting activity towards different metalloproteases of the heterobicyclic metalloprotease inhibiting compounds of the present invention may be measured using any suitable assay known in the art. A standard in vitro assay for measuring the metalloprotease inhibiting activity is described in Examples 1700 to 1704. The heterobicyclic metalloprotease inhibiting compounds show activity towards MMP-3, MMP-8, MMP-12, MMP-13, ADAMTS-4 and/or ADAMTS-5.

The heterobicyclic metalloprotease inhibiting compounds of the invention have an MMP-13 inhibition activity (IC₅₀MMP-13) ranging from below 0.1 nM to about 20 μM, and typically, from about 0.2 nM to about 2 μM. Heterobicyclic metalloprotease inhibiting compounds of the invention desirably have an MMP inhibition activity ranging from about 0.2 nM to about 20 nM. Table 1 lists typical examples of heterobicyclic metalloprotease inhibiting compounds of the invention that have an MMP-13 activity lower than 5 nM (Group A) and from 5 nM to 20 μM (Group B).

TABLE 1Summary of MMP-13 Activity for CompoundsGroupEx. #A32, 37, 49, 63, 66, 73, 115, 159, 235, 317, 318, 319, 322, 328, 332, 337, 339, 340,341, 343, 346, 348, 349, 351, 358, 359, 365, 379, 395, 397, 398, 399, 402, 403, 418,419, 423, 425, 428, 430, 440, 442, 443, 449, 453, 459, 469, 476, 480, 1748, 1749,1751, 1758, 1759, 1768, 1778, 1782, 1820, 1861, 1864, 1865, 1875, 1876, 1878,1880, 1887, 1890, 1894, 1912, 1920, 1922, 1948, 1949, 2065, 2081, 2093, 2095,2100, 2182, 2188, 2206, 2207, 2212, 2221, 2244, 2328, 2341.B3, 4, 36, 71, 86, 93, 113, 126, 156, 158, 161, 231, 244, 246, 280, 308, 323, 347, 355,363, 367, 400, 411, 420, 432, 461, 464, 466, 467, 479, 483, 1767, 1779, 1780, 1787,1805, 1821, 1829, 1872, 1884, 1881, 1891, 1893, 1895, 1911, 1913, 1917, 1921,1923, 1943, 1951, 1952, 2146, 2163, 2165, 2183, 2222, 2225, 2227, 2253, 2256,2258, 2261, 2263, 2267, 2268, 2269, 2283, 2284, 2285, 2288, 2291, 2294, 2295,2297, 2299, 2321, 2324, 2332, 2333, 2336, 2338, 2339, 2343, 2346, 2389, 2390,2392.

Heterobicyclic metalloprotease inhibiting compounds, in particular compounds of Formula (V) of the invention have an MMP-3 inhibition activity (IC₅₀MMP-3) ranging from below 5 nM to about 20 μM, and typically, from about 3 nM to about 2 μM. Heterobicyclic metalloprotease inhibiting compounds of the invention desirably have an MMP inhibition activity ranging from about 0.2 nM to about 20 nM. Table 2 lists typical examples of heterobicyclic metalloprotease inhibiting compounds of the invention that have an MMP-3 activity lower than 100 nM (Group A) and from 100 nM to 20 μM (Group B).

TABLE 2Summary of MMP-3 Activity for CompoundsGroupEx. #A2300, 2301, 2304, 2309, 2314, 2315, 2319, 2320, 2321, 2323,2330, 2331, 2332, 2333, 2342, 2346.B159, 318, 328, 346, 348, 349, 395, 397, 419, 459, 484,2346, 2303, 2305, 2310, 2316.

Some heterobicyclic metalloprotease inhibiting compounds of the invention have an MMP-8 inhibition activity (IC₅₀MMP-8) ranging from about 2 μM to about 20 μM. Examples of heterobicyclic metalloprotease inhibiting compounds of the invention that have an MMP-8 activity below 20 μM are Ex. # 31, 318, 346, 395 and 397.

Some heterobicyclic metalloprotease inhibiting compounds of the invention have an MMP-12 inhibition activity (IC₅₀MMP-12) ranging from below 1 μM to about 20 μM. Examples of heterobicyclic metalloprotease inhibiting compounds of the invention that have an MMP-12 activity below 20 μM are Ex. # 318, 322, 346, 395, 397, 418, 430, 440 and 459.

Heterobicyclic metalloprotease inhibiting compounds, in particular compounds of Formula (V) of the invention, show an MMP-3 mediated proteoglycan degradation ranging from below 50 nM to about 20 μM. Typical examples of heterobicyclic metalloprotease inhibiting compounds of the invention that have an IC₅₀-range of 20 to 40 nM in the MMP-3 Mediated Proteoglycan Degradation Assay (Ex. # 1705) are Ex. # 483 and 2343.

Heterobicyclic metalloprotease inhibiting compounds, in particular compounds of Formula (V) of the invention, of the invention show an inhibition of MMP-3 mediated pro-collagenase 3 activation ranging from below 50 nM to about 20 μM. Typical examples of heterobicyclic metalloprotease inhibiting compounds of the invention that have an IC₅₀-range of 10 to 30 nM in the Assay for Determining Inhibition of MMP-3 mediated Pro-Collagenase 3 Activation (Ex. # 1706) are Ex. # 483 and 2343.

The synthesis of metalloprotease inhibiting compounds of the invention and their biological activity assay are described in the following examples which are not intended to be limiting in any way.

Schemes

Provided below are schemes according to which compounds of the present invention may be prepared. In schemes described herein, each of R^AR^Band R^CR^Dmay be the same or different, and each may independently be selected from R¹R²and R²⁰R²¹as defined hereinabove. Each of X^a, Y^a, and Z^ashown in the schemes below may be the same or different, and each may independently be selected from N and CR⁴. X^bshown in the schemes below in each occurrence may be the same or different and is independently selected from O, S, and NR⁵¹. Y^bshown in the schemes below in each occurrence may be the same and is independently selected from CR⁴and N.

In some embodiments the compounds of Formula (I)-(III) are synthesized by the general methods shown in Scheme 1 to Scheme 3.
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Methyl acetopyruvate is condensed (e.g. MeOH/reflux, aqueous HCl/100° C. or glacial AcOH/95° C.) with an amino substituted 5-membered heterocycle (e.g. 1H-pyrazol-5-amine) to afford a bicyclic ring system as a separable mixture of regioisomer A and regioisomer B (Scheme 1).
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The regioisomer A of the bicyclic ring system from Scheme 1 (e.g. 7-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylic acid methyl ester) is oxidized (e.g. selenium dioxide/120-130° C. and then oxone®/room temperature) to afford the corresponding carboxylic acid (Scheme 2). Activated acid coupling (e.g. oxalyl chloride, PyBOP, PyBrOP, EDCI/HOAt or HATU/HOAt) with R^AR^BNH (e.g. 4-fluoro-3-methyl-benzylamine) in a suitable solvent gives the desired amide after purification. Saponification (e.g. aqueous LiOH/dioxane, NaOH/MeOH or TMSnOH/80° C.) and further activated acid coupling (e.g. oxalyl chloride, PyBOP, PyBrOP, EDCI/HOAt, HATU/HOAt, N-cyclohexyl-carbodiimide-N′-methyl-polystyrene or polystyrene-IIDQ) with R^CR^DNH gives the desired bicyclic bisamide inhibitor after purification. If necessary, the R group can be further manipulated (e.g. saponification of a COOMe group in R).
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The regioisomer B of the bicyclic ring system from Scheme 1 (e.g. 5-methyl-pyrazolo[1,5-a]pyrimidine-7-carboxylic acid methyl ester) is treated similarly as shown in Scheme 2 to give the desired bicyclic bisamide inhibitor after purification (Scheme 3). If necessary, the R group can be further manipulated (e.g. saponification of a COOMe group in R).

In some embodiments the compounds of Formula (I)-(III) are synthesized by the general methods shown in Scheme 4 to Scheme 8.
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2-Chloro-6-methyl-pyrimidine-4-carboxylic acid methyl ester is reduced (e.g. NaBH₄/MeOH) to the corresponding alcohol and protected with a suitable protecting group [PG, e.g. (2-methoxyethoxy)methyl] (Scheme 4). The obtained intermediate is stirred with hydrazine hydrate at 70° C. to afford the corresponding hydrazino pyrimidine after concentration. Cyclization with a suitable reagent (e.g. triethylortho formate) gives the protected hydroxymethyl substituted bicyclic ring system as a separable mixture of regioisomer A and regioisomer B.
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The regioisomer A of the protected hydroxymethyl substituted bicyclic ring system from Scheme 4 (e.g. 7-(2-methoxy-ethoxymethoxymethyl)-5-methyl-[1,2,4]triazolo[4,3-a]pyrimidine) is deprotected (e.g. HCI/THF) and then oxidized (e.g. KMnO₄in aqueous Na₂CO₃/50° C.) to afford the corresponding carboxy substituted bicyclic ring system (Scheme 5). Esterifcation (e.g. thionyl chloride/MeOH) and oxidation (e.g. selenium dioxide/70° C.) of this intermediate gives the corresponding carboxylic acid. Activated acid coupling (e.g. oxalyl chloride, PyBOP, PyBrOP, EDCI/HOAt or HATU/HOAt) with R^AR^BNH (e.g. 4-fluoro-3-methyl-benzylamine) in a suitable solvent gives the desired amide after purification. Saponification (e.g. aqueous LiOH/dioxane, NaOH/MeOH or TMSnOH/80° C.) and further activated acid coupling (e.g. oxalyl chloride, PyBOP, PyBrOP, EDCI/HOAt, HATU/HOAt) with R^CR^DNH gives the desired bicyclic bisamide inhibitor after purification. If necessary, the R group can be further manipulated (e.g. saponification of a COOMe group in R).
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The regioisomer B of the protected hydroxymethyl substituted bicyclic ring system from Scheme 4 (e.g. 5-(2-methoxy-ethoxymethoxymethyl)-7-methyl-[1,2,4]triazolo[4,3-a]pyrimidine) is treated similarly as shown in Scheme 5 to give the desired bicyclic bisamide inhibitor after purification (Scheme 6). If necessary, the R group can be further manipulated (e.g. saponification of a COOMe group in R).
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2-Chloro-6methyl-pyrimidine-4-carboxylic acid methyl ester is oxidized (e.g. selenium dioxide/105° C.) to the corresponding carboxylic acid (Scheme 7). Activated acid coupling (e.g. oxalyl chloride) with R^AR^BNH (e.g. 4-fluoro-3-methyl-benzylamine) in a suitable solvent gives the desired amide after purification. Saponification (e.g. aqueous LiOH/THF) and further activated acid coupling (e.g. PyBOP) with R^CR^DNH (e.g. 4-aminomethyl-benzoic acid methyl ester) gives the corresponding benzotriazol-1-yloxy substituted pyrimidine bisamide.
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A benzotriazol-1-yloxy substituted pyrimidine bisamide from Scheme 7 (e.g. 4-({[2-(benzotriazol-1-yloxy)-6-(4-fluoro-3-methyl-benzylcarbamoyl)-pyrimidine-4carbonyl]-amino}-methyl)-benzoic acid methyl ester) is stirred with hydrazine hydrate at room temperature to afford the corresponding hydrazino pyrimidine bisamide after concentration (Scheme 8). Cyclization with a suitable reagent (e.g. phosgene) gives the corresponding bicyclic bisamide inhibitor as a mixture of regioisomer A and regioisomer B. If necessary, the R group can be further manipulated (e.g. saponification of a COOMe group in R).

In some embodiments the compounds of Formula (IV)-(VI) are synthesized by the general methods shown in Scheme 9 to Scheme 12.
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An ester and amino substituted heterocycle (e.g. 3-amino-1H-pyrrole-2-carboxylic acid ethyl ester) is condensed (e.g. EtOH/reflux) with formamidine to give a hydroxy substituted bicyclic ring system (Scheme 9). This intermediate is then converted into the corresponding bromo derivative using a suitable reagent (e.g. POBr₃/80° C.). The resulting bromide is heated to (e.g. 80° C.) with a suitable catalyst (e.g. Pd(OAc)₂, dppf) and base (e.g. Et₃N) under a carbon monoxide atmosphere in a suitable solvent (e.g. MeOH) to give the corresponding bicyclic methylester after purification. Nitration (e.g. concentrated HNO₃/0° C. to room temperature) and saponification (e.g. aqueous LiOH) gives the corresponding nitro substituted bicyclic carboxylic acid. Activated acid coupling (e.g. EDCI/HOAt) with R^AR^BNH (e.g. 6-aminomethyl-4H-benzo[1,4]oxazin-3-one) in a suitable solvent gives the desired amide. This intermediate is stirred with a suitable catalyst (e.g. Pd/C) and acid (e.g. AcOH) under a hydrogen atmosphere to afford corresponding amino substituted bicyclic amide after purification.
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Commercially available 2-fluoro-3-oxo-butyric acid ethyl ester is condensed (e.g. MeOH/reflux) with thiourea to give the corresponding fluoro pyrimidinone derivative (Scheme 10). Removal of the sulphur with a catalyst (e.g. Raney-nickel) at elevated temperature (e.g. 100° C.) in a suitable solvent (e.g. H₂O) gives the corresponding fluoro pyrimidine derivative. This intermediate is converted into the corresponding bromo derivative by heating with base (e.g. K₂CO₃) and a suitable reagent (e.g. POBr₃) in a suitable solvent (e.g. CH₃CN). The resulting bromide is heated to (e.g. 80° C.) with a suitable catalyst (e.g. Pd(OAc)₂, dppf) and base (e.g. Et₃N) under a carbon monoxide atmosphere in a suitable solvent (e.g. MeOH) to give the corresponding fluoro pyrimidine carboxylic acid methyl ester after purification. Oxidation of the methyl group with a suitable reagent (e.g. selenium dioxide) in a suitable solvent (e.g. 1,4-dioxane) at elevated temperature (e.g. 120° C.) in a sealed vessel affords the corresponding fluoro pyrimidine monoacid monoester. Coupling of the acid derivative using an activated acid method (e.g. EDCI, HOAt, DMF, base) with R^AR^BNH (e.g. 3-chloro-4-fluoro benzylamine) affords the desired products after purification. Saponification of the remaining ester moiety with base (e.g. aqueous KOH) affords the corresponding free acid derivatives. This derivatives are converted to the corresponding amides via the formation of their acid chlorides using suitable conditions (e.g. oxalyl chloride, DMF, 0-5° C.), followed by treatment with anhydrous NH₃(e.g. 0.5M in 1,4-dioxane) and subsequent purification. Dehydration under suitable conditions (e.g. oxalyl chloride, DMF, pyridine, 0-5° C.) affords the corresponding nitriles after workup. Cyclization of these derivatives with a suitable reagent (e.g. hydrazine) in a suitable solvent (e.g. 1,4-dioxane) affords the corresponding 3-hydroxy-1H-pyrazolo[4,3-d]pyrimidin derivatives. (Scheme 10).
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The amino substituted bicyclic amide from scheme 9 (e.g. 3-amino-1H-pyrazolo[4,3-d]pyrimidine-7-carboxylic acid 3-chloro-4-fluoro-benzylamide) and the carbonyl compound (CO)R^CR^D(e.g. 4-fluorobenzaldehyde) is stirred with a suitable reducing agent (e.g. NaCNBH₃) and a small amount of acid (e.g. AcOH) in a suitable solvent (e.g. MeOH) to give the corresponding bicyclic inhibitor after purification (Scheme 11). If necessary, the R group can be further manipulated (e.g. saponification of a COOMe group in R).
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The amino substituted bicyclic amide from scheme 9 (e.g. 7-amino-5H-pyrrolo[3,2-d]pyrimidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-amide is stirred with the acid chloride R^CCOCl or with the acid anhydride (R^CCO)₂O (e.g. acetic anhydride) in a suitable solvent (e.g. pyridine) to give the corresponding bicyclic inhibitor after purification (Scheme 12). If necessary, the R group can be further manipulated (e.g. saponification of a COOMe group in R).

EXAMPLES AND METHODS

All reagents and solvents were obtained from commercial sources and used without further purification. Proton spectra (¹H-NMR) were recorded on a 400 MHz and a 250 MHz NMR spectrometer in deuterated solvents. Purification by column chromatography was performed using silica gel, grade 60, 0.06-0.2 mm (chromatography) or silica gel, grade 60, 0.04-0.063 mm (flash chromatography) and suitable organic solvents as indicated in specific examples. Preparative thin layer chromatography was carried out on silica gel plates with UV detection.

Preparative Examples 1-395, 805 and 836-1051 are directed to intermediate compounds useful in preparing the compounds of the present invention.

Preparative Example 1

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Step A

Under a nitrogen atmosphere a 1M solution of BH₃.THF complex in THF (140 mL) was added dropwise over a 3 h period to an ice cooled solution of commercially available 3-bromo-2-methyl-benzoic acid (20.0 g) in anhydrous THF (200 mL). Once gas evolution had subsided, the cooling bath was removed and mixture stirred at room temperature for 12 h. The mixture was then poured into a mixture of IN aqueous HCl (500 mL) and ice and then extracted with Et₂O (3×150 mL). The combined organic phases were dried (MgSO₄), filtered and concentrated to afford the title compound as a colorless solid (18.1 g, 97%). ¹H-NMR (CDCl₃) δ=7.50 (d, 1H), 7.30 (d, 1H), 7.10 (t, 1H), 4.70 (s, 2H), 2.40 (s, 3H).

Step B

Under a nitrogen atmosphere PBr₃(5.52 mL) was added over a 10 min period to an ice cooled solution of the title compound from Step A above (18.1 g) in anhydrous CH₂Cl₂(150 mL). The cooling bath was removed and mixture stirred at room temperature for 12 h. The mixture was cooled (0-5° C.), quenched by dropwise addition of MeOH (20 mL), washed with saturated aqueous NaHCO₃(2×150 mL), dried (MgSO₄), filtered and concentrated to afford the title compound as a viscous oil (23.8 g, 97%). ¹H-NMR (CDCl₃) δ=7.50 (d, 1H), 7.25 (d, 1H), 7.00 (t, 1H), 4.50 (s, 2H), 2.50 (s, 3H).

Step C

Under a nitrogen atmosphere a 1.5M solution of lithium diispropylamide in cyclohexane (63 mL) was added dropwise to a cooled (−78° C., acetone/dry ice) solution of ^tBuOAc in anhydrous THF (200 mL). The mixture was stirred at −78° C. for 1 h, then a solution of the title compound from Step B above (23.8 g) in THF (30 mL) was added and the mixture was stirred for 12 h while warming to room temperature. The mixture was concentrated, diluted with Et₂O (300 mL), washed with 0.5N aqueous HCl (2×100 mL), dried (MgSO₄), filtered and concentrated to afford the title compound as a pale-yellow viscous oil (21.5 g, 80%). ¹H-NMR (CDCl₃) δ=7.50 (d, 1H), 7.25 (d, 1H), 7.00 (t, 1H), 3.00 (t, 2H), 2.50 (t, 2H), 2.40 (s, 3H), 1.50 (s, 9H).

Step D

A mixture of the title compound from Step C above (21.5 g) and polyphosphoric acid (250 g) was placed in a preheated oil bath (140° C.) for 10 min while mixing the thick slurry occasionally with a spatula. The oil bath was removed, ice and H₂O (1 L) was added and the mixture was stirred for 2 h. The precipitate was isolated by filtration, washed with H₂O (2×100 mL) and dried to afford the title compound (16.7 g, 96%). ¹H-NMR (CDCl₃) δ=7.50 (d, 1H), 7.20 (d, 1H), 7.00 (t, 1H), 3.00 (t, 2H), 2.65 (t, 2H), 2.40 (s, 3H).

Step E

Under a nitrogen atmosphere oxalyl chloride (12.0 mL) was added dropwise to an ice cooled solution of the title compound from Step D above (11.6 g) in anhydrous CH₂Cl₂(100 mL). The resulting mixture was stirred for 3 h and then concentrated. The remaining dark residue was dissolved in anhydrous CH₂Cl₂(300 mL) and AlCl₃(6.40 g) was added. The mixture was heated to reflux for 4 h, cooled and poured into ice water (500 mL). The aqueous phase was separated and extracted with CH₂Cl₂(2×100 mL). The combined organic phases were dried (MgSO₄), filtered and concentrated to afford the title compound as a light brown solid (10.6 g, 98%). ¹H-NMR (CDCl₃) δ=7.65 (d, 1H), 7.50 (d, 1H), 3.05 (t, 2H), 2.70 (t, 2H), 2.40 (s, 3H).

Step F

Using a syringe pump, a solution of the title compound from Step E above (9.66 g) in anhydrous CH₂Cl₂(70 mL) was added over a 10 h period to a cooled (−20° C., internal temperature) mixture of a IM solution of (S)-(−)-2-methyl-CBS-oxazaborolidine in toluene (8.6 mL) and a 1M solution of BH₃.Me₂S complex in CH₂Cl₂(43.0 mL) in CH₂Cl₂(200 mL). The mixture was then quenched at −20° C. by addition of MeOH (100 mL), warmed to room temperature, concentrated and purified by flash chromatography (silica, Et₂O/CH₂Cl₂) to afford the title compound as a colorless solid (8.7 g, 90%). ¹H-NMR (CDCl₃) δ=7.50 (d, 1H), 7.20 (d, 1H), 5.25 (m, 1H), 3.10 (m, 1H), 2.90 (m, 1H), 2.50 (m, 1H), 2.35 (s, 3H), 2.00 (m, 1H).

Step G

Under a nitrogen atmosphere NEt₃(15.9 mL) and methanesulfonyl chloride (4.5 mL) were added subsequently to a cooled (−78° C., acetone/dry ice) solution of the title compound from Step F above (8.7 g) in anhydrous CH₂Cl₂(200 mL). The mixture was stirred at −78° C. for 90 min, then NH₃(˜150 mL) was condensed into the mixture using a dry ice condenser at a rate of ˜3 ml/min and stirring at −78° C. was continued for 2 h. Then the mixture was gradually warmed to room temperature allowing the NH₃to evaporate. 1N aqueous NaOH (200 mL) was added, the organic phase was separated and the aqueous phase was extracted with CH₂Cl₂(2×100 mL). The combined organic phases were dried (MgSO₄), filtered and concentrated. The remaining light brown oil was dissolved in Et₂O (200 mL) and a 4M solution of HCl in 1,4-dioxane (10 mL) was added. The formed precipitate was collected and dried to give the title compound (9.0 g, 90%). [M−NH₃Cl]⁺=209/211.

Step H

To an ice cooled solution of the title compound from Step G above (5.2 g) in anhydrous CH₂Cl₂(50 mL) were subsequently added di-tert-butyl dicarbonate (5.0 g) and NEt₃(9.67 mL). The resulting mixture was stirred for 3 h, concentrated, diluted with Et₂O (250 mL), washed with saturated aqueous NaHCO₃(100 mL) and saturated aqueous NaCl (100 mL), dried (MgSO₄), filtered and concentrated to afford the title compound as a colorless solid (7.28 g, 97%). ¹H-NMR (CDCl₃, free base) δ=7.40 (m, H), 7.00 (d, 1H), 4.30 (t, 1H) 2.90 (m, 1H), 2.80 (m, 1H), 2.60 (m, 1H), 2.30 (s, 3H), 1.80 (m, 1H).

Step I

Under a nitrogen atmosphere a mixture of the title compound from Step H above (7.2 g), Zn(CN)₂(5.2 g) and Pd(PPh₃)₄(2.6 g) in anhydrous DMF (80 mL) was heated to 100° C. for 18 h, concentrated and purified by flash chromatography (silica, CH₂Cl₂/EtOAc) to afford the title compound as an off-white solid (4.5 g, 75%). ¹H-NMR (CDCl₃) δ=7.50 (d, 1H), 7.20 (d, 1H) 5.15 (m, 1H), 4.75 (m, 1H), 2.95 (m, 1H), 2.80 (m, 1H), 2.70 (m, 1H), 2.40 (s, 3H), 1.90 (m, 1H), 1.50 (s, 9H).

Preparative Example 2

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Step A

The title compound from the Preparative Example 1, Step I (1.0 g) was suspended in 6N aqueous HCl (20 mL), heated to 100° C. for 12 h and concentrated to give the title compound as a colorless solid. (834 mg, >99%). [M−NH₃Cl]⁺=175.

Step B

Anhydrous HCl gas was bubbled through an ice cooled solution of the title compound from Step A above (1.0 g) in anhydrous MeOH (20 mL) for 2-3 min. The cooling bath was removed, the mixture was heated to reflux for 12 h, cooled to room temperature and concentrated to give the title compound as a colorless solid (880 mg, 83%). [M−NH₃Cl]⁺═189.

Preparative Example 3

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Step A

A mixture of commercially available 5-bromo-indan-1-one (1.76 g), hydroxylamine hydrochloride (636 mg) and NaOAc (751 mg) in MeOH (40 mL) was stirred at room temperature for 16 h and then diluted with H₂O (100 mL). The formed precipitate was collected by filtration, washed with H₂O (3×20 mL) and dried to afford the title compound as a colorless solid (1.88 g, >99%). [MH]⁺=226/228.

Step B

Under an argon atmosphere a 1M solution of LiAlH₄in Et₂O (42.4 mL) was slowly added to a cooled (−78° C., acetone/dry ice) solution of the title compound from Step A above (1.88 g) in Et₂O (20 mL). Then the cooling bath was removed and the mixture was heated to reflux for 5 h. The mixture was cooled (0-5° C.) and H₂O (1.6 mL), 15% aqueous NaOH (1.6 mL) and H₂O (4.8 mL) were carefully and sequentially added. The resulting mixture was filtered through a plug of celite® and concentrated to give the title compound as a clear oil (1.65 g, 94%). [MH]⁺=212/214.

Step C

To a boiling solution of the title compound from Step B above (1.13 g) in MeOH (2.3 mL) was added a hot solution of commercially available N-acetyl-L-leucine (924 mg) in MeOH (3 mL). The solution was allowed to cool to room temperature, which afforded a white precipitate. The precipitate was collected by filtration, washed with MeOH (2 mL) and recrystalized from MeOH (2×). The obtained solid was dissolved in a mixture of 10% aqueous NaOH (20 mL) and Et₂O (20 mL), the organic phase was separated and the aqueous phase was extracted with Et₂O. The combined organic phases were dried (MgSO₄), filtered and concentrated to give the title compound as a clear oil (99 mg, 18%). [MH]⁺=212/214.

Step D

To a solution of the title compound from Step C above (300 mg) in THF (10 mL) were subsequently added di-tert-butyl dicarbonate (370 mg) and NEt₃(237 μL). The resulting mixture was stirred at room temperature for 16 h, concentrated and purified by chromatography (silica, hexanes/EtOAc) to afford the title compound as a clear oil (460 mg, >99%). [MNa]⁺=334/336.

Step E

Under an argon atmosphere a mixture of the title compound from Step D above (460 mg), Zn(CN)₂(200 mg) and Pd(PPh₃)₄(89 mg) in anhydrous DMF (5 mL) was heated in a sealed vial to 110° C. for 18 h. The mixture was cooled to room temperature and diluted with Et₂O (20 mL) and H₂O (20 mL). The organic phase was separated and the aqueous phase was extracted with Et₂O (4×10 mL). The combined organic phases were washed with H₂O (3×10 mL) and saturated aqueous NaCl (10 mL), dried (MgSO₄), filtered, concentrated and purified by chromatography (silica, hexanes/EtOAc) to afford the title compound as a clear oil (170 mg, 47%). [MH]⁺=259.

Preparative Example 4

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Step A

The title compound from the Preparative Example 3, Step E (1.0 g) was suspended in 6N aqueous HCl (50 mL), heated under closed atmosphere to 110-112° C. for 20 h and concentrated to give the title compound (827 mg, >99%). [M−Cl]⁺=178.

Step B

The title compound from Step A above (827 mg) was dissolved in anhydrous MeOH (150 mL) and saturated with anhydrous HCl gas. The resulting mixture was heated to reflux for 20 h, cooled to room temperature and concentrated. The remaining oil was taken up in CH₂Cl₂and washed with saturated aqueous NaHCO₃, dried (MgSO₄), filtered and concentrated to give the title compound as an oil which slowly crystallized into a light brown solid (660 mg, 89%). [MH]⁺=192.

Preparative Example 5

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Step A

To a solution of hydroxylamine hydrochloride (2.78 g) in dry MeOH (100 mL) was added a 30 wt % solution of NaOMe in MeOH (7.27 mL). The resulting white suspension was stirred at room temperature for 15 min and a solution of the title compound from the Preparative Example 3, Step E (5.17 g) in dry MeOH (100 mL) was added. The mixture was heated to reflux for 20 h (complete conversion checked by HPLC/MS, [MH]⁺=292) and then cooled to room temperature. Diethyl carbonate (48.2 g) and a 30 wt % solution of NaOMe in MeOH (7.27 mL) were added successively and the resulting mixture was heated to reflux for 24 h. The mixture was concentrated, diluted with 1M aqueous NH₄Cl (200 mL) and extracted with CH₂Cl₂/MeOH (60:40, 500 mL) and CH₂Cl₂(3×200 mL). The combined organic layers were dried (MgSO₄), filtered, concentrated and purified by flash chromatography (silica, CH₂Cl₂/MeOH) to afford the title compound as a white solid (3.89 g, 61%) [MNa]⁺=340.

Preparative Example 6

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Step A

The title compound from the Preparative Example 1, Step I (1.37 mg) was treated similarly as described in the Preparative Example 5, Step A to afford the title compound as a white solid (845 mg, 51%). [MNa]⁺=354.

Preparative Example 7

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Step A

To an ice cooled solution of the title compound from the Preparative Example 2, Step B (5.94 g) in dry CH₂Cl₂(50 mL) were subsequently added di-tert-butyl dicarbonate (1.6 g) and NEt₃(1 mL). The mixture was stirred for 3 h, concentrated, diluted with Et₂O (250 mL), washed with saturated aqueous NaHCO₃(100 mL) and saturated aqueous NaCl (100 mL), dried (MgSO₄), filtered and concentrated to afford the title compound as a colorless solid (7.28 g, 97%). [MNa]⁺=328.

Step B

To a mixture of the title compound from Step A above (7.28 g) in THF (60 mL) was added 1M aqueous LiOH (60 mL). The mixture was stirred at 50° C. for 2 h, concentrated, diluted with H₂O, adjusted to pH 5 with HCl and extracted with EtOAc. The combined organic phases were dried (MgSO₄), filtered and concentrated to afford the title compound as colorless solid (1.87 g, 27%). [MNa]⁺=314.

Step C

At 80° C. N,N-dimethylformamide di-tert-butyl acetal (6.2 mL) was added to a solution of the title compound from Step B above (1.87 g) in dry toluene (15 mL). The mixture was stirred at 80° C. for 3 h, cooled to room temperature, concentrated and purified by chromatography (silica, CH₂Cl₂) to afford the title compound as a colorless solid (820 mg, 38%). [MNa]⁺=370.

Step D

To a solution of the title compound from Step C above (820 mg) in ^tBuOAc (40 mL) was added concentrated H₂SO₄(0.65 mL). The resulting mixture was stirred at room temperature for 5 h, concentrated, diluted with EtOAc, washed with saturated aqueous NaHCO₃and saturated aqueous NaCl, dried (MgSO₄), filtered and concentrated to afford the title compound as a colorless solid (640 mg, 99%). [M−NH₂]⁺=231.

Preparative Example 8

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Step A

To a solution of the title compound from the Preparative Example 3, Step E (153 mg) in EtOH (10 mL) were added NEt₃(0.16 mL) and hydroxylamine hydrochloride (81 mg). The mixture was heated to reflux for 4 h, then concentrated, dissolved in THF (5 mL) and pyridine (0.19 mL) and cooled to 0° C. Trifluoroacetic anhydride (0.25 mL) was added and the mixture was stirred for 16 h. Concentration and purification by chromatography (silica, hexanes/EtOAc) afforded the title compound as a white solid (217 mg, >99%). [MNa]⁺=392.

Preparative Example 9

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Step A

To a solution of the title compound from the Preparative Example 4, Step A (33.7 mg) in 1,4-dioxane/H₂O (1:1, 2 mL) were added NaOH (97.4 mg) and di-tert-butyl dicarbonate (68.7 mg). The resulting mixture was stirred at room temperature overnight, diluted with EtOAc, washed with IN aqueous HCl and saturated aqueous NaCl, dried (MgSO₄), and concentrated to give a white solid (34.6 mg, 71%). [MNa]⁺=300.

Step B

To a solution of the title compound from Step A above (34.6 mg) in CH₂Cl₂(1 mL) were added oxalyl chloride (33 μL) and DMF (2 μL). The mixture was stirred at room temperature for 2 h and concentrated. The remaining residue was dissolved in CH₂Cl₂(1 mL) and added to a cold (−78° C.) saturated solution of NH₃in CH₂Cl₂(1 mL). The mixture was stirred at −78° C. for 1 h, warmed to room temperature, concentrated, redissolved in CH₂Cl₂(5 mL), filtered, and concentrated to give a white solid (25.9 mg, 75%). [MNa]⁺=299.

Preparative Example 10

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Step A

To mixture of the title compound from the Preparative Example 7, Step B (536 mg) and allyl bromide (1.6 mL) in CHCl₃/THF (1:1, 20 mL) were added Bu₄NHSO₄(70 mg) and a 1M solution of LiOH in H₂O (10 mL) and the resulting biphasic mixture was stirred at 40° C. overnight. The organic phase was separated, concentrated, diluted with CHCl₃, washed with H₂O, dried (MgSO₄), filtered, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound (610 mg, >99%). [MNa]⁺=354.

Preparative Example 11

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Step A

To a solution of the title compound from the Preparative Example 9, Step A (97 mg) in dry DMF (5 mL) were added K₂CO₃(97 mg) and allyl bromide (22 μL). The mixture was stirred overnight, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound (81 mg, 68%). [MNa]⁺=340.

Preparative Example 12

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Step A

To a solution of commercially available 2-amino-4-chloro-phenol (5.0 g) and NaHCO₃(7.7 g) in acetone/H₂O was slowly added 2-bromopropionyl bromide (4 mL) at room temperature, before the mixture was heated to reflux for 3 h. The acetone was evaporated and the formed precipitate was isolated by filtration, washed with H₂O and dried to afford the title compound as brown crystals (6.38 g, 93%). [MH]⁺=198.

Preparative Example 13

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Step A

To a solution of commercially available 2-amino-4-chloro-phenol (5.0 g) and NaHCO₃(7.7 g) in acetone/H₂O (4:1, 200 mL) was slowly added 2-bromo-2-methylpropionyl bromide (8.3 mL) at room temperature, before the mixture was heated at ˜90° C. overnight. The acetone was evaporated and the formed precipitate was filtered off, washed with H₂O (100 mL) and recrystallized from acetone/H₂O (1:1) to afford the title compound as a pale brown solid (4.8 g, 33%). [MH]⁺=212.

Preparative Example 14

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Step A

To a solution of commercially available 7-hydroxy-3,4-dihydro-1H-quinolin-2-one (1.63 g) in THF (20 mL) was added NaH (95%, 0.28 g). The mixture was stirred at room temperature for 5 min, N-phenyl-bis(trifluoromethanesulfonimide) (4.0 g) was added and stirring at room temperature was continued for 2 h. The mixture was cooled to 0° C., diluted with H₂O (40 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with saturated aqueous NaCl, dried (MgSO₄), filtered, concentrated and purified by chromatography (silica, CH₂Cl₂MeOH) to afford the title compound (2.29 g, 78%). [MH]⁺=296.

Preparative Example 15

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Step A

Commercially available 5-chloro-2-methylbenzoxazole (1.5 g), KCN (612 mg), dipiperidinomethane (720 μL), Pd(OAc)₂(80 mg) and 1,5-bis-(diphenylphosphino)pentane (315 mg) were dissolved in dry toluene (20 mL), degassed and heated at 160° C. in a sealed pressure tube under an argon atmosphere for 24 h. The mixture was diluted with EtOAc, washed subsequently with saturated aqueous NH₄Cl and saturated aqueous NaCl, dried (MgSO₄), filtered, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound as a colorless solid (372 mg, 26%). ¹H-NMR (CDCl₃) δ=7.90 (s, 1H), 7.48-7.58 (s, 2H), 2.63 (s, 3H).

Preparative Example 16

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Step A

A solution of 5-bromo-2-fluorobenzylamine hydrochloride (5.39 g), K₂CO₃(7.74 g) and benzyl chloroformate (3.8 mL) in THF/H₂O was stirred at room temperature for 90 min. The resulting mixture was concentrated, diluted with EtOAc, washed with 10% aqueous citric acid, saturated aqueous NaHCO₃and saturated aqueous NaCl, dried (MgSO₄), filtered, concentrated and slurried in pentane. The formed precipitate was collected by filtration to give the title compound as colorless needles (7.74 g, >99%). [MH]⁺=338/340.

Preparative Example 17

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Step A

To a suspension of commercially available 5-bromo-2-fluoro-benzoic acid (4.52 g) in dry toluene (200 mL) were added NEt₃(3.37 mL) and diphenylphosphoryl azide (5.28 mL). The resulting clear solution was heated to reflux for 16½ h, then benzyl alcohol (2.51 mL) was added and heating to reflux was continued for 3 h. The mixture was concentrated and purified by flash chromatography (silica, cyclohexane/EtOAc) to afford the title compound (2.96 g, 46%). [MH]⁺=324/326.

Preparative Example 18

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Step A

A solution of commercially available 4-bromophenol (3.36 g), 3-chloro-butan-2-one (2.2 mL) and K₂CO₃(4 g) in acetone (40 mL) was heated to reflux for 3 h. Then an additional amount of 3-chloro-butan-2-one and K₂CO₃was added and heating to reflux was continued overnight. The mixture was concentrated, dissolved in EtOAc, washed with H₂O, 10% aqueous citric acid and saturated aqueous NaCl, dried (MgSO₄), filtered and concentrated. The obtained colorless oil was added dropwise at 100° C. to phosphorous oxychloride (4.7 mL). The resulting mixture was stirred at 100° C. for 1 h, cooled to room temperature and ice, followed by EtOAc was added. The organic layer was separated, washed subsequently with saturated aqueous NaCl and saturated aqueous NaHCO₃, concentrated and purified by chromatography (silica, cyclohexane) to afford the title compound as a bright yellow solid (2.55 g, 58%). ¹H-NMR (CDCl₃) δ=7.50 (s, 1H), 7.20-7.30 (m, 2H), 2.33 (s, 3H), 2.10 (s, 3H).

Preparative Example 19

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Step A

A 2.5M solution of BuLi in hexane (13.6 mL) was diluted in THF (50 mL) and cooled to −78° C. (dry ice/acetone). To this solution were subsequently added 2,2,6,6-tetramethylpiperidine (4.8 g) and commercially available 2-(trifluoromethyl)pyridine (5 g). The mixture was stirred at −78° C. for 2 h and then a solution of iodine (17.3 g) in THF (50 mL) was added. The cooling bath was removed and the mixture was stirred at room temperature overnight. Then the mixture was quenched with 1M aqueous Na₂S₂O₃(50 mL), the organic phase was separated and the aqueous phase was extracted with EtOAc. The combined organic phases were dried (MgSO₄), filtered, concentrated and purified by chromatography (silica, CH₂Cl₂) to afford the title compound as a pale yellow solid (6.3 g, 68%). ¹H-NMR (CDCl₃) δ=8.63 (dd, 1H), 8.36 (d, 1 H), 7.20 (dd, 1H).

Step B

A 2.5M solution of BuLi in hexane (7.2 mL) was diluted in THF (30 mL) and cooled to −78° C. (dry ice/acetone). To this solution were subsequently and dropwise added ⁱPr₂NH (2.5 mL) and the title compound from Step A above (4.9 g). The mixture was stirred at −78° C. for 2 h, quenched at −78° C. with MeOH (2 mL), concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound as yellow needles (1.6 g, 32%). ¹H-NMR (CDCl₃) δ=8.40 (d, 1H), 8.06 (s, 1H), 7.90 (d, 1H).

Preparative Example 20

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Step A

A suspension of commercially available 6-chloro-4H-benzo[1,4]oxazin-3-one (3.2 g) and CuCN (2.9 g) in dry N-methyl-pyrrolidin-2-one (15 mL) was placed in a preheated oil bath (˜250° C.). After stirring at this temperature overnight, the mixture was concentrated, diluted with H₂O (200 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were washed with H₂O (2×200 mL) and saturated aqueous NaCl (200 mL), dried (MgSO₄), filtered and concentrated. The remaining residue crystallized from EtOAc/toluene to afford the title compound as a tan solid (720 mg, 24%). [MH]⁺=175.

Preparative Examples 21-24

Following a similar procedure as described in the Preparative Example 20, except using the intermediates indicated in Table I-1 below, the following compounds were prepared.

TABLE I-1Prep.Ex. #intermediateproductyield21 embedded image

39% [MH]⁺ = 18922 embedded image

45% [MH]⁺ = 20323 embedded image

74% ¹H-NMR (CDCl₃) δ = 7.30(d, 1H), 7.06 (s, 1H), 7.03 (d, 1H).24 embedded image

64% [MH]⁺ = 173

Preparative Example 25

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Step A

A mixture of the title compound from the Preparative Example 18, Step A (2.55 g), Zn(CN)₂(1.0 g) and Pd(PPh₃)₄(653 mg) in dry DMF (10 mL) was degassed and heated at 85° C. under an argon atmosphere for 40 h. The mixture was concentrated, diluted with EtOAc, washed subsequently with 10% aqueous citric acid and saturated aqueous NaCl, dried (MgSO₄), concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound as colorless crystals (1.05 g, 54%). ¹H-NMR (CDCl₃) δ=7.72 (s, 1H), 7.35-7.50 (m, 2H), 2.40 (s, 3H), 2.18 (s, 3H).

Preparative Examples 26-30

Following a similar procedure as described in the Preparative Example 25, except using the intermediates indicated in Table I-2 below, the following compounds were prepared.

TABLE I-2Prep.Ex. #intermediateproductyield26 embedded image

>99% [MNa]⁺ = 26127 embedded image

94% [MH]⁺ = 17328 embedded image

86% [MH]⁺ = 17329 embedded image

98% ¹H-NMR (CDCl₃) δ = 7.10-7.75(m, 8H), 5.22(br s, 1H), 5.13(s, 2H), 4.42(d, 2H).30 embedded image

56% [MH]⁺ = 271

Preparative Example 31

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Step A

A solution of commercially available 3-cyano-benzenesulfonyl chloride (1.07 g) in a 33% solution of NH₃in H₂O (40 mL) was stirred at room temperature for 1 h, then concentrated to ˜20 mL and placed in an ice bath. The formed precipitate was separated by filtration, washed with H₂O and dried in vacuo to afford the title compound as a colorless solid (722 mg, 75%). [MH]⁺=183.

Preparative Example 32

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Step A

Commercially available 2-trifluoromethyl-pyrimidine-4-carboxylic acid methyl ester (1.0 g) was dissolved in a 7M solution of NH₃in MeOH and heated in a sealed pressure tube to 50° C. for 16 h. Cooling to room temperature and concentration afforded the title compound (941 mg, >99%). [MH]⁺=192.

Step B

A 2M solution of oxalyl chloride in CH₂Cl₂(520 μL) was diluted in DMF (3 mL) and then cooled to 0° C. Pyridine (168 μL) and a solution of the title compound from Step A above (100 mg) in DMF (1 mL) were added and the mixture was stirred at 0° C. for 3 h and then at room temperature overnight. The mixture was concentrated, diluted with EtOAc, washed with saturated aqueous NaHCO₃, dried (MgSO₄), filtered and concentrated to afford the title compound (60 mg, 65%). ¹H-NMR (CDCl₃) δ=9.20 (d, 1H), 7.85 (d, 1H).

Preparative Example 33

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Step A

A solution of commercially available 7-cyano-1,2,3,4-tetrahydroisoquinoline (103 mg) and sulfamide (69 mg) in dry 1,2-dimethoxyethane (10 mL) was heated to reflux overnight, concentrated, diluted with EtOAc, washed subsequently with 10% aqueous citric acid and saturated aqueous NaCl, dried (MgSO₄), filtered and concentrated to give the title compound as a colorless solid (165 mg, >99%). [MH]⁺=238.

Preparative Example 34

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Step A

To an ice cooled solution of the title compound from the Preparative Example 33, Step A (165 mg) in dry MeOH (20 mL) were added di-tert-butyl dicarbonate (300 mg) and NiCl₂.6H₂O (20 mg), followed by the careful portionwise addition of NaBH₄(220 mg). The resulting black mixture was stirred for 20 min at 0-5° C. (ice bath), then the ice bath was removed and stirring at room temperature was continued overnight. Then diethylenetriamine was added and the mixture was concentrated to dryness. The remaining residue was suspended in EtOAc washed subsequently with 10% aqueous citric acid, saturated aqueous NaHCO₃and saturated aqueous NaCl, dried (MgSO₄), filtered, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound as a colorless solid (109 mg, 46%). [MNa]⁺=364.

Preparative Example 35

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Step A

A solution of commercially available 7-cyano-1,2,3,4-tetrahydroisoquinoline (407 mg) in dry CH₂Cl₂(10 mL) was added iodosobenzene (1.13 g). The reaction mixture was stirred at room temperature overnight, diluted with CH₂Cl₂, washed subsequently with 10% aqueous citric acid and saturated aqueous NaCl, dried (MgSO₄), filtered, absorbed on silica and purified by chromatography (silica, CH₂Cl₂/MeOH). The obtained intermediate (240 mg) was dissolved in dry DMF (7 mL) and cooled to 0° C. An excess of NaH and methyl iodide were added subsequently and the mixture was stirred for 2 h while warming to room temperature. The mixture was diluted with EtOAc, washed subsequently with 1N aqueous HCl and saturated aqueous NaCl, dried (MgSO₄), filtered, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to give the title compound as a slowly crystallizing oil (104 mg, 22%). [MH]⁺=187.

Preparative Example 36

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Step A

To a solution of commercially available 7-Cyano-1,2,3,4-tetrahydroisoquinoline (158 mg) in acetic anhydride (5 mL) was added pyridine (0.2 mL). The mixture was stirred overnight and then concentrated to afford the crude title compound. [MNa]⁺=223.

Preparative Example 37

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Step A

The title compound from the Preparative Example 20, Step A (549 mg) was dissolved in dry DMF (7 mL) and cooled to 0° C. An excess of NaH and methyl iodide were added subsequently and the mixture was stirred for 2 h while warming to room temperature. The mixture was diluted with EtOAc, washed subsequently with 1N aqueous HCl and saturated aqueous NaCl, dried (MgSO₄), filtered, absorbed on silica and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound as colorless needles (311 mg, 52%). [MH]⁺=189.

Preparative Example 38

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Step A

Under an argon atmosphere a mixture of commercially available 4-fluoro-3-methoxybenzonitrile (5.0 g), AlCl₃(8.8 g) and NaCl (1.94 g) was heated (melted) to 190° C. for 45 min, cooled, poured on ice (200 mL) and extracted with CHCl₃(3×). The combined organic phases were washed with H₂O, dried (MgSO₄), filtered, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound as colorless needles (3.45 g, 76%). [MH]⁺=138.

Step B

A suspension of the title compound from Step A above (883 mg) and K₂CO₃(980 mg) in dry DMF (15 mL) was heated to 50° C. for 10 min and then cooled to −40° C. Chlorodifluoromethane (50 g) was condensed into the mixture and the resulting slurry was stirred at 80° C. with a dry ice condenser for 6 h and then at room temperature overnight without condenser. The mixture was concentrated, diluted with EtOAc, washed subsequently with 1N aqueous HCl and saturated aqueous NaCl, dried (MgSO₄), filtered and concentrated. Purification by chromatography (silica, cyclohexane/EtOAc) afforded the crude title compound as a colorless oil (1.31 g). [MH]⁺=188.

Preparative Example 39

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Step A

To a cooled (−30° C.) solution of ⁱPr₂NH (16.9 mL) in THF (140 mL) was dropwise added a 2.5M solution of BuLi in hexane (43.2 mL). The mixture was stirred between −20° C. and −30° C. for 20 min and then cooled to −78° C. To this solution dry HMPA (72 mL) was added dropwise not allowing the temperature of the mixture to exceed −70° C. The resultant mixture was cooled again to −78° C. and a solution of commercially available dimethylcyclohexane-1,4-dicarboxylate (20 g) in THF (20 mL) was added dropwise over a period of ˜10 min. Stirring at −78° C. was continued for 40 min, then 1-bromo-2-chloroethane (10 mL) was added over a period of 5 min, the cooling bath was removed and the mixture was allowed to warm to room temperature. The mixture was then quenched with saturated aqueous NH₄Cl, the volatiles were removed by evaporation and the mixture was diluted with cyclohexane and H₂O. The aqueous phase was separated and extracted with cyclohexane (2×). The combined organic phases were washed with H₂O and saturated aqueous NaCl, dried (MgSO₄), filtered and concentrated. The remaining residue was distilled (10⁻²mbar, 100° C.) to give the title compound as a pale yellow oil (17 g, 65%). [MH]⁺=263.

Step B

To a cooled (−30° C.) solution of ⁱPr₂NH (18.7 mL) in THF (180 mL) was dropwise added a 2.5M solution of BuLi in hexane (53.6 mL). The mixture was stirred between −20° C. and −30° C. for 20 min and then cooled to −78° C. This solution was canulated over a period of 30 min into a cooled (−78° C.) mixture of the title compound from Step A above (32 g) and HMPA (90 mL) in THF (440 mL) not allowing the temperature of the mixture to exceed −70° C. Stirring at −78° C. was continued for 25 min and then the mixture was allowed to warm to room temperature over a period of 1½ h. The mixture was kept at room temperature for 1 h and then quenched with saturated aqueous NH₄Cl. The volatiles were removed by evaporation and the mixture was diluted with cyclohexane and H₂O. The aqueous phase was separated and extracted with cyclohexane (3×). The combined organic phases were washed with H₂O and saturated aqueous NaCl, dried (MgSO₄), filtered and concentrated. The remaining residue was recrystallized from cyclohexane to give the title compound (13.8 g, 50%). [MH]⁺=227.

Step C

A mixture of the title compound from Step B above (20 g) and KOH (5.5 g) in MeOH/H₂O (10:1, 106 mL) was heated to reflux overnight, cooled to room temperature and concentrated. The residue was diluted with EtOAc and extracted with 1N aqueous NaOH (2×100 mL). The organic phase was dried (MgSO₄), filtered and concentrated to give the starting material as a white solid. The combined aqueous phases were adjusted with 2N aqueous HCl to pH 1-2 and extracted with EtOAc (4×250 mL). The combined turbid organic phases were filtered through a fluted filter, washed with saturated aqueous NaCl, dried (MgSO₄), filtered and concentrated to give the title compound as a colorless solid (13.1 g, 70%). [MH]⁺=213.

Step D

To a cooled (−40° C.) solution of the title compound from Step C above (500 mg) and NEt₃(1.23 mL) in THF (50 mL) was slowly added ethyl chloroformate (0.67 mL). The mixture was allowed to warm to −25° C. and stirred at this temperature for 1 h. A 7N solution of NH₃in MeOH (10 mL) was added and the mixture was stirred at −20° C. for 30 min. The cooling bath was removed and the mixture was stirred at room temperature for 15 min before it was concentrated. To the remaining residue were added H₂O (10 mL) and CH₂Cl₂(20 mL), the organic phase was separated and the aqueous phase was extracted with CH₂Cl₂(2×10 mL). The combined organic phases were washed with 1N aqueous KOH (10 mL), dried (MgSO₄), filtered and concentrated to afford the title compound (458 mg, 92%). [MH]⁺=212.

Preparative Example 40

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Step A

To a cooled (0° C.) mixture of the title compound from the Preparative Example 39, Step A (228 mg) and imidazole (147 mg) in pyridine (10 mL) was slowly added POCl³(0.40 mL). The mixture was stirred at 0° C. for 1 h and then added to a mixture of ice, NaCl and EtOAc. The organic phase was separated and washed with 1N aqueous HCl until the aqueous phase remained acidic. Drying (MgSO₄), filtration and concentration afforded the title compound (137 mg, 72%). [MH]⁺=194.

Preparative Example 41

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Step A

The title compound from the Preparative Example 40, Step A (137 mg) was treated similarly as described in the Preparative Example 34, Step A to afford the title compound (163 mg, 77%). [MNa]⁺=320.

Preparative Example 42

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Step A

To a solution of the title compound from the Preparative Example 41, Step A (2.0 g) in MeOH (10 mL) was added a solution of KOH (753 mg) in H₂O (2 mL). The mixture was heated to reflux for 15 h, concentrated to approximately half of its volume and diluted with H₂O (50 mL). EtOAc (100 mL) was added and the organic phase was separated. The aqueous phase was acidified to pH 4.5 and extracted with EtOAc (3×40 mL). The combined organic phases were washed with saturated aqueous NaCl (50 mL), dried (MgSO₄), filtered and concentrated to afford the title compound (1.1 g, 56%). [MNa]⁺=306.

Preparative Example 43

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Step A

A mixture of commercially available norbonene (15 g) and RuCl₃(0.3 g) in CHCl₃(100 mL) was stirred at room temperature for 5 min. Then a solution of NaIO₄(163 g) in H₂O (1200 mL) was added and the mixture was stirred at room temperature for 2 d. The mixture was filtered through a pad of celite® and the organic phase was separated. The aqueous phase was saturated with NaCl and extracted with EtOAc (3×500 mL). The combined organic phases were treated with MgSO₄and charcoal, filtered and concentrated to afford the crude title compound as thick slightly purple liquid (13.5 g, 53%). [MH]⁺=159.

Step B

To a solution of the title compound from Step A above (11.2 g) in MeOH (250 mL) was added concentrated H₂SO₄(0.5 mL) at room temperature. The mixture was heated to reflux for 15 h, cooled to room temperature, filtrated and concentrated. The remaining residue was diluted with EtOAc (100 mL), washed with saturated aqueous NaHCO₃(3×50 mL) and saturated aqueous NaCl (50 mL), dried (MgSO₄), filtered, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound as a colorless solid (8.43 g, 64%). [MH]⁺=187.

Step C

To a cooled (−20° C.) solution of ⁱPr₂NH (17.3 mL) in THF (230 mL) was dropwise added a 2.5M solution of BuLi in hexane (45.3 mL). The mixture was stirred between −20° C. and −30° C. for 20 min and then cooled to −78° C. To this solution dry HMPA (63.2 mL) was added dropwise not allowing the temperature of the mixture to exceed −70° C. The resultant mixture was cooled again to −78° C. and a solution of the title compound from Step B above (8.43 g) in THF (40 mL) was added dropwise over a period of 20 min. Then the mixture was stirred at 0° C. for 20 min and cooled again to −78° C. 1-Bromo-2-chloroethane (6.32 mL) was added over a period of 40 min, the cooling bath was removed and the mixture was allowed to warm to room temperature over a period of 2 h. The mixture was then quenched with saturated aqueous NH₄Cl (60 mL), concentrated to ⅕ volume and diluted with H₂O (120 mL). The aqueous phase was separated and extracted with cyclohexane (3×100 mL). The combined organic phases were washed with H₂O (100 mL) and saturated aqueous NaCl (100 mL), dried (MgSO₄), filtered, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound as a colorless solid (7.86 g, 82%). [MH]⁺=213.

Step D

To a solution of the title compound from Step C above (3.5 g) in MeOH (15 mL) was added a solution of KOH (1.6 g) in H₂O (1.75 mL). Using a microwave, the mixture was heated to 140° C. for 25 min before H₂O (30 mL) was added. The aqueous mixture was washed with cyclohexane (2×30 mL), adjusted to pH 1 with 1N aqueous HCl and extracted with CH₂Cl₂(2×30 mL). The combined organic phases were washed with saturated aqueous NaCl (15 mL), dried (MgSO₄), filtered, concentrated and purified by flash chromatography (silica, CH₂Cl₂/MeOH) to afford the title compound (2.3 g, 70%). [MH]⁺=199.

Preparative Example 44

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Step A

Preparative Example 45

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Step A

To a solution of title compound from the Preparative Example 7, Step B (35 mg) in DMF (3 mL) were added HATU (60 mg), HOAt (20 mg) and a 2M solution of MeNH₂in THF (150 μL). The mixture was stirred for 16 h, concentrated, diluted with EtOAc, washed with saturated aqueous NaHCO₃and saturated aqueous NaCl, dried (MgSO₄), filtered, concentrated and purified by chromatography (silica, CH₂Cl₂/acetone) to afford the title compound (35 mg, 95%). [MH]⁺=291.

Preparative Examples 46-53

Following similar procedures as described in the Preparative Examples 39 (method A), 44 (method B) or 45 (method C), except using the acids and amines indicated in Table I-3 below, the following compounds were prepared.

TABLE I-3Prep.method,Ex. #acid, amineproductyield46 embedded image

2M MeNH₂in THF embedded image

A, 79% [MH]⁺ = 29747 embedded image

2M Me₂NH in THF embedded image

B, 90% [MH]⁺ = 31148 embedded image

B, 44% [MH]⁺ = 35349 embedded image

7N NH₃in MeOH embedded image

A, 51% [MH]⁺ = 28350 embedded image

7N NH₃in MeOH embedded image

A, 37% [MH]⁺ = 19851 embedded image

2M MeNH₂in THF embedded image

B, 99% [MNa]⁺ = 29352 embedded image

2M Me₂NH in THF embedded image

B, 98% [MNa]⁺ = 30753 embedded image

2M Me₂NH in THF embedded image

C, 60% [MH]⁺ = 305

Preparative Example 54

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Step A

The title compound from the Preparative Example 50 (300 mg) was treated similarly as described in the Preparative Example 40, Step A to afford the title compound (250 mg, 92%). [MH]⁺=180.

Preparative Example 55

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Step A

To a suspension of the title compound from the Preparative Example 39, Step C (1.0 g) in acetone (7.5 mL) was added phenolphthaleine (1 crystal). To this mixture was added 1M aqueous NaOH until the color of the solution changed to red (pH˜8.5). Then a solution of AgNO₃(850 mg) in H₂O (1.25 mL) was added. The formed precipitate (Ag-salt) was collected by filtration, washed with H₂O, acetone and Et₂O and dried in vacuo at room temperature for 6 h and at 100° C. for 18 h. The obtained solid (1.28 g) was suspended in hexane (15 mL), bromine (643 mg) was added dropwise and the mixture was stirred at room temperature for 30 min. Then the mixture was placed in a preheated oil bath (80° C.) and stirred at the temperature for another 30 min. The mixture was filtered and the filter cake was washed with Et₂O (2×30 mL). The combined filtrates were washed with saturated aqueous NaHCO₃(2×25 mL), dried (MgSO₄), filtered and concentrated to afford the title compound (817 mg, 70%). [MH]⁺=247/249.

Preparative Example 56

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step A

To the title compound from the Preparative Example 55, Step A (600 mg) was added 1% aqueous NaOH (65 mL). The mixture was stirred at 100° C. (temperature of the oil bath) for 18 h, concentrated to 15 mL and diluted with 1N aqueous HCl (20 mL). The resulting mixture was acidified to pH 1 with 12N aqueous HCl and extracted with EtOAc (2×75 mL). The combined organic phases were dried (MgSO₄), filtered and concentrated to afford the crude title compound, which was not further purified (340 mg, 82%). [M−CO_2]⁺=188/190.

Preparative Example 57

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Step A

To a cooled (−30° C.) solution of the title compound from the Preparative Example 56, Step A (540 mg) and NEt₃(375 μL) in THF (25 mL) was added ethyl chloroformate (200 μL). The mixture was stirred at −30° C. for 1 h and then filtered. The precipitated salts were washed with THF (15 mL). The combined filtrates were cooled to −20° C. and a 33% solution of NH₃in H₂O (7 mL) was added. The mixture was stirred at −20° C. for 20 min, then the cooling bath was removed and the mixture was stirred at room temperature for 40 min. Then the mixture was concentrated and dissolved in THF (12 mL). Pyridine (690 μL) was added and the mixture was cooled to 0° C. Trifluoroacetic anhydride (600 μL) was added and the mixture was stirred at 0° C. for 2 h. Then the mixture was concentrated to 5 mL, diluted with MeOH (10 mL) and 10% aqueous K₂CO₃(5 mL) and stirred at room temperature for 2½ h. The MeOH was evaporated and Et₂O/EtOAc (9:1, 80 mL), H₂O (10 mL), saturated aqueous NaCl (10 mL) and saturated aqueous NH₄Cl (15 mL) were added. The organic phase was separated, washed with 0.1N aqueous HCl (30 mL), dried (MgSO₄), filtered and concentrated to afford the crude title compound, which was not further purified (222 mg, 86%). [MH]⁺=214/216.

Preparative Examples 58-80

Following a similar procedure as described in the Preparative Example 34, except using the nitriles indicated in Table I-4 below, the following compounds were prepared.

TABLE I-4Prep.Ex. #nitrileproductyield58 embedded image

68% [MNa]⁺ = 31059 embedded image

73% [MNa]⁺ = 28560 embedded image

68% [MNa]⁺ = 29861 embedded image

69% [MNa]⁺ = 31362 embedded image

41% [MNa]⁺ = 30163 embedded image

51% [MNa]⁺ = 31564 embedded image

62% [MNa]⁺ = 31565 embedded image

n.d. [MNa]⁺ = 31466 embedded image

98% [MH]⁺ = 30767 embedded image

67% [MH]⁺ = 27768 embedded image

18% ¹H-NMR (CDCl₃) δ = 8.80(d, 1H), 7.50(d, 1H), 5.40 (br s, 1H), 4.50 (br d, 2H), 1.40 (s, 9H)69 embedded image

n.d. [MNa]⁺ = 30970 embedded image

67% [MH]⁺ = 29271 embedded image

74% [MH]⁺ = 24372 embedded image

38% [M-isobutene]⁺ =28273 embedded image

24% [M-isobutene]⁺ =26274 embedded image

57% [MH]⁺ = 28475 embedded image

61% [MH]⁺ = 22676 embedded image

n.d. [MNa]⁺ = 30577 embedded image

75% [MNa]⁺ = 29978 embedded image

79% [MH]⁺ = 27779 embedded image

>99% [MNa]⁺ = 41180 embedded image

89% [MNa]⁺ = 397

Preparative Example 81

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Step A

To the title compound from the Preparative Example 55, Step A (677 mg) was added 10% aqueous NaOH (65 mL). The mixture was stirred at 100° C. (temperature of the oil bath) for 42 h, concentrated to 15 mL and diluted with 1N aqueous HCl (30 mL). The resulting mixture was acidified to pH 1 with 12N aqueous HCl and extracted with EtOAc (5×70 mL). The combined organic phases were dried (MgSO₄), filtered and concentrated to afford the title compound (540 mg, 89%). [MH]⁺=171.

Preparative Example 82

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Step A

To a cooled (−30° C.) solution of the title compound from the Preparative Example 81, Step A (540 mg) and NEt₃(590 μL) in THF (35 mL) was added ethyl chloroformate (320 μL). The mixture was stirred at −30° C. for 1 h and then filtered. The precipitated salts were washed with THF (20 mL). The combined filtrates were cooled to −20° C. and a 33% solution of NH₃in H₂O (10 mL) was added. The mixture was stirred at −20° C. for 20 min, then the cooling bath was removed and the mixture was stirred at room temperature for 40 min. The mixture was concentrated and dissolved in THF/CH₃CN (4:1, 25 mL). Pyridine (1.26 mL) was added and the mixture was cooled to 0° C. Trifluoroacetic anhydride (1.10 mL) was added and the mixture was stirred at 0° C. for 2 h. Then the mixture was concentrated to 5 mL, diluted with MeOH (18 mL) and 10% aqueous K₂CO₃(9 mL), stirred at room temperature overnight, concentrated to 10 mL, acidified to pH 1 with 1N aqueous HCl and extracted with CH₂Cl₂(4×75 mL). The combined organic phases were dried (MgSO₄), filtered, concentrated and purified by chromatography (silica, CH₂Cl₂/MeOH) to afford the title compound (433 mg, 90%). [MH]⁺=152.

Preparative Example 83

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Step A

To a suspension of LiAlH₄(219 mg) in THF (12 mL) was added a solution of the title compound from the Preparative Example 82, Step A (433 mg) in THF (35 mL) over a period of 20 min. The mixture was heated to reflux for 36 h and then cooled to 0° C. 1N aqueous NaOH (1 mL) was added and the mixture was stirred overnight while warming to room temperature. The mixture was filtered through a pad of celite® and the filter cake was washed with Et₂O (250 mL). The combined filtrates were concentrated to afford the title compound (410 mg, 92%). [MH]⁺=156.

Preparative Example 84

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Step A

To a solution of the title compound from the Preparative Example 83, Step A (390 mg) in THF (80 mL) were successively added ⁱPr₂NEt (0.66 mL) and di-tert-butyl dicarbonate (740 mg). The mixture was stirred at room temperature for 3 d, concentrated, diluted with EtOAc (100 mL), washed subsequently with H₂O (15 mL), 0.1N aqueous HCl and saturated aqueous NaCl, dried (MgSO₄), concentrated and purified by chromatography (silica, CH₂Cl₂/MeOH) to afford the title compound (196 mg, 30%). [MNa]⁺=278.

Step B

To a cooled (−78° C.) solution of the title compound from Step A above (85 mg) in CH₂Cl₂(4 mL) was added a solution of diethylaminosulfur trifluoride (73 μL) in CH₂Cl₂(4 mL). The mixture was stirred at −78° C. for 15 min and then poured on saturated aqueous NaHCO₃(40 mL). The organic phase was separated and the aqueous phase was extracted with CH₂Cl₂(3×40 mL). The combined organic phases were washed with saturated aqueous NaCl (30 mL), dried over MgSO₄, filtered, concentrated and purified by chromatography (silica, cycloheane/EtOAc) to afford the title compound (28 mg, 32%). [MNa]⁺=280.

Preparative Example 85

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Step A

To a solution of the title compound from the Preparative Example 42, Step A (50 mg) in DMF (1.6 mL) were added HATU (67 mg), ⁱPr₂NEt (68 μL) and N-hydroxyacetamidine (˜60%, 22 mg). Using a microwave, the mixture was heated in a sealed tube to 130° C. for 30 min. Additional HATU (130 mg) and N-hydroxyacetamidine (50 mg) were added and the mixture was again heated to 130° C. (microwave) for 30 min. Additional HATU (130 mg) and N-hydroxyacetamidine (59 mg) were added and the mixture was heated to 140° C. (microwave) for 30 min. The mixture was concentrated and purified by flash chromatography (silica, cyclohexane/EtOAc) to afford the title compound (18 mg, 32%). [MNa]⁺=322.

Preparative Example 86

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Step A

To a solution of the title compound from the Preparative Example 49 (150 mg) in THF (6 mL) was added methyl N-(triethylammoniosulfonyl) carbamate [“Burgess reagent”] (316 mg). The mixture was stirred at room temperature for 15 h, diluted with EtOAc (15 mL), filtered, concentrated and purified by flash chromatography (silica, CH₂Cl₂/MeOH) to afford the title compound (77 mg, 55%). [MH]⁺=265.

Preparative Example 87

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Step A

To a cooled (−40° C.) solution of the title compound from the Preparative Example 42, Step A (60 mg) and NEt₃(40 μL) in THF (5 mL) was added ethyl chloroformate (24 μL). The mixture was stirred at −40° C. for 1 h and then filtered. The precipitated salts were washed with THF (30 mL). The combined filtrates were cooled to 0° C. and a solution of NaBH₄(24 mg) in H₂O (430 μL) was added. The mixture was stirred at 0° C. for 1 h, then the cooling bath was removed and the mixture was stirred at room temperature for 1 h. The mixture was diluted with saturated aqueous NaHCO₃(5 mL) and saturated aqueous NaCl (5 mL) and extracted with EtOAc (3×20 mL). The combined organic phases were washed with saturated aqueous NaCl, dried (MgSO₄), filtered, concentrated and purified by chromatography (silica, CH₂Cl₂/MeOH) to afford the title compound (22 mg, 39%). [MH]⁺=292.

Preparative Example 88

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Step A

To a ice cooled solution of the title compound from the Preparative Example 42, Step A (95 mg) in CH₂Cl₂(5 mL) were successively added DMAP (61 mg), EDCl (96 mg) and methane sulfonamide (32 mg). The cooling bath was removed and the mixture was stirred at room temperature for 24 h. The mixture was diluted with CH₂Cl₂(20 mL), washed with 1M aqueous citric acid (15 mL) and saturated aqueous NaCl (15 mL), dried (MgSO₄), filtered, concentrated and purified by flash chromatography (silica, CH₂Cl₂/MeOH) to afford the title compound (63 mg, 51%). [MNa]⁺=383.

Preparative Example 89

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Step A

The title compound from the Preparative Example 42, Step A (95 mg) was treated similarly as described in the Preparative Example 88, Step A, except using 4-methoxy-phenyl sulfonamide (64 mg) to afford the title compound (58 mg, 38%). [MH]⁺=453.

Preparative Example 90

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Step A

To a solution of commercially available (4-amino-benzyl)-carbamic acid tert-butyl ester (229 mg) in dry CH₂Cl₂(1 mL) were successively added ¹PrOH (100 μL) and trimethylsilyl isocyanate (154 μL). The resulting reaction mixture was stirred at room temperature for 17½ h. Additional trimethylsilyl isocyanate (154 μL) was added and stirring at room temperature was continued for 75 h. The resulting reaction mixture was diluted with MeOH (5 mL), concentrated and purified by flash chromatography (silica, CH₂Cl₂/MeOH) to afford the title compound (263 mg, 99%). [MH]⁺=266.

Preparative Example 91

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Step A

To a solution of commercially available (4-amino-benzyl)-carbamic acid tert-butyl ester (229 mg) in dry CH₂Cl₂(1 mL) were successively added ⁱPr₂NEt (349 μL) and N-succinimidyl N-methylcarbamate (355 mg). The resulting reaction mixture was stirred at room temperature for 72 h, diluted with EtOAc (20 mL), washed with 0.1M aqueous NaOH (3×10 mL), dried (MgSO₄), filtered and concentrated to afford the title compound (269 mg, 96%). [MH]⁺=280.

Preparative Example 92

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Step A

To a solution of commercially available (4-amino-benzyl)-carbamic acid tert-butyl ester (222 mg) in dry pyridine (1 mL) was added N,N-dimethylcarbamoyl chloride (103 μL). The resulting dark red reaction mixture was stirred at room temperature for 17½ h and then diluted with H₂O (10 mL) and EtOAc (20 mL). The organic phase was separated and washed with 1M aqueous NH₄Cl (2×10 mL). The aqueous phases were combined and extracted with EtOAc (2×10 mL). The combined organic phases were dried (MgSO₄), filtered and concentrated to afford the title compound (284 mg, 97%). [MH]⁺=294.

Preparative Example 93

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Step A

To a solution of commercially available (3-aminomethyl-benzyl)-carbamic acid tert-butyl ester (236 mg) in DMF (3 mL) was added dimethyl-N-cyano-dithioiminocarbonate (146 mg). The mixture was stirred at room temperature overnight, a 7M solution of NH₃in MeOH (5 mL) and HgCl₂(300 mg) were added and stirring at room temperature was continued for 2 d. Concentration and purification by chromatography (silica, CHCl₃/MeOH) afforded the title compound as a white solid (260 mg, 85%). [MH]⁺=304.

Preparative Example 94

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Step A

To a solution of commercially available (3-amino-benzyl)-carbamic acid tert-butyl ester (97 mg) in DMF (5 mL) were added N-cyano-methylthioiminocarbonate (50 mg) and HgCl₂(120 mg). The reaction mixture was stirred at room temperature overnight, concentrated and purified by chromatography (silica, CHCl₃/MeOH) to afford the title compound as a pale yellow solid (53 mg, 43%). [MH]⁺=290.

Preparative Example 95

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Step A

A solution of commercially available 7-cyano-1,2,3,4-tetrahydroisoquinoline (2.75 g), K₂CO₃(3.60 g) and benzylchloroformate (2.7 mL) in THF/H₂O was stirred overnight and then concentrated. The residue was diluted with EtOAc, washed with 10% aqueous citric acid, saturated aqueous NaHCO₃and saturated aqueous NaCl, dried (MgSO₄) and concentrated. The residue was dissolved in MeOH (100 mL) and di-tert-butyl dicarbonate (7.60 g) and NiCl₂.6H₂O (400 mg) was added. The solution was cooled to 0° C. and NaBH₄(2.60 g) was added in portions. The mixture was allowed to reach room temperature and then vigorously stirred overnight. After the addition of diethylenetrianine (2 mL) the mixture was concentrated, diluted with EtOAc, washed subsequently with 10% aqueous citric acid, saturated aqueous NaHCO₃and saturated aqueous NaCl, dried (MgSO₄), concentrated and purified by chromatography (silica, CH₂Cl₂/MeOH) to afford the title compound as a colorless oil (1.81 g, 26%). [MH]⁺=397.

Preparative Example 96

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Step A

Amixture of the title compound from the Preparative Example 95, Step A (1.4 g) and Pd/C (10 wt %, 200 mg) in MeOH (40 mL) was hydrogenated at atmospheric pressure overnight, filtered and concentrated to afford the title compound as an off-white solid (960 mg, >99%.) [MH]⁺=263.

Preparative Example 97

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Step A

To a solution of the title compound from the Preparative Example 96, Step A (100 mg) in dry CH₂Cl₂(5 mL) were successively added ⁱPROH (500 μL) and trimethylsilyl isocyanate (100 μL). The resulting mixture was stirred at room temperature for 70 h, diluted with MeOH (5 mL), concentrated and purified by chromatography (silica, CH₂Cl₂/MeOH) to afford the title compound as a colorless solid (80 mg, 69%). [MNa]⁺=328.

Preparative Example 98

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Step A

To a solution of the title compound from the Preparative Example 96, Step A (100 mg) in dry CH₂Cl₂(5 mL) were successively added ⁱPr₂NEt (132 μL) and N-succinimidyl N-methylcarbamate (131 mg). The resulting mixture was stirred at room temperature for 72 h, diluted with EtOAc (5 mL), washed with 0.1M aqueous NaOH (3×10 mL), dried (MgSO₄), filtered, concentrated and purified by chromatography (silica, CH₂Cl₂/MeOH) to afford the title compound (92 mg, 76%). [MNa]⁺=342.

Preparative Example 99

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Step A

To a solution of the title compound from the Preparative Example 96, Step A (100 mg) in dry pyridine (2 mL) was added N,N-dimethylcarbamoyl chloride (38 μL). The resulting mixture was stirred at room temperature for 70 h, diluted with MeOH (5 mL), concentrated and purified by chromatography (silica, CH₂Cl₂/MeOH) to afford the title compound as a white solid (40 mg, 32%). [MNa]⁺=356.

Preparative Example 100

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Step A

To a suspension of the title compound from the Preparative Example 96, Step A (100 mg) and N-methylmorpholine (145 μL) in dry CH₂Cl₂/THF (5:1, 12 mL) was added methanesulfonyl chloride (88 μL). The mixture was stirred for 2 h, diluted with CH₂Cl₂, washed subsequently with 10% aqueous citric acid, saturated aqueous NaHCO₃and saturated aqueous NaCl, dried (MgSO₄), filtered, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound as a colorless solid (96.3 mg, 74%). [MNa]⁺=363.

Preparative Example 101

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Step A

To a suspension of the title compound from the Preparative Example 96, Step A (84 mg) and ⁱPr₂NEt (70 μL) in dry THF (10 mL) was added trifluoromethanesulfonyl chloride (50 μL) at −20° C. under an argon atmosphere. The cooling bath was removed and the mixture was stirred for 4 h, diluted with EtOAc, washed subsequently with 10% aqueous citric acid, saturated aqueous NaHCO₃and saturated aqueous NaCl, dried (MgSO₄), filtered, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound as colorless crystals (47 mg, 37%). [MNa]⁺=417.

Preparative Example 102

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Step A

To a solution of the title compound from the Preparative Example 26 (242 mg) in MeOH/H₂O (2:1, 30 mL) was added sodium perborate tetrahydrate (470 mg). The mixture was heated to 50° C. overnight, concentrated, diluted with EtOAc, washed subsequently with 10% aqueous citric acid and saturated aqueous NaCl, dried (MgSO₄), filtered and concentrated to give the title compound as colorless crystals (220 mg, 85%). [MNa]⁺=279.

Preparative Example 103

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Step A

Commercially available tert-butyl-N-[(5-bromo-2-thienyl)methyl]carbamate (2.0 g), Pd(OAc)₂(76 mg), dppp (282 mg) and NEt₃(2.9 mL) were dissolved in dry DMSO/MeOH (3:1, 60 mL) and stirred at 80° C. under a carbon monoxide atmosphere at 7 bar over the weekend. The mixture was concentrated, diluted with EtOAc, washed subsequently with 1N aqueous HCl, H₂O and saturated aqueous NaCl, dried (MgSO₄), filtered and concentrated. Purification by chromatography (silica, cyclohexane/EtOAc) afforded the title compound as colorless crystals (1.73 g, 94%). [MNa]⁺=294.

Preparative Example 104

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Step A

To an ice cooled solution of commercially available 5-ethyl-thiophene-3-carboxylic acid (3.0 g) in CH₂Cl₂(50 mL) were subsequently added oxalyl chloride (2.3 mL) and DMF (0.4 mL). The mixture was stirred at 0° C. for 1 h and then at room temperature for 3 h. The mixture was concentrated, diluted with CH₂Cl₂(3 mL) and then slowly added to condensed NH₃(˜30 mL) at ˜−40° C. The resulting mixture was stirred at ˜−30° C. for 1 h, slowly warmed to room temperature over a period of ˜10 h and then concentrated to give the title compound as a tan solid (2.0 g, 68%). [MH]⁺=156.

Step B

A vigorously stirred mixture of the title compound from Step A above (1.0 g) and Bu₄NBH₄(4.9 g) in dry CH₂Cl₂(30 mL) was heated at 55-62° C. for 24 h and then concentrated. The remaining oil was cooled to 0° C. and 1N aqueous HCl (15 mL) was slowly added over a period of 1 h. Then the mixture was heated to 100° C. for 1 h, cooled to room temperature, washed with Et₂O (100 mL), adjusted to pH −10 with concentrated aqueous KOH and extracted with Et₂O (100 mL). The organic extract was dried (MgSO₄), filtered and concentrated to give the title compound as an oil (0.25 g, 27%). [MH]⁺=142.

Preparative Example 105

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Step A

To an ice cooled mixture of commercially available 5-bromo-1-indanone (29.84 g) in MeOH (300 mL) was added NaBH₄(2.67 g). After 10 min the mixture was allowed to warm to room temperature. The mixture was stirred for 1½ h and then concentrated. The resulting oil was brought up in EtOAc (300 mL), washed with 1N aqueous NaOH (200 mL) and saturated aqueous NaCl (200 mL), dried (MgSO₄), filtered and concentrated to give a white solid (30.11 g, >99%). [M−OH]⁺=195.

Step B

A solution of the title compound from Step A above (9.03 g) and 4-toluenesulfonic acid monohydrate (150 mg) in benzene (300 mL) was heated to reflux for 1 h using a Dean Starks trap. Once cooled the reaction solution was washed with H₂O, dried (MgSO₄), filtered and concentrated to give a clear oil (7.86 g, 95%). ¹H-NMR (CDCl₃) δ=7.60 (s, 1H), 7.40 (dd, J=8.0, 1.7 Hz, 1H), 7.26 (d, J=8.0 Hz, 1H), 6.83 (dtd, J=5.7, 2.1, 1.1 Hz, 1 H), 6.55 (dt, J=5.5, 2.1 Hz, 1H), 3.39 (br s, 2H).

Preparative Example 106

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Step A

To an ice cooled vigorously stirred mixture of the title compound from the Preparative Example 105, Step B (9.99 g), (S,S)-(+)-N,N′-bis(3,5-di-tert-butyl-salicylindene)-1,2-cyclohexane-diaminomanganese(III) chloride (390 mg) and 4-phenylpyridine N-oxide (526 mg) in CH₂Cl₂(6.2 mL) was added a solution of NaOH (425 mg) in 1.25M aqueous NaClO (53.2 mL) by an addition funnel over 2½ h. After the addition was complete, stirring at 0° C. was continued for another 3 h. Hexanes (30 mL) was added, the resulting biphasic mixture was filtered through celite® and the filter cake was washed with CH₂Cl₂(3×20 mL). The supernatant was placed in a separatory funnel, the aqueous layer was removed and the organic layer was washed with saturated aqueous NaCl, dried (MgSO₄), filtered and concentrated. The resulting solid was dissolved in EtOH (100 mL) and a 28% solution of NH₃in H₂O (200 mL) was added. The solution was stirred at 110° C. for 30 min, cooled to room temperature and washed with CH₂Cl₂(4×200 mL). The combined organic layers were dried (MgSO₄), filtered and concentrated to give a dark brown solid (7.50 g). [M−NH₂]⁺=211. This solid was dissolved in CH₂Cl₂(150 mL) and NEt₃(5.5 mL) and di-tert-butyl-dicarbonate (7.87 g) were added subsequently. The resulting solution was stirred for 4 h at room temperature, then absorbed on silica and purified by chromatography (silica, hexanes/EtOAc) to give an off-white solid (6.87 g, 41%). [MNa]⁺=350.

Step B

A solution of the title compound from Step A above (6.87 g), Pd(PPh₃)₄(1.20 g) in MeOH (100 mL), DMSO (100 mL) and NEt₃(14 mL) was stirred at 80° C. under an atmosphere of carbon monoxide (1 atm) for 18 h. Once the mixture was cooled to room temperature, it was placed in a separatory funnel and EtOAc (200 mL) and 1N aqueous HCl (200 mL) were added. The layers were separated and the aqueous layer was washed with EtOAc (200 mL). The organic layers were combined, washed with 1N aqueous HCl (200 mL), saturated aqueous NaHCO₃(200 mL) and saturated aqueous NaCl (200 mL), dried (MgSO₄), filtered and absorbed on silica. Purification by chromatography (silica, hexanes/EtOAc) afforded an off-white solid (1.45 g, 23%). [MNa]⁺=330.

Preparative Example 107

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Step A

To an ice cooled vigorously stirred mixture of the title compound from the Preparative Example 105, Step B (3.92 g), (R,R)-(−)-N,N′-bis(3,5-di-tert-butyl-salicylindene)-1,2-cyclohexane-diaminomanganese(III) chloride (76.2 mg) and 4-phenylpyridine N-oxide (103 mg) in CH₂Cl₂(2.4 mL) was added a solution of NaOH (122 mg) in 1.25M aqueous NaClO (15.3 mL) by an addition funnel over 2½ h. After the addition was complete, stirring at 0° C. was continued for another 3 h. Hexanes (20 mL) was added, the resulting biphasic mixture was filtered through celite@ and the filter cake was washed with CH₂Cl₂(3×20 mL). The supernatant was placed in a separatory funnel, the aqueous layer was removed and the organic layer was washed with saturated aqueous NaCl, dried (MgSO₄), filtered and concentrated. The remaining brown solid was suspended in CH₃CN (10 mL) at −40C, trifluoromethane sulfonic acid (1.2 mL) was added and the resulting mixture was stirred at 40° C. for 1½ h. H₂O (20 mL) was added and the mixture was stirred at 110° C. for 5 h, while distilling off the CH₃CN. Once the reaction mixture was cooled to room temperature, the aqueous layer was washed with CH₂Cl₂(2×50 mL). The organic layers were discarded and the aqueous layer was basified with 3N aqueous NaOH and washed with EtOAc (3×50 mL). The EtOAc phases were combined, dried (MgSO₄), filtered and concentrated. [M−NH₂]⁺=211. The remaining solid residue was dissolved in CH₂Cl₂(30 mL) and NEt₃(515 μL) and di-tert-butyl-dicarbonate (707 g) were added subsequently. The resulting solution was stirred for 6 h at room temperature, then absorbed on silica and purified by chromatography (silica, hexanes/EtOAc) to give an off-white solid (774 mg, 12%). [MNa]⁺=350.

Step B

A solution of the title compound from Step A above (774 mg), Pd(PPh₃)₄(136 mg) in MeOH (10 mL), DMSO (10 mL) and NEt₃(1.6 mL) was stirred at 80° C. under an atmosphere of carbon monoxide (1 atm) for 18 h. Once the mixture was cooled to room temperature, it was placed in a separatory funnel and EtOAc (30 mL) and 1N aqueous HCl (30 mL) were added. The layers were separated and the aqueous layer was washed with EtOAc (30 mL). The organic layers were combined, washed with 1N aqueous HCl (30 mL), saturated aqueous NaHCO₃(30 mL) and saturated aqueous NaCl (30 mL), dried (MgSO₄), filtered and absorbed on silica. Purification by chromatography (silica, hexanes/EtOAc) afforded an off-white solid (333 mg, 46%). [MNa]⁺=330.

Preparative Example 108

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Step A

The title compound from the Preparative Example 107, Step A above (406 mg) was treated similarly as described in the Preparative Example 107, Step B, except using EtOH (10 mL) as the solvent to afford the title compound (353 mg, 89%). [MNa]⁺=344.

Preparative Example 109

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Step A

To a solution of commercially available trans-4-(tert-butoxycarbonylamino-methyl)-cyclohexanecarboxylic acid (262 mg) in dry THF (5 mL) was added 1,1′-carbonyldiimidazole (243 mg). The resulting clear colorless solution was stirred at room temperature for 1 h, then hydrazine monohydrate (219 μL) was added and stirring at room temperature was continued for 17 h. The mixture was concentrated and purified by flash chromatography (silica, CH₂Cl₂/MeOH). The isolated white solid was dissolved in EtOAc (50 mL) and washed with 0.01 M aqueous HCl (2×50 mL) and saturated aqueous NaCl (50 mL). The combined HCl layers were saturated with NaCl and extracted with EtOAc (2×100 mL). The combined EtOAc layers were dried (MgSO₄), filtered and concentrated to afford the title compound (264 mg, 97%). [MNa]⁺=294.

Preparative Example 110

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Step A

To a solution of the title compound from the Preparative Example 109, Step A (136 mg) in dry MeOH (12.5 mL) were successively added trifluoroacetic anhydride (104 μL) and ⁱPr₂NEt (130 μL). The resulting reaction mixture was stirred at room temperature for 23 h, concentrated and purified by flash chromatography (silica, CH₂Cl₂/MeOH) to afford the title compound (66 mg, 43%). [MNa]⁺=390.

Step B

To a solution of the title compound from Step A above (66 mg) in dry THF (3.6 mL) was added methyl N-(triethylammoniosulfonyl) carbamate [“Burgess reagent”] (88 mg). The resulting reaction mixture was heated in a sealed tube to 150° C. (microwave) for 15 min, concentrated and purified by flash chromatography (silica, CH₂Cl₂/MeOH) to afford the title compound (52 mg, 83%). [MNa]⁺=372.

Preparative Example 111

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Step A

To a suspension of the title compound from the Preparative Example 109, Step A (54.3 mg) in trimethyl orthoformate (2 mL) was added dry MeOH (200 μL). The resulting clear solution was heated in a sealed tube to 150° C. (microwave) for 24 h, concentrated and purified by flash chromatography (silica, CH₂Cl₂/MeOH) to afford the title compound (45.6 mg, 81%). [MNa]⁺=304.

Preparative Example 112

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Step A

To a solution of commercially available trans-4-(tert-butoxycarbonylamino-methyl)-cyclohexanecarboxylic acid (262 mg) and N-hydroxyacetamidine (19 mg) in DMF/CH₂Cl₂(9:1, 2 mL) were added N,N′-diisopropylcarbodiimide (33 mg) and HOBt (36 mg). The resulting mixture was stirred at room temperature for 2 h, concentrated, dissolved in EtOAc, washed subsequently with saturated aqueous NaHCO₃, 0.5N aqueous HCl and saturated aqueous NaCl, dried (MgSO₄), filtered and concentrated to afford the title compound (255 mg, 80%). [MH]⁺=314.

Step B

To a solution of the title compound from Step A above (55 mg) in EtOH (3 mL) was added a solution of NaOAc (12 mg) in H₂O (270 μL). Using a microwave, the mixture was heated in a sealed vial at 120° C. for 50 min. Concentration and purification by chromatography (silica, cyclohexane/EtOAc) afforded the title compound as a colorless oil (24 mg, 46%). [MH]⁺=296.

Preparative Example 113

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Step A

To a solution of commercially available trans-4-(tert-butoxycarbonylamino-methyl)-cyclohexanecarboxylic acid (520 mg) and acetic acid hydrazide (178 mg) in DMF (10 mL) were added N,N′-diisopropylcarbodiimide (303 mg) and HOBt (326 mg). The resulting mixture was stirred at room temperature for 2 h, concentrated, dissolved in EtOAc, washed with saturated aqueous NaHCO₃and saturated aqueous NaCl, dried (MgSO₄), filtered, concentrated and purified by chromatography (silica, CH₂Cl₂/MeOH) to afford the title compound (400 mg, 64%). [MH]⁺=314.

Step B

To a solution of the title compound from Step A above (216 mg) in dry THF (10 mL) was added methyl N-(triethylammoniosulfonyl) carbamate [“Burgess reagent”] (300 mg). Using a microwave, the mixture was heated in a sealed vial at 150° C. for 15 min. Concentration and purification by chromatography (silica, CH₂Cl₂/MeOH) afforded the title compound as a colorless oil (143 mg, 70%). [MH]⁺=296.

Preparative Example 114

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Step A

To a suspension of the title compound from the Preparative Example 44, Step A (552 mg) in dry THF (11 mL) was added methyl N-(triethylammoniosulfonyl) carbamate [“Burgess reagent”] (375 mg). The mixture was stirred at room temperature for 30 min, concentrated and purified by chromatography (silica, CH₂Cl₂/MeOH) to afford the title compound as a colorless solid (160 mg, 31%). [MH]⁺=239.

Step B

To a solution of hydroxylamine hydrochloride in dry MeOH (1 mL) were successively added a 30 wt % solution of NaOMe in MeOH (250 μL) and a solution of the title compound from Step A above (160 mg) in dry MeOH (3 mL). The mixture was heated to reflux for 24 h and then concentrated to afford the crude title compound, which was used without further purification (170 mg, 93%). [MH]⁺=272.

Step C

To a solution of the title compound from Step B above (170 mg) in toluene (5 mL) were successively added ⁱPr₂NEt (132 μL) and trifluoroacetic anhydride (280 μL). The mixture was heated to reflux for 2½ h, concentrated, dissolved in EtOAc, washed with saturated aqueous NaHCO₃and saturated aqueous NaCl, dried (MgSO₄), filtered, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound (46 mg, 20%). [MH]⁺=350.

Preparative Example 115

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Step A

To a suspension of the title compound from the Preparative Example 44, Step A (266 mg) in THF (5 mL) was added 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide [“Lawesson reagent”] (311 mg). The mixture was stirred at room temperature for 1 h, concentrated and purified by chromatography (silica, CH₂Cl₂/MeOH) to afford the title compound as a pale yellow solid (190 mg, 67%). [MH]⁺=273.

Step B

To a solution of the title compound from Step A above (190 mg) in DMF (5 mL) were added a 4M solution of HCl in 1,4-dioxane (6 μL) and 2-bromo-1,1-diethoxy-ethane (323 μL). Using a microwave, the mixture was heated in a sealed vial at 100° C. for 25 min. The mixture was concentrated, dissolved in EtOAc, washed with saturated aqueous NaHCO₃and saturated aqueous NaCl, dried (MgSO₄), filtered, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound (50 mg, 24%). [MH]⁺=297.

Preparative Example 116

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Step A

To a solution of commercially available N-(tert-butoxycarbonyl) alanine (227 mg) in DMF (3 mL) were successively added ethyl 2-oximinooxamate (158 mg) and HATU (684 mg). The mixture was stirred at room temperature for 2 h, concentrated, dissolved in EtOAc, washed with saturated aqueous NaHCO₃, 1N aqueous HCl and saturated aqueous NaCl, dried (MgSO₄), filtered and concentrated to afford the title compound as a colorless solid (163 mg, 45%). [MH]⁺=304.

Step B

To a solution of the title compound from Step A above (163 mg) in EtOH (15 mL) was added a solution of NaOAc (78 mg) in H₂O (1 mL). Using a microwave, the mixture was heated in a sealed vial at 120° C. for 50 min. Concentration and purification by chromatography (silica, cyclohexane/EtOAc) afforded the title compound as a colorless oil (46 mg, 30%). [MH]⁺=286.

Preparative Example 117

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Step A

A mixture of commercially available 3-chloro-5-trifluoromethoxy-benzonitrile (263 mg) and Bu4NBH₄in CH₂Cl₂(2 mL) was heated to reflux for 12 h. The reaction was quenched with 1M aqueous NaOH, extracted with CH₂Cl₂, dried (MgSO₄), filtered and concentrated to afford the title compound. [MH]⁺=226.

Preparative Example 118

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Step A

Commercially available 4-chloro-3-trifluoromethoxy-benzonitrile (227 mg) was treated similarly as described in the Preparative Example 117, Step A to afford the title compound. [MH]⁺=226.

Preparative Example 119

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Step A

A mixture of commercially available 3-cyanobenzaldehyde (263 mg), KCN (130 mg) and (NH₄)₂CO₃(769 mg) in EtOH/H₂O (1:1, 12 mL) was heated to 55° C. overnight, cooled, filtered and concentrated. The remaining aqueous mixture was extracted with Et₂O (3×10 mL). The combined organic phases were washed with saturated aqueous NaCl, dried (MgSO₄), filtered, concentrated and purified by chromatography (silica, hexanes/EtOAc) to give the title compound as a colorless solid (347 mg, 86%). [MH]⁺=202.

Preparative Examples 120-121

Following a similar procedure as described in the Preparative Example 119, except using the nitrites indicated in Table 1-5 below, the following compounds were prepared.

Table I-5

Prep.

Ex. #
protected amine
product
yield

120

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90% [MH]⁺ = 202

121

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n.d. [MH]⁺ = 216

Preparative Example 122

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Step A

A mixture of commercially available 3-cyanobenzaldehyde (262 mg), hydantoin (220 mg) and KOAc (380 mg) in AcOH (2 mL) was heated to reflux for 3 h and then poured on ice (20 g). The colorless precipitate was collected by filtration, washed with ice water and dried to give the title compound as a yellow solid. [MH]⁺=216.

Preparative Example 123

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Step A

A mixture of the title compound from the Preparative Example 119, Step A above (347 mg), 50% aqueous AcOH (2 mL) and Pd/C (10 wt %, 200 mg) in EtOH was hydrogenated at 50 psi overnight, filtered and concentrated to give the title compound as colorless solid (458 mg, >99%). [M−OAc]⁺=206.

Preparative Examples 124-126

Following a similar procedure as described in the Preparative Example 123, except using the nitrites indicated in Table I-6 below, the following compounds were prepared.

TABLE I-6Prep.Ex. #protected amineproductyield124 embedded image

50% (over 2 steps) [M-OAc]⁺ = 220125 embedded image

n.d. [M-OAc]⁺ = 220126 embedded image

76% [M-OAc]⁺ = 206

Preparative Example 127

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Step A

To the solution of commercially available 2-N-(tert-butoxycarbonylamino)acetaldehyde (250 mg) in MeOH/H₂O (1:1, 10 mL) were added KCN (130 mg) and (NH₄)₂CO₃(650 mg). The mixture was stirred at 55° C. overnight, then cooled to room temperature, acidified (pH 2) with 3N aqueous HCl and extracted with EtOAc (2×10 mL). The combined organic layers were washed with saturated aqueous NaCl, dried (MgSO₄) and concentrated to give a white solid (75 mg, 21%). [MH]⁺=230.

Preparative Example 128

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Step A

To a solution of the title compound from the Preparative Example 7, Step B (100 mg), N-methyl-N-methoxyamine hydrochloride (42.2 mg) in CH₂Cl₂(3 mL) and DMF (1 mL) were added EDCI (84.3 mg), HOBt (58 mg) and NaHCO₃(121 mg). The mixture was stirred at room temperature overnight, washed with saturated aqueous Na₂CO₃(5 mL) and 1N aqueous HCl (5 mL) and concentrated to give the desired product, which was used without further purification (97 mg, 84%). [MH]⁺=321.

Step B

To the title compound from Step A above (256 mg) in anhydrous Et₂O (10 mL) was added a 1M solution of LiAlH₄in Et₂O (4 mL). The mixture was stirred for 20 min and then cooled to 0° C. 1M aqueous NaOH (5 mL) was added dropwise, followed by the addition of Et₂O (10 mL). The organic phase was separated and the aqueous phase was extracted with Et₂O (2×5 mL). The combined organic layers were washed with saturated aqueous NaCl (5 mL), dried (MgSO₄), concentrated and purified by chromatography (silica, hexanes/EtOAc) to give a white solid (178 mg, 85%). [MH]⁺=262.

Step C

To the title compound from Step B above (178 mg) in MeOH/H₂O (1:1, 10 mL) were added KCN (67 mg) and (NH₄)₂CO₃(262 mg). The mixture was stirred at 55° C. overnight, then cooled to room temperature, acidified (pH 2) with 3N aqueous HCl and extracted with EtOAc (2×10 mL). The combined organic layers were washed with saturated aqueous NaCl, dried (MgSO₄) and concentrated to give a white solid (170 mg, 73%). [MH]⁺=346.

Preparative Example 129

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Step A

To the solution of commercially available 4-(tert-butoxycarbonylamino-methyl)-cyclohexanecarboxylic acid (515 mg), N-methyl-N-methoxyamine hydrochloride (390 mg) in CH₂Cl₂(20 mL) were added PyBOP (1.04 g) and NEt₃(0.84 mL). The mixture was stirred for 2 h at room temperature, washed with saturated aqueous Na₂CO₃(5 mL) and 1N aqueous HCl (5 mL), concentrated and and purified by chromatography (silica, hexanes/EtOAc) to give a white solid (544 mg, 91%). [MH]⁺=323.

Step B

To the title compound from Step A above (544 mg) in anhydrous Et₂O (10 mL) was added a 1M solution of LiAlH₄in Et₂O (1.8 mL). The mixture was stirred for 20 min and then cooled to 0° C. 1M aqueous NaOH (5 mL) was added dropwise, followed by the addition of Et₂O (10 mL). The organic phase was separated and the aqueous phase was extracted with Et₂O (2×5 mL). The combined organic layers were washed with saturated aqueous NaCl (5 mL), dried (MgSO₄), concentrated and purified by chromatography (silica, hexanes/EtOAc) to give a white solid (440 mg, >99%). [MH]⁺=242.

Step C

To the title compound from Step B above (440 mg) in MeOH/H₂O (1:1, 12 mL) was added were added KCN (178 mg) and (NH₄)₂CO₃(670 mg). The mixture was stirred at 55° C. overnight, then cooled to room temperature, acidified (pH 2) with 3N aqueous HCl and extracted with EtOAc (2×10 mL). The combined organic layers were washed with saturated aqueous NaCl, dried (MgSO₄) and concentrated to give a white solid (454 mg, 81%). [MH]⁺=312.

Preparative Example 130

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Step A

To a solution of commercially available 4-N-(tert-butoxycarbonylamino-methyl)-cyclohexanone (0.26 g) in EtOH/H₂O (1:1, 20 mL) were added NaCN (0.10 g) and (NH₄)₂CO₃(0.56 g). The resulting mixture was heated to reflux overnight, partially concentrated, diluted with H₂O and filtered to give a white solid (0.19 g, 56%). [MNa]⁺=320.

Preparative Example 131

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Step A

To a solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (1.3 mL) in EtOH (40 mL) was added commercially available (3-aminomethyl-benzyl)-carbamic acid tert-butyl ester (1.39 g). The mixture was stirred for 2 h, a 28% solution of NH₃in H₂O (40 mL) was added and stirring was continued for 2 h. Then the mixture was concentrated and slurried in MeOH (20 mL). The formed precipitate was collected by filtration to give the title compound (1.6 g, 82%). [MNa]⁺=354.

Preparative Example 132

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Step A

To a solution of commercially available (3-amino-benzyl)-carbamic acid tert-butyl ester (1.11 g) in EtOH (20 mL) was added 3,4-diethoxy-3-cyclobutene-1,2-dione (1.30 g). The mixture was heated to reflux for 2½ h, cooled to room temperature filtered and concentrated. The remaining solid residue was crystallized from refluxing EtOH to afford the title compound (687 mg, 40%). [MNa]⁺=369.

Step B

The title compound from Step A above (346 mg) was dissolved in a ˜7N solution of NH₃in MeOH (14.3 mL). The reaction mixture was stirred at room temperature for 3 h and then concentrated to afford the title compound (316 mg, >99%). [MNa]⁺=340.

Preparative Example 133

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Step A

To a suspension of the title compound from the Preparative Example 110, Step B (52 mg) in EtOAc (600 μL) was added a 4M solution of HCl in 1,4-dioxane (600 μL). The reaction mixture was stirred at room temperature for 1½ h and concentrated to afford the title compound (43 mg, 99%). [M−Cl]⁺=250.

Preparative Examples 134-207

Following a similar procedure as described in the Preparative Example 133, except using the protected amines indicated in Table I-7 below, the following compounds were prepared.

TABLE I-7Prep.Ex. #protected amineproductyield134 embedded image

>99% [M-NH₃Cl]⁺ = 156135 embedded image

>99% [M-Cl]⁺ = 159136 embedded image

99% [M-Cl]⁺ = 218137 embedded image

>99% [M-Cl]⁺ = 232138 embedded image

>99% [M-NH₃Cl]⁺ = 215139 embedded image

>99% [M-NH₃Cl]⁺ = 201140 embedded image

>99% [M-Cl]⁺ = 198141 embedded image

99% [M-Cl]⁺ = 207142 embedded image

64% [M-Cl]⁺ = 177143 embedded image

>99% [M-Cl]⁺ = 178144 embedded image

>99% [M-NH₃Cl]⁺ =195/197145 embedded image

67% (over 2 steps) [M-Cl]⁺ = 187146 embedded image

>99% [M-Cl]⁺ = 192147 embedded image

n.d. [M-NH₃Cl]⁺ =210/212148 embedded image

81% [M-Cl]⁺ = 222149 embedded image

77% [M-NH₃Cl]⁺ = 253150 embedded image

>99% [M-Cl]⁺ = 143151 embedded image

>99% [M-Cl]⁺ = 238152 embedded image

>99% [M-Cl]⁺ = 191153 embedded image

>99% [M-Cl]⁺ = 205154 embedded image

>99% [M-NH₃Cl]⁺ = 188155 embedded image

>99% [M-Cl]⁺ = 163156 embedded image

>99% [M-NH₃Cl]⁺ = 159157 embedded image

>99% [M-Cl]⁺ = 241158 embedded image

>99% [M-Cl]⁺ = 295159 embedded image

>99% [M-Cl]⁺ = 242160 embedded image

>99% [M-Cl]⁺ = 191161 embedded image

>99% [M-NH₃Cl]⁺ = 162162 embedded image

>99% [M-NH₃Cl]⁺ = 176163 embedded image

>99% [M-Cl]⁺ = 193164 embedded image

96% [M-Cl]⁺ = 139165 embedded image

>99% [M-Cl]⁺ = 157166 embedded image

>99% [M-NH₃Cl]⁺ = 155167 embedded image

>99% [M-Cl]⁺ = 192168 embedded image

95% [M-Cl]⁺ = 196169 embedded image

>99% [M-Cl]⁺ = 182170 embedded image

99% [M-Cl]⁺ = 157171 embedded image

99% [M-Cl]⁺ = 171172 embedded image

98% [M-Cl]⁺ = 185173 embedded image

93% [M-Cl]⁺ = 130174 embedded image

>99% [M-Cl]⁺ = 246175 embedded image

>99% [M-Cl]⁺ = 212176 embedded image

>99% [M-NH₃Cl]⁺ = 191177 embedded image

>99% [M-NH₃Cl]⁺ = 191178 embedded image

>99% [M-Cl]⁺ = 198179 embedded image

>99% [M-Cl]⁺ = 197180 embedded image

>99% [M-Cl]⁺ = 211181 embedded image

>99% [M-Cl]⁺ = 253182 embedded image

>99% [M-Cl]⁺ = 223183 embedded image

>99% [M-Cl]⁺ = 183184 embedded image

>99% [M-Cl]⁺ = 165185 embedded image

>99% [M-Cl]⁺ = 170186 embedded image

>99% [M-Cl]⁺ = 261187 embedded image

>99% [M-Cl]⁺ = 353188 embedded image

>99% [M-Cl]⁺ = 184189 embedded image

n.d. [M-Cl]⁺ = 196190 embedded image

n.d. [M-Cl]⁺ = 250191 embedded image

n.d. [M-Cl]⁺ = 197192 embedded image

n.d. [M-Cl]⁺ = 139193 embedded image

n.d. [M-Cl]⁺ = 286194 embedded image

n.d. [M-Cl]⁺ = 286195 embedded image

>99% [M-HCl₂]⁺ = 204196 embedded image

94% [M-HCl₂]⁺ = 190197 embedded image

99% [M-Cl]⁺ = 206198 embedded image

99% [M-Cl]⁺ = 220199 embedded image

99% [M-Cl]⁺ = 134200 embedded image

99% [M-Cl]⁺ = 205201 embedded image

92% [M-HCl₂]⁺ = 177202 embedded image

>99% [M-HCl₂]⁺ = 177203 embedded image

99% [M-Cl]⁺ = 166204 embedded image

99% [M-Cl]⁺ = 180205 embedded image

99% [M-Cl]⁺ = 194206 embedded image

98% [M-Cl]⁺ = 232207 embedded image

>99% [M-NH₃Cl]⁺ = 218

Preparative Example 208

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Step A

To a ice cooled solution of the title compound from the Preparative Example 73 (89 mg) in CHCl₃(3 mL) was added a solution of trifluoroacetic acid (1.5 mL) in CHCl₃(1.5 mL). The mixture was stirred at 0° C. for 5 min, then the cooling bath was removed and the mixture was stirred at room temperature for 1½ h. The mixture was concentrated, dissolved in CH₃CN (5 mL), again concentrated and dried in vacuo to afford the title compound (93 mg, >99%). [M−TFA]⁺=218/220.

Preparative Examples 209-210

Following a similar procedure as described in the Preparative Example 208, except using the protected amines indicated in Table I-8 below, the following compounds were prepared.

TABLE I-8Prep.Ex. #protected amineproductyield209 embedded image

>99% [M-TFA]⁺ = 158210 embedded image

93% [M-(NH₂•TFA)]⁺ = 160

Preparative Example 211

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Step A

Commercially available 3-aminomethyl-benzoic acid methyl ester hydrochloride (500 mg) was dissolved in a 33% solution of NH₃in H₂O (50 mL) and heated in a sealed pressure tube to 90° C. for 20 h. Cooling to room temperature and concentration afforded the title compound (469 mg, >99%). [M−Cl]⁺=151.

Preparative Example 212

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Step A

Commercially available 3-aminomethyl-benzoic acid methyl ester hydrochloride (100 mg) was dissolved in a 40% solution of MeNH₂in H₂O (20 mL) and heated in a sealed pressure tube to 90° C. for 20 h. Cooling to room temperature and concentration afforded the title compound (107 mg, >99%). [M−Cl]⁺=165.

Preparative Example 213

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Step A

A mixture of commercially available 2-hydroxy-5-methylaniline (5.2 g) and N,N′-carbonyldiimidazole (6.85 g) in dry THF (60 mL) was heated to reflux for 6 h, cooled to room temperature, poured on ice and adjusted to pH 4 with 6N aqueous HCl. The formed precipitate was isolated by filtration, dried and recrystallized from toluene to afford the title compound as a grey solid (4.09 g, 65%).

Step B

The title compound from Step A above (1.5 g), K₂CO₃(1.7 g) and methyl iodide (6 mL) were dissolved in dry DMF (15 mL). The mixture was stirred at 50° C. for 2 h, concentrated and acidified to pH 4 with 1N HCl. The precipitate was isolated by filtration and dried to afford the title compound as an off-white solid (1.48 g, 90%). ¹H-NMR (CDCl₃) δ=7.05 (s, 1H), 6.90 (d, 1H), 6.77 (s, 1H), 3.38 (s, 3H), 2.40 (s, 3H).

Step C

The title compound from Step B above (1.1 g), N-bromosuccinimide (1.45 g) and α,α′-azoisobutyronitrile (150 mg) were suspended in CCl₄(50 mL), degassed with argon and heated to reflux for 1 h. The mixture was cooled, filtered, concentrated and dissolved in dry DMF (20 mL). Then NaN₃(1 g) was added and the mixture was vigorously stirred for 3 h, diluted with EtOAc, washed subsequently with H₂O and saturated aqueous NaCl, dried (MgSO₄), filtered, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound as colorless needles (963 mg, 70%). ¹H-NMR (CDCl₃) δ=7.07 (s, 1H), 6.98 (d, 1H), 6.88 (s, 1H), 4.25 (s, 2H), 3.36 (s, 3H).

Step D

A mixture of he title compound from Step C above (963 mg) and PPh₃(1.36 g) in THF (30 mL) were stirred for 14 h, then H₂O was added and stirring was continued for 2 h. The mixture was concentrated and coevaporated twice with toluene. The remaining residue was diluted with dry dioxane and a 4M solution of HCl in 1,4dioxane (1.5 mL) was added. The formed precipitate was isolated by filtration and dried to afford the title compound as a colorless solid (529 mg, 52%). [M−Cl]⁺=179.

Preparative Example 214

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Step A

A mixture of the title compound from the Preparative Example 95, Step A (1.81 g) and Pd/C (10 wt %, 200 mg) in EtOH (50 mL) was hydrogenated at atmospheric pressure overnight, filtered and concentrated to a volume of ˜20 mL. 3,4-Diethoxy-3-cyclobutene-1,2-dione (0.68 mL) and NEt₃(0.5 mL) were added and the mixture was heated to reflux for 4 h. Concentration and purification by chromatography (silica, cyclohexane/EtOAc) afforded a slowly crystallizing colorless oil. This oil was dissolved in EtOH (20 mL) and a 28% solution of NH₃in H₂O (100 mL) was added. The mixture was stirred for 3 h, concentrated, slurried in H₂O, filtered and dried under reduced pressure. The remaining residue was dissolved in a 4M solution of HCl in 1,4-dioxane (20 mL), stirred for 14 h, concentrated, suspended in Et₂O, filtered and dried to afford the title compound as an off-white solid (1.08 g, 92%). [M−Cl]⁺=258.

Preparative Examples 215-216

Following a similar procedure as described in the Preparative Example 214, except using the intermediates indicated in Table I-9 below, the following compounds were prepared.

TABLE I-9Ex. #intermediateproductyield215 embedded image

n.d. [M-Cl]⁺ = 250216 embedded image

67% [M-NH₃Cl]⁺ = 236

Preparative Example 217

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Step A

Commercially available 5-acetyl-thiophene-2-carbonitrile (2.5 g) was stirred with hydroxylamine hydrochloride (0.6 g) and NaOAc (0.6 g) in dry MeOH (30 mL) for 1½ h. The mixture was concentrated, diluted with EtOAc, washed subsequently with H₂O and saturated aqueous NaCl dried (MgSO₄), filtered and absorbed on silica. Purification by chromatography (silica, cyclohexane/EtOAc) afforded the title compound as a colorless solid (844 mg, 31%). [MH]⁺=167.

Step B

To a solution of the title compound from Step A above (844 mg) in AcOH (30 mL) was added zinc dust (1.7 g). The mixture was stirred for 5 h, filtered, concentrated, diluted with CHCl₃, washed with saturated aqueous NaHCO₃, dried (MgSO₄) and filtered. Treatment with a 4M solution of HCl in 1,4-dioxane (2 mL) and concentration afforded the title compound as an off-white solid (617 mg, 64%). [M−NH₃Cl]⁺=136.

Preparative Example 218

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Step A

A suspension of commercially available 2,5-dibromobenzenesulfonyl chloride (1.0 g), Na₂SO₃(0.46 g) and NaOH (0.27 g) in H₂O (10 mL) was heated to 70° C. for 5 h. To the cooled solution was added methyl iodide (4 mL) and MeOH. The biphasic system was stirred vigorously at 50° C. overnight, concentrated and suspended in H₂O. Filtration afforded the title compound as colorless needles (933 mg, 99%). [MH]⁺=313/315/317.

Step B

Under an argon atmosphere in a sealed tube was heated a mixture of the title compound from Step A above (8.36 g) and CuCN (7.7 g) in degassed N-methylpyrrolidone (30 mL) to 160° C. overnight. Concentration, absorbtion on silica and purification by chromatography (silica, cyclohexane/EtOAc) afforded the title compound as beige crystals (1.08 g, 20%).

Step C

A mixture of the title compound from Step B above (980 mg) and 1,8-diazabicyclo-[5.4.0]undec-7-ene (0.72 mL) in degassed DMSO was heated to 50° C. for 45 min under an argon atmosphere. The solution was diluted with EtOAc, washed subsequently with 10% aqueous citric acid and saturated aqueous NaCl, dried (MgSO₄), concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound as a bright yellow solid (694 mg, 71%). ¹H-NMR (CD₃CN) δ=8.00-8.10 (m, 2H), 7.72 (d, 1H), 5.75 (br s, 2H), 5.70 (s, 1H).

Step D

A mixture of the title compound from Step C above (892 mg) and Pd/C (10 wt %, 140 mg) in DMF (10 mL) was hydrogenated at atmospheric pressure for 2 h and then filtered. Di-tert-butyl dicarbonate (440 mg) was added and the mixture was stirred overnight. The mixture was concentrated, diluted with EtOAc, washed subsequently with 10% aqueous citric acid and saturated aqueous NaCl, dried (MgSO₄), and concentrated. Purification by chromatography (silica, cyclohexane/EtOAc) afforded a colorless solid, which was stirred in a 4M solution of HCl in 1,4-dioxane (20 mL) overnight and then concentrated to give the title compound as colorless crystals (69 mg, 8%). [M−Cl]⁺=209.

Preparative Example 219

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Step A

A solution of commercially available 4-bromobenzoic acid (24 g) in chlorosulfonic acid (50 mL) was stirred at room temperature for 2 h and then heated to 150° C. for 3 h. The mixture was cooled to room temperature and poured on ice (600 mL). The formed precipitate was collected by filtration and washed with H₂O. To the obtained solid material were added H₂O (300 mL), Na₂SO₃(20 g) and NaOH (17 g) and the resulting mixture was stirred at 80° C. for 5 h. Then the mixture was cooled to room temperature and diluted with MeOH (250 mL). Iodomethane (100 mL) was slowly added and the mixture was heated to reflux overnight. Concentration, acidification, cooling and filtration afforded the title compound as a white powder (28.0 g, 84%). [MH]⁺=279/281.

Step B

To a solution of the title compound from Step A above (5.0 g) in dry MeOH (120 mL) was slowly added SOCl₂(4 mL). The resulting mixture was heated to reflux for 4 h, concentrated and diluted with NMP (20 mL). CuCN (1.78 g) was added and the resulting mixture was heated in a sealed tube under an argon atmosphere to 160° C. overnight. The mixture was concentrated, absorbed on silica and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound as colorless needles (976 mg, 23%). [MH]⁺=240.

Step C

To a solution of the title compound from Step B above (1.89 g) in MeOH (40 mL) and was added NaOMe (1.3 g). The mixture was heated to reflux for 90 min, cooled to room temperature, diluted with concentrated HCl (2 mL) and H₂O (10 mL) and heated again to reflux for 30 min. The mixture was concentrated, diluted with EtOAc, washed with saturated aqueous NaCl, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound as colorless crystals (682 mg, 36%). [MH]⁺=241.

Step D

A solution the title compound from Step C above (286 mg), NaOAc (490 mg) and hydroxylamine hydrochloride (490 mg) in dry MeOH (20 mL) was heated to reflux for 2½ h. The mixture was concentrated, dissolved in EtOAc, washed with saturated aqueous NaCl and concentrated to afford the title compound as an off-white solid (302 mg, 99%). ¹H-NMR (DMSO): δ=12.62 (s, 1H), 8.25-8.28 (m, 2H), 8.04 (d, 1H), 4.57 (s, 2H), 3.90 (s, 3H).

Step E

The title compound from Step D above (170 mg) was dissolved in MeOH (50 mL) and heated to 60° C. Then zinc dust (500 mg) and 6N aqueous HCl (5 mL) were added in portions over a period of 30 min. The mixture was cooled, filtered, concentrated, diluted with EtOAc, washed subsequently with a saturated aqueous NaHCO₃and saturated aqueous NaCl, dried (MgSO₄), filtered and concentrated to afford the title compound as a yellow oil (128 mg, 80%). [MH]⁺=242.

Preparative Example 220

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Step A

To a solution of commercially available 2-[(3-chloro-2-methylphenyl)thio]acetic acid (2.1 g) in DMF (3 drops) was added dropwise oxalyl chloride (5 mL). After 1.5 h the mixture was concentrated, redissolved in 1,2-dichloroethane (20 mL) and cooled to −10° C. AlCl₃(1.6 g) was added and the cooling bath was removed. The mixture was stirred for 1 h, poured on ice and extracted with CH₂Cl₂to afford the crude title compound as a brown solid (2.01 g). [MH]⁺=199.

Step B

To a solution of the title compound from Step A above (1.01 g) in CH₂Cl₂(40 mL) was added mCPBA (70-75%, 1.14 g) at room temperature. The mixture was stirred for 1 h, diluted with CH₂Cl₂, washed subsequently with 1N aqueous HCl, saturated aqueous NaHCO₃and saturated aqueous NaCl, dried (MgSO₄), filtered and concentrated. Purification by chromatography (silica, cyclohexane/EtOAc) afforded the title compound as a colorless solid (668 mg). [MH]⁺=231.

Step C

A mixture of the title compound from Step B above (430 mg), NaOAc (800 mg) and hydroxylamine hydrochloride (800 mg) in dry MeOH (20 mL) was heated to reflux for 2 h. The mixture was concentrated, dissolved in EtOAc, washed with saturated aqueous NaCl and concentrated to afford the title compound as colorless crystals (426 mg, 93%). [MH]⁺=246.

Step D

The title compound from Step C above (426 mg) was dissolved in MeOH (50 mL) and heated to 60° C. Then zinc dust (1.3 g) and 6N aqueous HCl (20 mL) were added in portions over a period of 30 min. The mixture was cooled, filtered, concentrated, diluted with CHCl₃, washed subsequently with a saturated aqueous NaHCO₃and saturated aqueous NaCl, dried (MgSO₄), filtered and concentrated to afford the title compound as an off-white solid (313 mg, 78%). [MH]⁺=232.

Preparative Example 221

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Step A

A mixture of commercially available 1-aza-bicyclo[2.2.2]octane-4-carbonitrile (0.5 g), AcOH (1 mL) and Pd/C (10 wt %, 200 mg) in THF (20 mL) was hydrogenated at atmospheric pressure ovemight, filtered and concentrated to afford the crude title compound as a brown solid. [M−OAc]⁺=141.

Preparative Example 222

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Step A

Commercially available 5-fluoroindanone (1.0 g) was treated simnilarly as described in the Preparative Example 220, Step C to afford the title compound as a colorless solid (1.3 g, >99%). [MH]⁺=166.

Step B

The title compound from Step A above (1.35 g) was treated similarly as described in the Preparative Example 217, Step B to afford the title compound as a colorless solid (36.5 mg). [M−NH₃Cl]⁺=135.

Preparative Example 223

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Step A

To an ice cooled solution of commercially available cis-4-hydroxymethyl -cyclohexanecarboxylic acid methyl ester (330 mg) in CH₂Cl₂/pyridine (3:1, 4 mL) was added 4-toluenesulfonic acid chloride (0.49 g). The mixture was stirred at room temperature overnight, cooled to 0° C., quenched with 2N aqueous HCl (35 mL) and extracted with CH₂Cl₂(3×40 mL). The combined organic phases were dried (MgSO₄), filtered and concentrated to afford the title compound (643 mg, >99%). [MH]⁺=327.

Step B

A mixture of the title compound from Step A above (643 mg) and NaN₃(636 mg) in DMA (5 mL) was stirred at 70° C. overnight. The mixture was concentrated and diluted with EtOAc (25 mL), H₂O (5 mL) and saturated aqueous NaCl (5 mL). The organic phase was separated, dried (MgSO₄), filtered, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound (299 mg, 77%). [MNa]⁺=220.

Step C

A mixture of the title compound from Step B above (299 mg) and Pd/C (10 wt %, 50 mg) in MeOH (10 mL) was hydrogenated at atmospheric pressure for 4 h, filtered and concentrated. The remaining residue was taken up in MeOH (7 mL), treated with 1N HCl in Et₂O (6 mL) and concentrated to afford the crude title compound (248 mg, 95%). [MH]⁺=172.

Preparative Example 224

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Step A

Commercially available cis-3-hydroxymethyl-cyclohexanecarboxylic acid methyl ester (330 mg) was treated similarly as described in the Preparative Example 223, Step A to afford the title compound (606 mg, 97%). [MH]⁺=327.

Step B

The title compound from Step A above (606 mg) was treated similarly as described in the Preparative Example 223, Step B to afford the title compound (318 mg, 87%). [MNa]⁺=220.

Step C

The title compound from Step B above (318 mg) was treated similarly as described in the Preparative Example 223, Step C to afford the crude title compound (345 mg, >99%). [MH]⁺=172.

Preparative Example 225

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Step A

To a suspension of commercially available (3-cyano-benzyl)-carbamic acid tert-butyl ester (50 mg) in CHCl₃(2 mL) were successively added triethylsilane (0.5 mL) and trifluoroacetic acid (5 mL). The mixture was stirred at room temperature for 2 h and then concentrated to afford the crude title compound. [M−TFA]⁺=134.

Preparative Example 226

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Step A

To a stirred solution of KOH (1.2 g) in EtOH (10 mL) was added commercially available bis(tert-butyldicarbonyl) amine (4.5 g). The mixture was stirred at room temperature for 1 h and then diluted with Et₂O. The formed precipitate was collected by filtration and washed with Et₂O (3×10 mL) to afford the title compound (3.4 g, 64%).

Preparative Example 227

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Step A

To a stirred solution of the title compound from the Preparative Example 226, Step A (160 mg) in DMF (2 mL) was added a solution of commercially available 5-bromomethyl -benzo[1,2,5]thiadiazole (115 mg) in DMF (1 mL). The mixture was stirred at 50° C. for 2 h, concentrated, diluted with EtOAc, washed with saturated aqueous NaHCO₃, dried (MgSO₄), filtered and concentrated to afford the crude title compound (180 mg, 71%). [MH]⁺=366.

Step B

A solution of the title compound from Step A above (180 mg) in trifluoroacetic acid (2 mL) was stirred at room temperature for 1 h at room temperature and then concentrated to afford the title compound (140 mg, >99%). [M−TFA]⁺=166.

Preparative Example 228

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Step A

Commercially available 5-bromomethyl-benzo[1,2,5]oxadiazole was treated similarly as described in the Preparative Example 227 to afford the title compound. [M−TFA]⁺=150.

Preparative Examule 229

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Step A

Commercially available (S)-(−)-1-(4-bromophenyl)ethylamine (2.0 g) was treated similarly as described in the Preparative Example 3, Step D to afford the title compound as a white solid (2.5 g, 92%). ¹H-NMR (CDCl₃) δ=7.43 (d, 2H), 7.17 (d, 2H), 4.72 (br s, 2H), 1.35 (br s, 12H).

Step B

The title compound from Step A above (4.0 g) was treated similarly as described in the Preparative Example 3, Step E to afford the title compound (2.0 g, 60%). [MH]⁺=247.

Step C

The title compound from Step B above (2.0 g) was treated similarly as described in the Preparative Example 2, Step A to afford the title compound (1.8 g, >99%). [M−Cl]⁺=166.

Step D

The title compound from Step C above (1.0 g) was treated similarly as described in the Preparative Example 2, Step B to afford the title compound (310 mg, 35%). [MH]⁺=180.

Preparative Example 230

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Step A

If one were to follow a similar procedure as described in the Preparative Example 229, except using commercially available (R)-(+)-1-(4-bromophenyl)ethylamine instead of (S)-(−)-1-(4-bromophenyl)ethylamine, one would obtain the title compound.

Preparative Example 231

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Step A

To a solution of commercially available 4-bromo-2-methyl-benzoic acid (1.5 g) in anhydrous CH₂Cl₂(10 mL) was added tert-butyl 2,2,2-trichloroacetimidate (3.0 mL). The resulting mixture was heated to reflux for 24 h, cooled to room temperature, concentrated and purified by chromatography (silica, CH₂Cl₂) to give the desired title compound (1.0 g, 52%). [MH]⁺=271.

Step B

A mixture of the title compound from Step A above (1.0 g), Zn(CN)₂(1.0 g) and Pd(PPh₃)₄(1.0 g) in anhydrous DMF (15 mL) was heated at 110° C. under a nitrogen atmosphere for 18 h, concentrated and purified by chromatography (silica, hexane/CH₂Cl₂) to give the desired title compound (0.6 g, 75%). [MH]⁺=218.

Step C

To a solution of the title compound from Step B above (0.55 g), in anhydrous CH₂Cl₂(30 mL) was added Bu₄NBH₄(1.30 g). The mixture was heated to reflux under a nitrogen atmosphere for 12 h and then cooled to room temperature. 1N aqueous NaOH (5 mL) was added and the mixture was stirred for 20 min before it was concentrated. The remaining residue was then taken up in Et₂O (150 mL), washed with 1N aqueous NaOH (25 mL) and saturated aqueous NaCl, dried (MgSO₄), filtered and concentrated to give the title compound (0.50 g, 89%). [MH]⁺=222.

Preparative Examule 232

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Step A

A solution of commercially available (R)-amino-thiophen-3-yl-acetic acid (0.50 g), 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (0.86 g) and NEt₃(0.65 mL) in 1,4-dioxane/H₂O (3:2, 7 mL) was stirred for 24 h, concentrated to ⅓ volume and diluted with H₂O (100 mL). The resulting aqueous mixture was extracted with Et₂O (100 mL), acidified with 1N aqueous HCl and extracted with Et₂O (2×80 mL). The combined organic layers were dried (MgSO₄), filtered and concentrated to give the desired title compound (0.7 g, 86%). [MH]⁺=258.

Step B

To a stirred mixture of the title compound from Step A above (0.43 g) and (NH₄)₂CO₃(0.48 g) in 1,4-dioxane/DMF (6:1, 3.5 mL) were added pyridine (0.4 mL) and di-tert-butyl dicarbonate (0.50 g). The mixture was stirred for 48 h, diluted with EtOAc (40 mL), washed with 1N aqueous HCl and saturated aqueous NaCl, dried (MgSO₄), filtered and concentrated to give the desired title compound, which was not further purified (0.35 g, 86%). [MH]⁺=257.

Step C

The title compound from Step B above (0.35 g) was taken up in a 4M solution of HCl in 1,4-dioxane (10 mL). The mixture was stirred overnight and concentrated to give the title compound (0.15 g, n.d.). [MH]⁺=157.

Preparative Examples 233-235

Following a similar procedure as described in the Preparative Example 232, except using the amino acids indicated in Table I-10 below, the following compounds were prepared.

TABLE I-10Prep.Ex. #amino acidproductyield233 embedded image

n.d. [M-Cl]⁺ = 194234 embedded image

n.d. [M-Cl]⁺ = 157235 embedded image

n.d. [M-Cl]⁺ = 113

Preparative Example 236

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Step A

Commercially available (R)-2-amino-4,4-dimethyl-pentanoic acid (250 mg) was treated similarly as described in the Preparative Example 232, Step A to afford the title compound (370 mg, 87%). [MNa]⁺=268.

Step B

The title compound from Step A above (370 mg) was treated similarly as described in the Preparative Example 232, Step B to afford the title compound. [MNa]⁺=267.

Step C

The title compound from Step B above was treated similarly as described in the Preparative Example 208, Step A to afford the title compound (30 mg, 14% over 2 steps). [M−TFA]⁺=145.

Preparative Example 237

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Step A

If one were to follow a similar procedure as described in the Preparative Example 232, Step A and Step B, except using commercially available (R)-amino-(4-bromo-phenyl)-acetic acid instead of (R)-amino-thiophen-3-yl-acetic acid in Step A, one would obtain the title compound.

Preparative Example 238

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Step A

If one were to follow a similar procedure as described in the Preparative Example 229, Step B to Step D, except using the title compound from the Preparative Example 237, Step A instead of (R)-amino-thiophen-3-yl-acetic acid, one would obtain the title compound.

Preparative Example 239

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Step A

To a solution of commercially available 1H-pyrazol-5-amine (86.4 g) in MeOH (1.80 L) was added commercially available methyl acetopyruvate (50.0 g). The mixture was heated to reflux for 5 h and then cooled to room temperature overnight. The precipitated yellow needles were collected by filtration and the supernatant was concentrated at 40° C. under reduced pressure to ˜⅔ volume until more precipitate began to form. The mixture was cooled to room temperature and the precipitate was collected by filtration. This concentration/precipitation/filtration procedure was repeated to give 3 batches. This material was combined and recrystallized from MeOH to give the major isomer of the title compound (81.7 g, 72%). [MH]⁺=192.

The remaining supernatants were combined, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the minor isomer of title compound (6.8 g, 6%). [MH]⁺=192.

Preparative Example 240

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Step A

To a solution of the major isomer of the title compound from the Preparative Example 239, Step A (2.0 g) in CH₂Cl₂(20 mL) were added acetyl chloride (3.0 mL) and SnCl₄(10.9 g). The resulting mixture was heated to reflux overnight, cooled and quenched with H₂O (10 mL). The aqueous phase was separated and extracted with CH₂Cl₂(2×). The combined organic phases were concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound (1.2 g, 49%). [MH]⁺=234.

Step B

Trifluoroacetic anhydride (4.6 mL) was added dropwise to an ice cooled suspension of urea hydrogen peroxide (5.8 g) in CH₂Cl₂(40 mL). The mixture was stirred for 30 min, then a solution of the title compound from Step A above (1.8 g) in CH₂Cl₂(20 mL) was added and the mixture was stirred at room temperature overnight. NaHSO₃(1.0 g) was added and the resulting mixture was diluted with saturated aqueous NaHCO₃(40 mL). The aqueous phase was separated and extracted with CH₂Cl₂. The combined organic phases were concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound (500 mg, 26%). ¹H-NMR (CDCl₃) δ=8.40 (s, 1H), 7.47 (d, 1H), 4.03 (s, 3H), 2.84 (d, 3H), 2.42 (s, 3H).

Preparative Example 241

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Step A

A mixture of commercially available 5-amino-3-methylpyrazole (1.44 g) and methyl acetopyruvate (0.97 g) in MeOH (20 mL) was heated to reflux for 2 h and then cooled to 0° C. The formed precipitate was collected by filtration to give the desired ester (1.78 g, 87%). [MH]⁺=206.

Preparative Example 242

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Step A

A mixture of commercially available 5-aminopyrazolone (5 g) and POCl₃(50 mL) was heated to 210° C. for 5 h, concentrated and quenched with MeOH (10 mL) at 0° C. Purification by chromatography (silica, hexanes/EtOAc) afforded the desired product (293 mg, 5%). [MH]⁺=118.

Step B

A mixture of the title compound from Step A above (117 mg) and methyl acetopyruvate (144 mg) in MeOH (5 mL) was heated to reflux for 2 h and then cooled to 0° C. The formed precipitate was collected by filtration to give the desired ester (200 mg, 89%). [MH]⁺=226.

Preparative Example 243

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Step A

Under a nitrogen atmosphere at 0° C. was slowly added 1,4-dioxane (350 mL) to NaH (60% in mineral oil, 9.6 g) followed by the slow addition of CH₃CN (12.6 mL). The mixture was allowed to warm to room temperature before ethyl trifluoroacetate (23.8 mL) was added. The mixture was stirred at room temperature for 30 min, heated at 100° C. for 5 h, cooled to room temperature and concentrated. The remaining solid was taken up in H₂O (400 mL), washed with Et₂O (300 mL), adjusted to pH ˜2 with concentrated HCl and extracted with CH₂Cl₂(300 mL). The CH₂Cl₂extract was dried (MgSO₄), filtered and concentrated to give a brown liquid, which was not further purified (12.5 g, 74%). [M−]⁻=136.

Step B

A mixture of the title compound from Step A above (12.5 g) and hydrazine monohydrate (6.0 g) in absolute EtOH (300 mL) was heated to reflux under a nitrogen atmosphere for 8 h, cooled to room temperature and concentrated. The remaining oil was taken up in CH₂Cl₂(150 mL), washed with saturated aqueous NaCl, dried (MgSO₄), filtered, concentrated and purified by chromatography (silica, CH₂Cl₂/MeOH) to give the title compound (0.25 g, 2%). [MH]⁺=152.

Step C

Using a microwave, a mixture of the title compound from Step B above (150 mg) and commercially available methyl acetopyruvate (150 mg) in MeOH (1 mL) in a sealed vial was heated at 120° C. for 12 min, concentrated and purified by chromatography (silica, CH₂Cl₂) to give the title compound (0.15 g, 58%). [MH]⁺=260.

Preparative Example 244

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Step A

To a suspension of selenium dioxide (9 g) in 1,4-dioxane (35 mL) was added commercially available 5,7-dimethyl-[1,2,4]triazolo[1,5-α]pyrimidine (3 g). The mixture was heated to reflux for 24 h, cooled to room temperature, filtered through a plug of celite® and concentrated. The remaining solid residue was taken up in MeOH (50 mL), oxone (7 g) was added and the mixture was heated to reflux for 24 h, cooled to room temperature, diluted with CH₂Cl₂(50 mL), filtered through a plug of celite® and concentrated. The remaining residue was dissolved in a saturated solution of HCl in MeOH (150 mL), heated to reflux under a nitrogen atmosphere for 24 h, filtered through a medium porosity fritted glass funnel, concentrated and partially purified by chromatography (silica, CH₂Cl₂/MeOH) to give the title compound, which was not further purified (0.2 g, 4%). [MH]⁺=238.

Preparative Example 245

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Step A

A solution of methyl pyruvate (13.6 mL) in ^tBuOMe (100 mL) was added dropwise to a cooled (−10° C.) solution of pyrrolidine (12.6 mL) in ^tBuOMe (100 mL) over a period of 30 min. The mixture was stirred at −10° C. for 15 min, then trimethylborate (8.0 mL) was added dropwise over a period of 2 min and stirring at −10° C. was continued for 2 h. NEt₃(55 mL) was added, followed by the dropwise addition of a solution of methyl oxalylchloride (24.6 mL) in ^tBuOMe (100 mL) over a period of 30 min. The resulting thick slurry was stirred for 30 min and then diluted with saturated aqueous NaHCO₃(250 mL) and CH₂Cl₂(200 mL). The aqueous phase was separated and extracted with CH₂Cl₂(2×100 mL). The combined organic phases were concentrated to give an oil, which was triturated with ^tBuOMe to afford the title compound as a yellowish solid (15.75 g, 45%). [MH]⁺=242.

Step B

To mixture of the title compound from Step A above (6 g) and commercially available 2-aminopyrazole (2.1 g) in MeOH (10 mL) was added 3N aqueous HCl (3 mL). The mixture was heated to reflux overnight and cooled. The precipitated title compound was collected by filtration. The supernatant was concentrated and purified by chromatography (silica, hexane/EtOAc) to afford additional solid material, which was combined with the collected precipitate to give title compound (3.7 g, 60%). [MH]⁺=250.

Preparative Example 246

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Step A

A mixture of commercially available 5-amino-1H-[1,2,4]triazole-3-carboxylic acid (20.3 g) and methyl acetopyruvate (20.0 g) in glacial AcOH (250 mL) was heated to 95° C. for 3 h. The mixture was concentrated and diluted with saturated aqueous NaHCO₃(200 mL) and CH₂Cl₂(500 mL). The organic phase was separated, dried (MgSO₄), filtered and concentrated to give a pale orange mixture of regioisomers (80:20, 21.3 g, 80%). Recrystallization of the crude material from hot THF (110 mL) afforded the major isomer of the title compound (13.0 g, 49%). [MH]⁺193.

The supernatant was concentrated and purified by chromatography (silica, hexanes/EtOAc) to afford the minor isomer of title compound. [MH]⁺=193.

Preparative Examples 247-248

Following a similar procedure as described in the Preparative Example 246, except using the amines indicated in Table I-11below, the following compounds were prepared.

TABLE I-11Prep.Ex. #amineproductyield247 embedded image

96% [MH]⁺ = 208248 embedded image

92% [MH]⁺ = 236

Preparative Example 249

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Step A

To a solution of the minor isomer of the title compound from the Preparative Example 239, Step A (500 mg) in CH₃CN (10 mL) were added AcOH (2 mL) and 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) [selectfluor®] (551 mg). The resulting mixture was stirred at 70° C. for 7 h, cooled to room temperature, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound (149 mg, 27%). [MH]⁺=210.

Preparative Example 250

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Step A

To a suspension of the major isomer of the title compound from the Preparative Example 239, Step A (10.0 g) in H₂O (1.0 L) was added 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) [selectfluoro] (18.6 g). The resulting mixture was stirred at 50° C. for 18 h, cooled to room temperature and extracted with CH₂Cl₂(3×350 mL). The combined organic phases were dried (MgSO₄), filtered, concentrated and purified by chromatography (silica, CH₂Cl₂/acetone) to afford the title compound (4.25 g, 39%). [MH]⁺=210.

Preparative Example 251

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Step A

To a stirred solution of Bu₄N(NO₃) (1.39 g) in CH₂Cl₂(10 mL) was added trifluoroacetic acid (579 μL). The resulting mixture was cooled to 0° C. and added to an ice cooled solution of the major isomer of the title compound from the Preparative Example 239, Step A (796 mg) in CH₂Cl₂(10 mL). The mixture was allowed to reach room temperature overnight, diluted with CHCl₃, washed with saturated aqueous NaHCO₃, dried (MgSO₄), filtered, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound (200 mg, 20%). [MH]⁺=237.

Preparative Example 252

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Step A

To a suspension of the minor isomer of the title compound from the Preparative Example 239, Step A (500 mg) in CHCl₃(10 mL) was added N-bromosuccinimide (465 mg). The resulting mixture was heated to reflux for 1 h, cooled to room temperature, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound (599 mg, 85%). [MH]⁺=270/272.

Preparative Example 253

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Step A

A mixture of the minor isomer of title compound from the Preparative Example 239, Step A (100 mg) and N-chlorosuccinimide (77 mg) in CCl₄(5 mL) was heated to reflux for 24 h, cooled, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound (98 mg, 83%). [MH]⁺=226.

Preparative Example 254

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Step A

A mixture of commercially available 2H-pyrazol-3-ylamine (2.0 g) and 2-fluoro-3-oxo-butyric acid methyl ester (4.4 g) in MeOH (15 mL) was heated at 80° C. for 16 h and then cooled to room temperature. The formed precipitate was isolated by filtration and dried to afford the title compound (4.2 g, 84%). [MH]⁺=168.

Step B

To a mixture of the title compound from Step A above (1.67 g) in CH₃CN (150 mL) were added K₂CO₃(4.15 g) and POBr₃(8.58 g). The mixture was heated to reflux for 16 h, concentrated, diluted with CHCl₃, washed with saturated aqueous NaHCO₃, dried (MgSO₄), filtered, concentrated and purified by chromatography (silica, CH₂Cl₂/MeOH) to afford the title compound as a colorless solid (690 mg, 30%). [MH]⁺=230/232.

Step C

The title compound from Step B above (28 mg) was treated similarly as described in the Preparative Example 103, Step A to afford the title compound (295 mg, 70%). [MH]⁺=210.

Preparative Example 255

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Step A

A mixture of the major isomer of title compound from the Preparative Example 246, Step A (1.34 g) and selenium dioxide (1.78 g) in 1,4-dioxane (20 ML) was heated to 120° C. under closed atmosphere for 12 h, cooled and filtered through celite®. To the filtrate were added oxone (1.70 g) and H₂O (400 μL) and the resulting suspension was stirred at room temperature overnight. Concentration and purification by chromatography (silica, CH₂Cl₂/MeOH) afforded the title compound (1 g, 64%). [MH]⁺=223.

Preparative Examples 256-270

Following a similar procedure as described in the Preparative Example 255, except using the intermediates indicated in Table I-12 below, the following compounds were prepared.

TABLE I-12Prep.Ex. #intermediateproductyield256 embedded image

69% [MH]⁺ = 223257 embedded image

70% [MH]⁺ = 238258 embedded image

77% [MH]⁺ = 266259 embedded image

34% [MH]⁺ = 222260 embedded image

24% [MH]⁺ = 222261 embedded image

60% [MH]⁺ = 240262 embedded image

71% [MH]⁺ = 240263 embedded image

87% [MH]⁺ = 280264 embedded image

46% [MH]⁺ = 267265 embedded image

n.d. [MH]⁺ = 300/302266 embedded image

80% [MH]⁺ = 256267 embedded image

55% [MH]⁺ = 236268 embedded image

82% [MH]⁺ = 256269 embedded image

68% [MH]⁺ = 290270 embedded image

80% [MH]⁺ = 240

Preparative Example 271

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Step A

A suspension of commercially available methyl acetopyruvate (3.60 g) in H₂O (10 mL) was heated to 40° C., then a mixture of commercially available 1H-tetrazol-5-amine (2.10 g) and concentrated HCl (2 mL) in H₂O (4 mL) was added and the mixture was heated to reflux for 1 h, before it was cooled to 0° C. The formed precipitate was filtered off, washed with H₂O, dried in vacuo and purified by flash chromatography (silica, CH₂Cl₂/acetone) to afford the title compound as a mixture of regioisomers (˜91:9, 2.15 g, 45%). [MH]⁺=194.

Step B

To a mixture of selenium dioxide (780 mg) in 1,4-dioxane (10 mL) was added dropwise a 5.5M solution of tert-butyl hydroperoxide in hexanes (5 mL). The mixture was stirred at room temperature for 30 min, then the title compound from Step A above (600 mg) was added and the mixture was heated to reflux for 24 h. The mixture was filtered through a plug of celite®, concentrated, diluted with H₂O (10 mL) and extracted with CHCl₃. The combined organic phases were dried (MgSO₄), filtered and concentrated to afford the crude title compound, which was used without further purification. [MH]⁺=224.

Preparative Example 272

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Step A

Commercially available 1H-tetrazol-5-amine (2.15 g) was treated similarly as described in the Preparative Example 271, Step A, except using ethyl acetopyruvate (4.00 g) to afford the title compound as a pale orange mixture of regioisomers (˜75:25, 4.20 g, 80%). [MH]⁺=208.

Step B

The title compound from Step B above (4.00 g) was treated similarly as described in the Preparative Example 271, Step B to afford the title compound as a orange red solid (1.30 g, 28%). [MH]⁺=238

Preparative Example 273

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Step A

To an ice cooled solution of commercially available 2-chloro-6-methyl-pyrimidine-4-carboxylic acid methyl ester (20.05 g) in MeOH (500 mL) was added NaBH₄(8.10 g) in small portions over a period of 3 h. The cooling bath was removed and the mixture was stirred at room temperature for 10 h. The mixture was poured into saturated aqueous NH₄Cl and extracted with EtOAc (3×100 mL). The combined organic layers were dried (MgSO₄), filtered and concentrated to afford the title compound as an off-white solid (17.26 g, >99%). [MH]⁺=159.

Step B

To an ice cooled suspension of the title compound from Step A above (17.08 g) in CH₂Cl₂(300 mL) were subsequently added ⁱPr₂NEt (30 mL) and (2-methoxyethoxy)methyl chloride (13.5 mL). The mixture was stirred at room temperature for 12 h, additional ⁱPr₂NEt (11 mL) and (2-methoxyethoxy)methyl chloride (6.1 mL) were added and stirring at room temperature was continued for 6 h. Then the mixture was concentrated and purified by chromatography (silica, hexane/EtOAc) to afford the title compound as a yellow oil (10.75 g, 42%). [MH]⁺=247.

Step C

Under a nitrogen atmosphere a solution of the title compound from Step B above (10.75 g) in MeOH (60 mL) was added dropwise to a stirred solution of hydrazine hydrate (10.60 mL) in MeOH (300 mL) at 70° C. The mixture was stirred at 70° C. for 14 h, cooled and concentrated. The remaining residue was diluted with CH₂Cl₂(200 mL), filtered and concentrated to afford the title compound as a yellow oil (10.00 g, 95%). [MH]⁺=243.

Step D

A suspension of the title compound from Step C above (9.50 g) in (EtO)₃CH (200 mL) was heated to reflux for 6 h. Then AcOH (5 mL) was added at heating to reflux was continued for 6 h. The mixture was cooled, concentrated and purified by chromatography (silica) to afford major isomer (7.05 g, 71%) and the minor isomer (2.35 g, 24%) of the title compound. [MH]⁺=253.

Preparative Example 274

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Step A

To a solution of the major isomer of title compound from the Preparative Example 273, Step D (9.40 g) in THF (200 mL) was added a 4M solution of HCl in 1,4-dioxane (37 mL). The mixture was stirred at room temperature for 2 h and then concentrated to afford the title compound (8.53 g, >99%). [MH]⁺=165.

Step B

The title compound from Step A above (8.53 g) and Na₂CO₃(4.26 g) were dissolved in H₂O (250 mL). The suspension was heated to 50° C. and KMnO₄(8.13 g) was added in small portions over a period of 30 min. The mixture was stirred at 50° C. for 2 h, cooled to room temperature, filtered through a pad of celite® and concentrated to afford the crude title compound, which was used without further purification (13.42 g). [MH]⁺=179.

Step C

SOCl₂(10.9 mL) was added dropwise to an ice cooled suspension of the title compound from Step B above (13.4 g) in MeOH (400 mL). The cooling bath was removed and the mixture was stirred at room temperature for 12 h. Concentration and purification by chromatography (silica, CH₂Cl₂/MeOH) afforded the title compound as an orange solid (2.23 g, 16%). [MH]⁺=193.

Step D

A mixture of the title compound from Step C above (1.21 g) and selenium dioxide (1.40 g) in 1,4-dioxane (20 mL) was heated to 70° C. for 4 h. Cooling to room temperature, filtration through a pad of celite® and concentration afforded the crude title compound as a red solid, which was used without further purification (1.4 g). [MH]⁺=223.

Preparative Example 275

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Step A

The minor isomer of title compound from the Preparative Example 273, Step D (2.35 g) was treated similarly as described in the Preparative Example 274, Step A to afford the title compound (1.53 g, >99%). [MH]⁺=165.

Step B

The title compound from Step A above (1.53 g) was treated similarly as described in the Preparative Example 274, Step B to afford the title compound. [MH]⁺=179.

Step C

The title compound from Step B above was treated similarly as described in the Preparative Example 274, Step C to afford the title compound. [MH]⁺=193.

Step D

The title compound from Step C above was treated similarly as described in the Preparative Example 274, Step D to afford the title compound. [MH]⁺=223.

Preparative Example 276

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Step A

A suspension of the title compound from the Preparative Example 255, Step A (2.22 g) in dry toluene (15 mL) was placed in a preheated oil bath (˜80° C.). Then N,N-dimethylformamide di-tert-butyl acetal (9.60 mL) was added carefully over a period of ˜10 min and the resulting black/brown mixture was stirred at ˜80° C. for 1 h. The mixture was cooled to room temperature, diluted with EtOAc (150 mL), washed with H₂O (2×150 mL) and saturated aqueous NaCl (150 mL), dried (MgSO₄), filtered, concentrated and purified by flash chromatography (silica, cyclohexane/EtOAc) to afford the title compound (1.39 g, 50%). [MH]⁺=279.

Step B

To a solution of the title compound from Step A above (1.39 g) in dry 1,2-dichloroethane (50 mL) was added trimethyltin hydroxide (1.01 g). The resulting yellow suspension was placed in a preheated oil bath (˜80° C.) and stirred at this temperature for 2 h. The mixture was cooled to room temperature, diluted with EtOAc (250 mL), washed with 5% aqueous HCl (2×250 mL) and saturated aqueous NaCl (250 mL), dried (MgSO₄), filtered, concentrated and vacuum dried for ˜15 h to afford a beige solid, which was used without further purification (756 mg, 57%). [MH]⁺=265.

Preparative Example 277

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Step A

The title compound from the Preparative Example 272, Step B (2.37 g) was treated similarly as described in the Preparative Example 276, Step A to afford the title compound (1.68 g, 57%). [MH]⁺=294.

Step B

The title compound from Step A above (1.36 g) was treated similarly as described in the Preparative Example 276, Step B to afford the title compound as a beige solid (1.20 g, 97%). [MH]⁺=266.

Preparative Example 278

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Step A

To a solution of the title compound from the Preparative Example 259 (94 mg) in DMF (3 mL) were added the title compound from the Preparative Example 7, Step D (94 mg), PyBrOP (216 mg) and ⁱPr₂NEt (123 μL). The mixture was stirred at room temperature for 2 h, concentrated and purified by chromatography (silica, CH₂Cl₂/acetone) to afford the title compound (60 mg, 37%). [MH]⁺=451.

Preparative Example 279

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Step A

To an ice cooled solution of the title compound from the Preparative Example 255, Step A (250 mg) and the title compound from the Preparative Example 214, Step A (329 mg) in DMF (10 mL) were added N-methylmorpholine (170 μL), HATU (570 mg) and HOAt (204 mg). The mixture was stirred overnight while warming to room temperature and then concentrated. The remaining residue was dissolved in CHCl₃, washed with saturated aqueous NaHCO₃, 1N aqueous HCl and saturated aqueous NaCl, dried (MgSO₄), filtered, absorbed on silica and purified by chromatography (silica, CH₂Cl₂/MeOH) to afford the title compound as a yellow/brown gummy solid (177 mg, 35%). [MH]⁺=462.

Preparative Example 280

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Step A

To a solution of the title compound from the Preparative Example 267 (236 mg) in anhydrous CH₂Cl₂(5 mL) was added oxalyl chloride (0.32 mL) at 0° C., followed by the addition of anhydrous DMF (0.1 mL). The mixture was allowed to warm to room temperature, stirred for 1 h and concentrated. To the remaining reddish solid residue was added anhydrous CH₂Cl₂(5 mL) at 0° C., followed by the addition of a solution of the title compound from the Preparative Example 138 (231 mg) and NEt₃(0.42 mL) in anhydrous CH₂Cl₂(5 mL). The mixture was allowed to warm to room temperature, stirred overnight, concentrated and purified by chromatography (silica, CH₂Cl₂/MeOH) to give the desired product (150 mg, 34%). [MH]⁺=449.

Preparative Example 281

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Step A

A solution of the title compound from the Preparative Example 271, Step B (˜670 mg), PyBOP (2.35 g) and ⁱPr₂NEt (780 μL) in DMF (5 mL) was stirred at room temperature for 1 h. Commercially available 4-fluoro-3-methyl benzylamine (500 mg) and ⁱPr₂NEt (780 μL) were added and stirring at room temperature was continued overnight. The mixture was concentrated, diluted with EtOAc, washed with H₂O and saturated aqueous NaCl, dried (MgSO₄), filtered, concentrated and purified by chromatography (silica, CH₂Cl₂/acetone) to afford the title compound as a single regioisomer (200 mg, 19% over two steps). [MH]⁺=345.

Preparative Example 282

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Step A

To a solution of the title compound from the Preparative Example 260 (506 mg) and the title compound from the Preparative Example 161 (555 mg) in DMF (15 mL) were added N-methylmorpholine (250 μL), EDCI (530 mg) and HOAt (327 mg). The mixture was stirred overnight and then concentrated. The remaining residue was dissolved in CHCl₃, washed with 10% aqueous citric acid and saturated aqueous NaCl, dried (MgSO₄), filtered, absorbed on silica and purified by chromatography (silica, CH₂Cl₂/MeOH) to afford the title compound as an orange solid (208 mg, 24%). [MH]⁺=382.

Preparative Examples 283-320

Following similar procedures as described in the Preparative Examples 279 (method A), 280 (method B), 281 (method C), 278 (method D) or 282 (method E), except using the acids and amines indicated in Table I-13 below, the following compounds were prepared.

TABLE I-13Prep.method,Ex. #acid, amineproductyield283 embedded image

B, 36% [MH]⁺ = 431284 embedded image

C, 47% [MH]⁺ = 388285 embedded image

C, n.d. [MH]⁺ = 421/423286 embedded image

C, 33% [MH]⁺ = 440287 embedded image

A, 41% [MH]⁺ = 347288 embedded image

A, 44% [MH]⁺ = 347289 embedded image

A, 76% [MH]⁺ = 458/460290 embedded image

D, 11% [MH]⁺ = 343291 embedded image

A, 83% [MH]⁺ = 381292 embedded image

A, 73% [MH]⁺ = 414293 embedded image

A, 32% [MNa]⁺ = 491294 embedded image

B, 76% [M-H]⁻ = 452295 embedded image

A, 7% (over 2 steps), [MH]⁺ = 410296 embedded image

A, n.d. [MH]⁺ = 344297 embedded image

B, 34% [MH]⁺ = 364298 embedded image

B, 72% [MH]⁺ = 363299 embedded image

A, 37% [MH]⁺ = 395300 embedded image

A, 79% [MH]⁺ = 381301 embedded image

A, 71% [MH]⁺ = 364302 embedded image

A, 43% [MH]⁺ = 435303 embedded image

E, 82% [MH]⁺ = 400304 embedded image

A, 67% [MNa]⁺ = 500305 embedded image

A, 73% [MNa]⁺ = 475306 embedded image

B, 34% [MH]⁺ = 449307 embedded image

B, 34% [MNa]⁺ = 491308 embedded image

B, 73% [M-H]⁻ = 501309 embedded image

A, 20% [MH]⁺ = 342310 embedded image

A, 21% [MH]⁺ = 401311 embedded image

A, 10% [MH]⁺ = 453312 embedded image

A, 73% [MH]⁺ = 414313 embedded image

A, 71% [MH]⁺ = 453314 embedded image

A, >99% [MH]⁺ = 397315 embedded image

A, 70% [MH]⁺ = 344316 embedded image

A, 33% [MH]⁺ = 359317 embedded image

A, 54% [MH]⁺ = 411318 embedded image

A, 60% [MH]⁺ = 387319 embedded image

A, 47% [MH]⁺ = 419320 embedded image

A, 29% [MH]⁺ = 401

Preparative Example 321

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Step A

To an ice cooled solution of the title compound from the Preparative Example 278, Step A (75 mg) in dry THF (10 mL) were successively added NaH (95%, 10 mg) and methyl iodide (250 μL). The cooling bath was removed and the resulting mixture was stirred at room temperature for 2 h. Concentration and purification by chromatography (silica, CHCl₃/MeOH) afforded the title compound as a colorless solid (52 mg, 69%). [MNa]⁺=473.

Preparative Example 322

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Step A

A mixture of commercially available 2-aminoimidazole sulfate (1.0 g), NH₄OAc (1.2 g) and methyl acetopyruvate (1.1 g) in AcOH (10 mL) was stirred at 120° C. for 3 h, then absorbed on silica and purified by chromatography (silica, EtOAc/MeOH) to give an off-white solid (396 mg, 14%). [MH]⁺=192.

Step B

A solution of the title compound from Step A above (14 mg) in THF (100 μL), MeOH (100 μL), and 1N aqueous LiOH (80 μL) was stirred at 0° C. for 2 h and then concentrated to give a yellow residue. [MH]⁺=178. A mixture of this residue, PyBOP (42 mg), 4-fluoro-3-methyl-benzylamine (11 mg), and NEt₃(20 μL) in DMF (200 μL) and THF (400 μL) was stirred for 4 h, then absorbed on silica and purified by chromatography (silica, EtOAc/MeOH) to give an off-white solid (12 mg, 55%). [MH]⁺=299.

Step C

A mixture of the title compound from Step B above (100 mg) and selenium dioxide (93 mg) in dioxane (1.5 mL) was stirred at 80° C. for 2 h. The mixture was cooled to room temperature and filtered through celite®. The filter cake was washed with dioxane (3×1 mL). To the supernatant were added oxone (206 mg) and H₂O (100 μL) and the resulting mixture was stirred for 4 h and then filtered. The supernatant was concentrated and then stirred in a premixed solution of acetyl chloride (100 μL) in MeOH (2 mL) in a sealed vial for 3 h at 65° C. The solution was absorbed on silica and purified by chromatography (silica, hexanes/EtOAc) to give a yellow solid (40 mg, 35%). [MH]⁺=343.

Preparative Examule 323

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Step A

A mixture of commercially available 4-nitroimidazole (5 g) and Pd/C (10 wt %, 500 mg) in a premixed solution of acetyl chloride (4 mL) in MeOH (100 mL) was hydrogenated in a Parr shaker at 35 psi for 5 h. The mixture was filtered through celite® and concentrated to give a black oil. [MH]⁺=115. This oil and methyl acetylpyruvate (6.4 g) were stirred in AcOH (70 mL) and MeOH (70 mL) at 65° C. for 18 h. The resulting mixture was absorbed on silica and purified by chromatography (silica, CH₂Cl₂/MeOH). Further purification of the resulting residue by chromatography (silica, EtOAc) afforded an orange solid (120 mg, 1.4%). [MH]⁺=192.

Step B

A mixture of the title compound from Step A above (50 mg) and selenium dioxide (116 mg) in dioxane (1 mL) was heated to 130° C. in a sealed tube for 6 h, cooled and filtered through celite®. The supernatant was concentrated to give a orange residue. [MH]⁺=222. This residue was stirred with 4-fluoro-3-methyl-benzylamine (27 EL), PyBOP (150 mg), and NEt₃(73 μL) in THF (2 mL) for 3 h, absorbed on silica and purified by chromatography (silica, hexanes/EtOAc) to give a yellow solid (22 mg, 24%). [MH]⁺=343.

Preparative Example 324

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Step A

A solution of the title compound from the Preparative Example 262 (0.5 g) and 4-fluoro-3-trifluoromethylbenzyl amine (1.6 g) in DMF (2.5 mL) was stirred at 48° C. for 10 h and then concentrated to an oil. The oil was taken up in EtOAc (120 mL), washed with 1N aqueous HCl (2×70 mL) and saturated aqueous NaCl (70 mL), dried (MgSO₄), filtered and concentrated. The remaining solid was washed with hexanes/Et₂O (1:1) and MeOH to give a yellow solid (0.31 g, 35%). [MH]⁺=401.

Preparative Examples 325-327

Following a similar procedure as described in the Preparative Example 324, except using the acids and amines indicated in Table I-14 below, the following compounds were prepared.

TABLE I-14Prep.Ex. #acid, amineproductyield325 embedded image

n.d. [MNa]⁺ = 355326 embedded image

(0.5 eq.)

33% [MH]⁺ = 344327 embedded image

65% [MH]⁺ = 381

Preparative Example 328

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Step A

A mixture of the title compound from the Preparative Example 245, Step B (10 mg), commercially available 4-fluorobenzylamine (5.3 mg) and scandium triflate (1 mg) in anhydrous DMF (1 mL) was heated to 60° C. for 12 h, concentrated and purified by chromatography (silica) to afford the title compound as a yellow solid (11.5 mg, 83%). [MH]⁺=329.

Preparative Example 329

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Step A

The title compound from the Preparative Example 245, Step B (10 mg) was treated similarly as described in the Preparative Example 328, Step A, except using commercially available 3-chloro-4-fluorobenzylamine instead of 4-fluorobenzylamine to afford the title compound as a yellow solid (11.5 mg, 79%). [MH]⁺=363.

Preparative Example 330

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Step A

Under an argon atmosphere a solution of commercially available [1,3,5]triazine-2,4,6-tricarboxylic acid triethyl ester (818 mg) and 3-aminopyrazole (460 mg) in dry DMF (8 mL) was heated to 100° C. overnight and then concentrated. The remaining residue was dissolved in CHCl₃, washed with 10% aqueous citric acid and saturated aqueous NaCl, dried (MgSO₄), filtered, concentrated and purified by chromatography (silica, CH₂Cl₂/MeOH) to afford the title compound as a colorless solid (409 mg, 56%). [MH]⁺=265.

Step B

A mixture of the title compound from Step A above (203 mg) and commercially available 3-chloro-4-fluorobenzylamine (160 mg) in dry DMF (3 mL) was heated to 70° C. overnight and concentrated. The remaining residue was dissolved in CHCl₃, washed with 10% aqueous citric acid and saturated aqueous NaCl, dried (MgSO₄), filtered, concentrated and purified by preparative thin layer chromatography (silica, CH₂Cl₂/MeOH) to afford the title compound from the Example 286 and the separated regioisomers of the title compound. [MH]⁺=378.

Preparative Example 331

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Step A

To a solution of NaOH (24 mg) in dry MeOH (3.2 mL) was added the title compound from the Preparative Example 315 (170 mg). The resulting suspension was stirred at room temperature for 1 h, acidified with 1N aqueous HCl and concentrated. The remaining residue was dissolved in EtOAc, washed with 1N aqueous HCl, dried (MgSO₄), filtered and concentrated to afford the title compound (130 mg, 80%). [MH]⁺=330.

Preparative Example 332

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Step A

To a solution of the title compound from the Preparative Example 280, Step A (45 mg) in dioxane (3 mL) was added 1M aqueous LiOH (0.12 mL). The resulting mixture was stirred at room temperature for 2 h, adjusted to pH 2 and concentrated to give a red solid, which was used without further purification (43 mg, 99%). [MH]⁺=435.

Preparative Example 333

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Step A

A mixture of the title compound from the Preparative Example 281, Step A (23 mg) and trimethyltin hydroxide (30 mg) in 1,2-dichloroethane (2 mL) was heated at 80° C. for 3 h, concentrated, diluted with EtOAc (5 mL), washed with 10% aqueous KHSO₄(5 mL) and saturated aqueous NaCl (5 mL), dried (MgSO₄), filtered and concentrated to afford the crude title compound (22 mg, 95%). [MH]⁺=331.

Preparative Examples 334-372

Following similar procedures as described in the Preparative Examples 331 (method A), 332 (method B) or 333 (method C), except using the esters indicated in Table I-15 below, the following compounds were prepared.

TABLE I-15Prep.method,Ex. #esterproductyield334 embedded image

B, >99% [MH]⁺ = 415335 embedded image

C, 97% [MH]⁺ = 374336 embedded image

C, 95% [MNa]⁺ = 462337 embedded image

A, 98% [MH]⁺ = 437338 embedded image

A, 78% [MH]⁺ = 333339 embedded image

A, 93% [MH]⁺ = 333340 embedded image

A, n.d. [MH]⁺ = 407/409341 embedded image

A, 98% [MH]⁺ = 329342 embedded image

A, 96% [MH]⁺ = 367343 embedded image

B, 61% [MH]⁺ = 400344 embedded image

A, 96% [MNa]⁺ = 477345 embedded image

C, n.d. [MH]⁺ = 396346 embedded image

B, 83% [MH]⁺ = 350347 embedded image

B, 97% [MH]⁺ = 349348 embedded image

B, n.d. [MH]⁺ = 330349 embedded image

A, 67% [MH]⁺ = 448350 embedded image

A, 91% [MH]⁺ = 381351 embedded image

A, >99% [MH]⁺ = 367352 embedded image

B, 85% [MH]⁺ = 350353 embedded image

A, 93% [MH]⁺ = 421354 embedded image

B, 96% [MH]⁺ = 368355 embedded image

B, 82% [MH]⁺ = 386356 embedded image

B, 98% [MH]⁺ = 455357 embedded image

B, >99% [MH]⁺ = 330358 embedded image

B, >99% [MH]⁺ = 489359 embedded image

A, n.d. [MH]⁺ = 315360 embedded image

A, 18% [MH]⁺ = 349361 embedded image

B, n.d. [MH]⁺ = 345362 embedded image

C, n.d. [MH]⁺ = 397363 embedded image

B, 61% [MH]⁺ = 414364 embedded image

B, >99% [MH]⁺ = 439365 embedded image

B, n.d. [MH]⁺ = 329366 embedded image

B, n.d. [MH]⁺ = 329367 embedded image

A, >99% [MH]⁺ = 383368 embedded image

A, n.d. [MH]⁺ = 345369 embedded image

A, n.d. [MH]⁺ = 397370 embedded image

A, n.d. [MH]⁺ = 373371 embedded image

A, 95% [MH]⁺ = 405372 embedded image

A, 95% [MH]⁺ = 387

Preparative Example 373

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Step A

The title compound from the Preparative Example 304 (142 mg) was dissolved in trifluoroacetic acid/H₂O (9:1, 1.5 mL), stirred at room temperature for 1 h and concentrated by co-evaporation with toluene (3×10 mL) to yield a citreous/white solid, which was used without further purification (114 mg, 91%). [MNa]⁺=445.

Preparative Examples 374-375

Following a similar procedure as described in the Preparative Example 373, except using the esters indicated in Table I-16 below, the following compounds were prepared.

TABLE I-16Prep.method,Ex. #esterproductyield374 embedded image

>99% [MH]⁺ = 402/404375 embedded image

97% [MH]⁺ = 419

Preparative Example 376

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Step A

A mixture of NaOMe (5.40 g), thiourea (5.35 g) and commercially available 2-fluoro-3-oxo-butyric acid ethyl ester (6.27 mL) in anhydrous MeOH (50 mL) was stirred at 100° C. (temperature of the oil bath) for 5½ h and then allowed to cool to room temperature. The obtained beige suspension was concentrated and diluted with H₂O (50 mL). To the resulting aqueous solution was added concentrated HCl (9 mL). The formed precipitate was collected by filtration and washed with H₂O (100 mL) to afford the title compound as a pale beige solid (5.6 g, 70%). [MH]⁺=161.

Step B

A suspension of the title compound from Step A above (5.6 g) and Raney®-nickel (50% slurry in H₂O, 8 mL) in H₂O (84 mL) was heated to reflux for 16 h. The mixture was allowed to cool to room temperature and then filtered. The filter cake was washed successively with MeOH and EtOAc and the combined filtrates were concentrated. The obtained viscous oily residue was diluted with EtOAc and concentrated to afford the title compound as a reddish solid (3.6 g, 80%). [MH]⁺=129.

Step C

A mixture of the title compound from Step B above (3.6 g), K₂CO₃(11.6 g) and POBr₃(24.0 g) in anhydrous CH₃CN (200 mL) was heated to reflux for 19 h, cooled to room temperature and concentrated. A mixture of ice (180 g) and H₂O (30 mL) was added and the mixture was stirred for 30 min. The aqueous mixture was extracted with CHCl₃(2×150 mL) and EtOAc (2×150 mL) and the combined organic extracts were washed with saturated aqueous NaCl, dried (MgSO₄), filtered and concentrated to afford the title compound as a yellow liquid (3.15 g, 58%). [MH]⁺=191/193.

Step D

Under a carbon monoxide atmosphere (7 bar) a mixture of the title compound from Step C above (2.91 g), Pd(OAc)₂(142 mg), 1,1′-bis-(diphenylphosphino)ferrocene (284 mg) and Et₃N (4.2mL) in anhydrous DMA/MeOH (1:1, 150 mL) was heated at 80° C. for 17 h. The mixture was cooled to room temperature, concentrated, absorbed on silica (500 mg) and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound as a beige solid (1.53 g, 59%). [MH]⁺=171.

Step E

The title compound from Step D above (473 mg) was treated similarly as described in the Preparative Example 255, Step A to afford the title compound (514 mg, 92%). [MH]⁺=201.

Preparative Example 377

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Step A

The title compound from the Preparative Example 376, Step E (360 mg) was treated similarly as described in the Preparative Example 279, Step A, except using commercially available 3-chloro-4-fluoro-benzylamine instead of the title compound from the Preparative Example 214, Step A to afford the title compound (195 mg, 32%). [MH]⁺=342.

Step B

The title compound from Step A above (195 mg) was treated similarly as described in the Preparative Example 331, Step A to afford the title compound (175 mg, 93%). [MH]⁺=328.

Step C

The title compound from Step B above (175 mg) was treated similarly as described in the Preparative Example 280, Step A, except using a commercially available 0.5M solution of NH₃in 1,4-dioxane instead of the title compound from the Preparative Example 138 to afford the title compound (160 mg, 92%). [MH]⁺=327.

Step D

A 2M solution of oxalyl chloride in CH₂Cl₂(450 μL) was diluted in DMF (8 mL) and then cooled to 0° C. Pyridine (144 μL) and a solution of the title compound from Step C above (146 mg) in DMF (2 mL) were added and the mixture was stirred at 0° C. for 3 h and then at room temperature overnight. The mixture was concentrated, diluted with EtOAc, washed with saturated aqueous NaHCO₃, dried (MgSO₄), filtered and concentrated to afford the title compound (57 mg, 41%). [MH]⁺=309.

Step E

To a stirring solution of the title compound from Step D above (9 mg) in 1,4-dioxane (3 mL) was added a 1M solution of hydrazine hydrate in 1,4-dioxane (45 μL). The mixture was stirred at room temperature for 3 h and then concentrated to afford the title compound (10 mg, >99%). [MH]⁺=321.

Preparative Example 378

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Step A

A suspension of commercially available 3-amino-1H-pyrrole-2-carboxylic acid ethyl ester hydrochloride (5.06 g) and formamidine acetate (4.20 g) in EtOH (35 mL) was heated to reflux overnight and cooled to room temperature. The formed precipitate was collected by filtration, washed with EtOH and dried to afford the title compound as colorless needles (3.65 g, >99%). [MH]⁺=136.

Step B

A mixture of the title compound from Step A above (491 mg) and POBr₃(4 g) was heated to 80° C. for 2 h. The mixture was cooled to room temperature, poured into saturated aqueous NaHCO₃and extracted with CHCl₃. The organic extracts were concentrated and purified by chromatography (silica, CH₂Cl₂/MeOH) to afford the title compound as an off-white solid (276 mg, 38%). [MH]⁺=198/200.

Step C

Under a carbon monoxide atmosphere (7 bar) a mixture of the title compound from Step B above (276 mg), Pd(OAc)₂(13 mg), 1,1′-bis-(diphenylphosphino)ferrocene (31 mg) and Et₃N (370 μL) in anhydrous DMA/MeOH (1:2, 15 mL) was heated at 80° C. for 3 d. The mixture was cooled to room temperature, concentrated, absorbed on silica and purified by chromatography (silica, CH₂Cl₂/MeOH) to afford the title compound as a brown solid (260 mg, >99%). [MH]⁺=178.

Step D

To the ice cooled title compound from Step C above (120 mg) was added concentrated HNO₃(ρ=1.5, 1 mL). The mixture was stirred at 0° C. (ice bath) for 30 min, the cooling bath was removed and stirring was continued for 30 min. Ice was added and the formed precipitate was collected by filtration and dried to afford the title compound as a brown solid (87 mg, 58%). [MH]⁺=223.

Step E

To the title compound from Step D above (87 mg) was added a solution of LiOH (47 mg) in H₂O. The resulting mixture was stirred for 2 h and then acidified with 1N aqueous HCl. The formed precipitate was collected by filtration and dried to afford the title compound as a brown solid (93 mg, >99%). [MH]⁺=209.

Preparative Example 379

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Step A

To a solution of the title compound from the Preparative 378, Step E above (93 mg) and the title compound from the Preparative Example 161 (110 mg) in DMF (5 mL) were added N-methylmorpholine (40 μL), EDCI (120 mg) and HOAt (60 mg). The mixture was stirred overnight and then concentrated. 10% aqueous citric acid was added and the formed precipitate was collected by filtration and dried to afford the title compound as a brown solid (91.5 mg, 63%). [MH]⁺=369.

Step B

A mixture of the title compound from Step A above (91 mg), AcOH (200 μL) and Pd/C (10 wt %, 55 mg) in THF/MeOH was hydrogenated at atmospheric pressure overnight, filtered, concentrated and diluted with saturated aqueous NaHCO₃. The formed precipitate was collected by filtration and purified by preparative thin layer chromatography (silica, CH₂Cl₂/MeOH) to afford the title compound as a brown solid (12 mg, 9%). [MH]⁺=339.

Preparative Example 380

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Step A

Commercially available 4-bromo-3-hydroxy-benzoic acid methyl ester (500 mg) was treated similarly as described in the Preparative Example 32, Step A to afford the title compound (475 mg, >99%). [MH]⁺=216.

Step B

The title compound from Step A above (475 mg) was treated similarly as described in the Preparative Example 32, Step B to afford the title compound as a colorless solid (316 mg, 73%). [MH]⁺=298.

Preparative Example 381

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Step A

Commercially available 5-bromo-2-fluoro-benzamide (500 mg) was treated similarly as described in the Preparative Example 25, Step A to afford the title compound as colorless needles (196 mg, 52%). [MH]⁺=165.

Preparative Example 382

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Step A

At room temperature commercially available 4-trifluoromethyl benzoic acid (4.90 g) was slowly added to a 90% solution of HNO₃(10 mL). H₂SO₄(12 mL) was added and the mixture was stirred at room temperature for 20 h. The mixture was poured on a mixture of ice (250 g) and H₂O (50 mL). After 30 min the precipitate was collected by filtration, washed with H₂O and air dried. Purification by chromatography (CH₂Cl₂/cyclohexane/AcOH) afforded the title compound as regioisomer A (2.30 g, 38%) and regioisomer B (1.44 g, 23%). ¹H-NMR (acetone-d₆) regioisomer A: δ=8.36 (s, 1H), 8.13-8.25 (m, 2H), regioisomer B: δ=8.58 (s, 1H), 8.50 (m, 1H), 8.20 (d, 1H).

Step B

A mixture of the regioisomer A from Step A above (1.44 g) and Pd/C (10 wt %, 400 mg) in MeOH (150 mL) was hydrogenated at atmospheric pressure for 1 h and filtered. The filter cake was washed with MeOH (50 mL) and the combined filtrates were concentrated to afford the title compound (1.20 g, 95%). [MH]⁺=206.

Step C

To a cooled to (0-5° C.) mixture of the title compound from Step B above (1.2 g) and concentrated H₂SO₄(6 mL) in H₂O (34 mL) was slowly added a solution of NaNO₃(420 mg) in H₂O (6 mL). The mixture was stirred at 0-5° C. for 45 min and then added to a mixture of H₂O (48 mL) and concentrated H₂SO₄(6 mL), which was kept at 135° C. (temperature of the oil bath). The resulting mixture was stirred at 135° C. (temperature of the oil bath) for 2½ h, cooled to room temperature, diluted with ice water (50 mL) and extracted with EtOAc (2×100 mL). The combined organic phases were washed with saturated aqueous NaCl (50 mL), dried (MgSO₄), filtered, concentrated and purified by chromatography (silica, CH₂Cl₂/cyclohexane/AcOH) to afford the title compound (797 mg, 66%). [MH]⁺=207.

Step D

To a cooled (−30° C.) solution of the title compound from Step C above (790 mg) and NEt₃(1.4 mL) in THF (45 mL) was added ethyl chloroformate (790 μL). The mixture was stirred at −30° C. to −20° C. for 1 h and then filtered. The precipitated salts were washed with THF (20 mL). The combined filtrates were cooled to −20° C. and a 33% solution of NH₃in H₂O (20 mL) was added. The mixture was stirred at −20° C. for 20 min, then the cooling bath was removed and the mixture was stirred at room temperature for 40 min. Then the mixture was concentrated and dissolved in THF (25 mL) and CH₃CN (6 mL). Pyridine (3.15 mL) was added and the mixture was cooled to 0° C. Trifluoroacetic anhydride (2.73 mL) was added and the mixture was stirred at 0° C. for 3 h. Then the mixture was concentrated in vacuo, diluted with MeOH (22 mL) and 10% aqueous K₂CO₃(22 mL) and stirred at room temperature for 48 h. The mixture was concentrated to ˜20 mL, acidified (pH ˜1) with 1N aqueous HCl and extracted with EtOAc (2×100 mL). The combined organic phases were dried (MgSO₄), filtered, concentrated and purified by chromatography (silica, CH₂Cl₂/MeOH) to afford the title compound (490 mg, 67%). [MH]⁺=188.

Preparative Examples 383-386

Following a similar procedure as described in the Preparative Example 34, except using the nitriles indicated in Table I-17 below, the following compounds were prepared.

TABLE I-17Prep.Ex. #nitrileproductyield383 embedded image

51% ¹H-NMR (DMSO-d₆) δ = 7.78(d, 1H), 7.58(t, 1H), 7.38(d, 1H), 7.32(s, 1H), 4.25(d, 2H), 1.52(s, 9H), 1.40(s, 9H)384 embedded image

53% [MNa]⁺ = 324/326385 embedded image

n.d. [MNa]⁺ = 291386 embedded image

n.d. [MH]⁺ = 292

Preparative Examples 387-389

Following a similar procedure as described in the Preparative Example 133, except using the protected amines indicated in Table I-18 below, the following compounds were prepared.

TABLE I-18Prep.protectedEx. #amineproductyield387 embedded image

>99% [M-Cl]⁺ = 201/203388 embedded image

n.d. [M-Cl]⁺ = 169389 embedded image

>99% [M-Cl]⁺ = 192

Preparative Example 390

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Step A

The title compound from the Preparative Example 383 (42 mg) was treated similarly as described in the Preparative Example 208, Step A to afford the title compound (32 mg, 98%). [M−TFA]⁺=165.

Preparative Example 391

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Step A

A solution of title compound from the Preparative Example 39, Step C (1.0 g) in SOCl₂(5 mL) was heated to reflux for 3 h, concentrated and coevaporated several times with cyclohexane to afford the corresponding acid chloride. A mixture of magnesium turnings (127 mg) and EtOH (100 μL) in dry benzene (2 mL) was heated to reflux until the dissolution of the magnesium started. A mixture of diethyl malonate (810 μl) and EtOH (700 μL) in benzene (3 mL) was added over a period of 30 min and heating to reflux was continued for 3 h (complete dissolution of the magnesium). The EtOH was then removed by azeotropic distillation with fresh portions of benzene and the volume was brought to ˜5 mL by addition of benzene. The mixture was heated to reflux, a solution of the acid chloride in benzene (5 mL) was added over a period of 30 min and heating to reflux was continued for 3½ h. The resulting viscous mixture was poured on a mixture of ice and 6N aqueous HCl . The organic phase was separated and the aqueous phase was extracted was benzene (2×10 mL). The combined organic phases were washed with H₂O, dried (MgSO₄), filtered and concentrated. The remaining residue was diluted with AcOH (25 mL) and concentrated HCl (25 mL), heated to reflux for 16 h, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound (665 mg, 76%). [MH]⁺=197.

Step B

A mixture of hydroxylamine hydrochloride (807 mg) and pyridine (4.5 mL) in EtOH (4.5 mL) was heated to reflux for 5 min, the title compound from Step A above (759 mg) was added and heating to reflux was continued for 3 h. The mixture was cooled, concentrated and diluted with cold 3N aqueous HCl (30 mL). The formed precipitate was collected by filtration, washed with H₂O and air dried to afford the title compound (590 mg, 72%). [MH]⁺=212.

Step C

A mixture of the title compound from Step B above (440 mg), 6N aqueous HCl (5 mL) and PtO2 (95 mg) in 90% aqueous EtOH (40 mL) was hydrogenated at atmospheric pressure for 36 h, filtered and concentrated to afford the crude title compound as a colorless solid (436 mg, 80%). [M−Cl]⁺=226.

Preparative ExamDles 392-393

Following similar procedures as described in the Preparative Examples 280, except using the acids and amines indicated in Table I-19 below, the following compounds were prepared.

TABLE I-19Prep.acid,Ex. #amineproductyield392 embedded image

69% [MH]⁺ = 330393 embedded image

41% [MH]⁺ = 429

Preparative Examples 394-395

Following similar procedures as described in the Preparative Examples 331, except using the esters indicated in Table I-20 below, the following compounds were prepared.

TABLE I-20Prep.Ex. #esterproductyield394 embedded image

95% [MH]⁺ = 316395 embedded image

95% [MH]⁺ = 415

The Preparative Example numbers 396 to 804 were intentionally excluded.

Preparative Example 805

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Step A

To a cooled (−40° C.) solution of the title compound from the Preparative Example 39, Step C (1.0 g) and NEt₃(890 μL) in THF (50 mL) was slowly added ethyl chloroformate (490 μL). The mixture was stirred at −25° C. for 1 h and then filtered. The precipitated salts were washed with THF (40 mL). The combined filtrates were cooled to 0° C. and a solution of NaBH₄(528 mg) in H₂O (9.4 mL) was added carefully. The mixture was stirred at 0° C. for 45 min, the cooling bath was removed and stirring was continued at room temperature for 45 min. Then the mixture was diluted with saturated aqueous NaHCO₃(40 mL) and saturated aqueous NaCl (40 mL). The organic phase was separated, dried (MgSO₄), filtered, concentrated and purified by chromatography (silica, CH₂Cl₂/acetone) to afford the title compound (910 mg, 97%). [MH]⁺=199.

Step B

To a mixture of the title compound from Step A above (20 mg) in CH₂Cl₂(2 ml) was added IBX-polystyrene (500 mg) and the mixture was stirred at room temperature for 5 h, filtered and concentrated to afford the title compound (19 mg, 97%). [MH]⁺=197.

The Preparative Example numbers 806 to 835 and the Table numbers I-21 to II-30 were intentionally excluded.

Preparative Example 836

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Step A

To a mixture of the commercial available 1-chloro-3-iodo-2-methylbenzene (2 52 g), tert.-butyl acrylate (4.35 mL) and NaOAc (1.65 g) in DMF (10 mL) was added Ru/Al₂O₃(5 wt %, 1.00 g). The reaction mixture was stirred at 150° C. for 12 h, extracted with EtOAc and Et₂O, washed with H₂O, dried (MgSO4), filtered and concentrated. The remaining residue was purified by short pad filtration (silica, cyclohexane/EtOAc) to afford the title compound as a liquid (2.40 g, 95%). [MH]⁺=253.

Step B

A mixture of the title compound from Step A above (2.4 g) and Pt/C (10 wt %, 200 mg) in MeOH (10 mL) was hydrogenated at 1.5 bar overnight, filtered and concentrated. The remaining residue was purified by short pad filtration (silica, CH₂Cl₂/MeOH) to afford the title compound as a liquid (2.39 g, 95%). [MH]⁺=255.

Step C

To a solution of the title compound from Step B above (2.1 g) in CH₂Cl₂(300 mL) was added dropwise pure CSA(2.5 mL) The resulting mixture was stirred at room temperature for 3 h, concentrated, diluted with EtOAc and Et₂O and carefully added to ice water. The organic phase was separated, washed with saturated aqueous NaHCO₃and saturated aqueous NaCl, dried (MgSO₄), filtered and concentrated to afford the title compound as a white solid (1.26 g, 85%). [MH]⁺=181.

Step D

Under an argon atmosphere a pressure reactor was charged with the title compound from Step C above (1.0 g), Na₂CO₃(1.1 g), Pd(OAc)₂(120 mg), H₂O (2 mL), dppp (410 mg) and DMA (20 mL). The reactor was purged with carbon monoxide, the reactor pressure was adjusted to 1 bar and placed in a preheated oil bath (135° C.). The reactor vessel was pressurized with carbon monoxide (6 bar) and heating to 135° C. was continued overnight. The resulting mixture was cooled to room temperature, purged with argon, diluted with H₂O (15 mL) and hexane (15 mL) and stirred at room temperature for 15 min. Activated carbon was added and stirring at room temperature was continued for 20 min. The mixture was filtered through a pad celite®, adjusted to pH =1-2 and extracted with EtOAc. The combined organic phases were dried (MgSO₄), filtered, concentrated and slurried in Et₂O. Filtration and drying in vacuo afforded the title compound (840 mg, 80%). [MH]⁺=191.

Step E

A mixture of the title compound from Step D above (100 g) and Na₂CO₃(55.7 g) in DMF (500 mL) was stirred at room temperature for 18 h and then quenched at 0-5° C. (ice bath) with H₂O (600 mL). The formed precipitate was collected by filtration, washed with H₂O (2×200 mL), dissolved in CH₂Cl₂, washed with H₂O, dried (MgSO₄), filtered and concentrated to afford the title compound (91 mg, 85%). [MH]⁺=205.

Step F

A solution of the title compound from Step E above (21.7 g) in CH₂Cl₂(50 mL) was added over a 10 h period to a cooled (−20° C.) mixture of a 1M solution of (S)-(−)-2-methyl -CBS-oxazaborolidine in toluene (21.2 mL) and a 1M solution of BH₃.Me₂S complex in CH₂Cl₂(107 mL) in CH₂Cl₂(150 mL). The mixture was then quenched at −20° C. by addition of MeOH (210 mL), warmed to room temperature and concentrated. The obtained solid residue was dissolved in CH₂Cl₂(210 mL), washed with 1M aqueous H₃PO₄(2×100 mL), saturated aqueous NaHCO₃(100 mL) and saturated aqueous NaCl (100 mL), dried (MgSO₄), filtered and concentrated to afford the title compound (21 g, 96%, ˜99% ee). [MH]⁺=207.

Step G

To an cooled (0° C.) mixture of the title compound from Step F above (50 g) and diphenylphosphoryl azide (70 mL) in toluene was added DBU (55 mL). The resulting mixture was stirred at 0° C. for 2 h and then at 20° C. for 16 h. The resulting biphasic mixture was washed with H₂O (750 mL), 1M aqueous H₃PO₄(650 mL), saturated aqueous NaHCO₃(650 mL) and saturated aqueous NaCl (650 mL), dried (MgSO₄) and filtered. The obtained filtrate was agitated with charcoal (25 g), filtered and concentrated to afford the crude title compound. [MH]⁺=232.

Step H

A mixture of the title compound from Step G above (2.5 g) and Pt/C (10 wt %, 250 mg) in toluene (78 mL) was hydrogenated at 200 psi for 21 h, filtered through celite® and extracted with 1M aqueous HCl. The aqueous phase was washed with EtOAc, basified with 1M aqueous K₃PO₄(400 ml), extracted with CH₂Cl₂(2×50 mL), dried (MgSO₄), filtered and concentrated to afford the title compound (1.8 g, 81%, 98.8% ee). [MH]⁺=206.

Preparative Example 837

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Step A

A suspension of commercially available 3,4-dihydroxybenzonitrile (2.00 g) and Na₂CO₃(4.91 g) in dry DMF (50 mL) was stirred at room temperature for 16 h. Into this mixture was condensed commercially available chlorodifluoromethane (˜50 g) using a dry ice condenser. The resulting slurry was stirred at 160° C. (temperature of the oil bath) for 5 h, cooled and stirred at room temperature overnight without condenser. The mixture was concentrated, diluted with EtOAc, washed with 5% aqueous NaOH, dried (MgSO₄), filtered, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound as an oil (49 mg, 1%). [MH]⁺=236.

Preparative Example 838

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Step A

To a suspension of commercially available 3-(2-oxopyrrolidin-1 -yl)benzoic acid (500 mg) in CH₂Cl₂(10 mL) was added a 2M solution of oxalyl chloride in CH₂Cl₂(1.83 mL). The resulting mixture was stirred at room temperature for 4 h and then concentrated to dryness. A 0.5M solution of NH₃in 1,4-dioxane (20 mL) was added and stirring at room temperature was continued for 16 h. The resulting mixture was diluted with 1,4-dioxane (20 mL), filtered and concentrated to afford the title compound (374 mg, 75%). [MH]⁺=205.

Step B

To a suspension of the title compound from Step A above (376 mg) in CH₂Cl₂(8 mL) was added trifluoroacetic anhydride (566 μL). The resulting mixture was stirred at room temperature for 2 d, an additional portion of trifluoroacetic anhydride (566 μL) was added and stirring at room temperature was continued for 1 d. The mixture was concentrated and purified by chromatography (silica, CH₂Cl₂/MeOH) to afford the title compound (63.1 mg, 18%). [MH]⁺=187.

Preparative Example 839

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Step A

In a sealed pressure tube a mixture of commercially available 2-chloropyridine-4-carbonitrile (1.00 g) in morpholine (30 mL) was heated to 130° C. for 13 h. The resulting mixture was concentrated and purified by chromatography (silica, CHCl₃/MeOH) to afford the title compound (256 mg, 19%). [MH]⁺=190.

Preparative Example 840

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Step A

A mixture of commercially available 4-fluoro-3-nitro-benzonitrile (1.5 g) and Pd/C (10 wt %, 400 mg) in EtOH (10 mL) was hydrogenated at atmospheric pressure overnight, filtered and concentrated to afford the title compound (1.2 g, >99%.) [MH]⁺=137.

Preparative Example 841

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Step A

A mixture of the title compound from the Preparative Example 840, Step A (566 mg), ⁱPr₂NEt (2.15 mL) and commercially available 1-(2-bromoethoxy)-2-bromoethane (627 μL) was stirred at 100° C. for 16 h and at 140° C. for 6 h. An additional portion of 1-(2-bromoethoxy)-2-bromoethane (627 μL) was added and stirring was continued at 160° C. for 6 h. The resulting mixture was concentrated and purified by chromatography (silica, CHCl₃/MeOH) to afford the title compound. [MH]⁺=207.

Preparative Example 842

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Step A

A mixture of the commercially available cubane-1,4-dicarboxylic acid dimethyl ester (1.65 g) and KOH (300 mg) in MeOH/H₂O (10:1, 11 mL) was heated to reflux overnight, cooled to room temperature, concentrated, diluted with EtOAc and extracted with 1N aqueous NaOH (2×10 mL). The combined aqueous phases were adjusted to pH 1-2 with 2N aqueous HCl and extracted with EtOAc (4×25 mL). The combined turbid organic phases were filtered through a fluted filter, washed with saturated aqueous NaCl, dried (MgSO₄), filtered and concentrated to give the title compound as a colorless solid (500 mg, 32%). [MH]⁺=207.

Step B

To a cooled (−40° C.) solution of the title compound from Step A above (490 mg) and NEt₃(400 μL) in THF (20 mL) was slowly added ethyl chloroformate (240 μL). The mixture was allowed to warm to −25° C. and stirred at this temperature for 1 h. A 0.5N solution of NH₃in 1,4-dioxane (5.5 mL) was added and the mixture was stirred at −20° C. for 30 min. The cooling bath was removed and stirring was continued for 15 min. The mixture was concentrated diluted H₂O (10 mL) and extracted with CH₂Cl₂(1×20 mL, 2×10 ML). The combined organic phases were washed with saturated aqueous NaCl (10 mL), dried (MgSO₄), filtered and concentrated to afford the title compound (208 mg, 42%). [MH]⁺=206.

Step C

DMF (10 mL) was cooled to 0-5° C. (ice bath) and a 2M solution of oxalyl chloride in CH₂Cl₂(650 μL) was added followed by a solution of the title compound from Step B above (208 mg) in DMF (10 mL). The resulting mixture was stirred at 0-5° C. (ice bath) for 5 h, diluted with EtOAc, washed with saturated aqueous NaHCO₃, dried (MgSO₄), filtered and concentrated to afford the title compound (140 mg, 75%). [MH]⁺=188.

Preparative Example 843

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Step A

To an ice cooled (0-5° C.) suspension of commercially available 4-amino-3-hydroxybenzoic acid (5 g) in MeOH (50 mL) was dropwise added thionyl chloride (10.9 mL). The ice bath was removed and the mixture was stirred at room temperature for 12 h, before it was concentrated to afford the title compound as a solid (5.34 g, >99%). [MH]⁺=168.

Step B

To a mixture of the title compound from Step A above (5.34 g) and NaHCO₃(10 g) in acetone/H₂O (1:1, 120 mL) was slowly added 2-bromopropionyl bromide (3 mL). The resulting mixture was heated to reflux for 2 h, cooled and stirred at 25° C. overnight. The formed precipitate was collected by filtration and washed several times with H₂O to afford the title compound (3.6 g, 50%). [MH]⁺=208.

Step C

To a solution of the title compound from Step B above (3.55 g) in THF/MeOH (2:1, 120 mL) was added 1M aqueous LiOH (50 mL). The resulting mixture was stirred at room temperature for 24 h, adjusted to pH 2 with 1M aqueous HCl and concentrated. The formed precipitate was collected by filtration and washed with H₂O to afford the crude title compound, which used without further purification (3.0 g, 90%). [MH]⁺=194.

Step D

To an ice cooled (0-5° C.) solution of the title compound from Step C above (1.00 g) in DMF (10 mL) was added 1,1′-carbonyldiimidazole (1.44 g). The resulting solution was stirred at 0-5° C. (ice bath) for 50 min, then a 0.5M solution of NH₃in 1,4-dioxane (20 mL) was added, the ice bath was removed and the mixture was stirred at room temperature overnight. The formed precipitate was collected by filtration and washed with H₂O and dried in vacuo to afford the title compound (795 mg, 80%). [MH]⁺=193.

Step E

DMF (10 mL) was cooled to 0-5° C. (ice bath) and a 2M solution of oxalyl chloride in CH₂Cl₂(2.5 mL) was added followed by a solution of the title compound from Step D above (795 mg) in DMF (10 mL). The resulting mixture was stirred at 0-5° C. (ice bath) for 5 h, diluted with EtOAc, washed with saturated aqueous NaHCO₃, dried (MgSO₄), filtered and concentrated to afford the title compound (140 mg, 90%). [MH]⁺=175.

Preparative Example 844

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Step A

At room temperature dimethylformamide dimethyl acetal (3 5 mL) was added to a solution of the commercially available 2-amino-5-cyanopyridine (2.4 g) in ⁱPrOH (10 mL). The resulting mixture was heated to reflux for 3 h and then cooled to 50° C. Hydroxylamine hydrochloride (1.8 g) was added and the mixture was aged under sonication at 50° C. for 6 h. All volatile components were evaporated and the remaining residue was purified by chromatography (silica, EtOAc/MeOH) to afford the title compound (2.6 g, 80%). [MH]⁺=163.

Step B

To an ice cooled (0-5° C.) solution of the title compound from Step A above (2.6 g) in 1,4-dioxane/DMF (1:1, 60 mL) trifluoroacetic anhydride (2.5 mL) was slowly added over a period of 10 min, keeping the internal temperature below 20° C. After the complete addition the ice bath was removed and the mixture was heated to 90° C. for 48 h. The mixture was cooled, concentrated and purified by chromatography (silica, EtOAc/MeOH) to afford the title compound (322 mg, 11%). [MH]⁺=145.

Preparative Example 845

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Step A

To a cooled (−78° C.) solution of the commercial available 2-hydroxy-isonicotinonitrile (1.08 g) in THF/DMF (1:1, 40 mL) was added NaH (260 mg) in portions. The mixture was stirred at −25° C. for 2 h and then cooled to −78° C. again. Iodomethane (680 μL) was added, the cooling bath was removed and the mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, washed with 10% aqueous KHSO₄(10 mL) and saturated aqueous NaCl (20 mL), dried (MgSO₄), filtered, concentrated and purified by chromatography (silica, CH₂Cl₂/acetone) to afford the title compound (600 mg, 49%). [MH]⁺=135.

Preparative Example 846

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Step A

Commercially available chlorodifluoromethane was passed through a cooled (−78° C.) suspension of the commercial available 2-hydroxy-isonicotinonitrile (230 mg) and Cs₂CO₃(650 mg) in 1,2-dichloroethane/DMA (10:1, 11 mL) for 30 min. The reaction vessel was sealed and—using a microwave—the chlorodifluoromethane saturated mixture was heated at 150° C. for 5 h. Then the mixture was cooled to room temperature, diluted with CHCl₃(20 mL), washed with H₂O (10 mL) and saturated aqueous NaCl (20 mL), dried (MgSO₄), filtered and concentrated to afford the crude title compound (200 mg, 55%). [MH]⁺=171.

Preparative Example 847

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Step A

A mixture of commercially available 4-bromomethyl-benzoic acid methyl ester (500 mg) and KCN (354 mg) in DMA (9 mL) was stirred at 60-70° C. (temperature of the oil bath) overnight, concentrated and diluted with Et₂O (200 mL) and H₂O (80 mL). The organic phase was separated, washed with H₂O (2×80 mL), dried (MgSO₄), filtered, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound (273 mg, 71%). [MH]⁺=176.

Preparative Examples 848-854

Following a similar procedure as described in the Preparative Example 25, except using the intermediates indicated in Table I-31 below, the following compounds were prepared.

TABLE I-31Prep.Ex. #intermediateproductyield848 embedded image

n.d. [MH]⁺ = 144849 embedded image

[MH]⁺ = 144850 embedded image

67% [MH]⁺ = 175851 embedded image

n.d.852

61% [MH]⁺ = 161853 embedded image

n.d.854

93% [MH]⁺ = 175

Preparative Examples 855-859

Following a similar procedure as described in the Preparative Example 37, except using the intermediates and reagents indicated in Table I-32 below, the following compounds were prepared.

TABLE I-32Prep.intermediate,Ex. #reagentproductyield855 embedded image

99% [MH]⁺ = 175856 embedded image

73% [MH]⁺ = 189857 embedded image

22% [MH]⁺ = 203858 embedded image

80% [MH]⁺ = 203859 embedded image

n.d. [MH]⁺ = 217

Preparative Example 860

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Step A

A solution of the title compound from the Preparative Example 840, Step A (100 mg) in acetic anhydride (3 mL) was stirred at room temperature for 2 h, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound as a white solid (77.6 mg, 60%). [MH]⁺=179.

Preparative Example 861

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Step A

To an ice cooled (0-5° C.) solution of the title compound from the Preparative Example 840, Step A (100 mg) in pyridine (2 mL) was added methanesulfonyl chloride (67.8 μL). The resulting mixture was stirred overnight while warming to room temperature, cooled to 0-5° C. (ice bath) again, neutralized with 1M aqueous HCl, diluted with H₂O and extracted with EtOAc. The combined organic phases were dried (MgSO₄), filtered, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound as a colorless solid (47.4 mg, 30%). [MH]⁺=215.

Preparative Example 862

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Step A

To a mixture of morpholinomethyl polystyrene (295 mg) in 1,2-dichlorethane (1 mL) were added commercially available 4-cyanobenzene-1-sulfonylchloride (50 mg) and commercially available 2-amino-3-methyl-butyric acid tert.-butyl ester hydrochloride (52 mg). The mixture was agitated at room temperature overnight, filtered and concentrated to afford the title compound as pale yellow solid, which was used without further purification. (75 mg, 90%). [MH]⁺=339.

Preparative Examples 863-867

Following a similar procedure as described in the Preparative Example 862, except using the acids and acid chlorides indicated in Table I-33 below, the following compounds were prepared.

TABLE I-33Prep.amine,Ex. #acid chlorideproductyield863 embedded image

92% [MH]⁺ = 339864 embedded image

86% [MH]⁺ = 339865 embedded image

88% [MH]⁺ = 339866 embedded image

88% [MH]⁺ = 339867 embedded image

87% [MH]⁺ = 339

Preparative Example 868

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Step A

Commercially available 3,4diamino-benzonitrile (1.02 g) was treated similarly as described in the Preparative Example 213, Step A to afford the title compound as a brown solid (1.18 g, 97%). [MH]⁺=160.

Step B

Title compound from Step A above (1.18 g) was treated similarly as described in the Preparative Example 213, Step B to afford the title compound as an off-white solid (1.14 g, 80%). [MH]⁺=188.

Step C

The title compound from Step A above (1.32 g) was treated similarly as described in the Preparative Example 213, Step C to afford the title compound as a white solid (496 mg, 38%). [MH]⁺=191.

Step D

The title compound from Step C above (1.32 g) was treated similarly as described in the Preparative Example 213, Step D to afford the title compound as white crystals (264 mg, >99%). [M−Cl]⁺=165.

Preparative Example 869

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Step A

To an ice cooled (0-5° C.) solution of the title compound from the Preparative Example 29 (1.10 g) in DMF (8 mL) were added NaH (102 mg) and iodomethane (500 μL). The ice bath was removed and the resulting mixture was stirred at room temperature overnight, concentrated and diluted with H₂O and extracted with EtOAc. The organic phase was separated, dried (MgSO₄), filtered and concentrated to afford the title compound (1.02 g, 88%). [MH]⁺=299

Preparative Examples 870-901

Following a similar procedure as described in the Preparative Example 34, except using the nitriles indicated in Table I-34 below, the following compounds were prepared.

TABLE I-34Prep.Ex. #nitrileproductyield870 embedded image

69% (over 2 steps) [MH]⁺ = 248871 embedded image

n.d. [MH]⁺ = 248872 embedded image

25% [MNa]⁺ = 362873 embedded image

66% [MNa]⁺ = 313874 embedded image

n.d. [MH]⁺ = 294875 embedded image

53% [MH]⁺ = 311876 embedded image

42% [MH]⁺ = 279877 embedded image

50% [MH]⁺ = 292878 embedded image

35% [MH]⁺ = 301879 embedded image

50% [MH]⁺ = 271880 embedded image

70% [MH]⁺ = 278881 embedded image

n.d. [MNa]⁺ = 261882 embedded image

n.d. [MNa]⁺ = 297883 embedded image

50% (over 2 steps) [MNa]⁺ = 298884 embedded image

40% ¹H-NMR (CDCl₃) δ = 7.96(d, 2H), 7.24(d, 2H), 4.98 (br s, 1H), 3.90(s, 3H), 3.30-3.40(m, 2H), 2.82(t, 2H), 1.40(s, 9H).885 embedded image

99% [MNa]⁺ = 274886 embedded image

45% [MH]⁺ = 443887 embedded image

62% [MH]⁺ = 443888 embedded image

49% [MH]⁺ = 443889 embedded image

68% [MH]⁺ = 443890 embedded image

62% [MH]⁺ = 443891 embedded image

64% [MH]⁺ = 443892 embedded image

89% [MH]⁺ = 279893 embedded image

52% [MH]⁺ = 293894 embedded image

>99% [MH]⁺ = 307895 embedded image

53% [MNa]⁺ = 329896 embedded image

81% [MNa]⁺ = 343897 embedded image

n.d. [MNa]⁺ = 300898 embedded image

n.d. [MNa]⁺ = 301899 embedded image

n.d. [MNa]⁺ = 425900 embedded image

8% [MNa]⁺ = 286901 embedded image

80% [MNa]⁺ = 314

Preparative Example 902

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Step A

A mixture of The title compound from the Preparative Example 885 (507 mg), ⁱPr₂NEt (6.5 mL) and iodomethane (700 μL) in DMF (8 mL) was stirred at room temperature over the weekend, concentrated and diluted with EtOAc (60 mL) and H₂O (20 mL). The organic phase was separated, washed with 0.1M aqueous HCl (15 mL) and saturated aqueous NaCl (15 mL), dried (MgSO₄), filtered and concentrated to afford the title compound (430 mg, 80%). ¹H-NMR (CDCl₃) δ=7.95 (d, 1H), 7.45-7.49 (m, 2H) 7.29-7.37 (m, 1H), 5.55 (br s, 1H), 4.49 (d, 2H), 3.90 (s, 3H), 1.40 (s, 9 H).

Preparative Example 903

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Step A

A mixture of commercially available N-(tert-butoxycarbonyl)-L-methionine (2.50 g), tert-butylamine (1.06 mL), EDCI (2.02 g), HOBt (1.99 g) and ⁱPr₂NEt (7.62 mL) in CH₂Cl₂(100 mL) was stirred at room temperature overnight and then diluted with H₂O. The aqueous phase was separated and extracted with CH₂Cl₂(2×). The combined organic phases were washed with saturated aqueous NaHCO₃and 1M aqueous HCl, dried (MgSO₄), filtered and concentrated to afford the title compound as a colorless solid (2.89 g, 95%). [MH]⁺=305.

Preparative Example 904

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Step A

Commercially available N-(tert-butoxycarbonyl)-L-alanine (1.00 g) was treated similarly as described in the Preparative Example 903, Step A to afford the title compound as a white solid (1.38 g, >99%). [MNa]⁺=267.

Preparative Example 905

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Step A

A solution of the title compound from the Preparative Example 903, Step A (1.89 g) in iodomethane (10 mL) was stirred at room temperature overnight and then concentrated to afford the title compound as a yellow solid (2.67 g, 97%). [M−S(CH₃)₂I]⁺=257.

Step B

Under an argon atmosphere NaH (166 mg, 60% in mineral oil) was added at once to an ice cooled (0-5° C. solution of the title compound from Step A above(1.85 g) in DMF (25 mL). The resulting mixture was stirred at 0-5° C. (ice bath) for 15 min and at room temperature for 2 h, diluted with H₂O and saturated aqueous NH₄Cl and extracted with EtOAc (3×). The combined organic phases were washed with H₂O and saturated aqueous NaCl, dried (MgSO₄), filtered, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound as a colorless oil (800 mg, 75%). [MNa]⁺=279.

Preparative Example 906

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Step A

The title compound from the Preparative Example 79 (2.50 g) was treated similarly as described in the Preparative Example 96, Step A to afford the title compound as an oil (1.63 g, >99%). [MNa]^+=277.

Step B

The title compound from Step A above (1.63 g) was treated similarly as described in the Preparative Example 97, Step A to afford the title compound as a white solid (1.43 g, 68%). [MNa]⁺=320.

Preparative Example 907

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Step A

To an ice cooled (0-5° C.) solution of commercially available (3-amino-benzyl)-carbamic acid tert-butyl ester (400 mg) in pyridine (5 mL) was added methanesulfonyl chloride (170 μL) before the stirring mixture was allowed to warm to room temperature overnight. The resulting mixture was cooled to 0-5° C. (ice bath), carefully neutralized with 1M aqueous HCl, diluted with H₂O and extracted with CH₂Cl₂. The organic phase was washed H₂O and saturated aqueous NaCl, dried (MgSO₄), filtered, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound as colorless crystals (407 mg, 75%). [MNa]⁺=323.

Preparative Example 908

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Step A

To a solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (790 μL) in MeOH (20 mL) was added commercially available (3-aminomethyl-benzyl)-carbamic acid tert-butyl ester (840 mg). The mixture was stirred for 2 h, 30% aqueous solution of methylamine (30 mL) was added and stirring was continued for 2 h. The formed precipitate was collected by filtration to afford the title compound as a white solid (1.17 g, 95%). [MNa]⁺=368.

Preparative Example 909

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Step A

Commercially available (3-aminomethyl-benzyl)-carbamic acid tert-butyl ester (1.39 g) was treated similarly as described in the Preparative Example 907, Step A, except using a 2M solution of dimethylamine in THF instead of 30% aqueous methylamine to afford the title compound as black needles (632 mg, 88%). [MNa]⁺=382.

Preparative Examples 910-911

Following a similar procedure as described in the Preparative Example 7, Step C, except using the acids indicated in Table I-35 below, the following compounds were prepared.

TABLE I-35Prep.Ex. #acidproductyield910 embedded image

>99% [MH]⁺ = 308911 embedded image

35% [MNa]⁺ = 356

Preparative Example 912

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Step A

The title compound from the Preparative Example 39, Step C (500 mg) was treated similarly as described in the Preparative Example 17, Step A to afford the title compound (460 mg, 60%). [MNa]⁺=306.

Preparative Example 913

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Step A

To a solution of the title compound from the Preparative Example 805, Step B (339 mg), 30% aqueous NH₄OH (240 μL) and KCN (124 mg) in MeOH/H₂O (2:1, 15 rmL) was added NH₄Cl (104 mg). The resulting mixture was stirred at 70° C. overnight, diluted with H₂O and extracted with EtOAc (2×). The combined organic phases were washed with saturated aqueous NaHCO₃and saturated aqueous NaCl, dried (MgSO₄), filtered and concentrated to afford the crude title compound (330 mg, 86%). [MH]⁺=223.

Step B

To a solution of the title compound from Step A above (330 mg) in THF (10 mL) were subsequently added di-tert-butyl dicarbonate (487 mg) and NaHCO₃(249 mg). The resulting mixture was stirred at room temperature overnight, concentrated, diluted with EtOAc, washed with saturated aqueous NH₄Cl and saturated aqueous NaCl, dried (MgSO₄), filtered and concentrated to afford the title compound (385 mg, 85%). [MNa]⁺=345.

Step C

To a solution of the title compound from Step B above (385 mg) in MeOH/H₂O (2:1, 15 mL) was added sodium perborate tetrahydrate (552 mg). The resulting mixture was stirred at 50° C. overnight, concentrated and diluted with EtOAc and saturated aqueous NH₄Cl. The organic phase was separated, washed with H₂O and saturated aqueous NaCl, dried (MgSO₄), filtered and concentrated to afford the title compound (393 mg, 97%). [MNa]⁺=363.

Preparative Examples 914-946

Following a similar procedure as described in the Preparative Example 133, except using the protected amines indicated in Table I-36 below, the following compounds were prepared.

TABLE I-36Prep.protectedEx. #amineproductyield914 embedded image

>99% [M-Cl]⁺ = 148915 embedded image

>99% (over 3 steps) [M-Cl]⁺ = 148916 embedded image

>99% [M-Cl]⁺ = 240917 embedded image

>99% [M-Cl]⁺ = 191918 embedded image

>99% [M-HCl₂]⁺ = 194919 embedded image

>99% [M-Cl]⁺ = 211920 embedded image

>99% [M-NH₃Cl]⁺ = 162921 embedded image

>99% [M-Cl]⁺ = 158922 embedded image

>99% [M-Cl]⁺ = 156923 embedded image

99% [M-Cl]⁺ = 192924 embedded image

99% [M-Cl]⁺ = 179925 embedded image

99% [M-Cl]⁺ = 149926 embedded image

>99% [M-Cl]⁺ = 156927 embedded image

n.d. [M-Cl]⁺ = 139928 embedded image

n.d. [M-Cl]⁺ = 175929 embedded image

95% [M-Cl]⁺ = 176930 embedded image

>99% [M-NH₃Cl]⁺ = 162931 embedded image

>99% [M-NH₃Cl]⁺ = 176932 embedded image

>99% [M-NH₃Cl]⁺ = 190933 embedded image

>99% [M-Cl]⁺ = 157934 embedded image

>99% [M-Cl]⁺ = 145935 embedded image

>99% [M-Cl]⁺ = 207936 embedded image

>99% [M-Cl]⁺ = 221937 embedded image

>99% [M-Cl]⁺ = 184938 embedded image

>99% [M-Cl]⁺ = 241939 embedded image

57% (over 3 steps) [M-NH₃Cl]⁺ = 161940 embedded image

37% (over 2 steps) [M-NH₃Cl]⁺ = 162941 embedded image

>99% [M-Cl]⁺ = 198942 embedded image

>99% [M-NH₃Cl]⁺ = 184943 embedded image

>99% [M-Cl]⁺ = 164944 embedded image

>99% [M-Cl]⁺ = 192945 embedded image

>99% [M-Cl]⁺ = 246946 embedded image

88% [M-Cl]⁺ = 260

Preparative Example 947

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Step A

A mixture of the title compound from the Preparative Example 852 (127 mg), Pd/C (10 wt %, 93 mg) and 50% aqueous AcOH (1 mL) in EtOH (5 mL) was hydrogenated at atmospheric pressure overnight, filtered and concentrated. The remaining residue was diluted with a 4M solution of HCl in 1,4-dioxane (3 mL), stirred at room temperature for 1 h and concentrated to afford the title compound as a white solid (148 mg, 93%). [M−NH₃Cl]⁺=148.

Preparative Examples 948-949

Following a similar procedure as described in the Preparative Example 947, except using the nitrites indicated in Table I-37 below, the following compounds were prepared.

TABLE I-37Prep.Ex. #nitrileproductyield948 embedded image

>99% [M-NH₃Cl]⁺ = 156949 embedded image

27% [M-NH₃Cl]⁺ = 202

Preparative Examples 950-951

Following a similar procedure as described in the Preparative Example 214, except using the intermediates and amines indicated in Table I-38 below instead of the title compound from the Preparative Example 95, Step A and NH₃, the following compounds were prepared.

TABLE I-38Prep.intermediate,Ex. #amineproductyield950 embedded image

40% aqueous MeNH₂ embedded image

n.d. [M-Cl]⁺ = 264951 embedded image

28% aqueous NH₃ embedded image

50% (over 3 steps) [M-Cl]⁺ = 264

Preparative Example 952

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Step A

Commercially available 4-aminomethyl-benzoic acid methyl ester hydrochloride (500 mg) was dissolved in a 33% solution of NH₃in H₂O (50 mL) and heated in a sealed pressure tube to 90° C. for 20 h. Cooling to room temperature and concentration afforded the title compound. [M−Cl]⁺=151.

Preparative Example 953

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Step A

Commercially available 6-acetyl-4H-benzo[1,4]oxazin-3-one (2.36 g) was treated similarly as described in the Preparative Example 217, Step A to afford the title compound as a colorless fluffy needles (2.19 g, 86%). [MH]⁺=207.

Step B

The title compound from Step B above (888 mg) was treated similarly as described in the Preparative Example 217, Step B to afford the title compound as a colorless solid (163 mg, 32%). [MH]⁺=193.

Preparative Example 954

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Step A

Commercially available 2-hydroxy-4-methylaniline (4.64 g) was treated similarly as described in the Preparative Example 213, Step A to afford the title compound as black needles (5.00 g, 89%).

Step B

A mixture of the title compound from Step A above (1.03 g) in acetic anhydride (20 mL) was heated to 80° C. for 2 h, concentrated, diluted with toluene (2 x), concentrated (2×) and dried in vacuo to afford the title compound as brown crystals (1.32 g, >99%).

Step C

The title compound from Step A above (1.32 g) was treated similarly as described in the Preparative Example 213, Step C to afford the title compound as a white solid (496 mg, 38%). [MH]⁺=191.

Step D

The title compound from Step C above (1.32 g) was treated similarly as described in the Preparative Example 213, Step D to afford the title compound as white crystals (264 mg, >99%). [M−Cl]⁺=165.

Preparative Example 955

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Step A

The title compound from Preparative Example 954, Step C (240 mg) was treated similarly as described in the Preparative Example 213, Step B to afford the title compound as a white solid (243 mg, 94%). [MH]⁺=205.

Step B

The title compound from Step A above (243 mg) was treated similarly as described in the Preparative Example 213, Step D to afford the title compound as a white solid (118 mg, 44%). [M−Cl]⁺=179.

Preparative Examples 956-957

Following a similar procedure as described in the Preparative Example 208, except using the protected amines indicated in Table I-39 below, the following compounds were prepared.

TABLE I-39Prep.protectedEx. #amineproductyield956 embedded image

>99% [M-TFA]⁺ = 180957 embedded image

>99% [M-TFA]⁺ = 164

Preparative Examples 958-965

Following a similar procedure as described in the Preparative Example 7, Step D, except using the protected amines indicated in Table I-40 below, the following compounds were prepared.

TABLE I-40Prep.protectedEx. #amineproductyield958 embedded image

58% [MH]⁺ = 208959 embedded image

20% [M-NH₂]⁺ = 217960 embedded image

84% [MH]⁺ = 343961 embedded image

63% [MH]⁺ = 343962 embedded image

55% [MH]⁺ = 343963 embedded image

51% [MH]⁺ = 343964 embedded image

50% [MH]⁺ = 343965 embedded image

50% [MH]⁺ = 343

Preparative Example 966

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Step A

A mixture of commercially available 4-bromomethyl-benzoic acid methyl ester (500 mg) and NaN₃(666 mg) in DMA (9 mL) was stirred at 60-70° C. (temperature of the oil bath) overnight, concentrated and diluted with Et₂O (200 mL) and H₂O (80 mL). The organic phase was separated, washed with H₂O (2×80 mL), dried (MgSO₄), filtered and concentrated to afford the title compound (375 mg, 90%). ¹H-NMR (CDCl₃) δ=8.03 (d, 2H), 7.39 (d, 2H), 4.40 (s, 2H), 3.90 (s, 3H).

Step B

A mixture of the title compound from Step A above (375 mg) and Pd/C (10 wt %, 150 mg) in MeOH (100 mL) was hydrogenated at atmospheric pressure for 1 h, filtered and concentrated to afford the title compound (291 mg, 90%). [MH]⁺=166.

Preparative Examples 967-968

Following a similar procedure as described in the Preparative Example 245, Step B, except using the aminopyrazoles indicated in Table I-41 below instead of 2-aminopyrazole, the following compounds were prepared.

TABLE I-41Prep.Ex. #aminopyrazoleproductyield967 embedded image

6% [MH]⁺ = 312968 embedded image

13% [MH]⁺ = 318

Preparative Example 969

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Step A

A mixture of title compound from the Preparative Example 262 (100 mg), di-tert.-butyl dicarbonate (182 mg) and DMAP (15 mg) in THF (2 mL) was stirred at room temperature for 3 h, concentrated and purified by chromatography (silica, hexanes/EtOAc) to afford title compound as yellow solid (84 mg, 68%). [MNa]⁺=318.

Step B

To a solution of the title compound from Step A (77 mg) in THF/MeOH (1:1, 2 mL) was added 1M aqueous LiOH (340 μL). The resulting mixture was stirred at room temperature for 2 h and then concentrated to afford the crude title compound, which was used without further purification (85 mg). [(M−Li)HNa]⁺=304.

Preparative Example 970

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Step A

The title compound from the Preparative Example 262 (50 mg) was treated similarly as described in the Preparative Example 969, Step B to afford the title compound. [(M−]⁻=224.

Preparative Example 971

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Step A

To the title compound from the Preparative Example 278, Step A (462 mg) in CHCl₃(5 mL) was added N-iodosuccinimide (277 mg). The resulting mixture was heated to reflux for 16 h, concentrated and purified by chromatography (silica, hexanes/EtOAc) to afford the title. compound (587 mg, >99%). [MNa]⁺=599.

Preparative Example 972

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Step A

The title compound from the Preparative Example 971, Step A (520 mg), Pd(OAc)₂(20 mg), dppf (200 mg) and KOAc (354 mg) were dissolved in dry DMSO (5.4 mL) and stirred at 60° C. under a carbon monoxide atmosphere at 1 atm for 16 h. The mixture was diluted with EtOAc, washed subsequently with 1N aqueous HCl and saturated aqueous NaCl, dried (MgSO₄), filtered and concentrated. Purification by chromatography (silica, CH₂Cl₂/MeOH) afforded the title compound as a yellow solid (391 mg, 88%). [M−]⁻=588.

Preparative Example 973

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Step A

The title compound from the Preparative Example 288 (210 mg) in CHCl₃(5 mL) was added N-iodosuccinimide (167 mg). The resulting mixture was stirred at 70° C. for 1 h, absorbed onto silica and purified by chromatography (silica, hexanes/EtOAc) to afford the title compound (365 mg, 97%). [MH]⁺=473.

Preparative Example 974

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Step A

The title compound from the Preparative Example 973, Step A (95 mg), Pd(OAc)₂(4.5 mg), dppf (45 mg) and KOAc (79 mg) were dissolved in dry DMSO (1.5 mL) and stirred at 60° C. under a carbon monoxide atmosphere at 1 atm for 4 h. The mixture was diluted with EtOAc, washed subsequently with 1N aqueous HCl (2×) and saturated aqueous NaCl, dried (MgSO₄), filtered and concentrated to afford the crude title compound, which was use with out further purification (92 mg). [MH]⁺=391.

Preparative Example 975

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Step A

A mixture of commercially available 5-nitro-1H-pyrazole-3-carboxylic acid methyl ester (1.45 g) and Pd/C (10 wt %, 106 mg) in MeOH (25 mL) was hydrogenated at 25 psi for 2 h, filtered through celite® and concentrated to afford the title compound (1.25 g, 88%). [MH]⁺=142.

Step B

A mixture of the title compound from Step A above (325 mg) and methyl acetopyruvate (330 mg) in MeOH (10 mL) was heated to reflux for 2 h and then cooled to room temperature. The formed precipitate was collected by filtration and dried to afford the title compound as a white solid (356 mg, 62%). [MH]⁺=250.

Step C

To a solution of the title compound from Step B above (229 mg) in 1,4-dioxane/MeOH (5:1, 12 mL) was added 1M aqueous NaOH (1 mL). The resulting mixture was stirred at room temperature overnight and then acidified. The formed precipitate was collected by filtration to afford the crude title compound as a white solid. (177 mg, 38%). [MH]⁺=236.

Step D

The title compound from Step C above (172 mg) was treated similarly as described in the Preparative Example 280, Step A to afford the title compound (171 mg, 65%). [MH]⁺=361.

Step E

The title compound from Step D above (151 mg) was treated similarly as described in the Preparative Example 274, Step D to afford the title compound. [MH]⁺=391.

Preparative Examples 976-982

TABLE I-42Prep.acid,method,Ex. #amineproductyield976 embedded image

E, 68% [MNa]⁺ = 435977 embedded image

E, 67% [M-H]⁻ = 602978 embedded image

E, 95% [MH]⁺ = 382979 embedded image

HCl•NH₃

E, 84% [MH]⁺ = 221980 embedded image

B, 42% (over 2 steps) [M-H]⁻ = 500981 embedded image

A, n.d. [MH]⁺ = 387982 embedded image

A, n.d. [MH]⁺ = 444

Preparative Examples 983-986

Following a similar procedure as described in the Preparative Example 328, Step A, except using the esters and nucleophiles indicated in Table I-43 below, the following compounds were prepared.

TABLE I-43Prep.ester,method,Ex. #nucleophileproductyield983 embedded image

39% [MH]⁺ = 423984 embedded image

32% [MH]⁺ = 429985 embedded image

NaOH

80% [MH]⁺ = 298986 embedded image

NaOH

94% [MH]⁺ = 304

Preparative Examples 987-993

Following similar procedures as described in the Preparative Examnples 331 (method A), 332 (method B) or 333 (method C), except using the esters indicated in Table I-44 below, the following compounds were prepared.

TABLE I-44Prep.method,Ex. #esterproductyield987 embedded image

A, >99% [MH]⁺ = 207988 embedded image

B, n.d. [MH]⁺ = 376989 embedded image

B, 99% [MH]⁺ = 486990 embedded image

C, 70% [MH]⁺ = 409991 embedded image

C, 67% [MH]⁺ = 415992 embedded image

A, n.d. [MH]⁺ = 373993 embedded image

A, n.d. [MH]⁺ = 430

Preparative Example 994

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Step A

The title compound from the Preparative Example 976 was treated similarly as described in the Preparative Example 373 to afford the title compound (>99%). [MH]⁺=357

Preparative Examples 995-996

Following a similar procedures as described in the Preparative Example 324, Step A, except using the esters and amines indicated in Table I-45 below, the following compounds were prepared.

TABLE I-45Prep.ester,Ex. #amineproductyield995 embedded image

74% [MH]⁺ = 409996 embedded image

87% [MH]⁺ = 415

Preparative Example 997

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Step A

A mixture of the title compound from the Preparative Example 339 (50 mg) and HSO₃Cl (500 μL) was stirred at 90° C. for 1 h, cooled and the cautiously poured onto ice (5 g). The formed precipitate was collected by filtration, dried in vacuo and then added to a premixed solution of acetyl chloride (100 μL) in MeOH (1 mL). The resulting mixture was stirred at 40° C. for 1 h and concentrated to afford the title compound (42 mg, 65%). [M−]⁻=425.

Preparative Example 998

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Step A

A mixture of the title compound from the Preparative Example 339 (168 mg) and HSO₃Cl (2 mL) was stirred at 90° C. for 2 h, cooled and the cautiously poured onto ice (15 g). The formed precipitate was collected by filtration, dried in vacuo and then added to solution of commercially available 2-chloroaniline (100 μL) in CHCl₃(5 mL). The resulting mixture was stirred at 70° C. for 18 h, concentrated and purified by chromatography (silica) to afford a residue containing the title compound (9 mg). [M−]⁻=519.

Preparative Example 999

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Step A

At 100° C. N,N-dimethylformamide di-tert-butyl acetal (3.6 mL) was added to a solution of commercial available pyridine-2,5-dicarboxylic acid 5-methyl ester (1.36 g) in dry toluene (10 mL). The mixture was stirred at 100° C. for 3 h, cooled to room temperature, concentrated, diluted with EtOAc (20 mL), washed with water (20 mL) and saturated aqueous NaCl (10 mL), dried (MgSO₄), filtered and concentrated to afford the crude title compound (726 mg, 40%). [MH]⁺=238.

Step B

Using a microwave, a mixture of the title compound from Step A above (600 mg) and trimethyltin hydroxide (1.35 mg) in 1,2-dichloroethane (20 mL) was heated at 100° C. for 1 h. The mixture was cooled to room temperature, diluted with CHCl₃(30 mL), washed with 10% aqueous KHSO₄(20 mL) and saturated aqueous NaCl (20 mL), dried (MgSO₄), filtered and concentrated to afford the crude title compound (307 mg, 55%). [MH]⁺=224.

Preparative Example 1000

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Step A

A mixture of the commercial available trans-dimethylcyclohexane-1,4-dicarboxylate (1 g) and KOH (300 mg) in THF/H₂O (10:1, 30 mL) was stirred at 100° C. overnight, cooled to room temperature and concentrated. The residue was diluted with EtOAc and adjusted to pH 1-2 with 1N aqueous HCl and extracted with EtOAc (3×50 mL). The combined organic phases were washed with saturated aqueous NaCl, dried (MgSO₄), filtered, concentrated and purified by chromatography (silica, CH₂Cl₂/MeOH) to afford the title compound (820 mg, 88%). [MH]⁺=187.

Preparative Example 1001

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Step A

Using a microwave, a suspension of commercially available 4-bromo-3-methyl-benzoic acid methyl ester (1.5 g) and CuCN (490 mg) in dry N-methyl-pyrrolidin-2-one (10 mL) was heated at 230° C. for 10 h. The mixture was cooled to room temperature, diluted with 35% aqueous NH₃(20 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with saturated aqueous NaCl (200 mL), dried (MgSO₄), filtered and concentrated to afford the title compound as a solid (590 mg, 67%). [MH]⁺=176.

Step B

To a solution of the title compound from Step A above (590 mg) in THF/MeOH (2:1, 60 mL) was added 1M aqueous LiOH (10 mL). The resulting mixture was stirred at room temperature for 2 h, adjusted to pH 2 and concentrated to afford the crude title compound as a solid, which was used without further purification (540 mg, 99%). [MH]⁺=162.

Preparative Examples 1002-1007

Following a similar procedure as described in the Preparative Example 805, Step A, except using the intermediates indicated in Table I-46 below, the following compounds were prepared.

TABLE I-46Prep.Ex. #intermediateproductyield1002 embedded image

52% [MH]⁺ = 2101003 embedded image

57% [MH]⁺ = 1681004 embedded image

51% [MH]⁺ = 1991005 embedded image

52% [MH]⁺ = 1731006 embedded image

61% [MH]⁺ = 1481007 embedded image

18% [MH]⁺ = 188

Preparative Examples 1008-1013

Following a similar procedure as described in the Preparative Example 805, Step B, except using the intermediates indicated in Table I-47 below, the following compounds were prepared.

TABLE I-47Prep.Ex. #intermediateproductyield1008 embedded image

99% [MH]⁺ = 2081009 embedded image

99% [MH]⁺ = 1661010 embedded image

92% [MH]⁺ = 1971011 embedded image

95% [MH]⁺ = 1711012 embedded image

95% [MH]⁺ = 1461013 embedded image

87% [MH]⁺ = 186

Preparative Example 1014

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Step A

To an ice cooled (0-5° C.) suspension of commercially available 4-bromo-2-methylbenzoic acid (3.22 g) in MeOH (60 mL) was dropwise added thionyl chloride (3.2 mL). The ice bath was removed and the mixture was stirred at room temperature for 12 h. The mixture was concentrated, diluted with EtOAc (20 mL), washed with H₂O (20 mL) and saturated aqueous NaCl (10 mL), dried (MgSO₄), filtered and concentrated to afford the title compound as a solid (2.94 g, 86%). [MH]⁺=230.

Step B

Using a microwave, a mixture of the title compound from Step A above (1.37 g), Pd(PPh₃)₄(135 mg) and tributyl(vinyl)tin (2.1 mL) in 1,4-dioxane (15 mL) was heated at 120° C. for 5 h. The mixture was cooled to room temperature and Florisil® was added. The resulting mixture was allowed to stand for 2 h and then filtered. The filter cake was washed with H₂O and EtOAc. The combined filtrates were washed with H₂O (20 mL) and saturated aqueous NaCl (20 mL), dried (MgSO₄), filtered, concentrated and purified by chromatography (silica, CH₂Cl₂/acetone) to afford the title compound (800 mg, 75%). [MH]⁺=177.

Step C

A slow flow of ozone was passed through a cooled (−78° C.) solution of the title compound from Step B above (627 mg) in CHCl₃(50 mL) over a period of 20 min. The mixture was purged with nitrogen and dimethylsulfide (1 mL) was added. The resulting mixture was stirred at −78° C. for 1 h, allowed to warm to room temperature, concentrated and purified by chromatography (silica, CH₂Cl₂/acetone) to afford the title compound (570 mg, 90%). [MH]⁺=179 .

Preparative Example 1015

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Step A

To an ice cooled (0-5° C.) mixture of commercially available L-prolinamide (25 g), NEt₃(30 mL) and DMAP (1.9 g) in CH₂Cl₂(1.2 L) was added fumaryl chloride (11.7 ml). The ice bath was removed and the resulting dark mixture was stirred at room temperature for 16 h. The mixture was cooled again to 0-5° C. (ice bath), trifluoroacetic anhydride (77 mL) was dropwise added and the resulting mixture was stirred for 2 d while warming to room temperature. Ice (500 g) was added followed by cautious addition of saturated aqueous NaHCO₃(600 mL). After the evolution of gas had ceased, the organic phase was separated and washed with saturated aqueous NaHCO₃(350 mL), H₂O (350 mL) and saturated aqueous NaCl (200 mL), dried (MgSO₄), filtered and concentrated to afford the title compound (28.6 g, 98%). ¹H-NMR (CDCl₃) δ=7.26 (s, 2H), 4.72-4.83 (m, 2H), 3.73-3.89 (m, 2H), 3.58-3.69 (m, 2H), 2.12-2.30 (m, 8H).

Step B

A slow flow of ozone was passed through a cooled (−78° C.) solution of the title compound from Step A above (9.6 g) in CHCl₃/MeOH (1:1, 180 mL) over a period of 3 h. The mixture was purged with nitrogen and dimethylsulfide (6 mL) was added. The resulting mixture was stirred at −78° C. for 1 h, allowed to warm to room temperature, concentrated and purified by chromatography (silica, CH₂Cl₂/MeOH) to afford the title compound as a ˜9:1 mixture of the corresponding methoxy hemiacetal and the free aldehyde (8.9 g, 69%). ¹H-NMR (D₂O) δ=7.90 (s, 1/10H), 5.50 (s, 9/10H), 4.72-4.81 (m, 1H), 3.60-3.84 (m, 2H), 3.32 (s, 3H), 2.10-2.38 (m, 4H).

Preparative Example 1016

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Step A

To an ice cooled (0-5° C.) mixture of commercially available thiazolidine (1 g), NEt₃(780 μL) and DMAP (136 mg) in CH₂Cl₂(56 mL) was added fumaryl chloride (604 μl). The ice bath was removed and the resulting dark mixture was stirred at room temperature overnight, filtered and concentrated to afford the crude title compound (2.69 g, 98%). [MH]⁺=259.

Step B

A slow flow of ozone was passed through a cooled (−78° C.) solution of the title compound from Step A above (833 mg) in CH₂Cl₂/MeOH (1:1, 16 mL) over a period of 45 min. The mixture was purged with nitrogen and dimethylsulfide (1.2 mL) was added. The resulting mixture was stirred at −78° C. for 1 h, allowed to warm to room temperature, concentrated and purified by chromatography (silica, EtOAc/MeOH) to afford the title compound (293 mg, 23%).

Preparative Example 1017

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Step A

Commercially available 4-formyl-benzenesulfonyl chloride (70 mg) was suspended in 1M aqueous HCl (3 mL) and stirred at room temperature for 2 h and then concentrated to afford the title compound, which was used without further purification.

Preparative Example 1018

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Step A

To a solution of commercially available trans-cyclobutane-1,2-dicarboxylic acid (1.5 g) in MeOH (50 mL) was added thionyl chloride (2.3 mL). The resulting mixture was heated to reflux for 2 h and then concentrated to afford the title compound as a yellow liquid (1.79 g, >99%). ¹H-NMR (CDCl₃) δ=3.67 (s, 6H), 3.33-3.43 (m, 2H), 2.11-2.19 (m, 4H).

Preparative Example 1019

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Step A

To a solution of commercially available trans-cyclopropane-1,2-dicarboxylic acid (1.0 g) in MeOH/H₂O (10:1, 7.7 mL) was added KOH (354 mg). The resulting mixture was stirred at room temperature for 6 h, diluted with H₂O (40 mL), washed with cyclohexane (2×30 mL), acidified to pH˜1 with a 1M aqueous HCl and extracted with EtOAc (3×40 mL). The combined organic phases were dried (MgSO₄), filtered and concentrated to afford the title compound as a colorless oil (685 mg, 75%). ¹H-NMR (CDCl₃) δ=3.70 (s, 3H), 2.11-2.27 (m, 2 H), 1.43-1.52 (m, 2H).

Preparative Examples 1020-1021

Following a similar procedure as described in the Preparative Example 1019, except using the bisesters indicated in Table I-48 below, the following compounds were prepared.

TABLE I-48Prep.Ex. #biesterproductyield1020 embedded image

80% ¹H-NMR (CDCl₃) δ = 3.70(s, 3H), 2.06-2.15(m, 2H), 1.63-1.73(m, 1H), 1.30-1.40(m, 1H).1021 embedded image

69% ¹H-NMR (CDCl₃) δ = 3.70(s, 3H), 3.38-3.48(m, 2H), 2.15-2.23(m, 4H).

Preparative Example 1022

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Step A

To a suspension of commercially available phthalic acid monomethyl ester (900 mg) in toluene (6 mL) were added DMF (1 drop) and thionyl chloride (2.3 mL). The resulting mixture was heated at 95° C. (temperature of the oil bath) for 1½ h, concentrated and dried in vacuo to afford the title compound as a pale yellow oil (964 mg, 97%). ¹H-NMR (CDCl₃) δ=7.81-7.87 (m, 1H), 7.72-7.76 (m, 1H), 7.58-7.64 (m, 2H), 3.91 (s, 3H).

Preparative Examples 1023-1026

Following a similar procedure as described in the Preparative Example 1022, except using the acids indicated in Table I-49 below, the following compounds were prepared.

TABLE I-49Prep.Ex. #acidproductyield1023 embedded image

92% ¹H-NMR (CDCl₃) δ = 8.73(t, 1H), 8.32 (dt, 1H), 8.27(dt, 1H), 7.60(t, 1H), 3.92(s, 3H).1024 embedded image

87% ¹H-NMR (CDCl₃) δ = 3.74(s, 3H), 2.58-2.68(m, 1H), 2.38-2.48(m, 1H), 1.54-1.70(m, 2H).1025 embedded image

91% ¹H-NMR (CDCl₃) δ = 3.75(s, 3H), 2.58-2.68(m, 1H), 2.27-2.37(m, 1H), 1.85-1.95(m, 1H), 1.40-1.50(m, 1H).1026 embedded image

91% ¹H-NMR (CDCl₃) δ = 3.84(q, 1H), 3.72 (s, 3H), 3.84(q, 1H), 2.10-2.38(m, 4H).

Preparative Example 1027

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Step A

To a solution of commercially available tert.-butylamine (66 μL) in pyridine (3 mL) was added the title compound from the Preparative Example 1024 (100 mg). The resulting mixture was stirred at room temperature overnight, concentrated and diluted with EtOAc (40 mL) and H₂O (15 mL). The organic phase was separated, washed with 1M aqueous HCl (15 mL) and H₂O (15 mL), dried (MgSO₄), filtered and concentrated to afford the title compound as a yellow oil (67.6 mg, 55%). [MH]⁺=200.

Step B

The title compound from Step A above (67.6 mg) in THF/H₂O (1:1, 6 mL) was added a 1M aqueous KOH (680 μL). The mixture was stirred at room temperature overnight. Additional 1M aqueous KOH (680 μL) was added and stirring at room temperature was continued for 4 h. The mixture was concentrated, acidified to pH˜1 with a 1M aqueous HCl and extracted with EtOAc (3×20 mL). The combined organic phases were dried (MgSO₄), filtered and concentrated to afford the title compound as a white solid (60 mg, 95%). [MH]⁺=186.

Preparative Examples 1028-1029

Following a similar procedure as described in the Preparative Example 1027, except using the acids indicated in Table I-50 below, the following compounds were prepared.

TABLE I-50Prep.Ex. #acidproductyield1028 embedded image

59% [MH]⁺ = 1741029 embedded image

37% [MH]⁺ = 186

Preparative Example 1030

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Step A

To a solution of potassium 1,1,1,3,3,3-hexamethyl-disilazane (3.29 g) in DMF (40 mL) was added a solution of commercially available (4-bromo-phenyl)-acetic acid ethyl ester (3.6 g) in DMF (10 mL). The resulting mixture was stirred at room temperature for 10 min, before bromoacetaldehyde diethylacetal (3.25 g) was added dropwise. After complete addition the mixture was heated at 45° C. for 1 h, cooled (ice bath), diluted with saturated aqueous NH₄Cl (5 mL) and ice water (45 mL) and extracted with cyclohexane (3×50 mL). The combined organic phases were concentrated, suspended in H₂O (7.5 mL) and cooled to 0-5° C. (ice bath). A 1:1 mixture of trifluoroacetic acid and CHCl₃(45 mL) was added and the mixture was stirred for 2 h. The mixture was poured into a mixture of 1M aqueous K₂CO₃(115 mL) and CH₂Cl₂(200 mL) and the pH was adjusted to pH˜7.5 by addition of solid K₂CO₃. The organic phase was separated and the aqueous phase was extracted with CH₂Cl₂(120 mL). The combined organic phases were washed with H₂O (200 mL) and saturated aqueous NaCl (200 ML), dried (MgSO₄), filtered, concentrated and purified by chromatography (silica, petroleum ether/EtOAc) to afford the title compound (3.35 g, 79%). ¹H-NMR (CDCl₃) δ=9.77 (s, 1H), 7.43-7.51 (m, 2H), 7.13-7.22 (m, 2H), 4.02-4.25 (m, 3H), 3.36 (dd, 1H), 2.78 (dd, 1H), 1.20 (t, 3H).

Preparative Example 1031

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Step A

Commercially available phenyl-acetic acid ethyl ester was treated similarly as described in the Preparative Example 1030, Step A to afford the title compound (88%). ¹H-NMR (CDCl₃) δ=9.78 (s, 1H), 7.21-7.38 (m, 5 H), 4.02-4.25 (m, 3H), 3.39 (dd, 1H), 2.80 (dd, 1H), 1.20 (t, 3H).

Preparative Example 1032

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Step A

The title compound from the Preparative Example 378, Step A (4 g) was added in portions to an ice cooled mixture of 90% HNO₃(8 mL) and 65% HNO₃(4 mL). After complete addition, conc. H₂SO₄(13.6 mL) was added slowly keeping the reaction temperature below 12° C. After the complete addition, the mixture was stirred at 0-5° C. (ice bath) for 2 h. The obtained clear yellow solution was then poured onto a mixture of ice (30 g) and H₂O (60 mL). The formed precipitate was collected by filtration, washed with H₂O (160 mL) and dried in vacuo to afford the title compound as a yellow solid (4.78 g, 89%). ¹H-NMR (DMSO-d₆) δ=13.50 (s, 1H), 12.58 (s, 1H), 8.52 (d, 1H), 8.10 (s, 1H).

Step B

The title compound from Step A above (4.78 g) was grinded in a mortar and added at 110-115° C. in portions to neat POBr₃(40 g). The obtained mixture was stirred at 110-115° C. overnight, cooled to 0-5° C. (ice bath) and hydrolyzed by careful addition with ice water (450 mL). The mixture was adjusted to pH˜8 by careful addition of solid NaHCO₃and then extracted with EtOAc (6×400 mL). The combined organic phase was dried (MgSO₄), filtered and concentrated to afford the title compound (1.30 g, 20%). [MH]⁺=243/245. The remaining aqueous phase was acidified (pH ˜1) by addition of 37% HCl. The formed precipitate was collected by filtration, washed with H₂O and dried in vacuo to afford a solid residue (2.7 g) containing a mixture of the title compound (70%) and the unreacted title compound from Step A (30%).

Step C

To a slurry of a mixture (2,7 g) of the title compound from Step B above (70%) and the title compound from Step A (30%) in MeOH/DMA (60:40, 125 mL) and MeOH (75 ml) was added NEt₃(3.5 mL). The resulting mixture was sonicated for 25 min while a stream of N₂was passed through the mixture. Pd(OAc)₂(130 mg) and dppf (252 mg) were added and the mixture was stirred at 80° C. under a carbon monoxide atmosphere at 6.5 bar until the bromo starting material was consumed. The mixture was filtered and the filter cake was washed with MeOH. The combined filtrate concentrated in vacuo, coated on silica and purified by chromatography (silica, CH₂Cl₂/MeOH) to afford the title compound as an orange solid (1 g, 41%). [MH]⁺=223.

Preparative Example 1033

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Step A

A mixture of the title compound from the Preparative Example 1032, Step C (832 mg) and Pd/C (10 wt %, 300 mg) in MeOH (80 mL) was hydrogenated at atmospheric pressure for 30 min, filtered and concentrated to afford the title compound as a red solid residue (719 mg, >99%). [MH]⁺=193.

Preparative Example 1034

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Step A

A mixture of the title compound from the Preparative Example 1033, Step A (540 mg), di-tert-butyl dicarbonate (590 mg) and NEt₃(400 μL) in THF/ACN (1:1, 24 mL) was stirred at room temperature overnight, concentrated, coated on silica and purified by chromatography (silica, CH₂Cl₂/MeOH) to afford the title compound as a yellow solid (300 mg, 32%). [MH]⁺=293.

Preparafive Example 1035

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Step A

A mixture of the title compound from the Preparative Example 1033, Step A (100 mg), acetyl chloride (32 μL) and NEt₃(67 μL) in THF/ACN (1:1, 100 mL) was stirred at room temperature overnight, concentrated and purified by chromatography (silica, CH₂Cl₂/MeOH) to afford the title compound as an orange solid (58.5 mg, 55%). [MH]⁺=235.

Preparative Examples 1036-1039

Following a similar procedure as described in the Preparative Example 1035, except using the acid chlorides indicated in Table I-51 below, the following compounds were prepared.

TABLE I-51Prep.acidEx. #chlorideproductyield1036 embedded image

n.d. [MH]⁺ = 2971037 embedded image

n.d. [MH]⁺ = 3551038 embedded image

n.d. [MH]⁺ = 3551039 embedded image

n.d. [MH]⁺ = 355

Preparative Example 1040

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Step A

A mixture of the title compound from the Preparative Example 1034, Step A (50 mg) in a 4M solution of HCl in 1,4-dioxane (1 mL) was stirred at room temperature for 1 h and then concentrated. The remaining residue was added to solution of NaBH₃CN (25 mg) in THF/MeOH (1:1, 1 mL). To the resulting solution was slowly added a solution of the title compound from the Preparative Example 1030, Step A (50 mg) in THF/MeOH (1:1, 1 mL) over a period of 2 h. Then the mixture was concentrated, diluted with saturated aqueous NaHCO₃and extracted with EtOAc (3×). The combined organic phases were dried (MgSO₄), filtered, absorbed onto silica and purified by chromatography (silica) to afford the title compound (23 mg, 28%). [MH]⁺=461/463.

Step B

To an ice cooled (0-5° C.) solution of the title compound from Step A above (13 mg) in THF (1 mL) was added a 1M solution of tert.-butyl magnesium chloride (60 μL). The resulting mixture was stirred at 0-5° C. (ice bath) for 1½ h, diluted with saturated aqueous NaHCO₃and extracted with EtOAc (3×). The combined organic phases were dried (MgSO₄), filtered, concentrated and purified by preparative thin layer chromatography (silica, EtOAc) to afford the title compound as a brown solid (7 mg, 60%). [MH]⁺=429/431.

Preparative Example 1041

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Step A

To a solution of the title compound from the Preparative Example 1034, Step A (150 mg) in THF/ACN/H₂O (1:1:1, 12.9 mL) was added a 1M aqueous KOH (770 μL). The mixture was stirred at room temperature for 1 h, concentrated and dried in vacuo to afford the title compound (162 mg, >99%). [(M−K)H₂]⁺=279.

Preparative Examples 1042-1046

Following a similar procedure as described in the Preparative Example 1041, except using the esters indicated in Table I-52 below, the following compounds were prepared.

TABLE I-52Prep.Ex. #esterproductyield1042 embedded image

n.d. [(M-K)H₂]⁺ = 221.1043 embedded image

n.d. [(M-K)H₂]⁺ = 2831044 embedded image

n.d. [(M-K)H₂]⁺ = 3411045 embedded image

n.d. [(M-K)H₂]⁺ = 3411046 embedded image

n.d. [(M-K)H₂]⁺ = 401/403

Preparative Example 1047

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Step A

To a solution of the title compound from the Preparative Example 1038 (24.6 mg) in THF/ACN/H₂O (1:1:1, 1.8 mL) was added a 1M aqueous KOH (69 μL). The mixture was stirred at room temperature for 1 h, concentrated and dried in vacuo to afford a ˜1:1 mixture of the carboxylate I ([(M−K)H₂]⁺=341) and the carboxylate II ([(M−K2)H₃]⁺=327).

Preparative Example 1048

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Step A

The title compound from the Preparative Example 376, Step E (400 mg) was treated similarly as described in the Preparative Example 279, Step A, except using the title compound from the Preparative Example 7, Step D (500 mg) instead of the title compound from the Preparative Example 214, Step A to afford the title compound (287 mg, 33%). [MH]⁺=430.

Step B

The title compound from Step A above (287 mg) was treated similarly as described in the Preparative Example 331, Step A to afford the title compound (260 mg, 94%). [MH]⁺=416.

Step C

The title compound from Step B above (260 mg) was treated similarly as described in the Preparative Example 280, Step A, except using a commercially available 0.5M solution of NH₃in 1,4-dioxane instead of the title compound from the Preparative Example 138 to afford the title compound (196 mg, 76%). [MH]⁺=415.

Step D

The title compound from Step C above (196 mg) was treated similarly as described in the Preparative Example 377, Step D to afford the title compound (113 mg, 61%). [MH]⁺=397.

Step E

The title compound from Step D above (113 mg) was treated similarly as described in the Preparative Example 377, Step E to afford the title compound (110 mg, 98%). [MH]⁺=409.

Preparative Example 1049

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Step A

The title compound from the Preparative Example 376, Step E (2.93 g) was treated similarly as described in the Preparative Example 279, Step A, except using the title compound from the Preparative Example 161 (3.35 g) instead of the title compound from the Preparative Example 214, Step A to afford the title compound (1.89 g, 36%). [MH]⁺=361.

Step B

The title compound from Step A above (1.89 g) was treated similarly as described in the Preparative Example 331, Step A to afford the crude title compound (2.0 g). [MH]⁺=347.

Step C

The crude title compound from Step B above (2.0 g) was treated similarly as described in the Preparative Example 280, Step A, except using a commercially available 0.5M solution of NH₃in 1,4-dioxane instead of the title compound from the Preparative Example 138 to afford the crude title compound (5.0 g). [MH]⁺=346.

Step D

The crude title compound from Step C above (4.6 g) was treated similarly as described in the Preparative Example 377, Step D to afford the title compound (233 mg, 5% over 3 steps). [MH]⁺=328.

Step E

The title compound from Step D above (233 mg) was treated similarly as described in the Preparative Example 377, Step E to afford the title compound (245 mg, 96%). [MH]⁺=340.

Preparative Example 1050

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Step A

The title compound from the Preparative Example 376, Step E (1.19 g) was treated similarly as described in the Preparative Example 279, Step A, except using commercially available 4-fluoro-3-trifluoromethyl-benzylamine instead of the title compound from the Preparative Example 214, Step A to afford the title compound (1.42 g, 64%). [MH]⁺=376.

Step B

The title compound from Step A above (1.42 g) was treated similarly as described in the Preparative Example 331, Step A to afford the crude title compound (1.36 g, 99%). [MH]⁺=347.

Step C

The title compound from Step B above (1.36 g) was treated similarly as described in the Preparative Example 280, Step A, except using a commercially available 0.5M solution of NH₃in 1,4-dioxane instead of the title compound from the Preparative Example 138 to afford the crude title compound (969 mg, >99%). [MH]⁺=361.

Step D

The crude title compound from Step C above (969 mg) was treated similarly as described in the Preparative Example 377, Step D to afford the title compound (152 mg, 24%). [MH]⁺=343.

Step E

The title compound from Step D above (110 mg) was treated similarly as described in the Preparative Example 377, Step E to afford the title compound (123 mg, >99%). [MH]⁺=355.

Preparative Example 1051

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Step A

The title compound from Preparative Example 377, Step D (22 mg) was treated similarly as described in the Preparative Example 377, Step E, except using commercially available methylhydrazine instead of hydrazine to afford the title compound (26 mg, >99%). [MH]⁺=335.

Example 1

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Step A

To a solution of the title compound from the Preparative Example 335 (40 mg) in DMF (2 mL) were added the title compound from the Preparative Example 4, Step B (34 mg), PyBOP (84 mg) and ⁱPr₂NEt (46 μL). The mixture was stirred overnight, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound (23 mg, 40%). ¹H-NMR (CDCl₃) δ=10.50 (br d, 1H), 9.00 (s, 1H), 8.85 (s, 1H), 8.30 (br t, 1H), 7.95 (s, 1H), 7.90 (d, 2H), 7.40 (d, 2H), 7.25-7.10 (m, 2H), 6.95 (m, 1H), 5.80 (m, 1H), 4.65 (d, 2H), 3.90 (s, 3H), 3.20-2.70 (m, 3H), 2.25 (s, 3H), 2.20-2.00 (m, 1H).

Example 2

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Step A

To a solution of the title compound from the Preparative Example 373, Step A (30 mg) and the title compound from the Preparative Example 228, Step A (30 mg) in DMF (3 mL) were added N-methylmorpholine (40 μL), EDCI (25 mg) and HOAt (13 mg). The mixture was stirred overnight and then concentrated. The remaining residue was dissolved in EtOAc, washed with saturated NaHCO₃, 1N aqueous HCl and saturated aqueous NaCl, dried (MgSO₄), filtered, concentrated and purified by chromatography (silica, CH₂Cl₂/MeOH) to afford the title compound as a colorless solid (35 mg, 90%). [MH]⁺=553.

Example 3

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Step A

To a solution of the title compound from the Preparative Example 331, Step A (31 mg) and the title compound from the Preparative Example 218, Step D (27 mg) in DMF (5 mL) were added N-methylmorpholine (13 μL), HATU (57 mg) and HOAt (16 mg). The mixture was stirred overnight and then concentrated. The remaining residue was dissolved in EtOAc, washed with saturated aqueous NaHCO₃, 1N aqueous HCl and saturated aqueous NaCl, dried (MgSO₄), filtered, concentrated and purified by chromatography (silica, CH₂Cl₂/MeOH) to afford the title compound as a colorless solid (57 mg, >99%). [MH]⁺=520.

Example 4

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Step A

To a solution of the title compound from the Preparative Example 349 (21.5 mg) in DMF (3 mL) were added cyclohexanemethylamine (30 μL), PyBrOP (29 mg) and HOAt (8 mg). The mixture was stirred over the weekend and then concentrated. The remaining residue was dissolved in CHCl₃, washed with saturated aqueous NaHCO₃, 1N aqueous HCl and saturated aqueous NaCl, dried (MgSO₄), filtered, concentrated and purified by preparative thin layer chromatography (silica, CH₂Cl₂/MeOH) to afford the title compound as an off-white solid (11.9 mg, 46%). [MH]⁺=543.

Example 5

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Step A

To a mixture of the title compound from the Preparative Example 324, Step A (106 mg), DMF (20 mL) and CH₂Cl₂(2.5 mL) at 0° C. was added oxalyl chloride (116 μL). The ice bath was removed and the mixture was stirred for 45 min and concentrated. The resulting residue was brought up in CH₂Cl₂(1.5 mL) and canulated into a mixture of the title compound from the Preparative Example 176, Step A (75 mg) and NEt₃(122 μL) in CH₂Cl₂(1 mL). The resulting mixture was stirred for 16 h and concentrated. The remaining solid was washed with MeOH (10 mL). The supernatant was concentrated and the resulting solid was washed with MeOH (10 mL). The yellow solids were combined to give the title compound (51 mg, 33%). [M−H]⁻=588.

Example 6

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Step A

To a mixture of N-cyclohexyl-carbodiimide-N′-methyl-polystyrene (43 mg) in DMF (100 μL) were added a 0.2M solution of the title compound from the Preparative Example 331, Step A in DMF (150 μL) and a 0.5M solution of HOBt in DMF (60 μL). The mixture was agitated for 30 min, then a 0.5M solution of (1,1-dioxidotetrahydrothien-3-yl)-methylamine in DMF (54 μL) was added and agitation at room temperature was continued for 12 h. The mixture was filtered, concentrated and dissolved in 1,2-dichloroethane (200 μL). (Polystyrylmethyl)-trimethylammonium bicarbonate (16 mg) was added and the mixture was agitated at room temperature for 2 h. Filtration and concentration afforded the title compound (13.1 mg, 95%). [MH]⁺=461.

Example 7

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Step A

To a mixture of polystyrene-IIDQ (131 mg) in DMF (800 μL) were added the title compound from the Preparative Example 331, Step A (39 mg) and a 0.5M solution of commercially available 4-aminomethyl-benzoic acid (40 mg). The mixture was agitated for 24 h, filtered and concentrated to afford the title compound (40 mg, 73%). [MH]⁺=463.

Examples 8-277

Following similar procedures as described in the Examples 1 (method A), 2 (method B), 3 (method C), 4 (method D), 5 (method E), 6 (method F) or 7 (method G), except using the acids and amines indicated in Table II-1 below, the following compounds were prepared.

TABLE II-1Ex.acid,method,#amineproductyield8 embedded image

B, 90% [MH]⁺ = 5799 embedded image

B, 80% [MH]⁺ = 64410 embedded image

B, 86% [MH]⁺ = 69811 embedded image

B, >99% [MH]⁺ = 64512 embedded image

B, 98% [MH]⁺ = 54213 embedded image

B, >99% [MH]⁺ = 59414 embedded image

B, 95% [MH]⁺ = 58215 embedded image

B, >99% [MH]⁺ = 58616 embedded image

B, n.d. [MH]⁺ = 57717 embedded image

B, n.d. [MH]⁺ = 56018 embedded image

B, n.d. [MH]⁺ = 56619 embedded image

B, n.d. [MH]⁺ = 53620 embedded image

B, n.d. [MH]⁺ = 53621 embedded image

B, n.d. [MH]⁺ = 59122 embedded image

B, n.d. [MH]⁺ = 55623 embedded image

B, n.d. [MH]⁺ = 59624 embedded image

B, 92% [MH]⁺ = 48325 embedded image

B, 85% [MH]⁺ = 50226 embedded image

B, 79% [MH]⁺ = 60627 embedded image

B, 88% [MH]⁺ = 59228 embedded image

B, 95% [MH]⁺ = 59929 embedded image

B, 18% [MH]⁺ = 48930 embedded image

B, 95% [MH]⁺ = 59531 embedded image

0.5M NH₃in 1,4-dioxane embedded image

B, 41% [MH]⁺ = 38532 embedded image

B, 87% [MH]⁺ = 53933 embedded image

B, 45% [MH]⁺ = 50734 embedded image

B, 77% [MH]⁺ = 48135 embedded image

B, 65% [MH]⁺ = 39936 embedded image

2M Me₂NH in THF embedded image

B, 35% [MH]⁺ = 41337 embedded image

B, 97% [MH]⁺ = 54738 embedded image

B, 84% [MH]⁺ = 58139 embedded image

B, 81% [MH]⁺ = 61240 embedded image

B, 85% [MH]⁺ = 57841 embedded image

B, n.d.% [MH]⁺ = 55442 embedded image

B, 68% [MH]⁺ = 56043 embedded image

C, 95% [MH]⁺ = 54344 embedded image

C, 56% [MH]⁺ = 46845 embedded image

D, >99% [MH]⁺ = 55746 embedded image

D, 47% [MH]⁺ = 59047 embedded image

D, >99% [MH]⁺ = 52148 embedded image

D, >99% [MH]⁺ = 50749 embedded image

D, 76% [MH]⁺ = 50150 embedded image

D, >99% [MH]⁺ = 51951 embedded image

D, 30% [MH]⁺ = 50152 embedded image

D, 77% [MH]⁺ = 59453 embedded image

C, 62% [MNa]⁺ = 66154 embedded image

C, 76% [MH]⁺ = 63655 embedded image

C, 85% [MH]⁺ = 58256 embedded image

C, 77% [MH]⁺ = 55757 embedded image

C, 91% [MNa]⁺ = 56258 embedded image

C, 85% [M-Boc]⁺ = 41259 embedded image

C, 98% [M-Boc]⁺ = 41260 embedded image

C, 92% [MH]⁺ = 46861 embedded image

C, 71% [MH]⁺ = 48262 embedded image

C, 86% [MH]⁺ = 49663 embedded image

C, 75% [MH]⁺ = 48364 embedded image

C, 81% [MH]⁺ = 56665 embedded image

C, 97% [MH]⁺ = 58066 embedded image

C, 87% [MH]⁺ = 54467 embedded image

C, 88% [MH]⁺ = 59868 embedded image

C, 71% [MH]⁺ = 53069 embedded image

E, 23% [MH]⁺ = 51770 embedded image

E, 39% [MH]⁺ = 51771 embedded image

E, 82% [MH]⁺ = 44172 embedded image

E, 59% [MH]⁺ = 55773 embedded image

E, 21% [MH]⁺ = 52374 embedded image

E, 73% [MH]⁺ = 57675 embedded image

E, 73% [MH]⁺ = 57676 embedded image

E, 38% [MH]⁺ = 59677 embedded image

E, 33% [M-H]⁻ = 58878 embedded image

E, 40% [M-H]⁻ = 58879 embedded image

E, 30% [M-H]⁻ = 56880 embedded image

E, 42% [M-H]⁻ = 56881 embedded image

E, 42% [M-H]⁻ = 58882 embedded image

E, 26% [M-H]⁻ = 55483 embedded image

E, 60% (over 2 steps) [M-H]⁻ = 55684 embedded image

E, 11% (over 2 steps) [M-H]⁻ = 55685 embedded image

C, 77% [MH]⁺ = 48386 embedded image

C, 66% [MH]⁺ = 48387 embedded image

C, >99% [MH]⁺ = 61488 embedded image

C, >99% [MH]⁺ = 61289 embedded image

C, 48% [MNa]⁺ = 63490 embedded image

C, 54% [MH]⁺ = 41091 embedded image

F, 87% [MH]⁺ = 39792 embedded image

F, >99% [MH]⁺ = 39993 embedded image

F, 61% [MH]⁺ = 44194 embedded image

F, 67% [MH]⁺ = 40995 embedded image

F, 40% [MH]⁺ = 43796 embedded image

F, 36% [MH]⁺ = 43397 embedded image

F, 54% [MH]⁺ = 46398 embedded image

F, 52% [MH]⁺ = 43799 embedded image

F, 48% [MH]⁺ = 437100 embedded image

F, 51% [MH]⁺ = 420101 embedded image

F, 56% [MH]⁺ = 459102 embedded image

F, 56% [MH]⁺ = 518103 embedded image

F, 23% [MH]⁺ = 504104 embedded image

F, 68% [MH]⁺ = 439105 embedded image

F, 56% [MH]⁺ = 439106 embedded image

F, 95% [MH]⁺ = 465107 embedded image

F, 93% [MH]⁺ = 447108 embedded image

G, 87% [MH]⁺ = 451109 embedded image

G, >99% [MH]⁺ = 462110 embedded image

G, 99% [MH]⁺ = 425111 embedded image

G, 85% [MH]⁺ = 426112 embedded image

F, 64% [MH]⁺ = 439113 embedded image

F, 97% [MH]⁺ = 447114 embedded image

G, 94% [MH]⁺ = 427115 embedded image

G, 26% [MH]⁺ = 491116 embedded image

G, 40% [MH]⁺ = 505117 embedded image

C, 54% [MH]⁺ = 411118 embedded image

C, 86% [MH]⁺ = 437119 embedded image

C, 21% [MH]⁺ = 477120 embedded image

C, 57% [MH]⁺ = 454121 embedded image

C, 31% [MH]⁺ = 544122 embedded image

C, 66% [MH]⁺ = 518123 embedded image

C, 26% [MH]⁺ = 518

Ex. #
acid, amine
product
method, yield

124

embedded image

C, 14% [MH]⁺ = 494

125

embedded image

C, 41% [MH]⁺ = 483

126

embedded image

C, 75% [MH]⁺ = 450

127

embedded image

C, 78% [MH]⁺ = 507

128

embedded image

C, 61% [MH]⁺ = 507

129

embedded image

C, 75% [MH]⁺ = 483

130

embedded image

C, 59% [MH]⁺ = 497

131

embedded image

C, 52% [MH]⁺ = 503

132

embedded image

C, 31% [MH]⁺ = 527

133

embedded image

C, 77% [MH]⁺ = 527

134

embedded image

C, 26% [MH]⁺ = 544

135

embedded image

C, 51% [MH]⁺ = 598

136

embedded image

C, 33% [MH]⁺ = 546

137

embedded image

C, 80% [MH]⁺ = 483

138

embedded image

C, 72% [MH]⁺ = 483

139

embedded image

C, 48% [MH]⁺ = 532

140

embedded image

C, 83% [MH]⁺ = 608

141

embedded image

C, 94% [MH]⁺ = 609

142

embedded image

C, 80% [MH]⁺ = 623

143

embedded image

C, 78% [MH]⁺ = 637

144

embedded image

C, 90% [MH]⁺ = 593

145

embedded image

C, 59% [MH]⁺ = 607

146

embedded image

C, 30% [MH]⁺ = 564

147

embedded image

C, 76% [MH]⁺ = 554

148

embedded image

C, 64% [MH]⁺ = 597

149

embedded image

C, 84% [MH]⁺ = 597

150

embedded image

C, 78% [MH]⁺ = 597

151

embedded image

C, 49% [MH]⁺ = 566

152

embedded image

C, 75% [M-“indene”]⁺ =362

153

embedded image

C, 82% [MH]⁺ = 495

154

embedded image

C, 29% [MH]⁺ = 496

155

embedded image

C, 56% [MH]⁺ = 518

157

embedded image

C, 5% [MH]⁺ = 514

158

embedded image

C, 52% [MH]⁺ = 506

159

embedded image

C, 38% [MH]⁺ = 610

160

embedded image

C, 19% [MH]⁺ = 702

161

embedded image

C, 25% [MH]⁺ = 549/551

162

embedded image

C, 48% [MH]⁺ = 504

163

embedded image

C, 41% [MH]⁺ = 546

164

embedded image

C, 48% [MH]⁺ = 509

165

embedded image

C, 55% [MH]⁺ = 528

166

embedded image

C, 20% [MH]⁺ = 528

167

embedded image

C, 71% [MH]⁺ = 508

168

embedded image

C, 72% [MH]⁺ = 526

169

embedded image

C, 41% [MH]⁺ = 565

170

embedded image

C, 68% [MH]⁺ = 512

171

embedded image

C, 72% [MH]⁺ = 530

172

embedded image

C, 78% [MH]⁺ = 580

173

embedded image

C, 79% [MH]⁺ = 512

174

embedded image

C, 75% [MH]⁺ = 596

175

embedded image

C, 83% [MH]⁺ = 560

176

embedded image

C, 82% [MH]⁺ = 578

177

embedded image

C, 21% [MH]⁺ = 546

178

embedded image

C, 15% [MH]⁺ = 580

179

embedded image

E, 21% [M − H]⁻ = 515

180

embedded image

E, 23% [M − H]⁻ = 529

181

embedded image

E, 24% [M − H]⁻ = 529

182

embedded image

E, 11% [M − H]⁻ = 526

183

embedded image

E, 34% [MH]⁺ = 507

184

embedded image

E, 52% [MH]⁺ = 563

185

embedded image

E, n.d. [MH]⁺ = 644

186

embedded image

E, n.d. [MH]⁺ = 644

187

embedded image

E, 57% [M − H]⁻ = 628

188

embedded image

B, n.d. [MH]⁺ = 627

189

embedded image

B, n.d. [MH]⁺ = 597

190

embedded image

D, 72% [MH]⁺ = 628

191

embedded image

A, 54% [MH]⁺ = 612

192

embedded image

A, 27% [MH]⁺ = 578

193

embedded image

A, 28% [MH]⁺ = 612

194

embedded image

A, 33% ¹H-NMR (CDCl₃) δ = 10.50 (br d, 1H), 9.00 (s, 1H), 8.85 (s, 1H), 8.35 (br t, 1H), 7.95 (d, 1H), 7.40 (d, 1H, 7.25-7.00 (m, 2H), 7.00P-6.90 (m, 1H), 5.80 (m, 1H), 4.65 (br d, 2H), 3.90 (s, 3H), 3.20-2.70 (m, 3H), 2.25 (s, 3H), 2.20-2.00 (m, 1H).

195

embedded image

A, n.d. [MH]⁺ = 594/596

196

embedded image

A, n.d. [MH]⁺ = 528/530

197

embedded image

A, 43% [MH]⁺ = 558

198

embedded image

C, 66% [MH]⁺ = 562

199

embedded image

C, 44% [MH]⁺ = 562

200

embedded image

C, 48% [MH]⁺ = 613

201

embedded image

C, n.d. [MH]⁺ = 550

202

embedded image

C, 65% [MH]⁺ = 523/525

203

embedded image

C, 52% [MH]⁺ = 543/545

204

embedded image

C, 54% ¹H-NMR (CDCL₃) δ = 10.25 (br d, 1H), 8.60 (s, 1H), 8.10 (m, 1H), 8.00 (d, 1H), 7.60 (d, 1H), 7.30 (d, 1H), 7.20-7.10 (m, 2H), 7.10-7.00 (m, 1H), 5.70 (m, 1H), 4.55 (d, 2H), 3.10-2.60 (m, 3H), 2.40 (s, 9H), 2.00-1.90 (m, 1H).

205

embedded image

C, 70% [MH]⁺ = 595

206

embedded image

C, 79% [MH]⁺ = 599

207

embedded image

C, 55% [MH]⁺ = 522

208

embedded image

C, 59% [MH]⁺ = 536

209

embedded image

C, 63% [MH]⁺ = 598

210

embedded image

C, 32% [M-“indene”]⁺ =398

211

embedded image

C, 66% [MH]⁺ = 623

212

embedded image

C, 61% [MH]⁺ = 571

213

embedded image

C, 86% [MH]⁺ = 585

214

embedded image

E, 60% [M − H]⁻ = 520

215

embedded image

E, 65% [M − H]⁻ = 520

216

embedded image

E, 49% [MH]⁺ = 539/541

217

embedded image

E, 90% [MH]⁺ = 533

218

embedded image

E, 80% [MH]⁺ = 550

219

embedded image

C, 45% [MH]⁺ = 452

220

embedded image

C, 43% [MH]⁺ = 461

221

embedded image

C, 46% [MH]⁺ = 572

222

embedded image

C, 47% [MH]⁺ = 586

223

embedded image

C, n.d. [MH]⁺ = 569

224

embedded image

C, n.d. [MH]⁺ = 517

225

embedded image

C, n.d. [MH]⁺ = 459

226

embedded image

C, n.d. [MH]⁺ = 546

227

embedded image

C, n.d. [MNa]⁺ = 584

228

embedded image

C, n.d. [MNa]⁺ = 669

229

embedded image

C, n.d. [MNa]⁺ = 696

230

embedded image

C, n.d. [MNa]⁺ = 624

231

embedded image

C, 60% (over 2 steps), [MH]⁺ = 517

232

embedded image

A, 51% [MH]⁺ = 530

233

embedded image

A, 7% (over 2 steps), [MH]⁺ = 451

234

embedded image

A, 20% (over 2 steps), [MH]⁺ = 451

235

embedded image

E, 35% [M − H]⁻ = 502

236

embedded image

E, 29% [M − H]⁻ = 488

237

embedded image

A, 98% [MH]⁺ = 471

238

embedded image

A, 16% [MH]⁺ = 517

239

embedded image

E, 52% [MNa]⁺ = 566

240

embedded image

E, 31% [M − H]⁻ = 576

241

embedded image

A, n.d. [MH]⁺ = 599

242

embedded image

E, 51% [MH]⁺ = 533

243

embedded image

E, 50% [MH]⁺ = 462

244

embedded image

E, 40% [MH]⁺ = 428

245

embedded image

E, 30% [MH]⁺ = 469

246

embedded image

E, 10% [MH]⁺ = 426

247

embedded image

E, 34% [MH]⁺ = 442

248

embedded image

E, 20% [MH]⁺ = 468

249

embedded image

E, 30% [MH]PHU + = 456

250

embedded image

E, 25% [MH]⁺ = 424

251

embedded image

E, 30% [MH]⁺ = 468

252

embedded image

E, 34% [MH]⁺ = 525

253

embedded image

E, 18% [MH]⁺ = 516

254

embedded image

E, n.d. [MH]⁺ = 579

255

embedded image

E, 42% [MH]⁺ = 444

256

embedded image

E, 70% [MH]⁺ = 630

257

embedded image

C, 10% [MH]⁺ = 518

258

embedded image

C, 29% [MH]⁺ = 518

259

embedded image

C, 96% [MH]⁺ = 564

260

embedded image

C, 91% [MH]⁺ = 547

261

embedded image

C, n.d. [MH]⁺ = 597

262

embedded image

C, 93% [MH]⁺ = 547

263

embedded image

C, 81% [MH]⁺ = 529

264

embedded image

C, 86% [MH]⁺ = 529

265

embedded image

C, 76% [MH]⁺ = 545

266

embedded image

C, n.d. [MH]⁺ = 543

267

embedded image

C, n.d. [MH]⁺ = 543

268

embedded image

C, n.d. [MH]⁺ = 537

269

embedded image

C, n.d. [MH]⁺ = 537

270

embedded image

C, n.d. [MH]⁺ = 557

271

embedded image

C, n.d. [MH]⁺ = 595

272

embedded image

C, 38% [MH]⁺ = 540

273

embedded image

C, n.d. [MH]⁺ = 537

274

embedded image

C, n.d. [MNa]⁺ = 584

275

embedded image

C, n.d. [MNa]⁺ = 602

276

embedded image

C, n.d. [MH]⁺ = 594

277

embedded image

C, n.d. [MH]⁺ = 614

Example 278

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Step A

To a solution of the title compound from the Preparative Example 315 (67 mg) in anhydrous DMF (500 μL) was added a solution of the title compound from the Preparative Example 229, Step D (75 mg). The resulting mixture was heated at 60° C. for 15 h, concentrated and purified by preparative thin layer chromatography (silica, CH₂Cl₂/MeOH) to give the desired title compound (39 mg, 41%). [MH]⁺=491.

Examples 279-284

Following a similar procedure as described in the Example 278, except using the esters and amines indicated in Table II-2 below, the following compounds were prepared.

TABLE II-2Ex.ester,#amineproductyield279 embedded image

47% [MH]⁺ = 477280 embedded image

48% [MH]⁺ = 462281 embedded image

43% [MH]⁺ = 439282 embedded image

60% [MH]⁺ = 552283 embedded image

50% [MH]⁺ = 458284 embedded image

53% [MH]⁺ = 442

Example 285

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Step A

To a solution of the title compound from the Preparative Example 244, Step A (200 mg) in anhydrous DMF (2 mL) was added commercially available 4-fluoro-3-methyl-benzylamine (120 mg). The resulting mixture was heated at 60° C. for 24 h, concentrated and purified by preparative thin layer chromatography (silica, CH₂Cl₂/MeOH) to give the title compound (30 mg, 8%). [MH]⁺=452.

Example 286

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Step A

A mixture of the title compound Preparative Example 330, Step A (203 mg) and commercially available 3-chloro 4-fluorobenzylamine (160 mg) in dry DMF (3 mL) was heated to 70° C. overnight and concentrated. The remaining residue was dissolved in CHCl₃, washed with 10% aqueous citric acid and saturated aqueous NaCl, dried (MgSO₄), filtered, concentrated and purified by preparative thin layer chromatography (silica, CH₂Cl₂/MeOH) to afford the title compound as a colorless solid (111 mg, 29%). [MH]⁺=492.

Example 287

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Step A

A solution of the title compound from the Preparative Example 331, Step A (26 mg) in a 7M solution of NH₃in MeOH (1 mL) was heated at 90° C. for 2 h. The formed precipitate was isolated by filtration to afford the title compound as a colorless solid (8.6 mg, 34%). [MH]⁺=329.

Example 288

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Step A

The title compound from the Preparative Example 294 (9.7 mg) and commercially available 4-aminomethyl-phenylamine (10 mg) were dissolved in N-methylpyrrolidin-2-one (0.5 mL). The mixture was heated in a sealed tube at 160° C. (microwave) for 15 min, diluted with EtOAc, washed with aqueous LiCl, concentrated and purified by chromatography (silica, CH₂Cl₂/MeOH) to afford the title compound (9.6 mg, 84%). [M−H]⁻=540.

Example 289

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Step A

The title compound from the Preparative Example 294 (154 mg) and commercially available 3-aminomethyl-phenylamine (57 mg) were dissolved in N-methylpyrrolidin-2-one (3 mL). The mixture was heated in a sealed tube at 160° C. (microwave) for 55 min, diluted with EtOAc, washed with aqueous LiCl, concentrated and purified by chromatography (silica, CH₂Cl₂/MeOH) to afford the title compound (110 mg, 84%). [M−H]⁻=540.

Example 290

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Step A

To a solution of the title compound from the Example 289, Step A (19.1 mg) in CH₂Cl₂(1 mL) were successively added pyridine (0.1 mL) and methanesulfonyl chloride (8.1 mg). The mixture was stirred for 1 d, concentrated and purified by chromatography (silica, CH₂Cl₂/MeOH) to afford the title compound (13.1 mg, 60%). [M−H]⁻=618.

Example 291

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Step A

To a solution of the title compound from the Preparative Example 342 (51 mg) in THF (5 mL) were added the title compound from the Preparative Example 149, EDCI (53 mg), HOBt (38 mg) and K₂CO₃(44 mg). The mixture was stirred for 16 h, absorbed on silica (500 mg) and purified by chromatography (silica, hexanes/EtOAc) to afford the title compound as a solid (79.3 mg, 92%). [M−]⁻=616.

Example 292

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Step A

To a solution of the title compound from the Example 291, Step A (50 mg) in MeOH/CH₂Cl₂(1:1, 2 mL) was added hydrazine (26 mg). The resulting mixture was stirred for 1 d, concentrated and and purified by chromatography (silica, CH₂Cl₂/MeOH) to afford the title compound as a yellow solid. (37.1 mg, 74%). [M−]⁻=615.

Example 293

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Step A

To a solution of the title compound from the Example 179 (2.5 mg) in toluene/MeOH (3:1, 2 mL) was added a 2M solution of (trimethylsilyl)diazomethane in Et₂O (portions à 10 μL) until complete consumption of the starting material. The mixture was concentrated and then triturated with Et₂O (4×) to give the title compound as a yellow solid (1.0 mg, 40%). [M−]⁻=529.

Example 294

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Step A

A mixture of the title compound from the Example 196 (52 mg) and Pd/C (10 wt %, 20 mg) in MeOH/EtOAc (1:1, 4 mL) was hydrogenated at atmospheric pressure for 18 h, filtered, concentrated and purified by chromatography (silica, CH₂Cl₂/acetone) to afford the title compound (19 mg, 43%). [MH]⁺=450.

Example 295

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Step A

Under an argon atmosphere a mixture of commercially available 2-chloro-6methyl-pyrimidine-4-carboxylic acid methyl ester (9.38 g) and selenium dioxide (8.93 g) in 1,4-dioxane (50 mL) was stirred at 105° C. for 12 h. The mixture was filtered twice through celite®, the filter cake was rinsed with 1,4-dioxane (2×100 mL) and the combined filtrates were concentrated to afford the title compound as viscous orange oil (8.0 g, 74%). [MH]⁺=217.

Step B

To an ice cooled solution of the title compound from Step A above (900 mg) in anhydrous CH₂Cl₂(20 mL) were subsequently and slowly added oxalyl chloride (870 μL) and DMF (3 drops). The cooling bath was removed and the mixture was stirred at room temperature until gas evolution ceased. The mixture was then concentrated and diluted with CH₂Cl₂. Pyridine (340 μL) and commercially available 4-fluoro-3-methylbenzylamine (530 μL) were added subsequently and the mixture was stirred at room temperature for 30 min. Filtration, absorption onto silica and purification by chromatography (silica, hexane/EtOAc) afforded the title compound as a yellow solid (670 mg, 48%). [MH]⁺=338.

Step C

To an ice cooled solution of the title compound from Step B above (670 mg) in ThF (20 mL) was slowly added 1M aqueous LiOH (3.98 mL). The mixture was stirred at 0° C. for 2 h, quenched with 1M aqueous HCl (4.0 mL), warmed to room temperature and concentrated. The remaining residue was triturated with THF, filtered and concentrated to afford the title compound as an orange solid. [MH]⁺=324.

Step D

The title compound from Step C above (256 mg), commercially available 4-aminomethyl-benzoic acid methyl ester hydrochloride (160 mg), PyBOP (800 mg) and NEt₃(202 μL) were dissolved in THF/DMF (2:1, 15 mL). The mixture was stirred at room temperature for 2 h, concentrated, diluted with EtOAc, washed with saturated aqueous NaHCO₃and saturated aqueous NaCl, dried (MgSO₄), filtered, concentrated and purified by chromatography (silica, CH₂Cl₂/acetone) to afford the title compound (196 mg, 44%). [MH]⁺=570.

Step E

To a stirred solution of the title compound from Step D above (50 mg) in anhydrous THF (5 mL) was added hydrazine hydrate (40 μL). The mixture was stirred at room temperature for 2 h and then concentrated. The residue was dissolved in anhydrous 1,2-dichloroethane (2 mL) and cooled to 0° C. A 20% solution of phosgene in toluene (500 μL) was added, the cooling bath was removed and the mixture was stirred at room temperature for 2 h. Concentration afforded the crude title compound as a mixture of two isomers, which was used without further purification. [MH]⁺=493.

Step F

To a solution of the title compound from StepE above (30 mg) in THF/MeOH (2:1, 1.5 mL) was added 1N aqueous LiOH (0.2 mL). The mixture was stirred at room temperature overnight, adjusted to pH 4.5 with 2N aqueous HCl and extracted with EtOAc. The organic phase was washed with saturated aqueous NaCl, dried (MgSO₄), filtered, concentrated and purified by preparative thin layer chromatography (silica, CH₂Cl₂/MeOH) to afford the title compound as a mixture of two isomers (3 mg, 8% over 2 steps). [MH]⁺=479.

Example 296

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Step A

To a solution of the title compound from the Preparative Example 331, Step A (329 mg) in DMF (10 mL) were successively added HATU (427 mg), HOAt (153 mg), commercially available trans-(4-aminomethyl-cyclohexyl)-carbamic acid tert-butyl ester (291 mg) and ⁱPr₂NEt (191 μL) and the mixture was stirred at room temperature for 5 h. Additional HATU (427 mg), trans-(4-aminomethyl-cyclohexyl)-carbamic acid tert-butyl ester (291 mg) and ⁱPr2NEt (191 μL) were successively added and stirring at room temperature was continued for 2 h. The mixture was diluted with EtOAc (100 mL), washed with 0.01N aqueous HCl (3×100 mL) and saturated aqueous NaCl (100 mL), dried (MgSO₄) and filtered. The filter cake was rinsed with CH₂Cl₂/MeOH (95:5, 500 mL) and the combined filtrates were concentrated and purified by chromatography (silica, CH₂Cl₂/MeOH) to afford the title compound as a colorless solid (493 mg, 91%). [MNa]⁺=562.

Step B

To a suspension of the title compound from Step A above (436 mg) in EtOAc (3.22 mL) was added a 4M solution of HCl in 1,4-dioxane (3.22 mL). The reaction mixture was stirred at room temperature for 2½ h, diluted with MeOH (10 mL), concentrated, suspended in CH₃CN/MeOH (4:1, 20 mL) and concentrated again to afford the title compound (384 mg, 99%). [M−Cl]⁺=440.

Examples 297-299

Following a similar procedure as described in the Example 296, Step B, except using the protected amines indicated in Table II-3 below, the following compounds were prepared.

TABLE II-3Ex.protected#amineproductyield297 embedded image

>99% [M-Cl]⁺ = 426298 embedded image

98% [M-Cl]⁺ = 412298 embedded image

98% [M-Cl]⁺ = 412

Example 299

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Step A

To a suspension of the title compound from the Example 296, Step B (23.8 mg) in dry CH₂Cl₂(1 mL) were added a iM solution of acetyl chloride in dry CH₂Cl₂(50 μL) and ⁱPr₂NEt (26.1 μL). The reaction mixture was stirred at room temperature for 1 h, concentrated and purified by flash chromatography (silica, CH₂Cl₂/MeOH) to afford the title compound as a beige/white solid (24.1 mg, >99%). [MH]⁺=482.

Examples 300-309

Following a similar procedure as described in the Example 299, except using the amines and the acid chlorides indicated in Table II-4 below, the following compounds were prepared.

TABLE II-4Ex.amine,#acid chlorideproductyield300 embedded image

92% [MH]⁺ = 524301 embedded image

99% [MH]⁺ = 518302 embedded image

73% [MH]⁺ = 468303 embedded image

75% [MH]⁺ = 504304 embedded image

97% [MH]⁺ = 454305 embedded image

94% [MH]⁺ = 490306 embedded image

89% [MH]⁺ = 454307 embedded image

95% [MH]⁺ = 490308 embedded image

71% [MH]⁺ = 544309 embedded image

83% [MH]⁺ = 519

Example 310

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Step A

To a solution of the title compound from the Example 298 (22.4 mg) in dry CH₂Cl₂(500 μL) were added ⁱPr2NEt (17.4 μL) and sulfamide (10.8 mg). The resulting reaction mixture was heated in a sealed tube to 140° C. (microwave) for 2 h, concentrated and purified by flash chromatography (silica, CH₂Cl₂/MeOH) to afford the title compound (11.7 mg, 48%). [MH]⁺=491.

Example 311

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Step A

To a suspension of the title compound from the Example 296, Step B (23.8 mg) in dry CH₂Cl₂(500 μL) was added KO^tBu (6.4 mg). The resulting reaction mixture was stirred at room temperature for 5 min, then ⁱPrOH (50 μL) and trimethylsilyl isocyanate (13.9 μL) were added and stirring at room temperature was continued for 19 h. The mixture was diluted with MeOH (5 mL), concentrated and purified by flash chromatography (silica, CH₂Cl₂/MeOH) to afford the title compound (15 mg, 62%). [MH]⁺=483.

Example 312

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Step A

To a solution of the title compound from the Example 296, Step B (20 mg) in DMF (2.5 mL) were successively added ⁱPr₂NEt (15 μL) and 2-iodoethanol (3.5 μL). Using a microwave, the mixture was heated in a sealed vial at 100° C. for 10 min. The mixture was concentrated and dissolved in dry THF (1 mL). Methyl N-(triethylammoniosulfonyl) carbamate [“Burgess reagent”] (27 mg) was added and using a microwave, the mixture was heated in a sealed vial at 130° C. for 7 min. Concentration and purification by chromatography (silica, CH₂Cl₂/MeOH) afforded the title compound as a colorless solid (1.7 mg, 6%). [MH]⁺=603.

Example 313

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Step A

To a suspension of the title compound from the Example 297 (23.1 mg) in dry CH₂Cl₂(500 μL) was added KO^tBu (6.4 mg). The resulting reaction mixture was stirred at room temperature for 5 min, then ⁱPrOH (50 μL) and trimethylsilyl isocyanate (13.9 μL) were added and stirring at room temperature was continued for 16 h. The mixture was diluted with MeOH (5 mL), concentrated and purified by flash chromatography (silica, CH₂Cl₂/MeOH) to afford the title compound (10 mg, 43%). [MH]⁺=469.

Example 314

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Step A

To a solution of the title compound from the Example 25 (43.9 mg) in THF (10 mL) was added a solution of LiOH (18 mg) in H₂O (10 mL). The solution was stirred for 5 h, acidified, concentrated and purified by preparative thin layer chromatography (silica, CH₂Cl₂/MeOH) to afford the title compound as a bright yellow solid (16.4 mg, 38%). [MH]⁺=488.

Example 315

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Step A

Using a microwave, a mixture of the title compound from the Example 5 (51 mg) and trimethyltin hydroxide (236 mg) in 1,2-dichloroethane (2 mL) in a sealed vial was stirred at 160° C. for 1 h. The contents were loaded onto a silica and purified by chromatography (silica, CH₂Cl₂/MeOH) to give a yellow solid (18 mg, 35%). [M−]⁻=574.

Examples 316-361

Following similar procedures as described in the Examples 314 (method A) or 315 (method B), except using the esters indicated in Table II-5 below, the following compounds were prepared.

TABLE II-5Ex.method,#esterproductyield316 embedded image

A, 60% [MH]⁺ = 576317 embedded image

A, 8% [MH]⁺ = 525318 embedded image

B, 40% [MH]⁺ = 533319 embedded image

B, 54% [MH]⁺ = 564320 embedded image

B, 40% [MH]⁺ = 546321 embedded image

A, 40% ¹H-NMR (CDCl₃) δ = 10.50(br d, 1H), 9.00 (s, 1H), 8.90 (s, 1H), 8.25 (d, 1H), 7.95 (s, 1H), 7.90 (d, 1H), 7.35 (d, 1H), 7.25-7.10 (m, 2H), 7.00(m, 1H), 5.75 (m, 1H), 4.70 (d, 2H), 3.20-2.80 (m, 3H), 2.26(s, 3H), 2.25-2.00 (m, 1H).322 embedded image

A, 31% [MH]⁺ = 488323 embedded image

A, 37% [MH]⁺ = 533324 embedded image

B, 66% [M-H]⁻ = 506325 embedded image

B, 71% [M-H]⁻ = 506326 embedded image

B, 70% [M-H]⁻ = 531327 embedded image

B, 82% [M-H]⁻ = 522328 embedded image

B, 45% [MH]⁺ = 503329 embedded image

B, 18% [MH]⁺ = 622330 embedded image

B, 15% [MH]⁺ = 543331 embedded image

B, 14% [M-H]⁻ = 501332 embedded image

B, 50% [MH]⁺ = 477333 embedded image

B, 32% [MH]⁺ = 463334 embedded image

A, 86% [MH]⁺ = 504335 embedded image

A, 51% [MH]⁺ = 504336 embedded image

B, 34% [M-H]⁻ = 574337 embedded image

B, 46% [M-H]⁻ = 554338 embedded image

B, 29% [M-H]⁻ = 554339 embedded image

B, 45% [M-H]⁻ = 540340 embedded image

B, 44% [M-H]⁻ = 540341 embedded image

B, 52% [MH]⁺ = 532342 embedded image

B, 42% [MH]⁺ = 495343 embedded image

B, 40% [MH]⁺ = 514344 embedded image

B, 35% [MH]⁺ = 494345 embedded image

B, 43% [MH]⁺ = 512346 embedded image

B, 39% [MH]⁺ = 551347 embedded image

B, 21% [MH]⁺ = 481348 embedded image

B, 41% [MH]⁺ = 498349 embedded image

B, 39% [MH]⁺ = 516350 embedded image

B, 32% [MH]⁺ = 566351 embedded image

B, 37% [MH]⁺ = 498352 embedded image

B, 44% [MH]⁺ = 582353 embedded image

B, 42% [MH]⁺ = 546354 embedded image

B, 46% [MH]⁺ = 564355 embedded image

B, 15% [MH]⁺ = 532356 embedded image

A, 11% [MH]⁺ = 504357 embedded image

B, 10% [MH]⁺ = 504358 embedded image

B, 68% [MH]⁺ = 489359 embedded image

B, 66% [MH]⁺ = 469360 embedded image

B, 94% [MH]⁺ = 469361 embedded image

B, 95% [MH]⁺ = 469

Example 362

embedded image

Step A

To a solution of the title compound from the Example 184 (109 mg) in THF (4 mL) were added morpholine (0.17 mL) and Pd(PPh₃)₄(23.8 mg). The mixture was stirred at room temperature for 3½ h, diluted with a 4M solution of HCl in 1,4-dioxane (490 μL) and concentrated. The remaining residue was purified by chromatography (silica, CH₂Cl₂/MeOH) and preparative thin layer chromatography (silica, CH₂Cl₂/MeOH) to give the title compound as a yellow solid (39.4 mg, 39%). [M−]⁻=521.

Examples 363-435

Following a similar procedure as described in the Example 362, except using the esters indicated in Table II-6 below, the following compounds were prepared.

TABLE II-6Ex.#esterproductyield363 embedded image

53% [M-H]⁻ = 588364 embedded image

n.d. [MH]⁺ = 609365 embedded image

n.d. [MH]⁺ = 557366 embedded image

42% [MH]⁺ = 573367 embedded image

42% (over 2 steps) [MH]⁺ = 550368 embedded image

37% [MH]⁺ = 555369 embedded image

48% [MH]⁺ = 558370 embedded image

90% [MH]⁺ = 572371 embedded image

49% [MH]⁺ = 583372 embedded image

49% [MNa]⁺ = 553373 embedded image

49% [MNa]⁺ = 567374 embedded image

37% (over 2 steps) [MH]⁺ = 529375 embedded image

20% (over 2 steps) [MH]⁺ = 477376 embedded image

34% (over 2 steps) [MH]⁺ = 419377 embedded image

29% (over 2 steps) [MH]⁺ = 506378 embedded image

90% [MH]⁺ = 579379 embedded image

90% [MH]⁺ = 579380 embedded image

41% [MH]⁺ = 604381 embedded image

77% [MH]⁺ = 658382 embedded image

71% [MH]⁺ = 605383 embedded image

67% [MH]⁺ = 502384 embedded image

75% [MH]⁺ = 554385 embedded image

18% [MH]⁺ = 542386 embedded image

62% [MH]⁺ = 556387 embedded image

33% [MH]⁺ = 537388 embedded image

69% [MH]⁺ = 520389 embedded image

22% [MH]⁺ = 526390 embedded image

8% [MH]⁺ =496391 embedded image

77% [MH]⁺ = 496392 embedded image

71% [MH]⁺ = 551393 embedded image

65% [MH]⁺ = 516394 embedded image

46% [MH]⁺ = 556395 embedded image

98% [MH]⁺ = 559396 embedded image

80% [MH]⁺ = 554397 embedded image

58% [MH]⁺ = 541398 embedded image

90% [MH]⁺ = 572399 embedded image

95% [MH]⁺ = 554400 embedded image

77% [MH]⁺ = 621401 embedded image

68% [MH]⁺ = 542402 embedded image

86% [MH]⁺ = 536403 embedded image

87% [MH]⁺ = 556404 embedded image

50% [MH]⁺ = 524405 embedded image

45% [MH]⁺ = 507406 embedded image

30% (over 2 steps) [MH]⁺ = 557407 embedded image

n.d. [MH]⁺ = 507408 embedded image

90% [MH]⁺ = 489409 embedded image

78% [MH]⁺ = 489410 embedded image

86% [MH]⁺ = 505411 embedded image

57% (over 2 steps) [MH]⁺ = 503412 embedded image

57% (over 2 steps) [MH]⁺ = 503413 embedded image

20% (over 2 steps) [MH]⁺ = 497414 embedded image

29% (over 2 steps) [MH]⁺ = 497415 embedded image

36% (over 2 steps) [MH]⁺ = 517416 embedded image

19% (over 2 steps) [MH]⁺ = 555417 embedded image

7% (over 2 steps) [MH]⁺ =497418 embedded image

82% (over 2 steps) [MH]⁺ = 554419 embedded image

82% (over 2 steps) [MH]⁺ = 614420 embedded image

40% [M-H]⁻ = 588421 embedded image

60% [MH]⁺ = 540422 embedded image

94% [MH]⁺ = 574423 embedded image

98% [MH]⁺ = 572424 embedded image

45% [MH]⁺ = 568425 embedded image

20% [MH]⁺ = 569426 embedded image

51% [MH]⁺ = 583427 embedded image

15% [MH]⁺ = 597428 embedded image

24% [MH]⁺ = 553429 embedded image

31% [MH]⁺ = 567430 embedded image

>99% [MH]⁺= 524431 embedded image

46% [MH]⁺ = 514432 embedded image

64% [MH]⁺ = 557433 embedded image

78% [MH]⁺ = 557434 embedded image

65% [MH]⁺ = 557435 embedded image

71% [MH]⁺ = 526

Example 436

embedded image

Step A

A solution of the title compound from the Example 83 (20 mg) in a mixture of trifluoroacetic acid (100 μL) and CH₂Cl₂(100 μL) was stirred for 30 min and then concentrated. The remaining residue was washed with Et₂O (200 μL) to give a yellow solid (17 mg, 92%). [MH]⁺=502.

Examples 437-464

Following a similar procedure as described in the Example 436, except using the esters as indicated in Table II-7 below, the following compounds were prepared.

TABLE II-7Ex. #ester437 embedded image

438

439

440

441

442

443

444

445

446

447

448

449

450

451

452

453

454

455

456

457

458

459

460

461

462

463

464

Ex. #productyield437 embedded image

n.d. [M − H]⁻ = 586438 embedded image

n.d. [M − H]⁻ = 586439 embedded image

95% [MH]⁺ = 572440 embedded image

89% [MH]⁺ = 522441 embedded image

98% [MH]⁺ = 556442 embedded image

35% [MH]⁺ = 506443 embedded image

98% [MH]⁺ = 506444 embedded image

96% [MH]⁺ = 540445 embedded image

74% [MH]⁺ = 502446 embedded image

96% [MH]⁺ = 486447 embedded image

79% [M − H]⁻ = 562448 embedded image

56% (over 2 steps) [MH]⁺ = 506449 embedded image

63% (over 2 steps) [MH]⁺ = 590450 embedded image

32% (over 2 steps) [MH]⁺ = 618451 embedded image

10% (over 2 steps) [MH]⁺ = 546452 embedded image

90% [MH]⁺ = 550453 embedded image

90% [MH]⁺ = 536454 embedded image

73% [M − H]⁻ = 488455 embedded image

53% [M − H]⁻ = 501456 embedded image

36% [MH]⁺ = 477457 embedded image

50% [MH]⁺ = 523458 embedded image

50% [MH]⁺ = 496459 embedded image

67% (over 2 steps) [MH]⁺ = 506460 embedded image

65% (over 2 steps) [MH]⁺ = 524461 embedded image

56% [MH]⁺ = 502462 embedded image

83% [M − H]⁻ = 520463 embedded image

>99% [MH]⁺ = 556464 embedded image

>99% [M − “indene”]⁺ = 362

Example 465

embedded image

Step A

To a solution of the title compound from the Example 360 (50 mg) in THF (1.5 mL) was added N,N′-carbonyldiimidazole (26 mg). The mixture was stirred at room temperature for 2 h, then a 0.5M solution of NH₃in 1,4-dioxane (5 mL) was added and stirring at room temperature was continued for 2 h. Concentration and purification by chromatography (silica, CH₂Cl₂/MeOH) afforded the title compound as a colorless solid (29 mg, 60%). [MH]⁺=468.

Example 466

embedded image

Step A

The title compound from the Example 361 (45 mg) was treated similarly as described in the Example 465, Step A to afford the title compound (21 mg, 48%). [MH]⁺=468.

Example 467

embedded image

Step A

A mixture of the title compound from the Example 321 (10 mg) and Pd/C (10 wt %, 5 mg) in EtOH was hydrogenated at atmospheric pressure for 5 h, filtered, concentrated and purified by preparative thin layer chromatography (silica, CHCl₃/MeOH) to afford the title compound (1 mg, 10%). [MH]⁺=503.

Example 468

embedded image

Step A

To a solution of the title compound from the Example 381 (26 mg) in DMF (3 mL) was added morpholine (80 μL), EDCI (10 mg) and HOAt (5 mg). The mixture was stirred overnight and then concentrated. The remaining residue was dissolved in EtOAc, washed with saturated aqueous NaHCO₃, 1N aqueous HCl and saturated aqueous NaCl, dried (MgSO₄), filtered, concentrated and purified by chromatography (silica, CH₂Cl₂/MeOH) to afford the title compound as a colorless solid (9.9 mg, 34%). [MH]⁺=727.

Example 469

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Step A

In a sealed vial was a mixture of the title compound from the Example 3, Step A (54 mg), dibutyltin oxide (15 mg) and azidotrimethylsilane (400 μL) in toluene (10 mL) under an argon atmosphere heated at 110° C. for 18 h. The reaction mixture was then diluted with MeOH, concentrated and purified by chromatography (silica, CH₂Cl₂/MeOH) to give the title compound as an off-white solid (8.6 mg, 15%). [MH]⁺=563.

Examples 470-477

Following a similar procedure as described in the Example 469, except using the nitrites indicated in Table II-8 below, the following compounds were prepared.

TABLE II-8Ex. #nitrile470 embedded image

471

472

473

474

475

476

477

Ex. #productyield470 embedded image

74% [MH]⁺ = 526471 embedded image

34% [MH]⁺ = 600472 embedded image

38% [MH]⁺ = 564473 embedded image

40% [MH]⁺ = 550474 embedded image

55% [MH]⁺ = 514475 embedded image

27% [MH]⁺ = 487476 embedded image

46% [MH]⁺ = 485477 embedded image

53% [MH]⁺ = 583

Example 478

embedded image

Step A

To a solution of the title compound from the Example 477 (80 mg) in DMF (3 mL) were added iodomethane (9 μL) and K₂CO₃(19 mg) and the mixture was stirred at room temperature overnight. Additional iodomethane (8 μL) was added and stirring at room temperature was continued for 2 h. The mixture was concentrated and purified by preparative thin layer chromatography (silica, EtOAc) to afford the major isomer (30 mg, 37%) and the minor isomer (15 mg, 18%) of the title compound. [MH]⁺=597.

Example 479

embedded image

Step A

To a stirring solution of the title compound from the Preparative Example 377, Step E (9 mg) in MeOH (3 mL) were added AcOH (a few drops), a 1M solution of commercially available 4-fluorobenzaldehyde in MeOH (30 μL) and NaBH(OAc)₃(5 mg). The mixture was stirred at room temperature overnight, concentrated, diluted with EtOAc, washed with saturated aqueous NaHCO₃and saturated aqueous NaCl, dried (MgSO₄), filtered, concentrated and purified by preparative thin layer chromatography (silica, cyclohexane/EtOAc) to afford the title compound as an off-white solid (5 mg, 42%). [MH]⁺=429.

Example 480-482

Following similar procedures as described in the Example 479, except using the aldehydes indicated in Table II-9 below, the following compounds were prepared.

TABLE II-9Ex. #aldehydeproductyield480 embedded image

>99% [MH]⁺ = 455481 embedded image

63% [MH]⁺ = 455482 embedded image

n.d. [MH]⁺ = 417

Example 483

embedded image

Step A

To a solution of the title compound from the Preparative Example 379, Step G (7 mg) in anhydrous pyridine (1 mL) was added Ac₂O (1 mL). The mixture was stirred at room temperature for 5 h, concentrated and slurried in MeOH. The formed precipitate was collected by filtration and dried to afford the title compound as a brown solid (5.1 mg, 64%). [MH]⁺=381.

Example 484

embedded image

Step A

A stirring solution of the title compound from the Preparative Example 377, Step G (9 mg) in MeOH/H₂O/THF (3:2:1, 6 mL) was adjusted to pH 6 with 3M aqueous NaOAc. 4-Formylbenzoic acid (6 mg) was added and the mixture was stirred at room temperature for 30 min. NaBH₃CN (5 mg) was added and stirring at room temperature was continued overnight. The mixture was concentrated and diluted with 0.1N aqueous HCl (5 mL). The formed precipitate was collected by filtration, washed with 0.1N aqueous HCl (8 mL) and dried to afford the title compound as an orange solid (7.8 mg, 61%). [MH]⁺=473.

Example 485

embedded image

Step A

The title compound from the Preparative Example 377, Step G (9 mg) was treated similarly as described in the Preparative Example 484, except using cyclohexanecarbaldehyde (0.04 mL) instead of 4-formylbenzoic acid to afford the title compound as a reddish glass (6.5 mg, 45%). [MH]⁺=531.

Examples 486-504

TABLE II-10Ex. #acid, amine486 embedded image

487

488

489

490

491

492

493

494

495

496

497

498

499

500

501

502

503

504

Ex. #productmethod, yield486 embedded image

B, n.d. [MH]⁺ = 526487 embedded image

B, 34% [MH]⁺ = 739488 embedded image

B, 75% [MH]⁺ = 738489 embedded image

B, n.d. [MH]⁺ = 1015490 embedded image

B, 31% [MH]⁺ = 491491 embedded image

C, 77% [MH]⁺ = 562492 embedded image

C, 69% [MH]⁺ = 494493 embedded image

C, 71% [MH]⁺ = 542494 embedded image

C, 69% [MH]⁺ = 560495 embedded image

C, 54% [MH]⁺ = 545496 embedded image

C, 55% [MH]⁺ = 563497 embedded image

C, 90% [MH]⁺ = 529498 embedded image

C, 90% [MH]⁺ = 495499 embedded image

C, n.d. [MH]⁺ = 522500 embedded image

C, 33% [M − “indene”]⁺ = 408501 embedded image

C, n.d. [MH]⁺ = 571502 embedded image

C, n.d. [MH]⁺ = 612503 embedded image

C, 40% [MNa]⁺ = 618504 embedded image

C, 40% ¹H-NMR (CDCl₃) δ = 10.34(d, 1H), 8.69(s, 1H, 8.08(t, 1H), 8.06(d, 1H), 7.78(d, 1H), 7.47(d, 1H), 7.20-7.24(m, 1H), 6.95-7.02 (m, 2H), 5.93-6.08(m, 2H), 5.72-5.82(m, 1H), 5.37(dd, 1H), 5.25(dd, 1H), 4.78(d, 2H), 4.67(d, 2H), 3.00-3.16(m, 1H), 2.71-2.95 (m, 2H), 2.50(s, 3H), 1.96-2.10 (m, 1H)

Examples 505-513

Following similar procedures as described in the Examples 314 (method A) or 315 (method B), except using the esters indicated in Table II-11 below, the following compounds were prepared.

TABLE II-11Ex. #ester505 embedded image

506

507

508

509

510

511

512

513

Ex. #productmethod, yield505 embedded image

A, 41% [MH]⁺ = 548506 embedded image

A, 49% [MH]⁺ = 480507 embedded image

A, 39% [MH]⁺ = 528508 embedded image

A, 49% [MH]⁺ = 546509 embedded image

A, n.d. [MH]⁺ = 531510 embedded image

A, n.d. [MH]⁺ = 549511 embedded image

B, n.d. [MH]⁺ = 515512 embedded image

B, n.d. [MH]⁺ = 481513 embedded image

A, n.d. [MH]⁺ = 508

Example 514-518

Following a similar procedure as described in the Example 362, except using the esters indicated in Table II-12 below, the following compounds were prepared.

TABLE II-12Ex. #ester514 embedded image

515

516

517

518

Ex. #productyield514 embedded image

n.d. [MH]⁺ = 486515 embedded image

17% [M − “indene”]⁺ = 408516 embedded image

n.d. [MH]⁺ = 549517 embedded image

n.d. [MH]⁺ = 572517 embedded image

>99% [MH]⁺ = 556518 embedded image

69% ¹H-NMR (CDCl₃) δ = 12.20-13.20(br s, 1H), 10.40-10.70(br s, 1H), 10.06(d, 1H), 9.73(t, 1H), 8.68(d, 1H), 8.07(s, 1H), 7.72(d, 1H), 7.49(d, 1H), 7.32(d, 1H), 7.04(s, 1H), 6.93 (d, 1H), 5.61-5.71(m, 1H), 4.52(d, 2H), 2.80-3.11(m, 2H), 2.61-2.72(m, 1H), 2.50(s, 3H), 1.96-2.10(m, 1H)

Example 519

embedded image

Step A

The title compound from the Example 487 (42 mg) was treated similarly as described in the Example 296, Step B to afford the title compound (44 mg, >99%). [M−Cl]⁺=639.

The Example numbers 520 to 1699 and the Table numbers II-13 to II-38 were intentionally excluded.

Example 1700
Assay for Determining MMP-13 Inhibition

The typical assay for MMP-13 activity is carried out in assay buffer comprised of 50 mM Tris, pH 7.5, 150 mM NaCl, 5 mM CaCl₂and 0.05% Brij-35. Different concentrations of tested compounds are prepared in assay buffer in 50 μL aliquots. 10 μL of a 50 nM stock solution of catalytic domain of MMP-13 enzyme (produced by Alantos) is added to the compound solution. The mixture of enzyme and compound in assay buffer is thoroughly mixed and incubated for 10 min at room temperature. Upon the completion of incubation, the assay is started by addition of 40 μL of a 12.5 μM stock solution of MMP-13 fluorescent substrate (Calbiochem, Cat. No. 444235). The time-dependent increase in fluorescence is measured at the 320 nm excitation and 390 nm emission by automatic plate multireader. The IC₅₀values are calculated from the initial reaction rates.

Example 1701
Assay for Determining MMP-3 Inhibition

The typical assay for MMP-3 activity is carried out in assay buffer comprised of 50 mM MES, pH 6.0, 10 mM CaCl₂and 0.05% Brij-35. Different concentrations of tested compounds are prepared in assay buffer in 50 μL aliquots. 10 μL of a 100 nM stock solution of the catalytic domain of MMP-3 enzyme (Biomol, Cat. No. SE-109) is added to the compound solution. The mixture of enzyme and compound in assay buffer is thoroughly mixed and incubated for 10 min at room temperature. Upon the completion of incubation, the assay is started by addition of 40 μL of a 12.5 μM stock solution of NFF-3 fluorescent substrate (Calbiochem, Cat. No. 480455). The time-dependent increase in fluorescence is measured at the 330 nm excitation and 390 nm emission by an automatic plate multireader. The IC₅₀values are calculated from the initial reaction rates.

Example 1702
Assay for Determining MMP-8 Inhibition

The typical assay for MMP-8 activity is carried out in assay buffer comprised of 50 mM Tris, pH 7.5, 150 mM NaCl, 5 mM CaCl₂and 0.05% Brij-35. Different concentrations of tested compounds are prepared in assay buffer in 50 μL aliquots. 10 μL of a 50 nM stock solution of activated MMP-8 enzyme (Calbiochem, Cat. No. 444229) is added to the compound solution. The mixture of enzyme and compound in assay buffer is thoroughly mixed and incubated for 10 min at 37° C. Upon the completion of incubation, the assay is started by addition of 40 μL of a 10 μM stock solution of OmniMMP fluorescent substrate (Biomol, Cat. No. P-126). The time-dependent increase in fluorescence is measured at the 320 nm excitation and 390 nm emission by an automatic plate multireader at 37° C. The IC₅₀values are calculated from the initial reaction rates.

Example 1703
Assay for Determining MMP-12 Inhibition

The typical assay for MMP-12 activity is carried out in assay buffer comprised of 50 mM Tris, pH 7.5, 150 mM NaCl, 5 mM CaCl₂and 0.05% Brij-35. Different concentrations of tested compounds are prepared in assay buffer in 50 μL aliquots. 10 μL of a 50 nM stock solution of the catalytic domain of MMP-12 enzyme (Biomol, Cat. No. SE-138) is added to the compound solution. The mixture of enzyme and compound in assay buffer is thoroughly mixed and incubated for 10 min at room temperature. Upon the completion of incubation, the assay is started by addition of 40 μL of a 12.5 μM stock solution of OmniMMP fluorescent substrate (Biomol, Cat. No. P-126). The time-dependent increase in fluorescence is measured at the 320 nm excitation and 390 nm emission by automatic plate multireader at 37° C. The IC₅₀values are calculated from the initial reaction rates.

Example 1704
Assay for Determiniing Aggrecanase-1 Inhibition

The typical assay for aggrecanase-1 activity is carried out in assay buffer comprised of 50 mM Tris, pH 7.5, 150 mM NaCl, 5 mM CaCl₂and 0.05% Brij-35. Different concentrations of tested compounds are prepared in assay buffer in 50 μL aliquots. 10 μL of a 75 nM stock solution of aggrecanase-1 (Invitek) is added to the compound solution. The mixture of enzyme and compound in assay buffer is thoroughly mixed. The reaction is started by addition of 40 μL of a 250 nM stock solution of aggrecan-IGD substrate (Invitek) and incubation at 37° C. for exact 15 min. The reaction is stopped by addition of EDTA and the samples are analysed by using aggrecanase ELISA (Invitek, InviLISA, Cat. No. 30510111) according to the protocol of the supplier. Shortly: 100 μL of each proteolytic reaction are incubated in a pre-coated micro plate for 90 min at room temperature. After 3 times washing, antibody-peroxidase conjugate is added for 90 min at room temperature. After 5 times washing, the plate is incubated with TMB solution for 3 min at room temperature. The peroxidase reaction is stopped with sulfurous acid and the absorbance is red at 450 nm. The IC₅₀values are calculated from the absorbance signal corresponding to residual aggrecanase activity.

Example 1705
Assay for Determining Inhibition of MMP-3 Mediated Proteoglycan Degradation

The assay for MMP-3 activity is carried out in assay buffer comprised of 50 mM MES, pH 6.0, 10 mM CaCl₂and 0.05% Brij-35. Articular cartilage is isolated fresh from the first phalanges of adult cows and cut into pieces (˜3 mg). Bovine cartilage is incubated with 50 nM human MMP-3 (Chemikon, cat. # 25020461) in presence or absence of inhibitor for 24 h at 37° C. Sulfated glycosaminoglycan (aggrecan) degradation products (sGAG) are detected in supernatant, using a modification of the colorimetric DMMB (1,9-dimethylmethylene blue dye) assay (Billinghurst et al., 2000, Arthritis & Rheumatism, 43 (3), 664). 10 μL of the samples or standard are added to 190 μL of the dye reagent in microtiter plate wells, and the absorbance is measured at 525 nm immediately. All data points are performed in triplicates.

Example 1706
Assay for Determining Inhibition of MMP-3 mediated Pro-Collagenase 3 Activation

The assay for MMP-3 mediated activation of pro-collagenase 3 (pro-MMP-13) is carried out in assay buffer comprised of 50 mM MES, pH 6.0, 10 mM CaCl2 and 0.05% Brij-35 (Nagase; J. Biol. Chem. 1994 Aug. 19;269(33):20952-7).

Different concentrations of tested compounds are prepared in assay buffer in 5 μL aliquots. 10 μL of a 100 nM stock solution of trypsin-activated (Knäuper V., et al., 1996 J. Biol. Chem. 271 1544-1550) human pro-MMP-3 (Chemicon; CC1035) is added to the compound solution. To this mixture, 35 μL of a 286 nM stock solution of pro-collagenase 3 (Invitek; 30100803) is added to the mixture of enzyme and compound. The mixture is thoroughly mixed and incubated for 5 h at 37° C. Upon the completion of incubation, 10 μL of the incubation mixture is added to 50 μL assay buffer comprised of 50 mM Tris, pH 7.5, 150 mM NaCl, 5 mM CaCl₂and 0.05% Brij-35 and the mixture is thoroughly mixed.

The assay to determine the MMP-13 activity is started by addition of 40 μL of a 10 μM stock solution of MMP-13 fluorogenic substrate (Calbiochem, Cat. No. 444235) in assay buffer comprised of 50 mM Tris, pH 7.5, 150 mM NaCl, 5 mM CaCl₂and 0.05% Brij-35 (Knäuper, V., et al., 1996. J. Biol. Chem. 271, 1544-1550). The time-dependent increase in fluorescence is measured at 320 nm excitation and 390 nm emission by an automatic plate multireader at room temperature. The IC₅₀values are calculated from the initial reaction rates.

Example 1707

embedded image

Step A

A mixture of the title compound from the Example 418 (130 mg), NEt₃(71 μL) and diphenylphosphoryl azide (104 μL) in ^tBuOH (4 mL) was heated to 70° C. overnight, concentrated and purified by chromatography (silica, cyuohexane/EtOAc) to afford the title compound (43 mg, 30%). [MH]⁺=645.

Step B

A solution of the title compound from Step A above (43 mg) in a mixture of trifluoroacetic acid (1 mL) and CH₂Cl₂(6 mL) was stirred at room temperature for 2 h, diluted with CH₃CN (3 mL) and then concentrated. The remaining residue was diluted with 0.1M aqueous HCl, concentrated, again diluted with 0.1M aqueous HCl and concentrated to afford the title compound (39 mg, >99%). [M−Cl]⁺=581.

Example 1708

embedded image

Step A

A mixture of the title compound from the Example 418 (40 mg), 2-chloro-N,N-dimethylacetamide (7.9 μL), NaI (11 mg) and NEt₃(10.5 μL) in EtOAc (3 mL) was heated to reflux for 3 h, cooled, filtered, washed with saturated aqueous NaS₂O₃, half saturated aqueous NaHCO₃and saturated aqueous NaCl (200 mL), dried (MgSO₄), filtered, concentrated and purified by preparative thin layer chromatography (silica, CH₂Cl₂/acetone) to afford the title compound (25 mg, 72%). [MH]⁺=659.

Example 1709

embedded image

Step A

The title compound from the Preparative Example 968 (109 mg) was treated similarly as described in the Preparative Example 328, Step A, except using commercially available 3,4-difluorobenzylamine instead of 4-fluorobenzylamine to afford title compound from the Preparative Example 984 (47 mg, 32%, [MH]⁺=429) and the title compound (4.1 mg, 3%). [M−H]⁻=538.

Example 1710

embedded image

Step A

To a solution of the title compound from the Preparative Example 355 (50 mg) in MeOH (5 mL) was added thionyl chloride (150 μL). The resulting mixture was heated to reflux for 2 h and then concentrated. The remaining residue was dissolved in EtOH (10 mL), hydrazine monohydrate (100 μL) was added and the resulting mixture was heated to reflux for 2 h and then cooled to room temperature. The formed precipitate was collected by filtration to afford the title compound (69 mg, >99%). [MH]⁺=400.

Example 1711

embedded image

Step A

To a solution of the title compound from the Example 1710, Step A (35 mg) in CHCl₃(2 mL) was added trifluoroacetic anhydride (1 mL). The resulting mixture was heated to 50° C. for 3 h, concentrated and dried in vacuo to afford the title compound (47 mg, >99%). [MH]⁺=496.

Examples 1712-1829

TABLE II-39Ex. #acid, amine1712 embedded image

1713

1714

1715

1716

1717

1718

1719

1720

1721

1722

1723

1724

1725

1726

1727

1728

1729

1730

1731

1732

1733

1734

1735

1736

1737

1738

1739

1740

1741

1742

1743

1744

1745

1746

1747

1748

1749

1750

1751

1752

1753

1754

1755

1756

1757

1758

1759

1760

1761

1762

1763

1764

1765

1766

1767

1768

1769

1770

1771

1772

1773

1774

1775

1776

1777

1778

1779

1780

1781

1782

1783

1784

1785

1786

1787

1788

1789

1790

1791

1792

1793

1794

1795

1796

1797

1798

1799

1800

1801

1802

1803

1804

1805

1806

1807

1808

1809

1810

1811

1812

1813

1814

1815

1816

1817

1818

1819

1820

1821

1822

1823

1824

1825

1826

1827

1828

1829

Ex. #productmethod, yield1712 embedded image

C, 53% [MH]⁺= 4821713 embedded image

B, 83% [MH]⁺= 6301714 embedded image

E, 29% [MH]⁺= 5061715 embedded image

E, 45% [MH]⁺= 4481716 embedded image

E, 30% [MH]⁺= 4481717 embedded image

E, 35% [MH]⁺= 4481718 embedded image

E, 55% [MH]⁺= 4361719 embedded image

E, 55% [MH]⁺= 4361720 embedded image

E, 40% [MH]⁺= 4621721 embedded image

E, 26% [MH]⁺= 5361722 embedded image

E, 25% [MH]⁺= 4871723 embedded image

E, 55% [MH]⁺= 4461724 embedded image

E, 40% [MH]⁺= 4561725 embedded image

E, n.d. [MH]⁺= 5221726 embedded image

E, 25% [MH]⁺= 5061727 embedded image

C, 76% [MNa]⁺= 6321728 embedded image

C, 76% [MH]⁺= 5841729 embedded image

C, 67% [MH]⁺= 5841730 embedded image

C, 47% [MNa]⁺= 6981731 embedded image

B, 91% [M − tBu]⁺= 5551732 embedded image

C, 48% [MNa]⁺= 5941733 embedded image

C, 90% [MNa]⁺= 6111734 embedded image

C, 77% [MNa]⁺= 6141735 embedded image

C, 53% [MNa]⁺= 6311736 embedded image

C, n.d. [MH]⁺= 5651737 embedded image

C, 20% [MH]⁺= 6151738 embedded image

C, n.d. [MH]⁺= 4671739 embedded image

C, n.d. [MH]⁺= 5181740 embedded image

C, 58% [MH]⁺= 5501741 embedded image

C, 36% [MH]⁺= 5181742 embedded image

C, 19% [MH]⁺= 5641743 embedded image

C, 86% [MH]⁺= 5071744 embedded image

C, 89% [MH]⁺= 4931745 embedded image

C, >99% [MH]⁺= 5251746 embedded image

C, 95% [MH]⁺= 5231747 embedded image

C, 72% [MH]⁺= 5331748 embedded image

C, 26% [MH]⁺= 4231749 embedded image

C, 32% [MH]⁺= 4391750 embedded image

C, 25% [MH]⁺= 4751751 embedded image

C, 51% [MH]⁺= 4931752 embedded image

C, n.d. [MH]⁺= 5471753 embedded image

B, 70% [MH]⁺= 4621754 embedded image

E, n.d. [MH]⁺= 4881755 embedded image

G, 70% [MH]⁺= 5611756 embedded image

G, 83% [MH]⁺= 5741757 embedded image

G, 66% [MH]⁺= 5541758 embedded image

G, 97% [MH]⁺= 5591759 embedded image

G, 79% [MH]⁺= 5161760 embedded image

G, 90% [MNa]⁺= 6191761 embedded image

G, 87% [MNa]⁺= 5961762 embedded image

G, 89% [MH]⁺= 5671763 embedded image

G, n.d. [MNa]⁺= 6141764 embedded image

G, n.d. [MNa]⁺= 6331765 embedded image

B, 91% [MH]⁺= 6371766 embedded image

B, 50% [MH]⁺= 4561767 embedded image

B, >99% [MNa]⁺= 5491768 embedded image

B, 83% [MNa]⁺= 5211769 embedded image

B, 82% [MNa]⁺= 5351770 embedded image

B, 86% [MNa]⁺= 5351771 embedded image

B, 87% [MNa]⁺= 5351772 embedded image

B, 55% [MH]⁺= 4571773 embedded image

B, 87% [MH]⁺= 5681774 embedded image

B, 84% [MH]⁺= 4681775 embedded image

B, 94% [MNa]⁺= 5631776 embedded image

B, 91% [MH]⁺= 4561777 embedded image

B, 98% [M − Boc]⁺= 4711778 embedded image

B, 93% [M − Boc]⁺= 4731779 embedded image

B, 78% [MH]⁺= 5091780 embedded image

B, 77% [MH]⁺= 4821781 embedded image

B, n.d. [MNa]⁺= 6521782 embedded image

B, 82% [MH]⁺= 4851783 embedded image

B, 68% [MH]⁺= 491/4931784 embedded image

B, n.d. [MNa]⁺= 6341785 embedded image

B, n.d. [MNa]⁺= 6361786 embedded image

B, n.d. [MNa]⁺= 6461787 embedded image

B, 88% [MH]⁺= 5241788 embedded image

B, 72% [MH]⁺= 5811789 embedded image

B, n.d. [MH]⁺= 5951790 embedded image

B, 88% [MH]⁺= 3671791 embedded image

E, 23% [MNa]⁺= 6421792 embedded image

C, 59% [MH]⁺= 5331793 embedded image

C, 79% [MH]⁺= 5331794 embedded image

C, 44% [MH]⁺= 5331795 embedded image

C, 59% [MH]⁺= 5471796 embedded image

C, 75% [MH]⁺= 5391797 embedded image

E, 67% [M − H]⁻= 6361798 embedded image

E, 85% [M − H]⁻= 6421799 embedded image

E, 55% [M − H]⁻= 5201800 embedded image

E, 65% [M − H]⁻= 6361801 embedded image

E, 44% [M − H]⁻= 6421802 embedded image

E, 81% [M − H]⁻= 5601803 embedded image

E, 31% [MH]⁺= 4111804 embedded image

E, n.d. [M − H]⁻= 7491805 embedded image

C, 17% [MH]⁺= 4521806 embedded image

C, 7% [(M − ⁱPr₂NEt)H]⁺=4531807 embedded image

F, 74% [MH]⁺= 7611808 embedded image

F, 73% [MH]⁺= 7611809 embedded image

F, 74% [MH]⁺= 7611810 embedded image

F, 58% [MH]⁺= 7611811 embedded image

F, 58% [MH]⁺= 7611812 embedded image

F, 68% [MH]⁺= 7611813 embedded image

C, 43% [MNa]⁺= 6231814 embedded image

C, 50% [MNa]⁺= 6371815 embedded image

C, 99% [MNa]⁺= 6511816 embedded image

C, 85% [MH]⁺= 6651817 embedded image

C, 50% [MNa]⁺= 6411818 embedded image

C, 47% [MNa]⁺= 6771819 embedded image

B, 19% [MH]⁺= 4561820 embedded image

B, 64% [MH]⁺= 5121821 embedded image

B, 74% [MH]⁺= 5241822 embedded image

C, n.d. [MH]⁺= 5291823 embedded image

C, 70% [MH]⁺= 4801824 embedded image

C, >99% [MH]⁺= 5791825 embedded image

C, 63% [MH]⁺= 5931826 embedded image

C, n.d. [MNa]⁺= 6071827 embedded image

C, n.d. [MH]⁺= 5381828 embedded image

C, 42% [MH]⁺= 5381829 embedded image

C, 17% [MH]⁺= 537

Example 1830

embedded image

Step A

To the title compound from the Example 1799 (500 mg) in CHCl₃(10 mL) was added N-iodosuccinimide (259 mg). The resulting mixture was stirred at 70° C. for 1 h, absorbed onto silica and purified by chromatography (silica) to afford the title compound (485 mg, 78%). [M−H]⁻=644.

Example 1831

embedded image

Step A

The title compound from the Example 1802 (309 mg) was treated similarly as described in the Example 1830, Step A to afford the title compound (365 mg, 97%). [M−]⁻=686.

Example 1832

embedded image

Step A

A mixture of the title compound from the Example 1830, Step A (30 mg), Pd(PPh₃)₄(5 mg) and NEt₃(50 μL) in DMSO/MeOH (1:1, 400 μL) was stirred at 80° C. under a carbon monoxide atmosphere at 1 atm for 18 h, diluted with 1N aqueous HCl and extracted with EtOAc (3×). The combined organic phases were washed with 1N aqueous HCl (2×) and saturated aqueous NaCl, dried (MgSO₄), filtered, absorbed onto silica and purified by chromatography (silica) to afford the title compound (27 mg, 99%). [M−H]⁻=576.

Example 1833

embedded image

Step A

The title compound from the Example 1831, Step A (393 mg) was treated similarly as described in the Example 1832, Step A to afford the title compound (195 mg, 55%). [M−]⁻=618.

Example 1834

embedded image

Step A

The title compound from the Example 1831, Step A (188 mg), Pd(OAc)₂(4.6 mg), dppf (32.2 mg) and KOAc (110 mg) were dissolved in dry DMSO (1.5 mL) and stirred at 60° C. under a carbon monoxide atmosphere at 1 atm for 18 h. The mixture was diluted with EtOAc, washed subsequently with 1N aqueous HCl (2×) and saturated aqueous NaCl, dried (MgSO₄), filtered, absorbed onto silica and purified by chromatography (silica) to afford the title compound (150 mg, 85%). [M−]⁻=604.

Example 1835

embedded image

Step A

A mixture of the title compound from the Example 1830, Step A (30 mg), Pd(PPh₃)₄(3 mg) and commercially available trimethyl(phenyl)tin (5 μL) in THF (250 μL) was stirred at 80° C. under an argon atmosphere for 2 d, absorbed onto silica and purified by chromatography (silica) to afford the title compound (9 mg, 66%). [M−]⁻=594.

Example 1836

embedded image

Step A

The title compound from the Example 1830, Step A (15 mg) was treated similarly as described in the Example 1835, Step A, except using commercially available (tributylstannyl)thiophene instead of trimethyl(phenyl)tin to afford the title compound (14 mg, 99%). [M−]⁻=600.

Example 1837

embedded image

Step A

A mixture of the title compound from the Example 1753 (7.8 mg) and Pd/C (10 wt %, 10 mg) in MeOH (5 mL) was hydrogenated at 30 psi for 12 h, filtered through celite® and concentrated to afford the title compound (6.0 mg, 95%). [MH]⁺=356.

Examples 1838-1853

Following a similar procedure as described in the Examples 288, except using the esters and amines indicated in Table II-40 below, the following compounds were prepared.

TABLE II-40Ex. #ester, amine1838 embedded image

1839

1840

1841

1842

1843

1844

1845

1846

1847

1848

1849

1850

1851

1852

1853

Ex. #productyield1838 embedded image

18% [MH]⁺= 5701839 embedded image

65% [M − H]⁻= 7211840 embedded image

>99% [M − H]⁻= 6011841 embedded image

48% [M − H]⁻= 6011842 embedded image

37% [M − H]⁻= 6781843 embedded image

40% [M − H]⁻= 7481844 embedded image

67% [M − H]⁻= 6411845 embedded image

73% [M − H]⁻= 6691846 embedded image

63% [M − H]⁻= 6831847 embedded image

68% [M − H]⁻= 6811848 embedded image

62% [M − H]⁻= 6771849 embedded image

70% [M − H]⁻= 6771850 embedded image

47% [M − H]⁻= 7051851 embedded image

42% [M − H]⁻= 7321852 embedded image

50% [MH]⁺= 3671853 embedded image

n.d. [MNa]⁺= 755

Example 1854

embedded image

Step A

To an ice cooled (0-5° C.) mixture of the title compound from the Example 1834, Step A (150 mg) and DMF (2 μL) in CH₂Cl₂(2.5 mL) was added oxalyl chloride (108 μL). The ice bath was removed and the mixture was stirred for 2 h and then concentrated. The resulting residue was brought up in acetone (1.5 mnL) and cooled to 0-5° C. (ice bath). A solution of NaN₃(100 mg) in H₂O (500 μL) was added and the ice bath was removed. The mixture was stirred at room temperature for 1 h, diluted with H₂O (5 mL) and extracted with toluene (3×5 mL). The combined organic phases were dried (MgSO₄), filtered, concentrated and diluted with toluene/tert.-butanol (1:1, 2 mL). Molecular sieves 4 Å (100 mg) were added and the resulting mixture was heated to 100° C. for 1½ h. Filtration, absorption onto silica and purification by chromatography (silica) to afforded the title compound (88 mg, 52%). [M−H]⁻=675.

Step B

To a solution of the title compound from Step a above (88 mg) in ^tBuOAc (1 mL) was added concentrated H₂SO₄(35 μL). The resulting mixture was stirred at room temperature for 1 h and then diluted with saturated aqueous NaHCO₃(4 mL) and EtOAc (2 mL). The aqueous phase was separated and extracted with EtOAc (2×) and CH₂Cl₂(2×). The combined organic phases were dried (MgSO₄), filtered, absorbed onto silica and purified by chromatography (silica) to afford the title compound (36 mg, 50%). [MH]⁺=577.

Example 1855

embedded image

Step A

To an ice cooled (0-5° C.) solution of commercially available benzenesulfonyl chloride (3.5 μL) in CH₂Cl₂(100 μL) were added NEt₃(6 μL) and a solution of the title compound from the Example 1854, Step B (12 mg) in CH₂Cl₂(100 μL). The ice bath was removed and the mixture was stirred at room temperature for 18 h and then concentrated. The remaining residue was purified by preparative thin layer chromatography (silica) to afford the title compound (3.1 mg, 21%). [M−]⁻=715.

Example 1856

embedded image

Step A

A mixture of the title compound from the Example 1854, Step B (12 mg) and commercially available phenyl isocyanate (3 μL) in CH₂Cl₂(200 μL) was stirred at room temperature for 3 d, concentrated and purified by chromatography (silica) to afford the title compound (11 mg, 76%). [M−H]⁻=694.

Example 1857

embedded image

Step A

To an ice cooled (0-5° C.) solution of commercially available benzoyl chloride (3 μL) in CH₂Cl₂(100 μL) were added NEt₃(6 μL) and a solution of the title compound from the Example 1854, Step B (12 mg) in CH₂Cl₂(100 μL). The ice bath was removed and the mixture was stirred at room temperature for 18 h and then concentrated. The remaining residue was purified by preparative thin layer chromatography (silica) to afford the title compound (11.2 mg, 79%). [M−]⁻=679.

Example 1858

embedded image

Step A

To a solution of the title compound from the Example HK119 (36 mg) in THF/H₂O (3:1, 2.4 mL) was added a 1M aqueous KOH (210 μL). The mixture was stirred at room temperature for 3 h, concentrated and diluted with EtOAc (150 mL) and 10% aqueous citric acid (40 mL). The organic phase was separated, dried (MgSO₄), filtered, concentrated and purified by chromatography (silica, CH₂Cl₂/MeOH) to afford the title compound as a yellow solid (20.9 mg, 56%). [MH]⁺=525.

Example 1859

embedded image

Step A

A solution of the title compound from the Example 1835, Step A (6 mg) and AlBr₃(7 mg) in tetrahydrothiophene was stirred at room temperature for 16 h, absorbed onto silica and purified by chromatography (silica) to afford the title compound (3 mg, 52%). [M−H]⁻=580.

Examples 1860-1879

Following similar procedures as described in the Examples 314 (method A), 315 (method B), 1858 (method C) or 1859 (method D), except using the esters indicated in Table II-41 below, the following compounds were prepared.

TABLE II-41Ex. #ester1860 embedded image

1861

1862

1863

1864

1865

1866

1867

1868

1869

1870

1871

1872

1873

1874

1875

1876

1877

1878

1879

Ex. #productmethod, yield1860 embedded image

B, 50% [M − H]⁻= 4901861 embedded image

A, n.d. [MH]⁺= 5331862 embedded image

B, 90% [MH]⁺= 5701863 embedded image

B, 43% [MH]⁺= 5601864 embedded image

B, 66% [MH]⁺= 5541865 embedded image

B, 20% [MH]⁺= 5451866 embedded image

B, 86% [MNa]⁺= 6281867 embedded image

C, 21% [MH]⁺= 5191868 embedded image

C, 56% [MH]⁺= 5191869 embedded image

C, 6% [MH]⁺= 5191870 embedded image

C, 15% [MH]⁺= 5331871 embedded image

D, 43% [M − H]⁻= 5621872 embedded image

D, 28% [M − H]⁻= 5861873 embedded image

B, 17% [MH]⁺= 5151874 embedded image

A, 21% [MH]⁺= 4661875 embedded image

A, 12% [MH]⁺= 5651876 embedded image

A, 34% [MH]⁺= 5791877 embedded image

A, 19% [MH]⁺= 5931878 embedded image

A, n.d. [MH]⁺= 5241879 embedded image

A, 29% [MH]⁺= 523

Examples 1880-1884

Following a similar procedure as described in the Example 362, except using the esters indicated in Table II-42 below, the following compounds were prepared.

TABLE II-42Ex. #ester1880 embedded image

1881

1882

1883

1884

Ex. #productyield1880 embedded image

75% [MH]⁺= 5321881 embedded image

43% [MH]⁺= 5711882 embedded image

43% [MH]⁺= 5741883 embedded image

19% [MH]⁺= 5911884 embedded image

28% (over 2 steps) [MH]⁺= 555

Examples 1885

embedded image

Step A

The title compound from the Example 1767 (27.5 mg) was stirred in formic acid (4 mL) at room temperature for 2 h and then concentrated to afford the title compound as a yellow solid (15.5 mg; 63%). [MH]⁺=471.

Examples 1886-1954

Following similar procedures as described in the Examples 436 (method A) or 1885 (method B), except using the esters as indicated in Table II-43 below, the following compounds were prepared.

TABLE II-43Ex. #ester1886 embedded image

1887

1888

1889

1890

1891

1892

1893

1894

1895

1896

1897

1898

1899

1900

1901

1902

1903

1904

1905

1906

1907

1908

1909

1910

1911

1912

1913

1914

1915

1916

1917

1918

1919

1920

1921

1922

1923

1924

1925

1926

1927

1928

1929

1930

1931

1932

1933

1934

1935

1936

1937

1938

1939

1940

1941

1942

1943

1944

1945

1946

1947

1948

1949

1950

1951

1952

1953

1954

Ex. #productmethod, yield1886 embedded image

A, 95% [M − H]⁻= 4781887 embedded image

A, 77% [M − H]⁻= 3881888 embedded image

A, 16% (over 2 steps) [M − H]⁻= 4641889 embedded image

A, 62% [M − H]⁻= 4501890 embedded image

A, >99% [MH]⁺= 5541891 embedded image

A, >99% [MH]⁺= 5281892 embedded image

A, >99% [MH]⁺= 5281893 embedded image

A, >99% [MH]⁺= 6201894 embedded image

A, >99% [MH]⁺= 5551895 embedded image

A, 6% (over 2 steps) [MH]⁺= 5091896 embedded image

A, >99% [MH]⁺= 5591897 embedded image

A, 99% [MH]⁺= 5141898 embedded image

A, 94% [M − H]⁻= 6651899 embedded image

A, >99% [M − H]⁻= 6011900 embedded image

A, >99% [M − (TFA + H)]⁻= 6361901 embedded image

A, >99% [M − (TFA + H)]⁻= 6221902 embedded image

A, >99% [M − H]⁻= 6921903 embedded image

A, >99% [M − H]⁻= 5851904 embedded image

A, >99% [M − H]⁻= 6131905 embedded image

A, 94% [M − H]⁻= 6271906 embedded image

A, >99% [M − H]⁻= 6251907 embedded image

A, 86% [M − H]⁻= 6211908 embedded image

A, 79% [M − H]⁻= 6531909 embedded image

A, 68% [M − H]⁻= 6491910 embedded image

A, >99% [M − (TFA + H)]⁻= 6761911 embedded image

A, 98% [MH]⁺= 5411912 embedded image

A, 89% [MH]⁺= 5181913 embedded image

A, 13% [MH]⁺= 5111914 embedded image

A, 12% (over 2 steps) [MH]⁺= 5361915 embedded image

A, 18% (over 2 steps) [MH]⁺= 5551916 embedded image

B, 73% [MH]⁺= 4431917 embedded image

B, 87% [MH]⁺= 4571918 embedded image

B, 59% [MH]⁺= 4571919 embedded image

B, 80% [MH]⁺= 4571920 embedded image

B, 74% [MH]⁺= 5121921 embedded image

B, 59% (over 2 steps) [MH]⁺= 5741922 embedded image

B, 56% (over 2 steps) [MH]⁺= 5561923 embedded image

B, 34% (over 2 steps) [MH]⁺= 5581924 embedded image

B, 53% (over 2 steps) [MH]⁺= 5681925 embedded image

A, 99% [MH]⁺= 5641926 embedded image

A, n.d. [M − H]⁻= 6751927 embedded image

A, 78% [M − H]⁻= 5801928 embedded image

A, 78% [M − H]⁻= 5861929 embedded image

A, 68% [M − H]⁻= 5801930 embedded image

A, 62% [M − H]⁻= 5861931 embedded image

A, 25% [M − H]⁻= 6931932 embedded image

A, 99% [M − H]⁻= 5611933 embedded image

A, 82% [M − H]⁻= 6171934 embedded image

A, 99% [M − H]⁻= 6371935 embedded image

A, 99% [M − H]⁻= 6571936 embedded image

A, 99% [M − H]⁻= 5481937 embedded image

A, 99% [M − H]⁻= 5621938 embedded image

A, 99% [M − H]⁻= 5471939 embedded image

A, 63% [M − H]⁻= 6591940 embedded image

A, 94% [M − H]⁻= 6381941 embedded image

A, n.d. [M − H]⁻= 6231942 embedded image

B, 46% [MH]⁺= 6491943 embedded image

B, 53% [MH]⁺= 6491944 embedded image

B, 39% [MH]⁺= 6491945 embedded image

B, 52% [MH]⁺= 6491946 embedded image

B, 62% [MH]⁺= 6491947 embedded image

B, 57% [MH]⁺= 6491948 embedded image

A, 99% [MH]⁺= 5451949 embedded image

A, 90% [MH]⁺= 5591950 embedded image

A, 48% [MH]⁺= 5731951 embedded image

A, 34% [MH]⁺= 5871952 embedded image

A, 90% [MH]⁺= 5631953 embedded image

A, 99% [MH]⁺= 5991954 embedded image

B, n.d. [MH]⁺= 587

Example 1955

embedded image

Step A

To a mixture of N-cyclohexyl-carbodiimide-N′-methyl-polystyrene (30 mg) in DMA (340 μL) were added a 0.2M solution of the title compound from the Preparative Example 337 in DMA (85 μL) and a 0.5M solution of HOBt in DMA (45 μL). The mixture was agitated for 15 min, then a 0.5M solution of morpholine in DMA (30 μL) was added and the mixture was heated in a sealed tube at 100° C. (microwave) for 5 min. (Plystyrylmethyl)-trimethylammomium bicarbonate (20 mg) was added and the mixture was agitated at room temperature for 3 h. Then the mixture was filtered, concentrated, diluted with formnic acid (100 μL) and stirred at room temperature for 5 h. Concentration afforded the title compound as a pale yellow solid, which was used without further purification. [MH]⁺=450.

Examples 1956-2138

Following a similar procedure as described in the Example 1955, except using amines indicated in Table II-44 below, the following compounds were prepared.

TABLE II-44Ex. #amine1956 embedded image

1957

1958

1959

1960

1961

1962

1963

1964

1965

1966

1967

1968

1969

1970

1971

1972

1973

1974

1975

1976

1977

1978

1979

1980

1981

1982

1983

1984

1985

1986

1987

1988

1989

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

2014

2015

2016

2017

2018

2019

2020

2021

2022

2023

2024

2025

2026

2027

2028

2029

2030

2031

2032

2033

2034

2035

2036

2037

2038

2039

2040

2041

2042

2043

2044

2045

2046

2047

2048

2049

2050

2051

2052

2053

2054

2055

2056

2057

2058

2059

2060

2061

2062

2063

2064

2065

2066

2067

2068

2069

2070

2071

2072

2073

2074

2075

2076

2077

2078

2079

2080

2081

2082

2083

2084

2085

2086

2087

2088

2089

2090

2091

2092

2093

2094

2095

2096

2097

2098

2099

2100

2101

2102

2103

2104

2105

2106

2107

2108

2109

2110

2111

2112

2113

2114

2115

2116

2117

2118

2119

2120

2121

2122

2123

2124

2125

2126

2127

2128

2129

2130

2131

2132

2133

2134

2135

2136

2137

2138

Ex. #productyield1956 embedded image

n.d. [MH]⁺= 4381957 embedded image

n.d. [MH]⁺= 5141958 embedded image

n.d. [MH]⁺= 5501959 embedded image

n.d. [MH]⁺= 4601960 embedded image

n.d. [MH]⁺= 5001961 embedded image

n.d. [MH]⁺= 4881962 embedded image

n.d. [MH]⁺= 4341963 embedded image

n.d. [MH]⁺= 4881964 embedded image

n.d. [MH]⁺= 5441965 embedded image

n.d. [MH]⁺= 4481966 embedded image

n.d. [MH]⁺= 4501967 embedded image

n.d. [MH]⁺= 4221968 embedded image

n.d. [MH]⁺= 4481969 embedded image

n.d. [MH]⁺= 4701970 embedded image

n.d. [MH]⁺= 4761971 embedded image

n.d. [MH]⁺= 4781972 embedded image

n.d. [MH]⁺= 4081973 embedded image

n.d. [MH]⁺= 4621974 embedded image

n.d. [MH]⁺= 4511975 embedded image

n.d. [MH]⁺= 4921976 embedded image

n.d. [MH]⁺= 5481977 embedded image

n.d. [MH]⁺= 3941978 embedded image

n.d. [MH]⁺= 4641979 embedded image

n.d. [MH]⁺= 5901980 embedded image

n.d. [MH]⁺= 5001981 embedded image

n.d. [MH]⁺= 5001982 embedded image

n.d. [MH]⁺= 4841983 embedded image

n.d. [MH]⁺= 4641984 embedded image

n.d. [MH]⁺= 4641985 embedded image

n.d. [MH]⁺= 4981986 embedded image

n.d. [MH]⁺= 4611987 embedded image

n.d. [MH]⁺= 4521988 embedded image

n.d. [MH]⁺= 5081989 embedded image

n.d. [MH]⁺= 5021990 embedded image

n.d. [MH]⁺= 4631991 embedded image

n.d. [MH]⁺= 5201992 embedded image

n.d. [MH]⁺= 5681993 embedded image

n.d. [MH]⁺= 4811994 embedded image

n.d. [MH]⁺= 5121995 embedded image

n.d. [MH]⁺= 5101996 embedded image

n.d. [MH]⁺= 4371997 embedded image

n.d. [MH]⁺= 4711998 embedded image

n.d. [MH]⁺= 4841999 embedded image

n.d. [MH]⁺= 4842000 embedded image

n.d. [MH]⁺= 4632001 embedded image

n.d. [MH]⁺= 5492002 embedded image

n.d. [MH]⁺= 4802003 embedded image

n.d. [MH]⁺= 4662004 embedded image

n.d. [MH]⁺= 5022005 embedded image

n.d. [MH]⁺= 5512006 embedded image

n.d. [MH]⁺= 4602007 embedded image

n.d. [MH]⁺= 4652008 embedded image

n.d. [MH]⁺= 4182009 embedded image

n.d. [MH]⁺= 5492010 embedded image

n.d. [MH]⁺= 5542011 embedded image

n.d. [MH]⁺= 5282012 embedded image

n.d. [MH]⁺= 4822013 embedded image

n.d. [MH]⁺= 6512014 embedded image

n.d. [MH]⁺= 527.6222015 embedded image

n.d. [MH]⁺= 5022016 embedded image

n.d. [MH]⁺= 5022017 embedded image

n.d. [MH]⁺= 5302018 embedded image

n.d. [MH]⁺= 5462019 embedded image

n.d. [MH]⁺= 5002020 embedded image

n.d. [MH]⁺= 5002021 embedded image

n.d. [MH]⁺= 5282022 embedded image

n.d. [MH]⁺= 5282023 embedded image

n.d. [MH]⁺= 5282024 embedded image

n.d. [MH]⁺= 5102025 embedded image

n.d. [MH]⁺= 4912026 embedded image

n.d. [MH]⁺= 5102027 embedded image

n.d. [MH]⁺= 5962028 embedded image

n.d. [MH]⁺= 4962029 embedded image

n.d. [MH]⁺= 4962030 embedded image

n.d. [MH]⁺= 6102031 embedded image

n.d. [MH]⁺= 5002032 embedded image

n.d. [MH]⁺= 5472033 embedded image

n.d. [MH]⁺= 4642034 embedded image

n.d. [MH]⁺= 5552035 embedded image

n.d. [MH]⁺= 5552036 embedded image

n.d. [MH]⁺= 5112037 embedded image

n.d. [MH]⁺= 5452038 embedded image

n.d. [MH]⁺= 5162039 embedded image

n.d. [MH]⁺= 5342040 embedded image

n.d. [MH]⁺= 4922041 embedded image

n.d. [MH]⁺= 4592042 embedded image

n.d. [MH]⁺= 4772043 embedded image

n.d. [MH]⁺= 4362044 embedded image

n.d. [MH]⁺= 5282045 embedded image

n.d. [MH]⁺= 5282046 embedded image

n.d. [MH]⁺= 5212047 embedded image

n.d. [MH]⁺= 5722048 embedded image

n.d. [MH]⁺= 5262049 embedded image

n.d. [MH]⁺= 5382050 embedded image

n.d. [MH]⁺= 5442051 embedded image

n.d. [MH]⁺= 5382052 embedded image

n.d. [MH]⁺= 4842053 embedded image

n.d. [MH]⁺= 5132054 embedded image

n.d. [MH]⁺= 5202055 embedded image

n.d. [MH]⁺= 4842056 embedded image

n.d. [MH]⁺= 5382057 embedded image

n.d. [MH]⁺= 4882058 embedded image

n.d. [MH]⁺= 4902059 embedded image

n.d. [MH]⁺= 4902060 embedded image

n.d. [MH]⁺= 4642061 embedded image

n.d. [MH]⁺= 4502062 embedded image

n.d. [MH]⁺= 4762063 embedded image

n.d. [MH]⁺= 5552064 embedded image

n.d. [MH]⁺= 5012065 embedded image

n.d. [MH]⁺= 5502066 embedded image

n.d. [MH]⁺= 5262067 embedded image

n.d. [MH]⁺= 5402068 embedded image

n.d. [MH]⁺= 5272069 embedded image

n.d. [MH]⁺= 5412070 embedded image

n.d. [MH]⁺= 5412071 embedded image

n.d. [MH]⁺= 5412072 embedded image

n.d. [MH]⁺= 5542073 embedded image

n.d. [MH]⁺= 5942074 embedded image

n.d. [MH]⁺= 5492075 embedded image

n.d. [MH]⁺= 6222076 embedded image

n.d. [MH]⁺= 5382077 embedded image

n.d. [MH]⁺= 6082078 embedded image

n.d. [MH]⁺= 6122079 embedded image

n.d. [MH]⁺= 6262080 embedded image

n.d. [MH]⁺= 6262081 embedded image

n.d. [MH]⁺= 6202082 embedded image

n.d. [MH]⁺= 5602083 embedded image

n.d. [MH]⁺= 5122084 embedded image

n.d. [MH]⁺= 4982085 embedded image

n.d. [MH]⁺= 4982086 embedded image

n.d. [MH]⁺= 4982087 embedded image

n.d. [MH]⁺= 4502088 embedded image

n.d. [MH]⁺= 4682089 embedded image

n.d. [MH]⁺= 4362090 embedded image

n.d. [MH]⁺= 4362091 embedded image

n.d. [MH]⁺= 4902092 embedded image

n.d. [MH]⁺= 4642093 embedded image

n.d. [MH]⁺= 5262094 embedded image

n.d. [MH]⁺= 5552095 embedded image

n.d. [MH]⁺= 5102096 embedded image

n.d. [MH]⁺= 5692097 embedded image

n.d. [MH]⁺= 5542098 embedded image

n.d. [MH]⁺= 4712099 embedded image

n.d. [MH]⁺= 4852100 embedded image

n.d. [MH]⁺= 5552101 embedded image

n.d. [MH]⁺= 5682102 embedded image

n.d. [MH]⁺= 5542103 embedded image

n.d. [MH]⁺= 5172104 embedded image

n.d. [MH]⁺= 4782105 embedded image

n.d. [MH]⁺= 5192106 embedded image

n.d. [MH]⁺= 5122107 embedded image

n.d. [MH]⁺= 5342108 embedded image

n.d. [MH]⁺= 5672109 embedded image

n.d. [MH]⁺= 4952110 embedded image

n.d. [MH]⁺= 4602111 embedded image

n.d. [MH]⁺= 4762112 embedded image

n.d. [MH]⁺= 4622113 embedded image

n.d. [MH]⁺= 5122114 embedded image

n.d. [MH]⁺= 5342115 embedded image

n.d. [MH]⁺= 5562116 embedded image

n.d. [MH]⁺= 5562117 embedded image

n.d. [MH]⁺= 5282118 embedded image

n.d. [MH]⁺= 5442119 embedded image

n.d. [MH]⁺= 5442120 embedded image

n.d. [MH]⁺= 5552121 embedded image

n.d. [MH]⁺= 5322122 embedded image

n.d. [MH]⁺= 5392123 embedded image

n.d. [MH]⁺= 5122124 embedded image

n.d. [MH]⁺= 4772125 embedded image

n.d. [MH]⁺= 4862126 embedded image

n.d. [MH]⁺= 4802127 embedded image

n.d. [MH]⁺= 5192128 embedded image

n.d. [MH]⁺= 5192129 embedded image

n.d. [MH]⁺= 5692130 embedded image

n.d. [MH]⁺= 5392131 embedded image

n.d. [MH]⁺= 5282132 embedded image

n.d. [MH]⁺= 5012133 embedded image

n.d. [MH]⁺= 4842134 embedded image

n.d. [MH]⁺= 5632135 embedded image

n.d. [MH]⁺= 4382136 embedded image

n.d. [MH]⁺= 4382137 embedded image

n.d. [MH]⁺= 5132138 embedded image

n.d. [MH]⁺= 513

Example 2139

embedded image

Step A

The title compound from the Example 1925 (3.6 mg) was treated similarly as described in the Example 314, except using NaOH instead of LiOH to afford the title compound as a yellow solid (2.2 mg, 60%). [MH]⁺=550.

Example 2140

embedded image

Step A

A solution of the title compound from the Example 1791 (5 mg) in a 7M solution of NH₃in MeOH (1 mL) was heated to reflux overnight, concentrated and purified by chromatography (silica) to afford the title compound as a yellow solid (4.5 mg, 90%). [MH]⁺=605.

Example 2141

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Step A

The title compound from the Preparative Example 974, Step A (6.4 mg) was treated similarly as described in the Example 2140, Step A to afford the title compound as a yellow solid (5.6 mg, 90%). [MH]⁺=485.

Example 2142

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Step A

The title compound from the Example 1833, Step A (15 mg) was treated similarly as described in the Example 2140, Step A to afford the title compound (2.5 mg, 17%). [M−H]⁻=603.

Examples 2143-2213

Following similar procedures as described in the Examples 1 (method A), 2 (method B), 3 (method C), 4 (method D), 5 (method E), 6 (method F) or 7 (method G), except using the acids and amines or alcohols indicated in Table II-45 below, the following compounds were prepared.

TABLE II-45Ex. #acid, amine or alcohol2143 embedded image

2144

2145

2146

2147

2148

2149

2150

2151

2152

2153

2154

2155

2156

2157

2158

2159

2160

2161

2162

2163

2164

2165

2166

2167

2168

2169

2170

2171

2172

2173

2174

2175

2176

2177

2178

2179

2180

2181

2182

2183

2184

2185

2186

2187

2188

2189

2190

2191

2192

2193

2194

2195

2196

2197

2198

2199

2200

2201

2202

2203

2204

2205

2206

2207

2208

2209

2210

2211

2212

2213

Ex. #productmethod, yield2143 embedded image

B, 74% [MH]⁺= 6292144 embedded image

B, 79% [MH]⁺= 6852145 embedded image

B, 77% [MH]⁺= 7412146 embedded image

B, 54% [MH]⁺= 6862147 embedded image

B, 95% [MH]⁺= 6242148 embedded image

B, 92% [MH]⁺= 6542149 embedded image

B, 94% [MNa]⁺= 7272150 embedded image

B, >99% [MH]⁺= 5722151 embedded image

B, 78% [MH]⁺= 7432152 embedded image

E, 68% [(MH₂) / 2]⁺= 3992153 embedded image

E, n.d. [M − H]⁻= 6792154 embedded image

E, n.d. [M − H]⁻= 7142155 embedded image

E, n.d. [M − H]⁻= 7092156 embedded image

E, 40% [M − H]⁻= 6862157 embedded image

E, 39% [M − H]⁻= 6932158 embedded image

E, 25% [M − H]⁻= 7142159 embedded image

E, 35% [M − H]⁻= 7142160 embedded image

E, 41% [M − H]⁻= 6692161 embedded image

E, 12% [M − H]⁻= 7372162 embedded image

E, 76% [M − H]⁻= 7052163 embedded image

E, 40% [MNa]⁺= 6102164 embedded image

E, 41% [MNa]⁺= 6242165 embedded image

E, 9% [MH]⁺= 6872166 embedded image

E, 62% [M − H]⁻= 6712167 embedded image

E, 87% [M − H]⁻= 6512168 embedded image

E, 99% [M − H]⁻= 6552169 embedded image

E, 78% [M − H]⁻= 6672170 embedded image

E, 65% [M − H]⁻= 6672171 embedded image

E, >99% [M − H]⁻= 6852172 embedded image

E, 83% [M − H]⁻= 6972173 embedded image

E, 80% [M − H]⁻= 7472174 embedded image

E, 77% [M − H]⁻= 6972175 embedded image

E, 59% [M − H]⁻= 7472176 embedded image

E, 76% [M − H]⁻= 6932177 embedded image

E, 85% [M − H]⁻= 6802178 embedded image

E, 65% [M − H]⁻= 6952179 embedded image

E, 70% [M − H]⁻= 6952180 embedded image

B, 39% [MH]⁺= 4982181 embedded image

B, 35% [MH]⁺= 4842182 embedded image

D, 40% [MH]⁺= 5902183 embedded image

B, 11% [MH]⁺= 6012184 embedded image

B, 22% [MH]⁺= 6712185 embedded image

B, 10% [MNa]⁺= 7132186 embedded image

B, 92% [MH]⁺= 6872187 embedded image

B, 76% [MH]⁺= 5682188 embedded image

B, 4% [MH]⁺= 5982189 embedded image

E, 4% ¹H-NMR (DMSO-d₆) δ = 10.07(t, 1H), 9.73(t, 1H), 8.60(d, 1H), 8.11(s, 1H), 7.58(d, 1H), 7.39(d, 2H), 7.15(d, 1H), 4.52(d, 2H), 4.00(t, 1H), 3.29(d, 2H), 2.31-2.12(m, 4H), 1.75-1.12(m, 20H).2190 embedded image

E, 73% [MNa]⁺= 7102191 embedded image

A, 99% [MH]⁺= 6952192 embedded image

E, 99% [MH]⁺= 6592193 embedded image

E, n.d. [MNa]⁺= 6812194 embedded image

A, 67% [MNa]⁺= 6712195 embedded image

E, 20% [MH]⁺= 5952196 embedded image

E, 20% [MH]⁺= 6332197 embedded image

E, 17% [MH]⁺= 5992198 embedded image

E, 75% [MH]⁺= 7012199 embedded image

E, 35% [MH]⁺= 6892200 embedded image

E, n.d. [MH]⁺= 6192201 embedded image

E, 66% [M − H]⁻= 6172202 embedded image

E, 73% [M − H]⁻= 6732203 embedded image

E, 72% [M − H]⁻= 6932204 embedded image

E, 65% [M − H]⁻= 7132205 embedded image

E, 23% [MNa]⁺= 7102206 embedded image

C, 30% [MH]⁺= 5242207 embedded image

C, 12% [MH]⁺= 5782208 embedded image

C, n.d. [MNa]⁺= 6042209 embedded image

C, 77% [MH]⁺= 4762210 embedded image

C, 46% [MH]⁺= 5262211 embedded image

C, 34% [MH]⁺= 5642212 embedded image

C, 40% [MH]⁺= 5392213 embedded image

C, 91% [MH]⁺= 524

Example 2214

embedded image

Step A

The title compound from the Example 2208 was treated similarly as described in the Example 296, Step B to afford the title compound. [M−Cl]⁺=482.

Example 2215

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Step A

To an ice cooled (0-5° C.) solution of the title compound from the Example 1834 (25 mg) in THF (1 mL) was added BH₃.THF complex (120 μL). The resulting mixture was stirred for 24 h while warming to room temperature, cooled to 0-5° C. (ice bath), hydrolyzed with 1M aqueous HCl (2 mL) and extracted with CH₂Cl₂(3×5 mL). The combined organic phases were dried (MgSO₄), filtered, concentrated and purified by chromatography (silica, hexanes/EtOAc) to afford the title compound as a yellow solid (5 mg, 23%). [MH]⁺=592.

Step B

To a solution of the title compound from Step A above (5 mg) in CH₂Cl₂(1 mL) were sequentially added molecular sieves 4 Å (100 mg), N-methylmorpholine N-oxide (2 mg) and TPAP (0.5 mg). The resulting black mixture was stirred at room temperature for 3 h, filtered through celite® and concentrated to afford the title compound (5 mg, 98%). [MH]⁺=590.

Step C

To a solution of the title compound from Step B above (5 mg) in MeOH (2 mL) were added NaBH₃CN (1.6 mg) and AcOH (50 μL). The resulting mixture was stirred at room temperature overnight, concentrated and purified by preparative thin layer chromatography (silica, hexanes/EtOAc) to afford the title compound as a yellow solid (2 mg, 35%). [MNa]⁺=723.

Examples 2216-2220

Following a similar procedure as described in the Example 1859, except using the esters indicated in Table II-46 below, the following compounds were prepared.

TABLE II-46Ex. #esterproductyield2216 embedded image

40% [M − H]⁻ = 6572217 embedded image

34% [M − H]⁻ = 6532218 embedded image

55% [M − H]⁻ = 6372219 embedded image

40% [M − H]⁻ = 6372220 embedded image

B, 35% [M − H]⁻ = 619

Examples 2221-2255

Following similar procedures as described in the Example 436 (method A) and the Example 1885 (method B), except using the esters as indicated in Table II-47 below, the following compounds were prepared.

TABLE II-47method,Ex. #esterproductyield2221 embedded image

B, 92% [MH]⁺ = 5982222 embedded image

B, 96% [MH]⁺ = 6712223 embedded image

B, >99% [MH]⁺ = 6712224 embedded image

B, 93% [MH]⁺ = 6872225 embedded image

A, 17% (over 2 steps) [MH]⁺ = 6232226 embedded image

A, 42% (over 2 steps) [MH]⁺ = 6582227 embedded image

A, 45% (over 2 steps) [MH]⁺ = 6532228 embedded image

A, 91% [MH]⁺ = 6302229 embedded image

A, 82% [MH]⁺ = 6372230 embedded image

A, 50% [MH]⁺ = 6582231 embedded image

A, 50% [MH]⁺ = 6582232 embedded image

A, 95% [MH]⁺ = 6132233 embedded image

A, 70% [MH]⁺ = 6812234 embedded image

A, 97% [MH]⁺ = 6492235 embedded image

A, 85% [MH]⁺ = 6292236 embedded image

A, >99% [MH]⁺ = 6412237 embedded image

A, >99% [MH]⁺ = 6912238 embedded image

A, 69% [MH]⁺ = 6412239 embedded image

A, 59% [MH]⁺ = 6912240 embedded image

A, >99% [MH]⁺ = 6372241 embedded image

A, 79% [M − (TFA + H)]⁻ =6242242 embedded image

A, >99% [MH]⁺ = 6392243 embedded image

A, >99% [MH]⁺ = 6392244 embedded image

B, 68% [MH]⁺ = 6312245 embedded image

B, 83% [MH]⁺ = 6322246 embedded image

A, 99% [MH]⁺ = 5492247 embedded image

A, 99% [MH]⁺ = 6392248 embedded image

A, 99% [MH]⁺ = 6032249 embedded image

A, 99% [MH]⁺ = 6252250 embedded image

A, 99% [MH]⁺ = 5932251 embedded image

A, 99% [MH]⁺ = 6542252 embedded image

A, 99% [MH]⁺ = 5432253 embedded image

A, 99% [MH]⁺ = 6452254 embedded image

A, 99% [MH]⁺ = 6332255 embedded image

A, n.d. [MH]⁺ = 561

Example 2256

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Step A

To a solution of the title compound from the Example 2205 (11 mg) in CH₂Cl₂(1 mL) was added a 50% aqueous solution of trifluoroacetic acid (1 mL). The resulting mixture was stirred at room temperature for 6 h, diluted with CH₂Cl₂(30 mL), washed with saturated aqueous NaHCO₃, dried (MgSO₄), filtered, concentrated and purified by chromatography (silica, CH₂Cl₂/MeOH) to afford the title compound (8.5 mg, 81%). [MNa]⁺=670.

Example 2257

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Step A

To a degassed solution of the title compound from the Preparative Example 377, Step E (30 mg) and the title compound from the Preparative Example 19, Step B (25 mg) in DMF (2 mL) were added Pd(OAc)₂(1 mg), BINAP (3 mg) and KOtBu (10 mg). The resulting mixture was heated to 180° C. (microwave) for 30 min, cooled, concentrated, diluted with EtOAc, washed with 0.1M aqueous HCl and saturated aqueous NaCl, dried (MgSO₄), filtered, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the title compound (6.5 mg, 15%). [MH]⁺=466.

Examples 2258-2296

Following a similar procedure as described in the Example 479, except using the amines and carbonyl compounds indicated in Table II-48 below, the following compounds were prepared.

TABLE II-48amine,Ex. #carbonyl compoundproductyield2258 embedded image

13% [MH]⁺ = 4282259 embedded image

53% [MH]⁺ = 5012260 embedded image

14% [MH]⁺ = 4612261 embedded image

46% [MH]⁺ = 4822262 embedded image

51% [MH]⁺ = 4752263 embedded image

42% [MH]⁺ = 4852264 embedded image

50% [MH]⁺ = 4792265 embedded image

27% [MH]⁺ = 4412266 embedded image

22% [MH]⁺ = 4502267 embedded image

32% [MH]⁺ = 4962268 embedded image

95% [MH]⁺ = 4902269 embedded image

54% [MH]⁺ = 5472270 embedded image

n.d. [MH]⁺ = 4832271 embedded image

n.d. [MH]⁺ = 4692272 embedded image

n.d. [MH]⁺ = 5342273 embedded image

n.d. [MNa]⁺ = 5732274 embedded image

n.d. [MNa]⁺ = 6072275 embedded image

n.d. [MNa]⁺ = 5572276 embedded image

n.d. [MNa]⁺ = 5922277 embedded image

73% [MH]⁺ = 4742278 embedded image

24% [MH]⁺ = 4942279 embedded image

n.d. [MH]⁺ = 5202280 embedded image

14% [MH]⁺ = 5192281 embedded image

10% [MH]⁺ = 4932282 embedded image

89% [MH]⁺ = 4892283 embedded image

86% [MH]⁺ = 4972284 embedded image

15% [MH]⁺ = 5352285 embedded image

80% [MH]⁺ = 4912286 embedded image

52% [MH]⁺ = 4132287 embedded image

82% [MH]⁺ = 4632288 embedded image

58% [MH]⁺ = 4662289 embedded image

82% [MH]⁺ = 3792290 embedded image

78% [MH]⁺ = 4692291 embedded image

40% [MH]⁺ = 4122292 embedded image

38% [MH]⁺ = 4612293 embedded image

67% [MH]⁺ = 4332294 embedded image

5% [MH]⁺ = 4912295 embedded image

7% [MH]⁺ = 3772296 embedded image

52% [MH]⁺ = 363

Example 2297

embedded image

Step A

To a solution of the title compound from Example 2268 (10 mg) in anhydrous CH₃CN (1.5 mL) was added trimethylsilyl bromide (2.6 μL) at 25° C. The resulting mixture was stirred at the title compound (1.0 mg, 11%). [MH]⁺=491.

Example 2298

embedded image

Step A

The crude ˜1:1 mixture of the carboxylate I and the carboxylate II from the Preparative Example 1047 was treated similarly as described in the Example 2 to afford the title compound I (5.3 mg, 16%, [MH]⁺=468) and the title compound II (4.8 mg, 11%, [MH]⁺=647).

Examples 2299-2312

TABLE II-49Ex. #acid, amineproductmethod, yield2299 embedded image

B, 50% (over 2 steps) [MH]⁺ = 4602300 embedded image

B, 34% (over 2 steps) [MH]⁺ = 3542301 embedded image

B, 31% (over 2 steps) [MH]⁺ = 3682302 embedded image

B, 46% (over 2 steps) [MH]⁺ = 3522303 embedded image

B, 47% (over 2 steps) [MH]⁺ = 3902304 embedded image

B, 40% (over 2 steps) [MH]⁺ = 3502305 embedded image

B, 32% (over 2 steps) [MH]⁺ = 3102306 embedded image

B, 24% (over 2 steps) [MH]⁺ = 3232307 embedded image

B, 30% (over 2 steps) [MH]⁺ = 3232308 embedded image

B, 8.8% (over 2 steps) [MH]⁺ = 2972309 embedded image

B, 20% (over 2 steps) [MH]⁺ = 3352310 embedded image

B, 37% (over 2 steps) [MH]⁺ = 3352311 embedded image

B, 88% [MH]⁺ = 4392312 embedded image

B, 95% (over 2 steps) [MH]⁺ = 561/563

Example 2313

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Step A

A mixture of the title compound from the Example 2311 (53 mg) in a 4M solution of HCl in 1,4-dioxane (3 mL) was stirred at room temperature for 3 h and then concentrated. The remaining residue was added to solution of NaBH₃CN (16 mg) in MeOH (2 mL). To the resulting solution was slowly added a solution of the title compound from the Preparative Example 1031, Step A (25 mg) in THF/MeOH (1:1, 1 mL) over a period of 7 h. Then the mixture was concentrated, diluted with saturated aqueous NaHCO₃and extracted with EtOAc (3×). The combined organic phases were dried (MgSO₄), filtered, absorbed onto silica and purified by chromatography (silica) to afford the title compound (23 mg, 36%). [MH]⁺=529.

Step B

To an ice cooled (0-5° C.) solution of the title compound from Step A above (9 mg) in THF (2 mL) was added a 1M solution of tert.-butyl magnesium chloride (60 μL). The resulting mixture was stirred at 0-5° C. (ice bath) for 1½ h, diluted with saturated aqueous NaHCO₃and extracted with EtOAc (3×). The combined organic phases were dried (MgSO₄), filtered, concentrated and purified by preparative thin layer chromatography (silica, EtOAc) to afford the title compound as a light yellow solid (1.7 mg, 20%). [MH]⁺=483.

Example 2314

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Step A

To the title compound from the Example 2311 (23.2 mg) was added a 4M solution of HCl in 1,4-dioxane (940 μL). The resulting mixture was stirred at room temperature for 3 h and then concentrated. The obtained residue was suspended in pyridine (800 μL), the title compound from Preparative Example 1022 (10.5 μL) was added and the resulting mixture was stirred at room temperature for 3 h. The mixture was concentrated, diluted with 10% aqueous citric acid (5 mL), sonicated for ˜1 min and allowed to stand at room temperature for 30 min. The formed precipitate was collected by filtration, washed with H₂O (5 mL) and dried in vacuo to afford the title compound as yellow solid (16.8 mg, 63%). [MH]⁺=501.

Examples 2315-2322

Following a similar procedure as described in the Example 2314, except using the acid chlorides indicated in Table II-50 below, the following compounds were prepared.

TABLE II-50Ex. #acid chlorideProductyield2315 embedded image

96% [MH]⁺ =4072316 embedded image

14% [MH]⁺ =4392317 embedded image

24% [MH]⁺ =4532318 embedded image

52% [MH]⁺ =4672319 embedded image

45% [MH]⁺ =4652320 embedded image

47% [MH]⁺ =4652321 embedded image

35% [MH]⁺ =4232322 embedded image

50% [MH]⁺ =479

Example 2323

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Step A

To a solution of the title compound from the Example 2314, Step A (13 mg) in THF/H₂O (1:1, 2mL) was added a 1M aqueous KOH (140 μL). The mixture was stirred at room temperature for 2 h, concentrated, diluted with a 0.1M aqueous HCl (3 mL), sonicated for ˜1 min and allowed to stand at room temperature for 30 min. The formed precipitate was collected by filtration, washed with H₂O (5 mL) and dried in vacuo to afford the title compound (11.7 mg, 92%). [MH]⁺=487.

Examples 2324-2336

Following similar procedures as described in the Examples 314 (method A), 315 (method B) or 2314 (method C), except using the esters indicated in Table II-51 below, the following compounds were prepared.

TABLE II-51method,Ex. #esterproductyield2324 embedded image

A, 57% (over 2 steps) [MH]⁺ =4562325 embedded image

A, 32% (over 2 steps) [MH]⁺ =4692326 embedded image

A, 100% [MH]⁺ =4872327 embedded image

B, 78% [MH]⁺ =4872328 embedded image

A, 98% [MH]⁺ =4802329 embedded image

A, 18% (over 2 steps) [MH]⁺ =506,2330 embedded image

C, 29% [MH]⁺ =4872331 embedded image

C, 9% [MH]⁺ =4872332 embedded image

C, 98% [MH]⁺ =4392333 embedded image

C, 69% [MH]⁺ =4532334 embedded image

C, 91% [MH]⁺ =4512335 embedded image

C, 92% [MH]⁺ =4652336 embedded image

A, >99% [MH]⁺ =521

Example 2337-2341

Following a similar procedures as described in the Examples 436 except the esters indicated in Table II-52 below, the following compounds were prepared.

TABLE II-52Ex. #esterProductyield2337 embedded image

66% (over 2 steps) [MH]⁺ = 4562338 embedded image

23% (over 2 steps) [MH]⁺ = 4952339 embedded image

18% (over 2 steps) [MH]⁺ = 5292340 embedded image

52% (over 2 steps) [MH]⁺ = 4792341 embedded image

32% (over 2 steps) [MH]⁺ = 514

Example 2342

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Step A

To a solution of the title compound from the Example 2311 (939 mg) in EtOAc (17.1 mL) was added at 4M solution of HCl in 1,4-dioxane (17.1 mL). The reaction mixture was stirred at room temperature for 20 h and concentrated to afford the title compound (850 mg, >99%). [M−Cl]⁺=339.

Example 2343

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Step A

To a solution of the title compound from the Example 2311 (22.5 mg) in CHCl₃(500 μL) was added and a 1:1 mixture of trifluoroacetic acid and CHCl₃(500 μL). The mixture was stirred at room temperature for 3 h, concentrated and dried in vacuo. The obtained residue was dissolved in DMF (500 μL) and ⁱPr₂NEt (10.2 μL) was added. The mixture was stirred at room temperature overnight, concentrated and diluted with EtOAc and 10% aqueous citric acid. The organic phase was separated, washed with 10% aqueous citric acid, saturated aqueous NaHCO₃and saturated aqueous NaCl, dried (MgSO₄), filtered, concentrated and purified by preparative thin layer chromatography (silica, CH₂Cl₂/MeOH) to afford the title compound as pale yellow solid (12.5 mg; 56%). [MH]⁺=435.

Example 2344

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Step A

To a solution of the title compound from the Preparative Example 1028 (4.5 mg) in THF (1 mL) was added 1,1′-carbonyldiimidazole (5.4 mg). The resulting solution was stirred at room temperature for 90 min, then a solution of the title compound from the Example 2342, Step A (8.1 mg) in DMF (1 mL) and ⁱPr₂NEt (5 μL) were added and stirring at room temperature was continued overnight. Additional 1,1′-carbonyldiimidazole (5.4 mg) was added and stirring at room temperature was continued for 8 h. The mixture was concentrated, diluted with a 0.1M aqueous HCl (3 mL) and H₂O (15 mL) and extracted with EtOAc (3×30 mL). The combined organic phases were washed with saturated aqueous NaCl, dried (MgSO₄), filtered, concentrated and purified by preparative thin layer chromatography (silica, CH₂Cl₂/MeOH) to afford the title compound (1.1 mg; 9%). [MH]⁺=494.

Example 2345

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Step A

The title compound from the Example 2342, Step A (10.2 mg) was treated similarly as described in the Example 2344, Step A, except using the title compound from the Preparative Example 1029 instead of the title compound from the Preparative Example 1028 to afford the title compound (1.1 mg, 7.9%). [MH]⁺=506.

Example 2346

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Step A

Using a microwave, a mixture of the title compound from Preparative Example 1049, Step E (3 mg), CsCO₃(9 mg) and acetyl chloride (3 μL) in 1,4-dioxane/CH₃CN (1:1, 1 ml) was heated at 110° C. for 20 min and then cooled to room temperature. The formed precipitate was collected by filtration, washed with MeOH/H₂O (1:1) and then dried in vacuo to afford the title compound as orange solid (1.6 mg, 47%). [MH]⁺=382.

Example 2347

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Step A

To a suspension of the title compound from the Example 2342, Step A (2.8 mg) in dry pyridine (75 μL) was added a 1.0M solution of thiophene-2-carbonyl chloride in 1,2-dichlorethane (75 μL). The resulting mixture was agitated (˜800 rpm) at room temperature for 15 h, concentrated and dried in vacuo for 12 h to afford the crude title compound. [MH]⁺=449.

Examples 2348-2387

Following similar procedures as described in the Example 2346 (method A) or 2347 (method B), except using the amines and acid chlorides indicated in Table II-53 below, the following compounds were prepared.

TABLE II-53method,Ex. #amine, acid chlorideproductyield2348 embedded image

A, 31% [MH]⁺ = 4692349 embedded image

A, 31% [MH]⁺ = 3632350 embedded image

B, n.d. [MH]⁺ = 5332351 embedded image

B, n.d. [MH]⁺ = 4932352 embedded image

B, n.d. [MH]⁺ = 4092353 embedded image

B, n.d. [MH]⁺ = 4712354 embedded image

B, n.d. [MH]⁺ = 4572355 embedded image

B, n.d. [MH]⁺ = 4872356 embedded image

B, n.d. [MH]⁺ = 4732357 embedded image

B, n.d. [MH]⁺ = 4872358 embedded image

B, n.d. [MH]⁺ = 4682359 embedded image

B, n.d. [MH]⁺ = 5272360 embedded image

B, n.d. [MH]⁺ = 4892361 embedded image

B, n.d. [MH]⁺ = 4862362 embedded image

B, n.d. [MH]⁺ = 3952363 embedded image

B, n.d. [MH]⁺ = 4612364 embedded image

B, n.d. [MH]⁺ = 4752365 embedded image

B, n.d. [MH]⁺ = 4912366 embedded image

B, n.d. [MH]⁺ = 4632367 embedded image

B, n.d. [MH]⁺ = 4252368 embedded image

B, n.d. [MH]⁺ = 5192369 embedded image

B, n.d. [MH]⁺ = 4492370 embedded image

B, n.d. [MH]⁺ = 4612371 embedded image

B, n.d. [MH]⁺ = 4212372 embedded image

B, n.d. [MH]⁺ = 4632373 embedded image

B, n.d. [MH]⁺ = 4672374 embedded image

B, n.d. [MH]⁺ = 4832375 embedded image

B, n.d. [MH]⁺ = 4732376 embedded image

B, n.d. [MH]⁺ = 4352377 embedded image

B, n.d. [MH]⁺ = 4492378 embedded image

B, n.d. [MH]⁺ = 4782379 embedded image

B, n.d. [MH]⁺ = 4992380 embedded image

B, n.d. [MH]⁺ = 4492381 embedded image

B, n.d. [MH]⁺ = 4622382 embedded image

B, n.d. [MH]⁺ = 4872383 embedded image

B, n.d. [MH]⁺ = 4682384 embedded image

B, n.d. [MH]⁺ = 4652385 embedded image

B, n.d. [MH]⁺ = 4992386 embedded image

B, n.d. [MH]⁺ = 4782387 embedded image

B, n.d. [MH]⁺ = 445

Example 2388

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Step A

The title compound from the Example 2286 (4.5 mg) was treated similarly as described in the Example 2, Step A, except using commercially available tert-butylamine instead of the title compound from the Preparative Example 228, Step A to afford the title compound (1.9 mg, 37%). [MH]⁺=468.

Example 2389

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Step A

To a solution of the title compound from the Example 2289 (20 mg) in anhydrous THF (2 mL) was added 1,1′-carbonyldiimidazole (35 mg). The resulting mixture was stirred at room temperature for 1 h and then cooled to 0-5° C. (ice bath). A 2M solution of methylamine in THF (1 mL) was added and the ice bath was removed. The mixture was stirred at room temperature for 3 h, concentrated, diluted with H₂O and 10% aqueous citric acid and extracted with EtOAc (3×). The combined organic phases were washed saturated aqueous NaCl (200 mL), dried (MgSO₄), filtered, concentrated and purified by preparative thin layer chromatography (silica, CH₂Cl₂/MeOH) to afford the title compound (14 mg, 85%). [MH]⁺=392.

Example 2390

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Step A

The title compound from the Example 2289 (20 mg) was treated similarly as described in the Example 2389, Step A, except using a 2M solution of dimethylamine in THF instead of a 2M solution of methylamine in THF to afford the title compound (17.9 mg, 83%). [MH]⁺=406.

Example 2391

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Step A

A mixture of the title compound from the Example 2285 (8.5 mg) and conc. HCl (4.5 mL) in THF (3 mL) was stirred at room temperature for 6 h, concentrated, absorbed on silica and purified by chromatography (silica, CH₂Cl₂/MeOH) to afford the title compound I (1.3 mg, 15%, [MH]⁺=509) and title compound II (4 mg, 47%, [MH]⁺=492).

Example 2392

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Step A

To a suspension of the Preparative Example 377, Step E (30 mg) in cyclohexane (5 mL) were added tert-butyl 2,2,2-trichloroacetimidate (44 mg) and BF₃.Et₂O (2 drops). The resulting mixture was stirred at room temperature overnight, concentrated, absorbed on silica and purified by chromatography (silica, CH₂Cl₂/MeOH) to afford the title compound (10.2 mg, 34%). [MH]⁺=377.

Number	Date	Country
60734991	Nov 2005	US
60706465	Aug 2005	US
60683470	May 2005	US

	Number	Date	Country
Parent	11440087	May 2006	US
Child	11602140	Nov 2006	US

Heterobicyclic metalloprotease inhibitors

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CROSS REFERENCE TO RELATED APPLICATIONS

Provisional Applications (3)

Continuation in Parts (1)