TREA

Substituted dihydropyrrolopyrazole compound

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Information

  • Patent Grant
  • 10131679
  • Patent Number
    10,131,679
  • Date Filed
    Friday, October 30, 2015
    9 years ago
  • Date Issued
    Tuesday, November 20, 2018
    6 years ago
Information
Abstract
Provided is a compound represented by formula (I) or a pharmacologically acceptable salt thereof:
Description
TECHNICAL FIELD

The present invention relates to a substituted dihydropyrrolopyrazole compound or a pharmacologically acceptable salt thereof which has excellent CDK7 inhibitory activity and is useful as a medicament (e.g., a medicament for the treatment or prevention of cancers or inflammatory diseases), or a prodrug thereof.


BACKGROUND ART

CDKs (cyclin-dependent kinases) are cell growth control factors that are involved in entry to DNA synthesis (S phase) of the cell cycle and a mitotic phase (M phase), etc., and many types of CDKs are known. Also, the activation of CDK is controlled in multiple stages through the phosphorylation or dephosphorylation of the threonine residue of active loop (T loop) in its three-dimensional structure. When the particular threonine residue of CDK is phosphorylated, it forms a complex with a particular cyclin and is activated. This complex, which is important for cell cycle control, includes CDK1, CDK2/cyclin A, CDK1/cyclins B1 to B3 and CDK2, CDK4, CDK5, CDK6/cyclin D1 to D3, and CDK2/cyclin E, which are respectively involved in the particular periods of the cell cycle. CDK7 forms a CDK-activating kinase (CAK) together with cyclin H and MAT1 in metazoans and participates in the phosphorylation of CDKs (e.g., CDK1, CDK2, CDK4, and CDK6) necessary for the progression of the cell cycle (see Non Patent Literature 1).


Cell overgrowth by the abnormal activation of CDKs is a common feature in many cancers, and it is known that this is associated with a loss of checkpoint functions involved in the cell cycle control of cancer cells (see Non Patent Literature 2). Also, CDKs are known to have functions other than cell cycle control, and CDK7 is known to promote the binding of RNA polymerase II (RNAPII) to DNA and elongation thereof to positively control the transcription through the phosphorylation of serine in the COOH-terminal domain of the RNAPII (see Non Patent Literature 3).


CDK7 inhibitors exhibit effects in cell growth tests of various cancer cells and cancer-bearing mouse models, and the inhibition is expected to be useful as anticancer agents (see Non Patent Literatures 4 and 5).


Furthermore, it has been reported that in collagen-induced rheumatism mouse models, amelioration of clinical scores or tissue damage, decrease in the levels of inflammation-induced cytokines such as IL-6, IL-1β, and IL-17, and anti-CII-IgG2α, and decrease in the proportion of Th17 cells are attained by inhibiting CDK7 (see Non Patent Literature 6).


The CDK7 inhibitors, which play an important role in the progression of the cell cycle, are further expected to also have effects on the suppression of infection by viruses such as HIV, EBV, and HCV, and cardiomegaly (see Non Patent Literatures 7 and 8). Examples of diseases for which the CDK7 inhibitors seem to be useful, in addition to those described above, include autoimmune diseases typified by psoriasis and multiple sclerosis, neurodegenerative diseases typified by Alzheimer's disease, etc., allergic diseases typified by atopic dermatitis, etc., chronic respiratory diseases typified by chronic obstructive pulmonary disease (COPD), etc., and fibrosis typified by idiopathic pulmonary fibrosis, etc. (see Non Patent Literatures 9 to 11 and Non Patent Literatures 16 to 18).


Although the development of many CDK inhibitors is currently underway, there are not many compounds having an excellent CDK7 inhibitory effect (see Non Patent Literature 15).


CITATION LIST
Patent Literature



  • Patent Literature 1: WO 2002/012242

  • Patent Literature 2: WO 2004/056827

  • Patent Literature 3: WO 2004/080457

  • Patent Literature 4: WO 2007/068637

  • Patent Literature 5: WO 2007/072153

  • Patent Literature 6: WO 2007/099171

  • Patent Literature 7: WO 2008/043745

  • Patent Literature 8: WO 2008/125945

  • Patent Literature 9: WO 2011/044264

  • Patent Literature 10: WO 2008/151304

  • Patent Literature 11: WO 2013/128028

  • Patent Literature 12: WO 2013/128029

  • Patent Literature 13: WO 2014/063068

  • Patent Literature 14: WO 2015/058126

  • Patent Literature 15: WO 2015/058140

  • Patent Literature 16: WO 2015/058163

  • Patent Literature 17: WO 2015/124941

  • Patent Literature 18: WO 2015/154022

  • Patent Literature 19: WO 2015/154038

  • Patent Literature 20: WO 2015/154039



Non Patent Literature



  • Non Patent Literature 1: Journal of Cell Science 2005, 118 (20), 5171-5180

  • Non Patent Literature 2: Nature Reviews Cancer 2009, 9, 153-166

  • Non Patent Literature 3: Biochim Biophys Acta 2004, 1677, 64-73

  • Non Patent Literature 4: Nature 2014, 511, 616-620

  • Non Patent Literature 5: Cancer Res 2009, 69, 6208-6215

  • Non Patent Literature 6: Clinical and Experimental Medicine, 2015, 15, 269-275

  • Non Patent Literature 7: Curr HIV Res 2003, 1 (2), 131-152

  • Non Patent Literature 8: Mol Cell Biol 1998, 18 (11), 6729-6736

  • Non Patent Literature 9: Br J Dermatol 2000, 143 (5), 950-956

  • Non Patent Literature 10: Biochem Biophys Res Commun 2013, 435 (3), 378-384

  • Non Patent Literature 11: Neurobiol Aging 2000, 6, 807-813

  • Non Patent Literature 12: Journal of Medicinal Chemistry 2012, 55 (10), 4728-4739

  • Non Patent Literature 13: Bioorganic & Medicinal Chemistry 2010, 18 (5), 1844-1853

  • Non Patent Literature 14: Chem Med Chem 2007, 2, 841-852

  • Non Patent Literature 15: Current Drug Targets, 2010, 11, 291-302

  • Non Patent Literature 16: Clinical & Experimental Allergy, 2011, 41, 673-687

  • Non Patent Literature 17: Cell Death and Differentiation, 2012, 19, 1950-1961

  • Non Patent Literature 18: Am. J. Physiol. Lung Cell Mol, 2004, 286, 727-733



SUMMARY OF INVENTION
Technical Problem

The present inventors have conducted studies on novel substituted dihydropyrrolopyrazole compounds with the aim of developing excellent CDK7 inhibitors and completed the present invention by finding that a novel substituted dihydropyrrolopyrazole compound having a particular structure or a pharmacologically acceptable salt thereof has excellent CDK7 inhibitory activity and is useful as a medicament (e.g., a medicament for the treatment or prevention of cancers or inflammatory diseases), and further finding even a compound that can serve as a prodrug of the compound.


Patent Literatures 1 to 9 and Non Patent Literatures 12 to 14 describe a compound having a 6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole skeleton, but do not disclose the compound according to the present invention or the pharmacologically acceptable salt thereof.


As compounds inhibiting CDK7, pyrazolopyrimidine derivatives are disclosed in Patent Literature 10, pyrazolotriazine derivatives are disclosed in Patent Literatures 11 and 12, phenyl derivatives are disclosed in Patent Literature 13 and Non Patent Literature 4, and heterocyclic compounds are disclosed in Patent Literatures 14 to 20; however, a compound having a 4,6-dihydropyrrolo[3,4-c]pyrazole skeleton is not disclosed.


Solution to Problem

The present invention provides a novel substituted dihydropyrrolopyrazole compound or a pharmacologically acceptable salt thereof which has excellent CDK7 inhibitory activity, or a prodrug thereof;


a pharmaceutical composition, preferably a pharmaceutical composition for the treatment or prevention of cancers, inflammatory diseases (e.g., autoimmune diseases), infection by viruses (HIV, EBV, HCV, etc.), neurodegenerative diseases (e.g., Alzheimer's disease), allergic diseases (e.g., atopic dermatitis), chronic respiratory diseases (e.g., chronic obstructive pulmonary disease (COPD)), fibrosis (e.g., idiopathic pulmonary fibrosis), circulatory diseases such as cardiomegaly, or impotence, comprising the substituted dihydropyrrolopyrazole compound or the pharmacologically acceptable salt thereof, or the prodrug thereof as an active ingredient;


use of the substituted dihydropyrrolopyrazole compound or the pharmacologically acceptable salt thereof, or the prodrug thereof for the production of a pharmaceutical composition for the treatment or prevention (preferably, treatment) of diseases (preferably, the diseases described above);


a method for treating or preventing (preferably, treating) diseases (preferably, the diseases described above) by administering a pharmaceutically effective amount of the substituted dihydropyrrolopyrazole compound or the pharmacologically acceptable salt thereof, or the prodrug thereof to a warm-blooded animal (preferably, a human); and a method for producing the substituted dihydropyrrolopyrazole compound or the pharmacologically acceptable salt thereof, or the prodrug thereof, or an intermediate thereof.


Examples of the cancers include urinary bladder cancer, breast cancer, large intestine cancer (e.g., colorectal cancer, for example, colon adenocarcinoma and colon adenoma), gastrointestinal stromal tumor, kidney cancer, epidermal cancer, liver cancer, lung cancer (e.g., adenocarcinoma, small-cell lung cancer, and non-small cell lung cancer), esophageal cancer, gallbladder cancer, ovary cancer, pancreatic cancer (e.g., exocrine pancreatic tumor), gastric cancer, cervical cancer, endometrial cancer, thyroid gland cancer, cancer of the nose, head and neck cancer, prostate cancer, skin cancer (e.g., squamous cell cancer), hematopoietic organ tumors of the lymphatic system (e.g., leukemia, acute lymphatic leukemia, chronic lymphatic leukemia, B cell lymphoma (e.g., diffuse large B cell lymphoma), T cell lymphoma, multiple myeloma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, and Burkitt's lymphoma), hematopoietic organ tumors of the myeloid system (e.g., acute or chronic myeloid leukemia, myelodysplastic syndrome, and promyelocytic leukemia), follicular carcinoma of thyroid, mesenchymal tumors (e.g., fibrosarcoma, Ewing's sarcoma, and rhabdomyosarcoma), tumors of the central or peripheral nervous system (e.g., astrocytoma, neuroblastoma, glioma, brain tumor, and schwannoma), melanoma, seminoma, teratoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, follicular carcinoma of thyroid, and Kaposi's sarcoma.


Examples of the autoimmune diseases include multiple sclerosis, Guillain-Barre syndrome, myasthenia gravis, chronic atrophic gastritis, autoimmune hepatitis, primary biliary cirrhosis, ulcerative colitis, Crohn's disease, primary sclerosing cholangitis, autoimmune pancreatitis, aortitis syndrome, Goodpasture's syndrome, rapidly progressive glomerulonephritis, megaloblastic anemia, autoimmune hemolytic anemia, autoimmune neutropenia, idiopathic thrombocytopenic purpura, Graves' disease, Hashimoto disease, primary hypothyroidism, idiopathic Addison's disease, type 1 diabetes mellitus, circumscribed scleroderma, epidermolysis bullosa acquisita, vitiligo vulgaris, autoimmune optic neuropathy, autoimmune inner ear disorder, idiopathic azoospermia, rheumatoid arthritis, systemic lupus erythematosus, drug-induced lupus erythematosus, Sjogren's syndrome, polymyositis, psoriasis, dermatomyositis, scleroderma, vasculitis syndrome, mixed connective-tissue disease, and inflammatory bowel disease. In this context, the inflammatory bowel disease (IBD) is a generic name for diseases that cause chronic inflammation or ulcer in the large intestinal or small intestinal mucosa, and examples thereof include Crohn disease and ulcerative colitis.


In one aspect, the present invention provides the following [1] to [24]:

  • [1] A compound represented by formula (I) or a pharmacologically acceptable salt thereof:




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wherein


L1 is an optionally substituted linear or branched C1-6 alkylene group, an optionally substituted linear or branched C2-6 alkenylene group, an optionally substituted linear or branched C2-6 alkynylene group, an optionally substituted C3-6 cycloalkylene group, or an optionally substituted C3-6 cycloalkenylene group,


L2 is a single bond, an oxygen atom, an optionally substituted nitrogen atom, an optionally substituted linear or branched C1-6 alkylene group, an optionally substituted linear or branched C2-6 alkenylene group, an optionally substituted linear or branched C2-6 alkynylene group, an optionally substituted C3-6 cycloalkylene group, or an optionally substituted C3-6 cycloalkenylene group,


L3 is a single bond, an optionally substituted linear or branched C1-6 alkylene group, an optionally substituted linear or branched C2-6 alkenylene group, an optionally substituted linear or branched C2-6 alkynylene group, an optionally substituted C3-6 cycloalkylene group, or an optionally substituted C3-6 cycloalkenylene group,


R1, R2, and R3 are each independently an optionally substituted linear or branched C1-4 alkyl group, an optionally substituted linear or branched C2-4 alkenyl group, an optionally substituted linear or branched C2-4 alkynyl group, an optionally substituted C6-10 aryl group, or an optionally substituted heterocyclic group,


R4 is a hydrogen atom, an optionally substituted linear or branched C1-6 alkyl group, an optionally substituted linear or branched C2-6 alkenyl group, an optionally substituted linear or branched C2-6 alkynyl group, an optionally substituted C3-6 cycloalkyl group, an optionally substituted C3-6 cycloalkenyl group, an optionally substituted C6-10 aryl group, or an optionally substituted heterocyclic group, and


R5 is a hydrogen atom, an optionally substituted linear or branched C1-16 alkyl group, an optionally substituted linear or branched C2-16 alkenyl group, an optionally substituted linear or branched C2-16 alkynyl group, an optionally substituted C3-6 cycloalkyl group, an optionally substituted C3-6 cycloalkenyl group, an optionally substituted C6-10 aryl group, or an optionally substituted heterocyclic group.

  • [2] The compound or a pharmacologically acceptable salt thereof according to [1], wherein L1 is an optionally substituted linear or branched C1-6 alkylene group or an optionally substituted C3-6 cycloalkylene group.
  • [3] A compound represented by formula (II) or a pharmacologically acceptable salt thereof:




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wherein


L2 is a single bond, an oxygen atom, an optionally substituted nitrogen atom, an optionally substituted linear or branched C1-6 alkylene group, an optionally substituted linear or branched C2-6 alkenylene group, an optionally substituted linear or branched C2-6 alkynylene group, an optionally substituted C3-6 cycloalkylene group, or an optionally substituted C3-6 cycloalkenylene group,


L3 is a single bond, an optionally substituted linear or branched C1-6 alkylene group, an optionally substituted linear or branched C2-6 alkenylene group, an optionally substituted linear or branched C2-6 alkynylene group, an optionally substituted C3-6 cycloalkylene group, or an optionally substituted C3-6 cycloalkenylene group,


R1, R2, and R3 are each independently an optionally substituted linear or branched C1-4 alkyl group, an optionally substituted linear or branched C2-4 alkenyl group, an optionally substituted linear or branched C2-4 alkynyl group, an optionally substituted C6-10 aryl group, or an optionally substituted heterocyclic group,


R4 is a hydrogen atom, an optionally substituted linear or branched C1-6 alkyl group, an optionally substituted linear or branched C2-6 alkenyl group, an optionally substituted linear or branched C2-6 alkynyl group, an optionally substituted C3-6 cycloalkyl group, an optionally substituted C3-6 cycloalkenyl group, an optionally substituted C6-10 aryl group, or an optionally substituted heterocyclic group, and


R5 is a hydrogen atom, an optionally substituted linear or branched C1-16 alkyl group, an optionally substituted linear or branched C2-16 alkenyl group, an optionally substituted linear or branched C2-16 alkynyl group, an optionally substituted C3-6 cycloalkyl group, an optionally substituted C3-6 cycloalkenyl group, an optionally substituted C6-10 aryl group, or an optionally substituted heterocyclic group.

  • [4] The compound or a pharmacologically acceptable salt thereof according to [3], wherein R1, R2, and R3 are each independently an optionally substituted linear or branched C1-4 alkyl group.
  • [5] A compound represented by formula (III) or a pharmacologically acceptable salt thereof:




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wherein


L2 is a single bond, an oxygen atom, an optionally substituted nitrogen atom, an optionally substituted linear or branched C1-6 alkylene group, an optionally substituted linear or branched C2-6 alkenylene group, an optionally substituted linear or branched C2-6 alkynylene group, an optionally substituted C3-6 cycloalkylene group, or an optionally substituted C3-6 cycloalkenylene group,


L3 is a single bond, an optionally substituted linear or branched C1-6 alkylene group, an optionally substituted linear or branched C2-6 alkenylene group, an optionally substituted linear or branched C2-6 alkynylene group, an optionally substituted C3-6 cycloalkylene group, or an optionally substituted C3-6 cycloalkenylene group,


R1, R2, and R3 are each independently an optionally substituted linear or branched C1-4 alkyl group, an optionally substituted linear or branched C2-4 alkenyl group, an optionally substituted linear or branched C2-4 alkynyl group, an optionally substituted C6-10 aryl group, or an optionally substituted heterocyclic group,


R4 is a hydrogen atom, an optionally substituted linear or branched C1-6 alkyl group, an optionally substituted linear or branched C2-6 alkenyl group, an optionally substituted linear or branched C2-6 alkynyl group, an optionally substituted C3-6 cycloalkyl group, an optionally substituted C3-6 cycloalkenyl group, an optionally substituted C6-10 aryl group, or an optionally substituted heterocyclic group, and


R5 is a hydrogen atom, an optionally substituted linear or branched C1-16 alkyl group, an optionally substituted linear or branched C2-16 alkenyl group, an optionally substituted linear or branched C2-16 alkynyl group, an optionally substituted C3-6 cycloalkyl group, an optionally substituted C3-6 cycloalkenyl group, an optionally substituted C6-10 aryl group, or an optionally substituted heterocyclic group.

  • [6] The compound or a pharmacologically acceptable salt thereof according to [5], wherein R1, R2, and R3 are each independently an optionally substituted linear or branched C1-4 alkyl group.
  • [7] A compound represented by formula (IV) or a pharmacologically acceptable salt thereof:




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wherein


L2 is a single bond, an oxygen atom, an optionally substituted nitrogen atom, an optionally substituted linear or branched C1-6 alkylene group, an optionally substituted linear or branched C2-6 alkenylene group, an optionally substituted linear or branched C2-6 alkynylene group, an optionally substituted C3-6 cycloalkylene group, or an optionally substituted C3-6 cycloalkenylene group,


L3 is a single bond, an optionally substituted linear or branched C1-6 alkylene group, an optionally substituted linear or branched C2-6 alkenylene group, an optionally substituted linear or branched C2-6 alkynylene group, an optionally substituted C3-6 cycloalkylene group, or an optionally substituted C3-6 cycloalkenylene group,


R1, R2, and R3 are each independently an optionally substituted linear or branched C1-4 alkyl group, an optionally substituted linear or branched C2-4 alkenyl group, an optionally substituted linear or branched C2-4 alkynyl group, an optionally substituted C6-10 aryl group, or an optionally substituted heterocyclic group,


R4 is a hydrogen atom, an optionally substituted linear or branched C1-6 alkyl group, an optionally substituted linear or branched C2-6 alkenyl group, an optionally substituted linear or branched C2-6 alkynyl group, an optionally substituted C3-6 cycloalkyl group, an optionally substituted C3-6 cycloalkenyl group, an optionally substituted C6-10 aryl group, or an optionally substituted heterocyclic group, and


R5 is a hydrogen atom, an optionally substituted linear or branched C1-16 alkyl group, an optionally substituted linear or branched C2-16 alkenyl group, an optionally substituted linear or branched C2-16 alkynyl group, an optionally substituted C3-6 cycloalkyl group, an optionally substituted C3-6 cycloalkenyl group, an optionally substituted C6-10 aryl group, or an optionally substituted heterocyclic group.

  • [8] The compound or a pharmacologically acceptable salt thereof according to [7], wherein R1, R2, and R3 are each independently an optionally substituted linear or branched C1-4 alkyl group.
  • [9] A compound represented by formula (V) or (VI) or a pharmacologically acceptable salt thereof:




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wherein


L1 is an optionally substituted linear or branched C1-6 alkylene group, an optionally substituted linear or branched C2-6 alkenylene group, an optionally substituted linear or branched C2-6 alkynylene group, an optionally substituted C3-6 cycloalkylene group, or an optionally substituted C3-6 cycloalkenylene group,


L2 is a single bond, an oxygen atom, an optionally substituted nitrogen atom, an optionally substituted linear or branched C1-6 alkylene group, an optionally substituted linear or branched C2-6 alkenylene group, an optionally substituted linear or branched C2-6 alkynylene group, an optionally substituted C3-6 cycloalkylene group, or an optionally substituted C3-6 cycloalkenylene group,


L3 is a single bond, an optionally substituted linear or branched C1-6 alkylene group, an optionally substituted linear or branched C2-6 alkenylene group, an optionally substituted linear or branched C2-6 alkynylene group, an optionally substituted C3-6 cycloalkylene group, or an optionally substituted C3-6 cycloalkenylene group,


R1, R2, and R3 are each independently an optionally substituted linear or branched C1-4 alkyl group, an optionally substituted linear or branched C2-4 alkenyl group, an optionally substituted linear or branched C2-4 alkynyl group, an optionally substituted C6-10 aryl group, or an optionally substituted heterocyclic group,


R4 is a hydrogen atom, an optionally substituted linear or branched C1-6 alkyl group, an optionally substituted linear or branched C2-6 alkenyl group, an optionally substituted linear or branched C2-6 alkynyl group, an optionally substituted C3-6 cycloalkyl group, an optionally substituted C3-6 cycloalkenyl group, an optionally substituted C6-10 aryl group, or an optionally substituted heterocyclic group, and


R6 is a hydrogen atom, an optionally substituted linear or branched C1-16 alkyl group, an optionally substituted linear or branched C2-16 alkenyl group, an optionally substituted linear or branched C2-16 alkynyl group, an optionally substituted C3-6 cycloalkyl group, an optionally substituted C3-6 cycloalkenyl group, an optionally substituted linear or branched C1-6 alkoxy group, an optionally substituted C6-10 aryl group, or an optionally substituted heterocyclic group,


R7 is an optionally substituted linear or branched C1-16 alkyl group, an optionally substituted linear or branched C2-16 alkenyl group, an optionally substituted linear or branched C2-16 alkynyl group, an optionally substituted C3-6 cycloalkyl group, an optionally substituted C3-6 cycloalkenyl group, an optionally substituted C6-10 aryl group, or an optionally substituted heterocyclic group, and


R8 and R9 are each independently a hydrogen atom or a C1-4 alkyl group.

  • [10] The compound or a pharmacologically acceptable salt thereof according to [9], wherein L1 is an optionally substituted linear or branched C1-6 alkylene group or an optionally substituted C3-6 cycloalkylene group, and R1, R2, and R3 are each independently an optionally substituted linear or branched C1-4 alkyl group.
  • [11] A compound selected from a compound group consisting of
  • (S)—N-(2-hydroxy-1-phenylethyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (S)—N-(2-hydroxy-1-phenylethyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (S)—N-(2-hydroxy-1-phenylethyl)-6,6-dimethyl-3-[2-methyl-2-(trimethylsilyl)propaneamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (S)-3-[1-(ethyldimethylsilyl)cyclobutanecarboxamido]-N-(2-hydroxy-1-phenylethyl)-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (S)-3-[2-(ethyldimethylsilyl)-2-methylpropaneamido]-N-(2-hydroxy-1-phenylethyl)-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (S)—N-(2-hydroxy-1-phenylethyl)-N,6,6-trimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (S)-2-[(2-methoxypropan-2-yl)oxy]-1-phenylethyl6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate,
  • (S)-2-hydroxy-1-phenylethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate,
  • 2-Methoxy-1-phenylethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate,
  • N-[5-(4-hydroxy-3-phenylbutanoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide,
  • N-[5-(3-hydroxy-3-phenylpropanoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide,
  • (R)—N-(3-hydroxy-1-phenylpropyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (R)—N-(3-hydroxy-1-phenylpropyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (R)—N-(4-hydroxy-1-phenylbutyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (R)—N-(5-hydroxy-1-phenylpentyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (S)—N-(2-hydroxy-2-methyl-1-phenylpropyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (S)—N-(2-hydroxy-2-methyl-1-phenylpropyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • N-(3-hydroxy-2,2-dimethyl-1-phenylpropyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (R)—N-(3-hydroxy-3-methyl-1-phenylbutyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (S)—N-(2-methoxy-1-phenylethyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (S)—N-[2-(difluoromethoxy)-1-phenylethyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (S)—N-(2-ethoxy-1-phenylethyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (R)—N-(3-methoxy-1-phenylpropyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • Sodium
  • (S)-2-{6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylacetate,
  • (R)—N-(2-hydroxy-1-phenylethyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • N-[1-(2-fluorophenyl)-2-hydroxyethyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (S)—N-[1-(3-fluorophenyl)-2-hydroxyethyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (S)—N-[1-(4-fluorophenyl)-2-hydroxyethyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • N-[2-hydroxy-1-(pyridin-2-yl)ethyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • N-[2-hydroxy-1-(pyridin-3-yl)ethyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • N-[1-(benzo[d][1,3]dioxol-4-yl)-2-hydroxyethyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (S)—N-(1-cyclohexyl-2-hydroxyethyl)-6,6-dimethyl-3-[1-(trimethylsilyl) cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (S)—N-(1-hydroxy-3-methylbutan-2-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (S)—N-(1-hydroxypropan-2-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • N-(2-hydroxyethyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • N-(2-hydroxy-2-phenylethyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • N-(2-hydroxypropyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • N-[(2S)-1-hydroxy-3-methyl-1-phenylbutan-2-yl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • N-(4-hydroxy-1-phenyl-2-butyn-1-yl)-6,6-dimethyl-3-[1-(trimethylsilyl) cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (S)-2-{6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylethyl acetate,
  • (S)-2-{6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylethyl propionate,
  • (S)-2-{6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylethyl butanoate,
  • (S)-2-{6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylethyl pentanoate,
  • (S)-2-{6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylethyl octanoate,
  • (S)-2-{6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylethyl dodecanoate,
  • (S)-2-{6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylethyl palmitate,
  • (S)-2-{6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylethyl isobutanoate,
  • (S)-2-{6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylethyl pivalate,
  • (S)-2-{6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylethyl 3-methyl butanoate,
  • (S)-2-{6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylethyl benzoate,
  • (S)-2-{6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylethyl ethyl carbonate,
  • Sodium
  • (S)-4-(2-{6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylethoxy)-4-oxobutanoate,
  • (S)-(2-{6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylethoxy) methyl pivalate,
  • (S)-2-acetoxy-1-phenylethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate,
  • (S)-benzyl
  • 2-{6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylacetate,
  • (S)-methyl
  • 2-{6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylacetate,
  • N-(2,2-difluoro-3-hydroxy-1-phenylpropyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • N-(2-isopropoxy-1-phenylethyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • 6,6-Dimethyl-N-(2-phenoxy-1-phenylethyl)-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (S)—N-[1-(2-chlorophenyl)-2-hydroxyethyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (S)—N-[2-hydroxy-1-(o-tolyl)ethyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (S)—N-(1-hydroxy-3-phenylpropan-2-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • N-(2-hydroxy-3-methylbutyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (R)—N-(1-hydroxy-3-phenylpropan-2-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (R)—N-(2-hydroxy-2-phenylethyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (S)—N-(2-hydroxy-2-phenylethyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • 2-Hydroxy-2-phenylethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate,
  • (R)—N-[6,6-dimethyl-5-(2-phenoxypropanoyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide,
  • (S)—N-[6,6-dimethyl-5-(2-phenoxypropanoyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide,
  • N-[6,6-dimethyl-5-(2-phenoxyacetyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide,
  • (R)—N-[6,6-dimethyl-5-(2-phenoxypropanoyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclopropanecarboxamide,
  • N-{5-[3-(benzyloxy)-2-phenoxypropanoyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide,
  • N-[5-(3-hydroxy-2-phenoxypropanoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide,
  • N-{5-[2-(4-chlorophenoxy)propanoyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide,
  • N-{5-[2-(2-chlorophenoxy)propanoyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide,
  • N-{5-[2-(cyclohexyloxy)propanoyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide,
  • N-{5-[2-(3-chlorophenoxy)propanoyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide,
  • N-[5-(2-methoxypropanoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide,
  • N-[5-(3-methoxy-2-phenoxypropanoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide,
  • N-{6,6-dimethyl-5-[2-(pyridin-3-yloxy)propanoyl]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide,
  • N-{5-[3-(dimethylamino)-2-phenoxypropanoyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide,
  • N-[6,6-dimethyl-5-(2-phenoxy-2-phenylacetyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide,
  • N-{5-[3-(3,3-difluoropyrrolidin-1-yl)-2-phenoxypropanoyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide,
  • N-[5-(3-hydroxy-2-phenylpropanoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide,
  • (S)—N-[5-(3-hydroxy-2-phenylpropanoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide,
  • (R)—N-{5-[3-(benzyloxy)-2-phenylpropanoyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide,
  • (R)—N-[5-(3-hydroxy-2-phenylpropanoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide,
  • (R)—N-[5-(2-methoxy-2-phenylacetyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide,
  • (S)—N-[5-(2-methoxy-2-phenylacetyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide,
  • N-[5-(3-methoxy-2-phenylpropanoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide,
  • N-[5-(4-methoxy-2-phenylbutanoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide,
  • (S)—N-[5-(3-hydroxy-2-phenylpropanoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclopropanecarboxamide,
  • (R)—N-[5-(2-methoxy-2-phenylacetyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclopropanecarboxamide,
  • (R)—N-{5-[2-(difluoromethoxy)-2-phenylacetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide,
  • (R)—N-[5-(2-ethoxy-2-phenylacetyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide,
  • (R)-1-(ethyldimethylsilyl)-N-[5-(2-methoxy-2-phenylacetyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]cyclobutanecarboxamide,
  • (R)—N-[5-(2-cyclopropoxy-2-phenylacetyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide,
  • (R)—N-[5-(2-isopropoxy-2-phenylacetyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide,
  • (R)—N-{6,6-dimethyl-5-[2-phenyl-2-(trifluoromethoxy)acetyl]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide,
  • (R)—N-[6,6-dimethyl-5-(2-phenyl-2-propoxyacetyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide,
  • N-{5-[2-(4-fluorophenyl)-2-methoxyacetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide,
  • N-{5-[2-(3-fluorophenyl)-2-methoxyacetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide,
  • (R)—N-{5-[2-(2-fluorophenyl)-2-methoxyacetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide,
  • N-{5-[2-methoxy-2-(thiophen-2-yl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide,
  • (−)-N-{5-[2-methoxy-2-(thiophen-2-yl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide,
  • (+)-N-{5-[2-methoxy-2-(thiophen-2-yl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide,
  • N-{[1-(hydroxymethyl)cyclobutyl](phenyl)methyl}-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (R)—N-[2-(1-hydroxycyclopropyl)-1-phenylethyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (R)—N-(3-ethyl-3-hydroxy-1-phenylpentyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (R)—N-[1-(4-fluorophenyl)-3-hydroxy-3-methylbutyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (R)—N-[1-(3-fluorophenyl)-3-hydroxy-3-methylbutyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (R)—N-[1-(2-fluorophenyl)-3-hydroxy-3-methylbutyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (R)—N-(5-hydroxy-2,5-dimethylhexan-3-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • N-[1-(4-fluorophenyl)-3-hydroxy2,2-dimethylpropyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • N-[1-(3-fluorophenyl)-3-hydroxy-2,2-dimethylpropyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (−)-N-[1-(3-fluorophenyl)-3-hydroxy-2,2-dimethylpropyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (+)-N-[1-(3-fluorophenyl)-3-hydroxy-2,2-dimethylpropyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • N-[1-(2-fluorophenyl)-3-hydroxy-2,2-dimethylpropyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • N-(1-hydroxy-2,2,4-trimethylpentan-3-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (R)—N-(3-hydroxy-3-methyl-1-phenylbutyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • N-(3-hydroxy-2,2-dimethyl-1-phenylpropyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (−)-N-(3-hydroxy-2,2-dimethyl-1-phenylpropyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (+)-N-(3-hydroxy-2,2-dimethyl-1-phenylpropyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (R)—N-[5-(2-butoxy-2-phenylacetyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide, and
  • N-(3-methoxy-2,2-dimethyl-1-phenylpropyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide
  • or a pharmacologically acceptable salt thereof.
  • [12]


(R)—N-[1-(4-fluorophenyl)-3-hydroxy-3-methylbutyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide or a pharmacologically acceptable salt thereof.

  • [13]


(−)-N-(3-hydroxy-2,2-dimethyl-1-phenylpropyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropane-1-carboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide or a pharmacologically acceptable salt thereof.

  • [14]


(R)—N-[5-(2-methoxy-2-phenylacetyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide or a pharmacologically acceptable salt thereof.

  • [15]


(R)—N-[6,6-dimethyl-5-(2-phenyl-2-propoxyacetyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide or a pharmacologically acceptable salt thereof.

  • [16]


(R)—N-{5-[2-(2-fluorophenyl)-2-methoxyacetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide or a pharmacologically acceptable salt thereof.

  • [17]


(R)—N-[5-(2-ethoxy-2-phenylacetyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide or a pharmacologically acceptable salt thereof.

  • [18]


(R)—N-[5-(2-cyclopropoxy-2-phenylacetyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide or a pharmacologically acceptable salt thereof.

  • [19]


(R)—N-[5-(2-isopropoxy-2-phenylacetyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide or a pharmacologically acceptable salt thereof.

  • [20]


(+)-N-{5-[2-methoxy-2-(thiophen-2-yl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide or a pharmacologically acceptable salt thereof.

  • [21]


(−)-N-[1-(3-fluorophenyl)-3-hydroxy-2,2-dimethylpropyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide or a pharmacologically acceptable salt thereof.

  • [22]


N-{5-[2-(3-fluorophenyl)-2-methoxyacetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide or a pharmacologically acceptable salt thereof.

  • [23]


N-[1-(4-fluorophenyl)-3-hydroxy-2,2-dimethylpropyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide or a pharmacologically acceptable salt thereof.

  • [24]


(R)—N-[1-(3-fluorophenyl)-3-hydroxy-3-methylbutyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide or a pharmacologically acceptable salt thereof.

  • [25]


(R)—N-{6,6-dimethyl-5-[2-phenyl-2-(trifluoromethoxy)acetyl]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide or a pharmacologically acceptable salt thereof.

  • [26]


(R)—N-[2-(1-hydroxycyclopropyl)-1-phenylethyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide or a pharmacologically acceptable salt thereof.

  • [27]


(R)—N-(3-hydroxy-3-methyl-1-phenylbutyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide or a pharmacologically acceptable salt thereof.

  • [28]


(R)—N-[5-(2-methoxy-2-phenylacetyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclopropanecarboxamide or a pharmacologically acceptable salt thereof.

  • [29]


(R)—N-{5-[2-(difluoromethoxy)-2-phenylacetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide or a pharmacologically acceptable salt thereof.

  • [30]


(R)-1-(ethyldimethylsilyl)-N-[5-(2-methoxy-2-phenylacetyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]cyclobutanecarboxamide or a pharmacologically acceptable salt thereof.

  • [31]


N-{[1-(hydroxymethyl)cyclobutyl](phenyl)methyl}-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide or a pharmacologically acceptable salt thereof.

  • [32] A pharmaceutical composition comprising the compound or a pharmacologically acceptable salt thereof according to any of [1] to [31].
  • [33] The pharmaceutical composition according to [32], wherein the pharmaceutical composition is a CDK7 inhibitor or a prophylactic agent.
  • [34] The pharmaceutical composition according to [32] or [33], wherein the pharmaceutical composition is for treating or preventing a cancer or an inflammatory disease.
  • [35] The pharmaceutical composition according to [34], wherein the inflammatory disease is an autoimmune disease.
  • [36] The pharmaceutical composition according to [35], wherein the autoimmune disease is rheumatoid arthritis or psoriasis.
  • [37] A method for treating or preventing a cancer or an inflammatory disease, comprising administering the compound or the pharmacologically acceptable salt thereof according to any of [1] to [31] to a subject in need thereof.
  • [38] The method according to [37], wherein the inflammatory disease is an autoimmune disease.
  • [39] The method according to [38], wherein the autoimmune disease is rheumatoid arthritis or psoriasis.
  • [40] Use of the compound or the pharmacologically acceptable salt thereof according to any of [1] to [31] for the production of a pharmaceutical composition which is a CDK7 inhibitor or a prophylactic agent.
  • [41] Use of the compound or the pharmacologically acceptable salt thereof according to any of [1] to [31] for inhibiting CDK7.
  • [42] Use of the compound or the pharmacologically acceptable salt thereof according to any of [1] to [31] for treating or preventing a cancer or an inflammatory disease.
  • [43] Use according to [42], wherein the inflammatory disease is an autoimmune disease.
  • [44] Use according to [43], wherein the autoimmune disease is rheumatoid arthritis or psoriasis.
  • [45] The compound or the pharmacologically acceptable salt thereof according to any of [1] to [31] for use as an active ingredient for a pharmaceutical composition.
  • [46] The compound or the pharmacologically acceptable salt thereof according to [45], wherein the pharmaceutical composition is a pharmaceutical composition for the treatment of a cancer or an inflammatory disease.
  • [47] The compound or the pharmacologically acceptable salt thereof according to [46], wherein the inflammatory disease is an autoimmune disease.
  • [48] The compound or the pharmacologically acceptable salt thereof according to [47], wherein the autoimmune disease is rheumatoid arthritis or psoriasis.


Specific examples of the compound represented by formula (I) of the present invention can include compounds as shown in Tables 1 to 164 described below. In Tables 1 to 164 described below, Me represents a methyl group, Et represents an ethyl group, nPr represents a n-propyl group, iPr represents an isopropyl group, cPr represents a cyclopropyl group, nBu represents a n-butyl group, iBu represents an isobutyl group, tBu represents a tert-butyl group, cHex represents a cyclohexyl group, Ph represents a phenyl group, 2-F-Ph represents a 2-fluorophenyl group, 3-F-Ph represents a 3-fluorophenyl group, 4-F-Ph represents a 4-fluorophenyl group, 2-Cl-Ph represents a 2-chlorophenyl group, 3-Cl-Ph represents a 3-chlorophenyl group, 4-Cl-Ph represents a 4-chlorophenyl group, 2-Me-Ph represents a 2-methylphenyl group, 3-Me-Ph represents a 3-methylphenyl group, 4-Me-Ph represents a 4-methylphenyl group, 2-Py represents a 2-pyridyl group, 3-Py represents a 3-pyridyl group, 4-Py represents a 4-pyridyl group, Bn represents a benzyl group, “-” represents a single bond, “(R)—” and “(S)—” each represent the configuration of a carbon atom with “*” in the following formulas (I), (II), (III), (IV), (Va), (Vb), (Vc), (VIa), (VIb), and (VIc), “racemic” represents being a racemate, “(+)” represents being a dextrorotatory optically active form, and “(−)” represents being a levorotatory optically active form. As for each chemical structure described as L1, L2, or L3 in the tables, the atom positioned on the left side of the chemical structure binds to a silicon atom, a carbonyl group, or a carbon atom with “*” in the corresponding formula. In the case of, for example, a compound of compound No. I-21, CH2—C(Me)2 corresponding to L1 means that the methylene carbon atom (CH2) binds to a silicon atom and the quaternary carbon atom (C) binds to a carbonyl group, and C≡CCH2 corresponding to L3 means that the quaternary carbon atom (C) binds to a carbon atom with “*” and the methylene carbon atom (CH2) binds to an oxygen atom adjacent to R5.









TABLE 1







(I)




embedded image





















Com-











pound








Con-


No.
R1
R2
R3
L1
L2
R4
L3
R5
figuration





I-1 
Me
Me
Me
CH2
O
Ph
CH2
H
racemic


I-2 
Me
Me
Me
CH2
O
Ph
CH2
H
(S)-


I-3 
Me
Me
Me
CH2
O
Ph
CH2
Me
racemic


I-4 
Me
Me
Me
CH2
O
Ph
CH2
Me
(S)-


I-5 
Me
Me
Me
CH2
O
Ph
(CH2)2
H
racemic


I-6 
Me
Me
Me
CH2
O
Ph
(CH2)2
H
(R)-


I-7 
Me
Me
Me
CH2
O
Ph
(CH2)2
Me
racemic


I-8 
Me
Me
Me
CH2
O
Ph
(CH2)2
Me
(R)-


I-9 
Me
Me
Me
CH2
O
Ph
C≡CCH2
H
racemic


I-10
Me
Me
Me
CH2
O
Ph
C≡CCH2
H
(S)-


I-11
Me
Me
Me
CH2
O
Ph
C≡CCH2
Me
racemic


I-12
Me
Me
Me
CH2
O
Ph
C≡CCH2
Me
(S)-


I-13
Me
Me
Me
CH2C(Me)2
O
Ph
CH2
H
racemic


I-14
Me
Me
Me
CH2C(Me)2
O
Ph
CH2
H
(S)-


I-15
Me
Me
Me
CH2C(Me)2
O
Ph
CH2
Me
racemic


I-16
Me
Me
Me
CH2C(Me)2
O
Ph
CH2
Me
(S)-


I-17
Me
Me
Me
CH2C(Me)2
O
Ph
(CH2)2
H
racemic


I-18
Me
Me
Me
CH2C(Me)2
O
Ph
(CH2)2
H
(R)-


I-19
Me
Me
Me
CH2C(Me)2
O
Ph
(CH2)2
Me
racemic


I-20
Me
Me
Me
CH2C(Me)2
O
Ph
(CH2)2
Me
(R)-


I-21
Me
Me
Me
CH2C(Me)2
O
Ph
C≡CCH2
H
racemic


I-22
Me
Me
Me
CH2C(Me)2
O
Ph
C≡CCH2
H
(S)-


I-23
Me
Me
Me
CH2C(Me)2
O
Ph
C≡CCH2
Me
racemic


I-24
Me
Me
Me
CH2C(Me)2
O
Ph
C≡CCH2
Me
(S)-


I-25
Me
Me
Me
CH2CH═CH
O
Ph
CH2
H
racemic


I-26
Me
Me
Me
CH2CH═CH
O
Ph
CH2
H
(S)-


I-27
Me
Me
Me
CH2CH═CH
O
Ph
CH2
Me
racemic


I-28
Me
Me
Me
CH2CH═CH
O
Ph
CH2
Me
(S)-


I-29
Me
Me
Me
CH2CH═CH
O
Ph
(CH2)2
H
racemic


I-30
Me
Me
Me
CH2CH═CH
O
Ph
(CH2)2
H
(R)-


I-31
Me
Me
Me
CH2CH═CH
O
Ph
(CH2)2
Me
racemic


I-32
Me
Me
Me
CH2CH═CH
O
Ph
(CH2)2
Me
(R)-


I-33
Me
Me
Me
CH2CH═CH
O
Ph
C≡CCH2
H
racemic


I-34
Me
Me
Me
CH2CH═CH
O
Ph
C≡CCH2
H
(S)-


I-35
Me
Me
Me
CH2CH═CH
O
Ph
C≡CCH2
Me
racemic


I-36
Me
Me
Me
CH2CH═CH
O
Ph
C≡CCH2
Me
(S)-


I-37
Me
Me
Me
CH2C≡C
O
Ph
CH2
H
racemic


I-38
Me
Me
Me
CH2C≡C
O
Ph
CH2
H
(S)-


I-39
Me
Me
Me
CH2C≡C
O
Ph
CH2
Me
racemic


I-40
Me
Me
Me
CH2C≡C
O
Ph
CH2
Me
(S)-


I-41
Me
Me
Me
CH2C≡C
O
Ph
(CH2)2
H
racemic


I-42
Me
Me
Me
CH2C≡C
O
Ph
(CH2)2
H
(R)-


I-43
Me
Me
Me
CH2C≡C
O
Ph
(CH2)2
Me
racemic


I-44
Me
Me
Me
CH2C≡C
O
Ph
(CH2)2
Me
(R)-


I-45
Me
Me
Me
CH2C≡C
O
Ph
C≡CCH2
H
racemic


I-46
Me
Me
Me
CH2C≡C
O
Ph
C≡CCH2
H
(S)-


I-47
Me
Me
Me
CH2C≡C
O
Ph
C≡CCH2
Me
racemic


I-48
Me
Me
Me
CH2C≡C
O
Ph
C≡CCH2
Me
(S)-


I-49
Me
Me
Me
1,2-Cyclo-
O
Ph
CH2
H
racemic






propylene







I-50
Me
Me
Me
1,2-Cyclo-
O
Ph
CH2
H
(S)-






propylene
















TABLE 2







(I)




embedded image





















Com-








Con-


pound








figu-


No.
R1
R2
R3
L1
L2
R4
L3
R5
ration





I-51
Me
Me
Me
1,2-Cyclo-
O
Ph
CH2
Me
racemic






propylene







I-52
Me
Me
Me
1,2-Cyclo-
O
Ph
CH2
Me
(S)-






propylene







I-53
Me
Me
Me
1,2-Cyclo-
O
Ph
(CH2)2
H
racemic






propylene







I-54
Me
Me
Me
1,2-Cyclo-
O
Ph
(CH2)2
H
(R)-






propylene







I-55
Me
Me
Me
1,2-Cyclo-
O
Ph
(CH2)2
Me
racemic






propylene







I-56
Me
Me
Me
1,2-Cyclo-
O
Ph
(CH2)2
Me
(R)-






propylene







I-57
Me
Me
Me
1,2-Cyclo-
O
Ph
C≡CCH2
H
racemic






propylene







I-58
Me
Me
Me
1,2-Cyclo-
O
Ph
C≡CCH2
H
(S)-






propylene







I-59
Me
Me
Me
1,2-Cyclo-
O
Ph
C≡CCH2
Me
racemic






propylene







I-60
Me
Me
Me
1,2-Cyclo-
O
Ph
C≡CCH2
Me
(S)-






propylene







I-61
Me
Me
Me
5,5-
O
Ph
CH2
H
racemic






Spiro[2.3]











hexylene







I-62
Me
Me
Me
5,5-
O
Ph
CH2
H
(S)-






Spiro[2.3]











hexylene







I-63
Me
Me
Me
5,5-
O
Ph
CH2
Me
racemic






Spiro[2.3]











hexylene







I-64
Me
Me
Me
5,5-
O
Ph
CH2
Me
(S)-






Spiro[2.3]











hexylene







I-65
Me
Me
Me
5,5-
O
Ph
(CH2)2
H
racemic






Spiro[2.3]











hexylene







I-66
Me
Me
Me
5,5-
O
Ph
(CH2)2
H
(R)-






Spiro[2.3]











hexylene







I-67
Me
Me
Me
5,5-
O
Ph
(CH2)2
Me
racemic






Spiro[2.3]











hexylene







I-68
Me
Me
Me
5,5-
O
Ph
(CH2)2
Me
(R)-






Spiro[2.3]











hexylene







I-69
Me
Me
Me
5,5-
O
Ph
C≡CCH2
H
racemic






Spiro[2.3]











hexylene







I-70
Me
Me
Me
5,5-
O
Ph
C≡CCH2
H
(S)-






Spiro[2.3]











hexylene







I-71
Me
Me
Me
5,5-
O
Ph
C≡CCH2
Me
racemic






Spiro[2.3]











hexylene







I-72
Me
Me
Me
5,5-
O
Ph
C≡CCH2
Me
(S)-






Spiro[2.3]











hexylene







I-73
Me
Me
Me
4,4-Cyclo-
O
Ph
CH2
H
racemic






pentenylene







I-74
Me
Me
Me
4,4-Cyclo-
O
Ph
CH2
H
(S)-






pentenylene







I-75
Me
Me
Me
4,4-Cyclo-
O
Ph
CH2
Me
racemic






pentenylene







I-76
Me
Me
Me
4,4-Cyclo-
O
Ph
CH2
Me
(S)-






pentenylene







I-77
Me
Me
Me
4,4-Cyclo-
O
Ph
(CH2)2
H
racemic






pentenylene







I-78
Me
Me
Me
4,4-Cyclo-
O
Ph
(CH2)2
H
(R)-






pentenylene







I-79
Me
Me
Me
4,4-Cyclo-
O
Ph
(CH2)2
Me
racemic






pentenylene







I-80
Me
Me
Me
4,4-Cyclo-
O
Ph
(CH2)2
Me
(R)-






pentenylene







I-81
Me
Me
Me
4,4-Cyclo-
O
Ph
C≡CCH2
H
racemic






pentenylene







I-82
Me
Me
Me
4,4-Cyclo-
O
Ph
C≡CCH2
H
(S)-






pentenylene







I-83
Me
Me
Me
4,4-Cyclo-
O
Ph
C≡CCH2
Me
racemic






pentenylene







I-84
Me
Me
Me
4,4-Cyclo-
O
Ph
C≡CCH2
Me
(S)-






pentenylene







I-85
Me
Me
Me
CH2
NH
Ph
CH2
H
racemic


I-86
Me
Me
Me
CH2
NH
Ph
CH2
H
(S)-


I-87
Me
Me
Me
CH2
NH
Ph
CH2
Me
racemic


I-88
Me
Me
Me
CH2
NH
Ph
CH2
Me
(S)-


I-89
Me
Me
Me
CH2
NH
Ph
(CH2)2
H
racemic


I-90
Me
Me
Me
CH2
NH
Ph
(CH2)2
H
(R)-


I-91
Me
Me
Me
CH2
NH
Ph
(CH2)2
Me
racemic


I-92
Me
Me
Me
CH2
NH
Ph
(CH2)2
Me
(R)-


I-93
Me
Me
Me
CH2
NH
Ph
C≡CCH2
H
racemic


I-94
Me
Me
Me
CH2
NH
Ph
C≡CCH2
H
(S)-


I-95
Me
Me
Me
CH2
NH
Ph
C≡CCH2
Me
racemic


I-96
Me
Me
Me
CH2
NH
Ph
C≡CCH2
Me
(S)-


I-97
Me
Me
Me
CH2C(Me)2
NH
Ph
CH2
H
racemic


I-98
Me
Me
Me
CH2C(Me)2
NH
Ph
CH2
H
(S)-


I-99
Me
Me
Me
CH2C(Me)2
NH
Ph
CH2
Me
racemic


 I-100
Me
Me
Me
CH2C(Me)2
NH
Ph
CH2
Me
(S)-
















TABLE 3







(I)




embedded image





















Com-








Con-


pound








figu-


No.
R1
R2
R3
L1
L2
R4
L3
R5
ration





I-101
Me
Me
Me
CH2C(Me)2
NH
Ph
(CH2)2
H
racemic


I-102
Me
Me
Me
CH2C(Me)2
NH
Ph
(CH2)2
H
(R)-


I-103
Me
Me
Me
CH2C(Me)2
NH
Ph
(CH2)2
Me
racemic


I-104
Me
Me
Me
CH2C(Me)2
NH
Ph
(CH2)2
Me
(R)-


I-105
Me
Me
Me
CH2C(Me)2
NH
Ph
C≡CCH2
H
racemic


I-106
Me
Me
Me
CH2C(Me)2
NH
Ph
C≡CCH2
H
(S)-


I-107
Me
Me
Me
CH2C(Me)2
NH
Ph
C≡CCH2
Me
racemic


I-108
Me
Me
Me
CH2C(Me)2
NH
Ph
C≡CCH2
Me
(S)-


I-109
Me
Me
Me
CH2CH═CH
NH
Ph
CH2
H
racemic


I-110
Me
Me
Me
CH2CH═CH
NH
Ph
CH2
H
(S)-


I-111
Me
Me
Me
CH2CH═CH
NH
Ph
CH2
Me
racemic


I-112
Me
Me
Me
CH2CH═CH
NH
Ph
CH2
Me
(S)-


I-113
Me
Me
Me
CH2CH═CH
NH
Ph
(CH2)2
H
racemic


I-114
Me
Me
Me
CH2CH═CH
NH
Ph
(CH2)2
H
(R)-


I-115
Me
Me
Me
CH2CH═CH
NH
Ph
(CH2)2
Me
racemic


I-116
Me
Me
Me
CH2CH═CH
NH
Ph
(CH2)2
Me
(R)-


I-117
Me
Me
Me
CH2CH═CH
NH
Ph
C≡CCH2
H
racemic


I-118
Me
Me
Me
CH2CH═CH
NH
Ph
C≡CCH2
H
(S)-


I-119
Me
Me
Me
CH2CH═CH
NH
Ph
C≡CCH2
Me
racemic


I-120
Me
Me
Me
CH2CH═CH
NH
Ph
C≡CCH2
Me
(S)-


I-121
Me
Me
Me
CH2C≡C
NH
Ph
CH2
H
racemic


I-122
Me
Me
Me
CH2C≡C
NH
Ph
CH2
H
(S)-


I-123
Me
Me
Me
CH2C≡C
NH
Ph
CH2
Me
racemic


I-124
Me
Me
Me
CH2C≡C
NH
Ph
CH2
Me
(S)-


I-125
Me
Me
Me
CH2C≡C
NH
Ph
(CH2)2
H
racemic


I-126
Me
Me
Me
CH2C≡C
NH
Ph
(CH2)2
H
(R)-


I-127
Me
Me
Me
CH2C≡C
NH
Ph
(CH2)2
Me
racemic


I-128
Me
Me
Me
CH2C≡C
NH
Ph
(CH2)2
Me
(R)-


I-129
Me
Me
Me
CH2C≡C
NH
Ph
C≡CCH2
H
racemic


I-130
Me
Me
Me
CH2C≡C
NH
Ph
C≡CCH2
H
(S)-


I-131
Me
Me
Me
CH2C≡C
NH
Ph
C≡CCH2
Me
racemic


I-132
Me
Me
Me
CH2C≡C
NH
Ph
C≡CCH2
Me
(S)-


I-133
Me
Me
Me
1,2-Cyclo-
NH
Ph
CH2
H
racemic






propylene







I-134
Me
Me
Me
1,2-Cyclo-
NH
Ph
CH2
H
(S)-






propylene







I-135
Me
Me
Me
1,2-Cyclo-
NH
Ph
CH2
Me
racemic






propylene







I-136
Me
Me
Me
1,2-Cyclo-
NH
Ph
CH2
Me
(S)-






propylene







I-137
Me
Me
Me
1,2-Cyclo-
NH
Ph
(CH2)2
H
racemic






propylene







I-138
Me
Me
Me
1,2-Cyclo-
NH
Ph
(CH2)2
H
(R)-






propylene







I-139
Me
Me
Me
1,2-Cyclo-
NH
Ph
(CH2)2
Me
racemic






propylene







I-140
Me
Me
Me
1,2-Cyclo-
NH
Ph
(CH2)2
Me
(R)-






propylene







I-141
Me
Me
Me
1,2-Cyclo-
NH
Ph
C≡CCH2
H
racemic






propylene







I-142
Me
Me
Me
1,2-Cyclo-
NH
Ph
C≡CCH2
H
(S)-






propylene







I-143
Me
Me
Me
1,2-Cyclo-
NH
Ph
C≡CCH2
Me
racemic






propylene







I-144
Me
Me
Me
1,2-Cyclo-
NH
Ph
C≡CCH2
Me
(S)-






propylene







I-145
Me
Me
Me
5,5-Spiro[2.3]
NH
Ph
CH2
H
racemic






hexylene







I-146
Me
Me
Me
5,5-Spiro[2.3]
NH
Ph
CH2
H
(S)-






hexylene







I-147
Me
Me
Me
5,5-Spiro[2.3]
NH
Ph
CH2
Me
racemic






hexylene







I-148
Me
Me
Me
5,5-Spiro[2.3]
NH
Ph
CH2
Me
(S)-






hexylene







I-149
Me
Me
Me
5,5-Spiro[2.3]
NH
Ph
(CH2)2
H
racemic






hexylene







I-150
Me
Me
Me
5,5-Spiro[2.3]
NH
Ph
(CH2)2
H
(R)-






hexylene
















TABLE 4







(I)




embedded image





















Com-








Con-


pound








figu-


No.
R1
R2
R3
L1
L2
R4
L3
R5
ration





I-151
Me
Me
Me
5,5-
NH
Ph
(CH2)2
Me
racemic






Spiro[2.3]











hexylene







I-152
Me
Me
Me
5,5-
NH
Ph
(CH2)2
Me
(R)-






Spiro[2.3]











hexylene







I-153
Me
Me
Me
5,5-
NH
Ph
C≡CCH2
H
racemic






Spiro[2.3]











hexylene







I-154
Me
Me
Me
5,5-
NH
Ph
C≡CCH2
H
(S)-






Spiro[2.3]











hexylene







I-155
Me
Me
Me
5,5-
NH
Ph
C≡CCH2
Me
racemic






Spiro[2.3]











hexylene







I-156
Me
Me
Me
5,5-
NH
Ph
C≡CCH2
Me
(S)-






Spiro[2.3]











hexylene







I-157
Me
Me
Me
4,4-Cyclo-
NH
Ph
CH2
H
racemic






pentenylene







I-158
Me
Me
Me
4,4-Cyclo-
NH
Ph
CH2
H
(S)-






pentenylene







I-159
Me
Me
Me
4,4-Cyclo-
NH
Ph
CH2
Me
racemic






pentenylene







I-160
Me
Me
Me
4,4-Cyclo-
NH
Ph
CH2
Me
(S)-






pentenylene







I-161
Me
Me
Me
4,4-Cyclo-
NH
Ph
(CH2)2
H
racemic






pentenylene







I-162
Me
Me
Me
4,4-Cyclo-
NH
Ph
(CH2)2
H
(R)-






pentenylene







I-163
Me
Me
Me
4,4-Cyclo-
NH
Ph
(CH2)2
Me
racemic






pentenylene







I-164
Me
Me
Me
4,4-Cyclo-
NH
Ph
(CH2)2
Me
(R)-






pentenylene







I-165
Me
Me
Me
4,4-Cyclo-
NH
Ph
C≡CCH2
H
racemic






pentenylene







I-166
Me
Me
Me
4,4-Cyclo-
NH
Ph
C≡CCH2
H
(S)-






pentenylene







I-167
Me
Me
Me
4,4-Cyclo-
NH
Ph
C≡CCH2
Me
racemic






pentenylene







I-168
Me
Me
Me
4,4-Cyclo-
NH
Ph
C≡CCH2
Me
(S)-






pentenylene







I-169
Me
Me
Me
CH2
CH2
Ph
CH2
H
racemic


I-170
Me
Me
Me
CH2
CH2
Ph
CH2
H
(S)-


I-171
Me
Me
Me
CH2
CH2
Ph
—
H
racemic


I-172
Me
Me
Me
CH2
CH2
Ph
—
H
(S)-


I-173
Me
Me
Me
CH2
CH2
Ph
CH2
Me
racemic


I-174
Me
Me
Me
CH2
CH2
Ph
CH2
Me
(S)-


I-175
Me
Me
Me
CH2
CH2
Ph
C(Me)2
H
racemic


I-176
Me
Me
Me
CH2
CH2
Ph
C(Me)2
H
(S)-


I-177
Me
Me
Me
CH2
CH2
Ph
C(Me)2
Me
racemic


I-178
Me
Me
Me
CH2
CH2
Ph
C(Me)2
Me
(S)-


I-179
Me
Me
Me
CH2
CH2
Ph
(CH2)2
H
racemic


I-180
Me
Me
Me
CH2
CH2
Ph
(CH2)2
H
(S)-


I-181
Me
Me
Me
CH2
CH2
Ph
(CH2)2
Me
racemic


I-182
Me
Me
Me
CH2
CH2
Ph
(CH2)2
Me
(S)-


I-183
Me
Me
Me
CH2
CH2
Ph
C≡CCH2
H
racemic


I-184
Me
Me
Me
CH2
CH2
Ph
C≡CCH2
H
(S)-


I-185
Me
Me
Me
CH2
CH2
Ph
C≡CCH2
Me
racemic


I-186
Me
Me
Me
CH2
CH2
Ph
C≡CCH2
Me
(S)-


I-187
Me
Me
Me
CH2C(Me)2
CH2
Ph
CH2
H
racemic


I-188
Me
Me
Me
CH2C(Me)2
CH2
Ph
CH2
H
(S)-


I-189
Me
Me
Me
CH2C(Me)2
CH2
Ph
—
H
racemic


I-190
Me
Me
Me
CH2C(Me)2
CH2
Ph
—
H
(S)-


I-191
Me
Me
Me
CH2C(Me)2
CH2
Ph
CH2
Me
racemic


I-192
Me
Me
Me
CH2C(Me)2
CH2
Ph
CH2
Me
(S)-


I-193
Me
Me
Me
CH2C(Me)2
CH2
Ph
C(Me)2
H
racemic


I-194
Me
Me
Me
CH2C(Me)2
CH2
Ph
C(Me)2
H
(S)-


I-195
Me
Me
Me
CH2C(Me)2
CH2
Ph
C(Me)2
Me
racemic


I-196
Me
Me
Me
CH2C(Me)2
CH2
Ph
C(Me)2
Me
(S)-


I-197
Me
Me
Me
CH2C(Me)2
CH2
Ph
(CH2)2
H
racemic


I-198
Me
Me
Me
CH2C(Me)2
CH2
Ph
(CH2)2
H
(S)-


I-199
Me
Me
Me
CH2C(Me)2
CH2
Ph
(CH2)2
Me
racemic


I-200
Me
Me
Me
CH2C(Me)2
CH2
Ph
(CH2)2
Me
(S)-
















TABLE 5







(I)




embedded image





















Com-








Con-


pound








figu-


No.
R1
R2
R3
L1
L2
R4
L3
R5
ration





I-201
Me
Me
Me
CH2C(Me)2
CH2
Ph
C≡CCH2
H
racemic


I-202
Me
Me
Me
CH2C(Me)2
CH2
Ph
C≡CCH2
H
(S)-


I-203
Me
Me
Me
CH2C(Me)2
CH2
Ph
C≡CCH2
Me
racemic


I-204
Me
Me
Me
CH2C(Me)2
CH2
Ph
C≡CCH2
Me
(S)-


I-205
Me
Me
Me
CH2CH═CH
CH2
Ph
CH2
H
racemic


I-206
Me
Me
Me
CH2CH═CH
CH2
Ph
CH2
H
(S)-


I-207
Me
Me
Me
CH2CH═CH
CH2
Ph
—
H
racemic


I-208
Me
Me
Me
CH2CH═CH
CH2
Ph
—
H
(S)-


I-209
Me
Me
Me
CH2CH═CH
CH2
Ph
CH2
Me
racemic


I-210
Me
Me
Me
CH2CH═CH
CH2
Ph
CH2
Me
(S)-


I-211
Me
Me
Me
CH2CH═CH
CH2
Ph
C(Me)2
H
racemic


I-212
Me
Me
Me
CH2CH═CH
CH2
Ph
C(Me)2
H
(S)-


I-213
Me
Me
Me
CH2CH═CH
CH2
Ph
C(Me)2
Me
racemic


I-214
Me
Me
Me
CH2CH═CH
CH2
Ph
C(Me)2
Me
(S)-


I-215
Me
Me
Me
CH2CH═CH
CH2
Ph
(CH2)2
H
racemic


I-216
Me
Me
Me
CH2CH═CH
CH2
Ph
(CH2)2
H
(S)-


I-217
Me
Me
Me
CH2CH═CH
CH2
Ph
(CH2)2
Me
racemic


I-218
Me
Me
Me
CH2CH═CH
CH2
Ph
(CH2)2
Me
(S)-


I-219
Me
Me
Me
CH2CH═CH
CH2
Ph
C≡CCH2
H
racemic


I-220
Me
Me
Me
CH2CH═CH
CH2
Ph
C≡CCH2
H
(S)-


I-221
Me
Me
Me
CH2CH═CH
CH2
Ph
C≡CCH2
Me
racemic


I-222
Me
Me
Me
CH2CH═CH
CH2
Ph
C≡CCH2
Me
(S)-


I-223
Me
Me
Me
CH2C≡C
CH2
Ph
CH2
H
racemic


I-224
Me
Me
Me
CH2C≡C
CH2
Ph
CH2
H
(S)-


I-225
Me
Me
Me
CH2C≡C
CH2
Ph
—
H
racemic


I-226
Me
Me
Me
CH2C≡C
CH2
Ph
—
H
(S)-


I-227
Me
Me
Me
CH2C≡C
CH2
Ph
CH2
Me
racemic


I-228
Me
Me
Me
CH2C≡C
CH2
Ph
CH2
Me
(S)-


I-229
Me
Me
Me
CH2C≡C
CH2
Ph
C(Me)2
H
racemic


I-230
Me
Me
Me
CH2C≡C
CH2
Ph
C(Me)2
H
(S)-


I-231
Me
Me
Me
CH2C≡C
CH2
Ph
C(Me)2
Me
racemic


I-232
Me
Me
Me
CH2C≡C
CH2
Ph
C(Me)2
Me
(S)-


I-233
Me
Me
Me
CH2C≡C
CH2
Ph
(CH2)2
H
racemic


I-234
Me
Me
Me
CH2C≡C
CH2
Ph
(CH2)2
H
(S)-


I-235
Me
Me
Me
CH2C≡C
CH2
Ph
(CH2)2
Me
racemic


I-236
Me
Me
Me
CH2C≡C
CH2
Ph
(CH2)2
Me
(S)-


I-237
Me
Me
Me
CH2C≡C
CH2
Ph
C≡CCH2
H
racemic


I-238
Me
Me
Me
CH2C≡C
CH2
Ph
C≡CCH2
H
(S)-


I-239
Me
Me
Me
CH2C≡C
CH2
Ph
C≡CCH2
Me
racemic


I-240
Me
Me
Me
CH2C≡C
CH2
Ph
C≡CCH2
Me
(S)-


I-241
Me
Me
Me
1,2-Cyclo-
CH2
Ph
CH2
H
racemic






propylene







I-242
Me
Me
Me
1,2-Cyclo-
CH2
Ph
CH2
H
(S)-






propylene







I-243
Me
Me
Me
1,2-Cyclo-
CH2
Ph
—
H
racemic






propylene







I-244
Me
Me
Me
1,2-Cyclo-
CH2
Ph
—
H
(S)-






propylene







I-245
Me
Me
Me
1,2-Cyclo-
CH2
Ph
CH2
Me
racemic






propylene







I-246
Me
Me
Me
1,2-Cyclo-
CH2
Ph
CH2
Me
(S)-






propylene







I-247
Me
Me
Me
1,2-Cyclo-
CH2
Ph
C(Me)2
H
racemic






propylene







I-248
Me
Me
Me
1,2-Cyclo-
CH2
Ph
C(Me)2
H
(S)-






propylene







I-249
Me
Me
Me
1,2-Cyclo-
CH2
Ph
C(Me)2
Me
racemic






propylene







I-250
Me
Me
Me
1,2-Cyclo-
CH2
Ph
C(Me)2
Me
(S)-






propylene
















TABLE 6







(I)




embedded image





















Com-








Con-


pound








figur-


No.
R1
R2
R3
L1
L2
R4
L3
R5
ation





I-251
Me
Me
Me
1,2-Cyclo-
CH2
Ph
(CH2)2
H
racemic






propylene







I-252
Me
Me
Me
1,2-Cyclo-
CH2
Ph
(CH2)2
H
(S)-






propylene







I-253
Me
Me
Me
1,2-Cyclo-
CH2
Ph
(CH2)2
Me
racemic






propylene







I-254
Me
Me
Me
1,2-Cyclo-
CH2
Ph
(CH2)2
Me
(S)-






propylene







I-255
Me
Me
Me
1,2-Cyclo-
CH2
Ph
C≡CCH2
H
racemic






propylene







I-256
Me
Me
Me
1,2-Cyclo-
CH2
Ph
C≡CCH2
H
(S)-






propylene







I-257
Me
Me
Me
1,2-Cyclo-
CH2
Ph
C≡CCH2
Me
racemic






propylene







I-258
Me
Me
Me
1,2-Cyclo-
CH2
Ph
C≡CCH2
Me
(S)-






propylene







I-259
Me
Me
Me
5,5-Spiro-
CH2
Ph
CH2
H
racemic






[2.3]hexyl-











ene







I-260
Me
Me
Me
5,5-Spiro-
CH2
Ph
CH2
H
(S)-






[2.3]hexyl-











ene







I-261
Me
Me
Me
5,5-Spiro-
CH2
Ph
—
H
racemic






[2.3]hexyl-











ene







I-262
Me
Me
Me
5,5-Spiro-
CH2
Ph
—
H
(S)-






[2.3]hexyl-











ene







I-263
Me
Me
Me
5,5-Spiro-
CH2
Ph
CH2
Me
racemic






[2.3]hexyl-











ene







I-264
Me
Me
Me
5,5-Spiro-
CH2
Ph
CH2
Me
(S)-






[2.3]hexyl-











ene







I-265
Me
Me
Me
5,5-Spiro-
CH2
Ph
C(Me)2
H
racemic






[2.3]hexyl-











ene







I-266
Me
Me
Me
5,5-Spiro-
CH2
Ph
C(Me)2
H
(S)-






[2.3]hexyl-











ene







I-267
Me
Me
Me
5,5-Spiro-
CH2
Ph
C(Me)2
Me
racemic






[2.3]hexyl-











ene







I-268
Me
Me
Me
5,5-Spiro-
CH2
Ph
C(Me)2
Me
(S)-






[2.3]hexyl-











ene







I-269
Me
Me
Me
5,5-Spiro-
CH2
Ph
(CH2)2
H
racemic






[2.3]hexyl-











ene







I-270
Me
Me
Me
5,5-Spiro-
CH2
Ph
(CH2)2
H
(S)-






[2.3]hexyl-











ene







I-271
Me
Me
Me
5,5-Spiro-
CH2
Ph
(CH2)2
Me
racemic






[2.3]hexyl-











ene







I-272
Me
Me
Me
5,5-Spiro-
CH2
Ph
(CH2)2
Me
(S)-






[2.3]hexyl-











ene







I-273
Me
Me
Me
5,5-Spiro-
CH2
Ph
C≡CCH2
H
racemic






[2.3]hexyl-











ene







I-274
Me
Me
Me
5,5-Spiro-
CH2
Ph
C≡CCH2
H
(S)-






[2.3]hexyl-











ene







I-275
Me
Me
Me
5,5-Spiro-
CH2
Ph
C≡CCH2
Me
racemic






[2.3]hexyl-











ene







I-276
Me
Me
Me
5,5-Spiro-
CH2
Ph
C≡CCH2
Me
(S)-






[2.3]hexyl-











ene







I-277
Me
Me
Me
4,4-Cyclo-
CH2
Ph
CH2
H
racemic






pentenylene







I-278
Me
Me
Me
4,4-Cyclo-
CH2
Ph
CH2
H
(S)-






pentenylene







I-279
Me
Me
Me
4,4-Cyclo-
CH2
Ph
—
H
racemic






pentenylene







I-280
Me
Me
Me
4,4-Cyclo-
CH2
Ph
—
H
(S)-






pentenylene







I-281
Me
Me
Me
4,4-Cyclo-
CH2
Ph
CH2
Me
racemic






pentenylene







I-282
Me
Me
Me
4,4-Cyclo-
CH2
Ph
CH2
Me
(S)-






pentenylene







I-283
Me
Me
Me
4,4-Cyclo-
CH2
Ph
C(Me)2
H
racemic






pentenylene







I-284
Me
Me
Me
4,4-Cyclo-
CH2
Ph
C(Me)2
H
(S)-






pentenylene







I-285
Me
Me
Me
4,4-Cyclo-
CH2
Ph
C(Me)2
Me
racemic






pentenylene







I-286
Me
Me
Me
4,4-Cyclo-
CH2
Ph
C(Me)2
Me
(S)-






pentenylene







I-287
Me
Me
Me
4,4-Cyclo-
CH2
Ph
(CH2)2
H
racemic






pentenylene







I-288
Me
Me
Me
4,4-Cyclo-
CH2
Ph
(CH2)2
H
(S)-






pentenylene







I-289
Me
Me
Me
4,4-Cyclo-
CH2
Ph
(CH2)2
Me
racemic






pentenylene







I-290
Me
Me
Me
4,4-Cyclo-
CH2
Ph
(CH2)2
Me
(S)-






pentenylene







I-291
Me
Me
Me
4,4-Cyclo-
CH2
Ph
C≡CCH2
H
racemic






pentenylene







I-292
Me
Me
Me
4,4-Cyclo-
CH2
Ph
C≡CCH2
H
(S)-






pentenylene







I-293
Me
Me
Me
4,4-Cyclo-
CH2
Ph
C≡CCH2
Me
racemic






pentenylene







I-294
Me
Me
Me
4,4-Cyclo-
CH2
Ph
C≡CCH2
Me
(S)-






pentenylene
















TABLE 7







(I)




embedded image





















Com-








Con-


pound








figur-


No.
R1
R2
R3
L1
L2
R4
L3
R5
ation





I-295
Me
Me
Me
5,5-Spiro-
NH
Ph
CH2C(Me)2
H
racemic






[2.3]hexyl-











ene







I-296
Me
Me
Me
5,5-Spiro-
NH
Ph
CH2C(Me)2
H
(R)-






[2.3]hexyl-











ene







I-297
Me
Me
Me
5,5-Spiro-
NH
Ph
CH2C(Me)2
Me
racemic






[2.3]hexyl-











ene







I-298
Me
Me
Me
5,5-Spiro-
NH
Ph
CH2C(Me)2
Me
(R)-






[2.3]hexyl-











ene







I-299
Me
Me
Me
5,5-Spiro-
NH
Ph
C(Me)2CH2
H
racemic






[2.3]hexyl-











ene







I-300
Me
Me
Me
5,5-Spiro-
NH
Ph
C(Me)2CH2
H
(+)






[2.3]hexyl-











ene







I-301
Me
Me
Me
5,5-Spiro-
NH
Ph
C(Me)2CH2
H
(−)






[2.3]hexyl-











ene







I-302
Me
Me
Me
5,5-Spiro-
NH
Ph
C(Me)2CH2
Me
racemic






[2.3]hexyl-











ene







I-303
Me
Me
Me
5,5-Spiro-
NH
Ph
C(Me)2CH2
Me
(+)






[2.3]hexyl-











ene







I-304
Me
Me
Me
5,5-Spiro-
NH
Ph
C(Me)2CH2
Me
(−)






[2.3]hexyl-











ene







I-305
Me
Me
Me
4,4-Cyclo-
NH
Ph
CH2C(Me)2
H
racemic






pentenylene







I-306
Me
Me
Me
4,4-Cyclo-
NH
Ph
CH2C(Me)2
H
(R)-






pentenylene







I-307
Me
Me
Me
4,4-Cyclo-
NH
Ph
CH2C(Me)2
Me
racemic






pentenylene







I-308
Me
Me
Me
4,4-Cyclo-
NH
Ph
CH2C(Me)2
Me
(R)-






pentenylene







I-309
Me
Me
Me
4,4-Cyclo-
NH
Ph
C(Me)2CH2
H
racemic






pentenylene







I-310
Me
Me
Me
4,4-Cyclo-
NH
Ph
C(Me)2CH2
H
(+)






pentenylene







I-311
Me
Me
Me
4,4-Cyclo-
NH
Ph
C(Me)2CH2
H
(−)






pentenylene







I-312
Me
Me
Me
4,4-Cyclo-
NH
Ph
C(Me)2CH2
Me
racemic






pentenylene







I-313
Me
Me
Me
4,4-Cyclo-
NH
Ph
C(Me)2CH2
Me
(+)






pentenylene







I-314
Me
Me
Me
4,4-Cyclo-
NH
Ph
C(Me)2CH2
Me
(−)






pentenylene







I-315
Me
Me
Me
1,2-Cyclo-
—
Ph
—
H
racemic






propylene







I-316
Me
Me
Me
1,2-Cyclo-
—
Ph
—
H
(S)-






propylene







I-317
Me
Me
Me
1,2-Cyclo-
—
Ph
—
Me
racemic






propylene







I-318
Me
Me
Me
1,2-Cyclo-
—
Ph
—
Me
(S)-






propylene







I-319
Me
Me
Me
5,5-Spiro-
—
Ph
—
H
racemic






[2.3]hexyl-











ene







I-320
Me
Me
Me
5,5-Spiro-
—
Ph
—
H
(S)-






[2.3]hexyl-











ene







I-321
Me
Me
Me
5,5-Spiro-
—
Ph
—
Me
racemic






[2.3]hexyl-











ene







I-322
Me
Me
Me
5,5-Spiro-
—
Ph
—
Me
(S)-






[2.3]hexyl-











ene







I-323
Me
Me
Me
4,4-Cyclo-
—
Ph
—
H
racemic






pentenylene







I-324
Me
Me
Me
4,4-Cyclo-
—
Ph
—
H
(S)-






pentenylene







I-325
Me
Me
Me
4,4-Cyclo-

Ph
—
Me
racemic






pentenylene







I-326
Me
Me
Me
4,4-Cyclo-
—
Ph
—
Me
(S)-






pentenylene







I-327
Me
Me
Me
1,2-Cyclo-
—
Ph
CH2
H
racemic






propylene







I-328
Me
Me
Me
1,2-Cyclo-
—
Ph
CH2
H
(S)-






propylene







I-329
Me
Me
Me
1,2-Cyclo-
—
Ph
CH2
Me
racemic






propylene







I-330
Me
Me
Me
1,2-Cyclo-
—
Ph
CH2
Me
(S)-






propylene







I-331
Me
Me
Me
1,2-Cyclo-
—
Ph
(CH2)2
H
racemic






propylene







I-332
Me
Me
Me
1,2-Cyclo-
—
Ph
(CH2)2
H
(S)-






propylene







I-333
Me
Me
Me
1,2-Cyclo-
—
Ph
(CH2)2
Me
racemic






propylene







I-334
Me
Me
Me
1,2-Cyclo-
—
Ph
(CH2)2
Me
(S)-






propylene







I-335
Me
Me
Me
5,5-Spiro-
—
Ph
CH2
H
racemic






[2.3]hexyl-











ene







I-336
Me
Me
Me
5,5-Spiro-
—
Ph
CH2
H
(S)-






[2.3]hexyl-











ene







I-337
Me
Me
Me
5,5-Spiro-
—
Ph
CH2
Me
racemic






[2.3]hexyl-











ene







I-338
Me
Me
Me
5,5-Spiro-
—
Ph
CH2
Me
(S)-






[2.3]hexyl-











ene







I-339
Me
Me
Me
5,5-Spiro-
—
Ph
(CH2)2
H
racemic






[2.3]hexyl-











ene







I-340
Me
Me
Me
5,5-Spiro-
—
Ph
(CH2)2
H
(S)-






[2.3]hexyl-











ene







I-341
Me
Me
Me
5,5-Spiro-
—
Ph
(CH2)2
Me
racemic






[2.3]hexyl-











ene







I-342
Me
Me
Me
5,5-Spiro-
—
Ph
(CH2)2
Me
(S)-






[2.3]hexyl-











ene







I-343
Me
Me
Me
4,4-Cyclo-
—
Ph
CH2
H
racemic






pentenylene







I-344
Me
Me
Me
4,4-Cyclo-
—
Ph
CH2
H
(S)-






pentenylene







I-345
Me
Me
Me
4,4-Cyclo-
—
Ph
CH2
Me
racemic






pentenylene
















TABLE 8







(I)




embedded image





















Com-








Con-


pound








figur-


No.
R1
R2
R3
L1
L2
R4
L3
R5
ation





I-346
Me
Me
Me
4,4-Cyclo-
—
Ph
CH2
Me
(S)-






pentenylene







I-347
Me
Me
Me
4,4-Cyclo-
—
Ph
(CH2)2
H
racemic






pentenylene







I-348
Me
Me
Me
4,4-Cyclo-
—
Ph
(CH2)2
H
(S)-






pentenylene







I-349
Me
Me
Me
4,4-Cyclo-
—
Ph
(CH2)2
Me
racemic






pentenylene







I-350
Me
Me
Me
4,4-Cyclo-
—
Ph
(CH2)2
Me
(S)-






pentenylene
















TABLE 9







(II)




embedded image




















Com-










pound







Configur-


No.
R1
R2
R3
L2
R4
L3
R5
ation





II-1
Me
Me
Me
O
Ph
CH2
H
racemic


II-2
Me
Me
Me
O
Ph
CH2
H
(S)-


II-3
Me
Et
Me
O
Ph
CH2
H
racemic


II-4
Me
Et
Me
O
Ph
CH2
H
(S)-


II-5
Me
Me
Me
O
Ph
CH2
Me
racemic


II-6
Me
Me
Me
O
Ph
CH2
Me
(S)-


II-7
Me
Et
Me
O
Ph
CH2
Me
racemic


II-8
Me
Et
Me
O
Ph
CH2
Me
(S)-


II-9
Me
Me
Me
O
Ph
CH2
CHF2
racemic


II-10
Me
Me
Me
O
Ph
CH2
CHF2
(S)-


II-11
Me
Et
Me
O
Ph
CH2
CHF2
racemic


II-12
Me
Et
Me
O
Ph
CH2
CHF2
(S)-


II-13
Me
Me
Me
O
Ph
CH2
Et
racemic


II-14
Me
Me
Me
O
Ph
CH2
Et
(S)-


II-15
Me
Et
Me
O
Ph
CH2
Et
racemic


II-16
Me
Et
Me
O
Ph
CH2
Et
(S)-


II-17
Me
Me
Me
O
Ph
CH2
iPr
racemic


II-18
Me
Me
Me
O
Ph
CH2
iPr
(S)-


II-19
Me
Et
Me
O
Ph
CH2
iPr
racemic


II-20
Me
Et
Me
O
Ph
CH2
iPr
(S)-


II-21
Me
Me
Me
O
Ph
CH2
cPr
racemic


II-22
Me
Me
Me
O
Ph
CH2
cPr
(S)-


II-23
Me
Et
Me
O
Ph
CH2
cPr
racemic


II-24
Me
Et
Me
O
Ph
CH2
cPr
(S)-


II-25
Me
Me
Me
O
Ph
CH2
Ph
racemic


II-26
Me
Me
Me
O
Ph
CH2
Ph
(S)-


II-27
Me
Et
Me
O
Ph
CH2
Ph
racemic


II-28
Me
Et
Me
O
Ph
CH2
Ph
(S)-


II-29
Me
Me
Me
O
Ph
C(Me)2
H
racemic


II-30
Me
Me
Me
O
Ph
C(Me)2
H
(S)-


II-31
Me
Et
Me
O
Ph
C(Me)2
H
racemic


II-32
Me
Et
Me
O
Ph
C(Me)2
H
(S)-


II-33
Me
Me
Me
O
Ph
C(Me)2
Me
racemic


II-34
Me
Me
Me
O
Ph
C(Me)2
Me
(S)-


II-35
Me
Et
Me
O
Ph
C(Me)2
Me
racemic


II-36
Me
Et
Me
O
Ph
C(Me)2
Me
(S)-


II-37
Me
Me
Me
O
Ph
C(Me)2
CHF2
racemic


II-38
Me
Me
Me
O
Ph
C(Me)2
CHF2
(S)-


II-39
Me
Et
Me
O
Ph
C(Me)2
CHF2
racemic


II-40
Me
Et
Me
O
Ph
C(Me)2
CHF2
(S)-


II-41
Me
Me
Me
O
Ph
C(Me)2
Et
racemic


II-42
Me
Me
Me
O
Ph
C(Me)2
Et
(S)-


II-43
Me
Et
Me
O
Ph
C(Me)2
Et
racemic


II-44
Me
Et
Me
O
Ph
C(Me)2
Et
(S)-


II-45
Me
Me
Me
O
Ph
C(Me)2
iPr
racemic


II-46
Me
Me
Me
O
Ph
C(Me)2
iPr
(S)-


II-47
Me
Et
Me
O
Ph
C(Me)2
iPr
racemic


II-48
Me
Et
Me
O
Ph
C(Me)2
iPr
(S)-


II-49
Me
Me
Me
O
Ph
C(Me)2
cPr
racemic


II-50
Me
Me
Me
O
Ph
C(Me)2
cPr
(S)-
















TABLE 10







(II)




embedded image




















Com-










pound







Configur-


No.
R1
R2
R3
L2
R4
L3
R5
ation





II-51
Me
Et
Me
O
Ph
C(Me)2
cPr
racemic


II-52
Me
Et
Me
O
Ph
C(Me)2
cPr
(S)-


II-53
Me
Me
Me
O
Ph
C(Me)2
Ph
racemic


II-54
Me
Me
Me
O
Ph
C(Me)2
Ph
(S)-


II-55
Me
Et
Me
O
Ph
C(Me)2
Ph
racemic


II-56
Me
Et
Me
O
Ph
C(Me)2
Ph
(S)-


II-57
Me
Me
Me
O
Ph
(CH2)2
H
racemic


II-58
Me
Me
Me
O
Ph
(CH2)2
H
(R)-


II-59
Me
Et
Me
O
Ph
(CH2)2
H
racemic


II-60
Me
Et
Me
O
Ph
(CH2)2
H
(R)-


II-61
Me
Me
Me
O
Ph
(CH2)2
Me
racemic


II-62
Me
Me
Me
O
Ph
(CH2)2
Me
(R)-


II-63
Me
Et
Me
O
Ph
(CH2)2
Me
racemic


II-64
Me
Et
Me
O
Ph
(CH2)2
Me
(R)-


II-65
Me
Me
Me
O
Ph
(CH2)2
CHF2
racemic


II-66
Me
Me
Me
O
Ph
(CH2)2
CHF2
(R)-


II-67
Me
Et
Me
O
Ph
(CH2)2
CHF2
racemic


II-68
Me
Et
Me
O
Ph
(CH2)2
CHF2
(R)-


II-69
Me
Me
Me
O
Ph
(CH2)2
Et
racemic


II-70
Me
Me
Me
O
Ph
(CH2)2
Et
(R)-


II-71
Me
Et
Me
O
Ph
(CH2)2
Et
racemic


II-72
Me
Et
Me
O
Ph
(CH2)2
Et
(R)-


II-73
Me
Me
Me
O
Ph
(CH2)2
iPr
racemic


II-74
Me
Me
Me
O
Ph
(CH2)2
iPr
(R)-


II-75
Me
Et
Me
O
Ph
(CH2)2
iPr
racemic


II-76
Me
Et
Me
O
Ph
(CH2)2
iPr
(R)-


II-77
Me
Me
Me
O
Ph
(CH2)2
cPr
racemic


II-78
Me
Me
Me
O
Ph
(CH2)2
cPr
(R)-


II-79
Me
Et
Me
O
Ph
(CH2)2
cPr
racemic


II-80
Me
Et
Me
O
Ph
(CH2)2
cPr
(R)-


II-81
Me
Me
Me
O
Ph
(CH2)2
Ph
racemic


II-82
Me
Me
Me
O
Ph
(CH2)2
Ph
(R)-


II-83
Me
Et
Me
O
Ph
(CH2)2
Ph
racemic


II-84
Me
Et
Me
O
Ph
(CH2)2
Ph
(R)-


II-85
Me
Me
Me
O
Ph
CH2C(Me)2
H
racemic


II-86
Me
Me
Me
O
Ph
CH2C(Me)2
H
(R)-


II-87
Me
Et
Me
O
Ph
CH2C(Me)2
H
racemic


II-88
Me
Et
Me
O
Ph
CH2C(Me)2
H
(R)-


II-89
Me
Me
Me
O
Ph
CH2C(Me)2
Me
racemic


II-90
Me
Me
Me
O
Ph
CH2C(Me)2
Me
(R)-


II-91
Me
Et
Me
O
Ph
CH2C(Me)2
Me
racemic


II-92
Me
Et
Me
O
Ph
CH2C(Me)2
Me
(R)-


II-93
Me
Me
Me
O
Ph
CH2C(Me)2
CHF2
racemic


II-94
Me
Me
Me
O
Ph
CH2C(Me)2
CHF2
(R)-


II-95
Me
Et
Me
O
Ph
CH2C(Me)2
CHF2
racemic


II-96
Me
Et
Me
O
Ph
CH2C(Me)2
CHF2
(R)-


II-97
Me
Me
Me
O
Ph
CH2C(Me)2
Et
racemic


II-98
Me
Me
Me
O
Ph
CH2C(Me)2
Et
(R)-


II-99
Me
Et
Me
O
Ph
CH2C(Me)2
Et
racemic


II-100
Me
Et
Me
O
Ph
CH2C(Me)2
Et
(R)-
















TABLE 11







(II)




embedded image




















Com-










pound







Configur-


No.
R1
R2
R3
L2
R4
L3
R5
ation





II-101
Me
Me
Me
O
Ph
CH2C(Me)2
iPr
racemic


II-102
Me
Me
Me
O
Ph
CH2C(Me)2
iPr
(R)-


II-103
Me
Et
Me
O
Ph
CH2C(Me)2
iPr
racemic


II-104
Me
Et
Me
O
Ph
CH2C(Me)2
iPr
(R)-


II-105
Me
Me
Me
O
Ph
CH2C(Me)2
cPr
racemic


II-106
Me
Me
Me
O
Ph
CH2C(Me)2
cPr
(R)-


II-107
Me
Et
Me
O
Ph
CH2C(Me)2
cPr
racemic


II-108
Me
Et
Me
O
Ph
CH2C(Me)2
cPr
(R)-


II-109
Me
Me
Me
O
Ph
CH2C(Me)2
Ph
racemic


II-110
Me
Me
Me
O
Ph
CH2C(Me)2
Ph
(R)-


II-111
Me
Et
Me
O
Ph
CH2C(Me)2
Ph
racemic


II-112
Me
Et
Me
O
Ph
CH2C(Me)2
Ph
(R)-


II-113
Me
Me
Me
NH
Ph
CH2
H
racemic


II-114
Me
Me
Me
NH
Ph
CH2
H
(S)-


II-115
Me
Et
Me
NH
Ph
CH2
H
racemic


II-116
Me
Et
Me
NH
Ph
CH2
H
(S)-


II-117
Me
Me
Me
N(Me)
Ph
CH2
H
racemic


II-118
Me
Me
Me
N(Me)
Ph
CH2
H
(S)-


II-119
Me
Et
Me
N(Me)
Ph
CH2
H
racemic


II-120
Me
Et
Me
N(Me)
Ph
CH2
H
(S)-


II-121
Me
Me
Me
NH
Ph
CH2
Me
racemic


II-122
Me
Me
Me
NH
Ph
CH2
Me
(S)-


II-123
Me
Et
Me
NH
Ph
CH2
Me
racemic


II-124
Me
Et
Me
NH
Ph
CH2
Me
(S)-


II-125
Me
Me
Me
N(Me)
Ph
CH2
Me
racemic


II-126
Me
Me
Me
N(Me)
Ph
CH2
Me
(S)-


II-127
Me
Et
Me
N(Me)
Ph
CH2
Me
racemic


II-128
Me
Et
Me
N(Me)
Ph
CH2
Me
(S)-


II-129
Me
Me
Me
NH
Ph
CH2
CHF2
racemic


II-130
Me
Me
Me
NH
Ph
CH2
CHF2
(S)-


II-131
Me
Et
Me
NH
Ph
CH2
CHF2
racemic


II-132
Me
Et
Me
NH
Ph
CH2
CHF2
(S)-


II-133
Me
Me
Me
N(Me)
Ph
CH2
CHF2
racemic


II-134
Me
Me
Me
N(Me)
Ph
CH2
CHF2
(S)-


II-135
Me
Et
Me
N(Me)
Ph
CH2
CHF2
racemic


II-136
Me
Et
Me
N(Me)
Ph
CH2
CHF2
(S)-


II-137
Me
Me
Me
NH
Ph
CH2
Et
racemic


II-138
Me
Me
Me
NH
Ph
CH2
Et
(S)-


II-139
Me
Et
Me
NH
Ph
CH2
Et
racemic


II-140
Me
Et
Me
NH
Ph
CH2
Et
(S)-


II-141
Me
Me
Me
N(Me)
Ph
CH2
Et
racemic


II-142
Me
Me
Me
N(Me)
Ph
CH2
Et
(S)-


II-143
Me
Et
Me
N(Me)
Ph
CH2
Et
racemic


II-144
Me
Et
Me
N(Me)
Ph
CH2
Et
(S)-


II-145
Me
Me
Me
NH
Ph
CH2
iPr
racemic


II-146
Me
Me
Me
NH
Ph
CH2
iPr
(S)-


II-147
Me
Et
Me
NH
Ph
CH2
iPr
racemic


II-148
Me
Et
Me
NH
Ph
CH2
iPr
(S)-


II-149
Me
Me
Me
N(Me)
Ph
CH2
iPr
racemic


II-150
Me
Me
Me
N(Me)
Ph
CH2
iPr
(S)-
















TABLE 12







(II)




embedded image




















Com-










pound







Configur-


No.
R1
R2
R3
L2
R4
L3
R5
ation





II-151
Me
Et
Me
N(Me)
Ph
CH2
iPr
racemic


II-152
Me
Et
Me
N(Me)
Ph
CH2
iPr
(S)-


II-153
Me
Me
Me
NH
Ph
CH2
cPr
racemic


II-154
Me
Me
Me
NH
Ph
CH2
cPr
(S)-


II-155
Me
Et
Me
NH
Ph
CH2
cPr
racemic


II-156
Me
Et
Me
NH
Ph
CH2
cPr
(S)-


II-157
Me
Me
Me
N(Me)
Ph
CH2
cPr
racemic


II-158
Me
Me
Me
N(Me)
Ph
CH2
cPr
(S)-


II-159
Me
Et
Me
N(Me)
Ph
CH2
cPr
racemic


II-160
Me
Et
Me
N(Me)
Ph
CH2
cPr
(S)-


II-161
Me
Me
Me
NH
Ph
CH2
Ph
racemic


II-162
Me
Me
Me
NH
Ph
CH2
Ph
(S)-


II-163
Me
Et
Me
NH
Ph
CH2
Ph
racemic


II-164
Me
Et
Me
NH
Ph
CH2
Ph
(S)-


II-165
Me
Me
Me
N(Me)
Ph
CH2
Ph
racemic


II-166
Me
Me
Me
N(Me)
Ph
CH2
Ph
(S)-


II-167
Me
Et
Me
N(Me)
Ph
CH2
Ph
racemic


II-168
Me
Et
Me
N(Me)
Ph
CH2
Ph
(S)-


II-169
Me
Me
Me
NH
Ph
C(Me)2
H
racemic


II-170
Me
Me
Me
NH
Ph
C(Me)2
H
(S)-


II-171
Me
Et
Me
NH
Ph
C(Me)2
H
racemic


II-172
Me
Et
Me
NH
Ph
C(Me)2
H
(S)-


II-173
Me
Me
Me
N(Me)
Ph
C(Me)2
H
racemic


II-174
Me
Me
Me
N(Me)
Ph
C(Me)2
H
(S)-


II-175
Me
Et
Me
N(Me)
Ph
C(Me)2
H
racemic


II-176
Me
Et
Me
N(Me)
Ph
C(Me)2
H
(S)-


II-177
Me
Me
Me
NH
Ph
C(Me)2
Me
racemic


II-178
Me
Me
Me
NH
Ph
C(Me)2
Me
(S)-


II-179
Me
Et
Me
NH
Ph
C(Me)2
Me
racemic


II-180
Me
Et
Me
NH
Ph
C(Me)2
Me
(S)-


II-181
Me
Me
Me
N(Me)
Ph
C(Me)2
Me
racemic


II-182
Me
Me
Me
N(Me)
Ph
C(Me)2
Me
(S)-


II-183
Me
Et
Me
N(Me)
Ph
C(Me)2
Me
racemic


II-184
Me
Et
Me
N(Me)
Ph
C(Me)2
Me
(S)-


II-185
Me
Me
Me
NH
Ph
C(Me)2
CHF2
racemic


II-186
Me
Me
Me
NH
Ph
C(Me)2
CHF2
(S)-


II-187
Me
Et
Me
NH
Ph
C(Me)2
CHF2
racemic


II-188
Me
Et
Me
NH
Ph
C(Me)2
CHF2
(S)-


II-189
Me
Me
Me
N(Me)
Ph
C(Me)2
CHF2
racemic


II-190
Me
Me
Me
N(Me)
Ph
C(Me)2
CHF2
(S)-


II-191
Me
Et
Me
N(Me)
Ph
C(Me)2
CHF2
racemic


II-192
Me
Et
Me
N(Me)
Ph
C(Me)2
CHF2
(S)-


II-193
Me
Me
Me
NH
Ph
C(Me)2
Et
racemic


II-194
Me
Me
Me
NH
Ph
C(Me)2
Et
(S)-


II-195
Me
Et
Me
NH
Ph
C(Me)2
Et
racemic


II-196
Me
Et
Me
NH
Ph
C(Me)2
Et
(S)-


II-197
Me
Me
Me
N(Me)
Ph
C(Me)2
Et
racemic


II-198
Me
Me
Me
N(Me)
Ph
C(Me)2
Et
(S)-


II-199
Me
Et
Me
N(Me)
Ph
C(Me)2
Et
racemic


II-200
Me
Et
Me
N(Me)
Ph
C(Me)2
Et
(S)-
















TABLE 13







(II)




embedded image




















Com-










pound







Configur-


No.
R1
R2
R3
L2
R4
L3
R5
ation





II-201
Me
Me
Me
NH
Ph
C(Me)2
iPr
racemic


II-202
Me
Me
Me
NH
Ph
C(Me)2
iPr
(S)-


II-203
Me
Et
Me
NH
Ph
C(Me)2
iPr
racemic


II-204
Me
Et
Me
NH
Ph
C(Me)2
iPr
(S)-


II-205
Me
Me
Me
N(Me)
Ph
C(Me)2
iPr
racemic


II-206
Me
Me
Me
N(Me)
Ph
C(Me)2
iPr
(S)-


II-207
Me
Et
Me
N(Me)
Ph
C(Me)2
iPr
racemic


II-208
Me
Et
Me
N(Me)
Ph
C(Me)2
iPr
(S)-


II-209
Me
Me
Me
NH
Ph
C(Me)2
cPr
racemic


II-210
Me
Me
Me
NH
Ph
C(Me)2
cPr
(S)-


II-211
Me
Et
Me
NH
Ph
C(Me)2
cPr
racemic


II-212
Me
Et
Me
NH
Ph
C(Me)2
cPr
(S)-


II-213
Me
Me
Me
N(Me)
Ph
C(Me)2
cPr
racemic


II-214
Me
Me
Me
N(Me)
Ph
C(Me)2
cPr
(S)-


II-215
Me
Et
Me
N(Me)
Ph
C(Me)2
cPr
racemic


II-216
Me
Et
Me
N(Me)
Ph
C(Me)2
cPr
(S)-


II-217
Me
Me
Me
NH
Ph
C(Me)2
Ph
racemic


II-218
Me
Me
Me
NH
Ph
C(Me)2
Ph
(S)-


II-219
Me
Et
Me
NH
Ph
C(Me)2
Ph
racemic


II-220
Me
Et
Me
NH
Ph
C(Me)2
Ph
(S)-


II-221
Me
Me
Me
N(Me)
Ph
C(Me)2
Ph
racemic


II-222
Me
Me
Me
N(Me)
Ph
C(Me)2
Ph
(S)-


II-223
Me
Et
Me
N(Me)
Ph
C(Me)2
Ph
racemic


II-224
Me
Et
Me
N(Me)
Ph
C(Me)2
Ph
(S)-


II-225
Me
Me
Me
NH
Ph
(CH2)2
H
racemic


II-226
Me
Me
Me
NH
Ph
(CH2)2
H
(R)-


II-227
Me
Et
Me
NH
Ph
(CH2)2
H
racemic


II-228
Me
Et
Me
NH
Ph
(CH2)2
H
(R)-


II-229
Me
Me
Me
N(Me)
Ph
(CH2)2
H
racemic


II-230
Me
Me
Me
N(Me)
Ph
(CH2)2
H
(R)-


II-231
Me
Et
Me
N(Me)
Ph
(CH2)2
H
racemic


II-232
Me
Et
Me
N(Me)
Ph
(CH2)2
H
(R)-


II-233
Me
Me
Me
NH
Ph
(CH2)2
Me
racemic


II-234
Me
Me
Me
NH
Ph
(CH2)2
Me
(R)-


II-235
Me
Et
Me
NH
Ph
(CH2)2
Me
racemic


II-236
Me
Et
Me
NH
Ph
(CH2)2
Me
(R)-


II-237
Me
Me
Me
N(Me)
Ph
(CH2)2
Me
racemic


II-238
Me
Me
Me
N(Me)
Ph
(CH2)2
Me
(R)-


II-239
Me
Et
Me
N(Me)
Ph
(CH2)2
Me
racemic


II-240
Me
Et
Me
N(Me)
Ph
(CH2)2
Me
(R)-


II-241
Me
Me
Me
NH
Ph
(CH2)2
CHF2
racemic


II-242
Me
Me
Me
NH
Ph
(CH2)2
CHF2
(R)-


II-243
Me
Et
Me
NH
Ph
(CH2)2
CHF2
racemic


II-244
Me
Et
Me
NH
Ph
(CH2)2
CHF2
(R)-


II-245
Me
Me
Me
N(Me)
Ph
(CH2)2
CHF2
racemic


II-246
Me
Me
Me
N(Me)
Ph
(CH2)2
CHF2
(R)-


II-247
Me
Et
Me
N(Me)
Ph
(CH2)2
CHF2
racemic


II-248
Me
Et
Me
N(Me)
Ph
(CH2)2
CHF2
(R)-


II-249
Me
Me
Me
NH
Ph
(CH2)2
Et
racemic


II-250
Me
Me
Me
NH
Ph
(CH2)2
Et
(R)-
















TABLE 14







(II)




embedded image




















Com-










pound







Configur-


No.
R1
R2
R3
L2
R4
L3
R5
ation





II-251
Me
Et
Me
NH
Ph
(CH2)2
Et
racemic


II-252
Me
Et
Me
NH
Ph
(CH2)2
Et
(R)-


II-253
Me
Me
Me
N(Me)
Ph
(CH2)2
Et
racemic


II-254
Me
Me
Me
N(Me)
Ph
(CH2)2
Et
(R)-


II-255
Me
Et
Me
N(Me)
Ph
(CH2)2
Et
racemic


II-256
Me
Et
Me
N(Me)
Ph
(CH2)2
Et
(R)-


II-257
Me
Me
Me
NH
Ph
(CH2)2
iPr
racemic


II-258
Me
Me
Me
NH
Ph
(CH2)2
iPr
(R)-


II-259
Me
Et
Me
NH
Ph
(CH2)2
iPr
racemic


II-260
Me
Et
Me
NH
Ph
(CH2)2
iPr
(R)-


II-261
Me
Me
Me
N(Me)
Ph
(CH2)2
iPr
racemic


II-262
Me
Me
Me
N(Me)
Ph
(CH2)2
iPr
(R)-


II-263
Me
Et
Me
N(Me)
Ph
(CH2)2
iPr
racemic


II-264
Me
Et
Me
N(Me)
Ph
(CH2)2
iPr
(R)-


II-265
Me
Me
Me
NH
Ph
(CH2)2
cPr
racemic


II-266
Me
Me
Me
NH
Ph
(CH2)2
cPr
(R)-


II-267
Me
Et
Me
NH
Ph
(CH2)2
cPr
racemic


II-268
Me
Et
Me
NH
Ph
(CH2)2
cPr
(R)-


II-269
Me
Me
Me
N(Me)
Ph
(CH2)2
cPr
racemic


II-270
Me
Me
Me
N(Me)
Ph
(CH2)2
cPr
(R)-


II-271
Me
Et
Me
N(Me)
Ph
(CH2)2
cPr
racemic


II-272
Me
Et
Me
N(Me)
Ph
(CH2)2
cPr
(R)-


II-273
Me
Me
Me
NH
Ph
(CH2)2
Ph
racemic


II-274
Me
Me
Me
NH
Ph
(CH2)2
Ph
(R)-


II-275
Me
Et
Me
NH
Ph
(CH2)2
Ph
racemic


II-276
Me
Et
Me
NH
Ph
(CH2)2
Ph
(R)-


II-277
Me
Me
Me
N(Me)
Ph
(CH2)2
Ph
racemic


II-278
Me
Me
Me
N(Me)
Ph
(CH2)2
Ph
(R)-


II-279
Me
Et
Me
N(Me)
Ph
(CH2)2
Ph
racemic


II-280
Me
Et
Me
N(Me)
Ph
(CH2)2
Ph
(R)-


II-281
Me
Me
Me
NH
Ph
(CH2)3
H
racemic


II-282
Me
Me
Me
NH
Ph
(CH2)3
H
(R)-


II-283
Me
Et
Me
NH
Ph
(CH2)3
H
racemic


II-284
Me
Et
Me
NH
Ph
(CH2)3
H
(R)-


II-285
Me
Me
Me
N(Me)
Ph
(CH2)3
H
racemic


II-286
Me
Me
Me
N(Me)
Ph
(CH2)3
H
(R)-


II-287
Me
Et
Me
N(Me)
Ph
(CH2)3
H
racemic


II-288
Me
Et
Me
N(Me)
Ph
(CH2)3
H
(R)-


II-289
Me
Me
Me
NH
Ph
(CH2)4
H
racemic


II-290
Me
Me
Me
NH
Ph
(CH2)4
H
(R)-


II-291
Me
Et
Me
NH
Ph
(CH2)4
H
racemic


II-292
Me
Et
Me
NH
Ph
(CH2)4
H
(R)-


II-293
Me
Me
Me
N(Me)
Ph
(CH2)4
H
racemic


II-294
Me
Me
Me
N(Me)
Ph
(CH2)4
H
(R)-


II-295
Me
Et
Me
N(Me)
Ph
(CH2)4
H
racemic


II-296
Me
Et
Me
N(Me)
Ph
(CH2)4
H
(R)-


II-297
Me
Me
Me
NH
Ph
CH2C(Me)2
H
racemic


II-298
Me
Me
Me
NH
Ph
CH2C(Me)2
H
(R)-


II-299
Me
Et
Me
NH
Ph
CH2C(Me)2
H
racemic


II-300
Me
Et
Me
NH
Ph
CH2C(Me)2
H
(R)-
















TABLE 15







(II)




embedded image




















Com-










pound







Configur-


No.
R1
R2
R3
L2
R4
L3
R5
ation





II-301
Me
Me
Me
N(Me)
Ph
CH2C(Me)2
H
racemic


II-302
Me
Me
Me
N(Me)
Ph
CH2C(Me)2
H
(R)-


II-303
Me
Et
Me
N(Me)
Ph
CH2C(Me)2
H
racemic


II-304
Me
Et
Me
N(Me)
Ph
CH2C(Me)2
H
(R)-


II-305
Me
Me
Me
NH
Ph
CH2C(Me)2
Me
racemic


II-306
Me
Me
Me
NH
Ph
CH2C(Me)2
Me
(R)-


II-307
Me
Et
Me
NH
Ph
CH2C(Me)2
Me
racemic


II-308
Me
Et
Me
NH
Ph
CH2C(Me)2
Me
(R)-


II-309
Me
Me
Me
N(Me)
Ph
CH2C(Me)2
Me
racemic


II-310
Me
Me
Me
N(Me)
Ph
CH2C(Me)2
Me
(R)-


II-311
Me
Et
Me
N(Me)
Ph
CH2C(Me)2
Me
racemic


II-312
Me
Et
Me
N(Me)
Ph
CH2C(Me)2
Me
(R)-


II-313
Me
Me
Me
NH
Ph
CH2C(Me)2
CHF2
racemic


II-314
Me
Me
Me
NH
Ph
CH2C(Me)2
CHF2
(R)-


II-315
Me
Et
Me
NH
Ph
CH2C(Me)2
CHF2
racemic


II-316
Me
Et
Me
NH
Ph
CH2C(Me)2
CHF2
(R)-


II-317
Me
Me
Me
N(Me)
Ph
CH2C(Me)2
CHF2
racemic


II-318
Me
Me
Me
N(Me)
Ph
CH2C(Me)2
CHF2
(R)-


II-319
Me
Et
Me
N(Me)
Ph
CH2C(Me)2
CHF2
racemic


II-320
Me
Et
Me
N(Me)
Ph
CH2C(Me)2
CHF2
(R)-


II-321
Me
Me
Me
NH
Ph
CH2C(Me)2
Et
racemic


II-322
Me
Me
Me
NH
Ph
CH2C(Me)2
Et
(R)-


II-323
Me
Et
Me
NH
Ph
CH2C(Me)2
Et
racemic


II-324
Me
Et
Me
NH
Ph
CH2C(Me)2
Et
(R)-


II-325
Me
Me
Me
N(Me)
Ph
CH2C(Me)2
Et
racemic


II-326
Me
Me
Me
N(Me)
Ph
CH2C(Me)2
Et
(R)-


II-327
Me
Et
Me
N(Me)
Ph
CH2C(Me)2
Et
racemic


II-328
Me
Et
Me
N(Me)
Ph
CH2C(Me)2
Et
(R)-


II-329
Me
Me
Me
NH
Ph
CH2C(Me)2
iPr
racemic


II-330
Me
Me
Me
NH
Ph
CH2C(Me)2
iPr
(R)-


II-331
Me
Et
Me
NH
Ph
CH2C(Me)2
iPr
racemic


II-332
Me
Et
Me
NH
Ph
CH2C(Me)2
iPr
(R)-


II-333
Me
Me
Me
N(Me)
Ph
CH2C(Me)2
iPr
racemic


II-334
Me
Me
Me
N(Me)
Ph
CH2C(Me)2
iPr
(R)-


II-335
Me
Et
Me
N(Me)
Ph
CH2C(Me)2
iPr
racemic


II-336
Me
Et
Me
N(Me)
Ph
CH2C(Me)2
iPr
(R)-


II-337
Me
Me
Me
NH
Ph
CH2C(Me)2
cPr
racemic


II-338
Me
Me
Me
NH
Ph
CH2C(Me)2
cPr
(R)-


II-339
Me
Et
Me
NH
Ph
CH2C(Me)2
cPr
racemic


II-340
Me
Et
Me
NH
Ph
CH2C(Me)2
cPr
(R)-


II-341
Me
Me
Me
N(Me)
Ph
CH2C(Me)2
cPr
racemic


II-342
Me
Me
Me
N(Me)
Ph
CH2C(Me)2
cPr
(R)-


II-343
Me
Et
Me
N(Me)
Ph
CH2C(Me)2
cPr
racemic


II-344
Me
Et
Me
N(Me)
Ph
CH2C(Me)2
cPr
(R)-


II-345
Me
Me
Me
NH
Ph
CH2C(Me)2
Ph
racemic


II-346
Me
Me
Me
NH
Ph
CH2C(Me)2
Ph
(R)-


II-347
Me
Et
Me
NH
Ph
CH2C(Me)2
Ph
racemic


II-348
Me
Et
Me
NH
Ph
CH2C(Me)2
Ph
(R)-


II-349
Me
Me
Me
N(Me)
Ph
CH2C(Me)2
Ph
racemic


II-350
Me
Me
Me
N(Me)
Ph
CH2C(Me)2
Ph
(R)-
















TABLE 16







(II)




embedded image




















Com-







Con-


pound







figu-


No.
R1
R2
R3
L2
R4
L3
R5
ration





II-351
Me
Et
Me
N(Me)
Ph
CH2C(Me)2
Ph
racemic


II-352
Me
Et
Me
N(Me)
Ph
CH2C(Me)2
Ph
(R)-


II-353
Me
Me
Me
NH
Ph
C(Me)2CH2
H
racemic


II-354
Me
Me
Me
NH
Ph
C(Me)2CH2
H
(S)-


II-355
Me
Et
Me
NH
Ph
C(Me)2CH2
H
racemic


II-356
Me
Et
Me
NH
Ph
C(Me)2CH2
H
(S)-


II-357
Me
Me
Me
N(Me)
Ph
C(Me)2CH2
H
racemic


II-358
Me
Me
Me
N(Me)
Ph
C(Me)2CH2
H
(S)-


II-359
Me
Et
Me
N(Me)
Ph
C(Me)2CH2
H
racemic


II-360
Me
Et
Me
N(Me)
Ph
C(Me)2CH2
H
(S)-


II-361
Me
Me
Me
NH
Ph
CF2CH2
H
racemic


II-362
Me
Me
Me
NH
Ph
CF2CH2
H
(S)-


II-363
Me
Et
Me
NH
Ph
CF2CH2
H
racemic


II-364
Me
Et
Me
NH
Ph
CF2CH2
H
(S)-


II-365
Me
Me
Me
N(Me)
Ph
CF2CH2
H
racemic


II-366
Me
Me
Me
N(Me)
Ph
CF2CH2
H
(S)-


II-367
Me
Et
Me
N(Me)
Ph
CF2CH2
H
racemic


II-368
Me
Et
Me
N(Me)
Ph
CF2CH2
H
(S)-


II-369
Me
Me
Me
NH
Ph
CH═CHCH2
H
racemic


II-370
Me
Me
Me
NH
Ph
CH═CHCH2
H
(S)-


II-371
Me
Et
Me
NH
Ph
CH═CHCH2
H
racemic


II-372
Me
Et
Me
NH
Ph
CH═CHCH2
H
(S)-


II-373
Me
Me
Me
N(Me)
Ph
CH═CHCH2
H
racemic


II-374
Me
Me
Me
N(Me)
Ph
CH═CHCH2
H
(S)-


II-375
Me
Et
Me
N(Me)
Ph
CH═CHCH2
H
racemic


II-376
Me
Et
Me
N(Me)
Ph
CH═CHCH2
H
(S)-


II-377
Me
Me
Me
NH
Ph
C≡CCH2
H
racemic


II-378
Me
Me
Me
NH
Ph
C≡CCH2
H
(S)-


II-379
Me
Et
Me
NH
Ph
C≡CCH2
H
racemic


II-380
Me
Et
Me
NH
Ph
C≡CCH2
H
(S)-


II-381
Me
Me
Me
N(Me)
Ph
C≡CCH2
H
racemic


II-382
Me
Me
Me
N(Me)
Ph
C≡CCH2
H
(S)-


II-383
Me
Et
Me
N(Me)
Ph
C≡CCH2
H
racemic


II-384
Me
Et
Me
N(Me)
Ph
C≡CCH2
H
(S)-


II-385
Me
Me
Me
NH
Ph
1,1-Cyclopropylene
H
racemic


II-386
Me
Me
Me
NH
Ph
1,1-Cyclopropylene
H
(S)-


II-387
Me
Et
Me
NH
Ph
1,1-Cyclopropylene
H
racemic


II-388
Me
Et
Me
NH
Ph
1,1-Cyclopropylene
H
(S)-


II-389
Me
Me
Me
N(Me)
Ph
1,1-Cyclopropylene
H
racemic


II-390
Me
Me
Me
N(Me)
Ph
1,1-Cyclopropylene
H
(S)-


II-391
Me
Et
Me
N(Me)
Ph
1,1-Cyclopropylene
H
racemic


II-392
Me
Et
Me
N(Me)
Ph
1,1-Cyclopropylene
H
(S)-


II-393
Me
Me
Me
NH
Ph
1,2-Cyclopropynylene
H
racemic


II-394
Me
Me
Me
NH
Ph
1,2-Cyclopropynylene
H
(S)-


II-395
Me
Et
Me
NH
Ph
1,2-Cyclopropynylene
H
racemic


II-396
Me
Et
Me
NH
Ph
1,2-Cyclopropynylene
H
(S)-


II-397
Me
Me
Me
N(Me)
Ph
1,2-Cyclopropynylene
H
racemic


II-398
Me
Me
Me
N(Me)
Ph
1,2-Cyclopropynylene
H
(S)-


II-399
Me
Et
Me
N(Me)
Ph
1,2-Cyclopropynylene
H
racemic


II-400
Me
Et
Me
N(Me)
Ph
1,2-Cyclopropynylene
H
(S)-
















TABLE 17







(II)




embedded image




















Compound










No.
R1
R2
R3
L2
R4
L3
R5
Configuration





II-401
Me
Me
Me
NH
Ph
C(═O)
H
racemic


II-402
Me
Me
Me
NH
Ph
C(═O)
H
(S)-


II-403
Me
Et
Me
NH
Ph
C(═O)
H
racemic


II-404
Me
Et
Me
NH
Ph
C(═O)
H
(S)-


II-405
Me
Me
Me
N(Me)
Ph
C(═O)
H
racemic


II-406
Me
Me
Me
N(Me)
Ph
C(═O)
H
(S)-


II-407
Me
Et
Me
N(Me)
Ph
C(═O)
H
racemic


II-408
Me
Et
Me
N(Me)
Ph
C(═O)
H
(S)-


II-409
Me
Me
Me
NH
Ph
C(═O)
Bn
racemic


II-410
Me
Me
Me
NH
Ph
C(═O)
Bn
(S)-


II-411
Me
Et
Me
NH
Ph
C(═O)
Bn
racemic


II-412
Me
Et
Me
NH
Ph
C(═O)
Bn
(S)-


II-413
Me
Me
Me
N(Me)
Ph
C(═O)
Bn
racemic


II-414
Me
Me
Me
N(Me)
Ph
C(═O)
Bn
(S)-


II-415
Me
Et
Me
N(Me)
Ph
C(═O)
Bn
racemic


II-416
Me
Et
Me
N(Me)
Ph
C(═O)
Bn
(S)-


II-417
Me
Me
Me
NH
Ph
C(═O)
Me
racemic


II-418
Me
Me
Me
NH
Ph
C(═O)
Me
(S)-


II-419
Me
Et
Me
NH
Ph
C(═O)
Me
racemic


II-420
Me
Et
Me
NH
Ph
C(═O)
Me
(S)-


II-421
Me
Me
Me
N(Me)
Ph
C(═O)
Me
racemic


II-422
Me
Me
Me
N(Me)
Ph
C(═O)
Me
(S)-


II-423
Me
Et
Me
N(Me)
Ph
C(═O)
Me
racemic


II-424
Me
Et
Me
N(Me)
Ph
C(═O)
Me
(S)-


II-425
Me
Me
Me
NH
H
CH2
H



II-426
Me
Et
Me
NH
H
CH2
H



II-427
Me
Me
Me
N(Me)
H
CH2
H



II-428
Me
Et
Me
N(Me)
H
CH2
H



II-429
Me
Me
Me
NH
H
CH(Me)
H



II-430
Me
Et
Me
NH
H
CH(Me)
H



II-431
Me
Me
Me
N(Me)
H
CH(Me)
H



II-432
Me
Et
Me
N(Me)
H
CH(Me)
H



II-433
Me
Me
Me
NH
H
CH(iPr)
H



II-434
Me
Et
Me
NH
H
CH(iPr)
H



II-435
Me
Me
Me
N(Me)
H
CH(iPr)
H



II-436
Me
Et
Me
N(Me)
H
CH(iPr)
H



II-437
Me
Me
Me
NH
H
CH(Ph)
H



II-438
Me
Et
Me
NH
H
CH(Ph)
H



II-439
Me
Me
Me
N(Me)
H
CH(Ph)
H



II-440
Me
Et
Me
N(Me)
H
CH(Ph)
H



II-441
Me
Me
Me
NH
Me
CH2
H
racemic


II-442
Me
Me
Me
NH
Me
CH2
H
(S)-


II-443
Me
Et
Me
NH
Me
CH2
H
racemic


II-444
Me
Et
Me
NH
Me
CH2
H
(S)-


II-445
Me
Me
Me
N(Me)
Me
CH2
H
racemic


II-446
Me
Me
Me
N(Me)
Me
CH2
H
(S)-


II-447
Me
Et
Me
N(Me)
Me
CH2
H
racemic


II-448
Me
Et
Me
N(Me)
Me
CH2
H
(S)-


II-449
Me
Me
Me
NH
iPr
CH2
H
racemic


II-450
Me
Me
Me
NH
iPr
CH2
H
(S)-
















TABLE 18







(II)




embedded image




















Com-







Con-


pound







figu-


No.
R1
R2
R3
L2
R4
L3
R5
ration





II-451
Me
Et
Me
NH
iPr
CH2
H
racemic


II-452
Me
Et
Me
NH
iPr
CH2
H
(S)-


II-453
Me
Me
Me
N(Me)
iPr
CH2
H
racemic


II-454
Me
Me
Me
N(Me)
iPr
CH2
H
(S)-


II-455
Me
Et
Me
N(Me)
iPr
CH2
H
racemic


II-456
Me
Et
Me
N(Me)
iPr
CH2
H
(S)-


II-457
Me
Me
Me
NH
cHex
CH2
H
racemic


II-458
Me
Me
Me
NH
cHex
CH2
H
(S)-


II-459
Me
Et
Me
NH
cHex
CH2
H
racemic


II-460
Me
Et
Me
NH
cHex
CH2
H
(S)-


II-461
Me
Me
Me
N(Me)
cHex
CH2
H
racemic


II-462
Me
Me
Me
N(Me)
cHex
CH2
H
(S)-


II-463
Me
Et
Me
N(Me)
cHex
CH2
H
racemic


II-464
Me
Et
Me
N(Me)
cHex
CH2
H
(S)-


II-465
Me
Me
Me
NH
1,3-Benzodioxol-4-yl
CH2
H
racemic


II-466
Me
Me
Me
NH
1,3-Benzodioxol-4-yl
CH2
H
(S)-


II-467
Me
Et
Me
NH
1,3-Benzodioxol-4-yl
CH2
H
racemic


II-468
Me
Et
Me
NH
1,3-Benzodioxol-4-yl
CH2
H
(S)-


II-469
Me
Me
Me
N(Me)
1,3-Benzodioxol-4-yl
CH2
H
racemic


II-470
Me
Me
Me
N(Me)
1,3-Benzodioxol-4-yl
CH2
H
(S)-


II-471
Me
Et
Me
N(Me)
1,3-Benzodioxol-4-yl
CH2
H
racemic


II-472
Me
Et
Me
N(Me)
1,3-Benzodioxol-4-yl
CH2
H
(S)-


II-473
Me
Me
Me
NH
2-F—Ph
CH2
H
racemic


II-474
Me
Me
Me
NH
2-F—Ph
CH2
H
(S)-


II-475
Me
Et
Me
NH
2-F—Ph
CH2
H
racemic


II-476
Me
Et
Me
NH
2-F—Ph
CH2
H
(S)-


II-477
Me
Me
Me
N(Me)
2-F—Ph
CH2
H
racemic


II-478
Me
Me
Me
N(Me)
2-F—Ph
CH2
H
(S)-


II-479
Me
Et
Me
N(Me)
2-F—Ph
CH2
H
racemic


II-480
Me
Et
Me
N(Me)
2-F—Ph
CH2
H
(S)-


II-481
Me
Me
Me
NH
3-F—Ph
CH2
H
racemic


II-482
Me
Me
Me
NH
3-F—Ph
CH2
H
(S)-


II-483
Me
Et
Me
NH
3-F—Ph
CH2
H
racemic


II-484
Me
Et
Me
NH
3-F—Ph
CH2
H
(S)-


II-485
Me
Me
Me
N(Me)
3-F—Ph
CH2
H
racemic


II-486
Me
Me
Me
N(Me)
3-F—Ph
CH2
H
(S)-


II-487
Me
Et
Me
N(Me)
3-F—Ph
CH2
H
racemic


II-488
Me
Et
Me
N(Me)
3-F—Ph
CH2
H
(S)-


II-489
Me
Me
Me
NH
4-F—Ph
CH2
H
racemic


II-490
Me
Me
Me
NH
4-F—Ph
CH2
H
(S)-


II-491
Me
Et
Me
NH
4-F—Ph
CH2
H
racemic


II-492
Me
Et
Me
NH
4-F—Ph
CH2
H
(S)-


II-493
Me
Me
Me
N(Me)
4-F—Ph
CH2
H
racemic


II-494
Me
Me
Me
N(Me)
4-F—Ph
CH2
H
(S)-


II-495
Me
Et
Me
N(Me)
4-F—Ph
CH2
H
racemic


II-496
Me
Et
Me
N(Me)
4-F—Ph
CH2
H
(S)-


II-497
Me
Me
Me
NH
2-Py
CH2
H
racemic


II-498
Me
Me
Me
NH
2-Py
CH2
H
(S)-


II-499
Me
Et
Me
NH
2-Py
CH2
H
racemic


II-500
Me
Et
Me
NH
2-Py
CH2
H
(S)-
















TABLE 19







(II)




embedded image




















Compound







Con-


No.
R1
R2
R3
L2
R4
L3
R5
figuration





II-501
Me
Me
Me
N(Me)
2-Py
CH2
H
racemic


II-502
Me
Me
Me
N(Me)
2-Py
CH2
H
(S)-


II-503
Me
Et
Me
N(Me)
2-Py
CH2
H
racemic


II-504
Me
Et
Me
N(Me)
2-Py
CH2
H
(S)-


II-505
Me
Me
Me
NH
3-Py
CH2
H
racemic


II-506
Me
Me
Me
NH
3-Py
CH2
H
(S)-


II-507
Me
Et
Me
NH
3-Py
CH2
H
racemic


II-508
Me
Et
Me
NH
3-Py
CH2
H
(S)-


II-509
Me
Me
Me
N(Me)
3-Py
CH2
H
racemic


II-510
Me
Me
Me
N(Me)
3-Py
CH2
H
(S)-


II-511
Me
Et
Me
N(Me)
3-Py
CH2
H
racemic


II-512
Me
Et
Me
N(Me)
3-Py
CH2
H
(S)-


II-513
Me
Me
Me
NH
4-Py
CH2
H
racemic


II-514
Me
Me
Me
NH
4-Py
CH2
H
(S)-


II-515
Me
Et
Me
NH
4-Py
CH2
H
racemic


II-516
Me
Et
Me
NH
4-Py
CH2
H
(S)-


II-517
Me
Me
Me
N(Me)
4-Py
CH2
H
racemic


II-518
Me
Me
Me
N(Me)
4-Py
CH2
H
(S)-


II-519
Me
Et
Me
N(Me)
4-Py
CH2
H
racemic


II-520
Me
Et
Me
N(Me)
4-Py
CH2
H
(S)-


II-521
Me
Me
Me
CH2
Ph
CH2
H
racemic


II-522
Me
Me
Me
CH2
Ph
CH2
H
(S)-


II-523
Me
Et
Me
CH2
Ph
CH2
H
racemic


II-524
Me
Et
Me
CH2
Ph
CH2
H
(S)-


II-525
Me
Me
Me
CH2
Ph
—
H
racemic


II-526
Me
Me
Me
CH2
Ph
—
H
(S)-


II-527
Me
Et
Me
CH2
Ph
—
H
racemic


II-528
Me
Et
Me
CH2
Ph
—
H
(S)-


II-529
Me
Me
Me
CH2
Ph
CH2
Me
racemic


II-530
Me
Me
Me
CH2
Ph
CH2
Me
(S)-


II-531
Me
Et
Me
CH2
Ph
CH2
Me
racemic


II-532
Me
Et
Me
CH2
Ph
CH2
Me
(S)-


II-533
Me
Me
Me
CH2
Ph
C(Me)2
H
racemic


II-534
Me
Me
Me
CH2
Ph
C(Me)2
H
(S)-


II-535
Me
Et
Me
CH2
Ph
C(Me)2
H
racemic


II-536
Me
Et
Me
CH2
Ph
C(Me)2
H
(S)-


II-537
Me
Me
Me
CH2
Ph
C(Me)2
Me
racemic


II-538
Me
Me
Me
CH2
Ph
C(Me)2
Me
(S)-


II-539
Me
Et
Me
CH2
Ph
C(Me)2
Me
racemic


II-540
Me
Et
Me
CH2
Ph
C(Me)2
Me
(S)-


II-541
Me
Me
Me
CH2
Ph
(CH2)2
H
racemic


II-542
Me
Me
Me
CH2
Ph
(CH2)2
H
(S)-


II-543
Me
Et
Me
CH2
Ph
(CH2)2
H
racemic


II-544
Me
Et
Me
CH2
Ph
(CH2)2
H
(S)-


II-545
Me
Me
Me
CH2
Ph
(CH2)2
Me
racemic


II-546
Me
Me
Me
CH2
Ph
(CH2)2
Me
(S)-


II-547
Me
Et
Me
CH2
Ph
(CH2)2
Me
racemic


II-548
Me
Et
Me
CH2
Ph
(CH2)2
Me
(S)-


II-549
Me
Me
Me
CH2
Ph
CH2C(Me)2
H
racemic


II-550
Me
Me
Me
CH2
Ph
CH2C(Me)2
H
(S)-
















TABLE 20







(II)




embedded image




















Com-










pound







Con-


No.
R1
R2
R3
L2
R4
L3
R5
figuration





II-551
Me
Et
Me
CH2
Ph
CH2C(Me)2
H
racemic


II-552
Me
Et
Me
CH2
Ph
CH2C(Me)2
H
(S)-


II-553
Me
Me
Me
CH2
Ph
CH2C(Me)2
Me
racemic


II-554
Me
Me
Me
CH2
Ph
CH2C(Me)2
Me
(S)-


II-555
Me
Et
Me
CH2
Ph
CH2C(Me)2
Me
racemic


II-556
Me
Et
Me
CH2
Ph
CH2C(Me)2
Me
(S)-


II-557
Me
Me
Me
—
Ph
CH2
H
racemic


II-558
Me
Me
Me
—
Ph
CH2
H
(S)-


II-559
Me
Me
Me
—
Ph
CH2
Me
racemic


II-560
Me
Me
Me
—
Ph
CH2
Me
(S)-


II-561
Me
Me
Me
CH═CH
Ph
CH2
H
racemic


II-562
Me
Me
Me
CH═CH
Ph
CH2
H
(S)-


II-563
Me
Me
Me
CH═CH
Ph
CH2
Me
racemic


II-564
Me
Me
Me
CH═CH
Ph
CH2
Me
(S)-


II-565
Me
Me
Me
C≡C
Ph
CH2
H
racemic


II-566
Me
Me
Me
C≡C
Ph
CH2
H
(S)-


II-567
Me
Me
Me
C≡C
Ph
CH2
Me
racemic


II-568
Me
Me
Me
C≡C
Ph
CH2
Me
(S)-


II-569
Me
Me
Me
1,2-Cyclo-
Ph
CH2
H
racemic






propylene






II-570
Me
Me
Me
1,2-Cyclo-
Ph
CH2
H
(S)-






propylene






II-571
Me
Me
Me
1,2-Cyclo-
Ph
CH2
Me
racemic






propylene






II-572
Me
Me
Me
1,2-Cyclo-
Ph
CH2
Me
(S)-






propylene






II-573
Me
Me
Me
1,2-Cyclo-
Ph
CH2
H
racemic






propynylene






II-574
Me
Me
Me
1,2-Cyclo-
Ph
CH2
H
(S)-






propynylene






II-575
Me
Me
Me
1,2-Cyclo-
Ph
CH2
Me
racemic






propynylene






II-576
Me
Me
Me
1,2-Cyclo-
Ph
CH2
Me
(S)-






propynylene
















TABLE 21







(II)




embedded image




















Compound










No.
R1
R2
R3
L2
R4
L3
R5
Configuration





II-577
Me
Me
Me
O
Ph
C(Me)2CH2
H
racemic


II-578
Me
Me
Me
O
Ph
C(Me)2CH2
H
(+)


II-579
Me
Me
Me
O
Ph
C(Me)2CH2
H
(−)


II-580
Me
Et
Me
O
Ph
C(Me)2CH2
H
racemic


II-581
Me
Et
Me
O
Ph
C(Me)2CH2
H
(+)


II-582
Me
Et
Me
O
Ph
C(Me)2CH2
H
(−)


II-583
Me
Me
Me
O
Ph
C(Me)2CH2
Me
racemic


II-584
Me
Me
Me
O
Ph
C(Me)2CH2
Me
(+)


II-585
Me
Me
Me
O
Ph
C(Me)2CH2
Me
(−)


II-586
Me
Et
Me
O
Ph
C(Me)2CH2
Me
racemic


II-587
Me
Et
Me
O
Ph
C(Me)2CH2
Me
(+)


II-588
Me
Et
Me
O
Ph
C(Me)2CH2
Me
(−)


II-589
Me
Me
Me
O
Ph
C(Me)2CH2
CHF2
racemic


II-590
Me
Me
Me
O
Ph
C(Me)2CH2
CHF2
(+)


II-591
Me
Me
Me
O
Ph
C(Me)2CH2
CHF2
(−)


II-592
Me
Me
Me
O
Ph
C(Me)2CH2
Et
racemic


II-593
Me
Me
Me
O
Ph
C(Me)2CH2
Et
(+)


II-594
Me
Me
Me
O
Ph
C(Me)2CH2
Et
(−)


II-595
Me
Me
Me
NH
Ph
C(Me)2CH2
H
(+)


II-596
Me
Me
Me
NH
Ph
C(Me)2CH2
H
(−)


II-597
Me
Et
Me
NH
Ph
C(Me)2CH2
H
(+)


II-598
Me
Et
Me
NH
Ph
C(Me)2CH2
H
(−)


II-599
Me
Me
Me
NH
Ph
C(Me)2CH2
Me
racemic


II-600
Me
Me
Me
NH
Ph
C(Me)2CH2
Me
(+)


II-601
Me
Me
Me
NH
Ph
C(Me)2CH2
Me
(−)


II-602
Me
Et
Me
NH
Ph
C(Me)2CH2
Me
racemic


II-603
Me
Et
Me
NH
Ph
C(Me)2CH2
Me
(+)


II-604
Me
Et
Me
NH
Ph
C(Me)2CH2
Me
(−)


II-605
Me
Me
Me
NH
Ph
C(Me)2CH2
CHF2
racemic


II-606
Me
Me
Me
NH
Ph
C(Me)2CH2
CHF2
(+)


II-607
Me
Me
Me
NH
Ph
C(Me)2CH2
CHF2
(−)


II-608
Me
Et
Me
NH
Ph
C(Me)2CH2
CHF2
racemic


II-609
Me
Et
Me
NH
Ph
C(Me)2CH2
CHF2
(+)


II-610
Me
Et
Me
NH
Ph
C(Me)2CH2
CHF2
(−)


II-611
Me
Me
Me
NH
Ph
C(Me)2CH2
Et
racemic


II-612
Me
Me
Me
NH
Ph
C(Me)2CH2
Et
(+)


II-613
Me
Me
Me
NH
Ph
C(Me)2CH2
Et
(−)


II-614
Me
Et
Me
NH
Ph
C(Me)2CH2
Et
racemic


II-615
Me
Et
Me
NH
Ph
C(Me)2CH2
Et
(+)


II-616
Me
Et
Me
NH
Ph
C(Me)2CH2
Et
(−)


II-617
Me
Me
Me
NH
Ph
C(Me)2CH2
iPr
racemic


II-618
Me
Me
Me
NH
Ph
C(Me)2CH2
iPr
(+)


II-619
Me
Me
Me
NH
Ph
C(Me)2CH2
iPr
(−)


II-620
Me
Et
Me
NH
Ph
C(Me)2CH2
iPr
racemic


II-621
Me
Et
Me
NH
Ph
C(Me)2CH2
iPr
(+)


II-622
Me
Et
Me
NH
Ph
C(Me)2CH2
iPr
(−)


II-623
Me
Me
Me
NH
Ph
C(Me)2CH2
cPr
racemic


II-624
Me
Me
Me
NH
Ph
C(Me)2CH2
cPr
(+)


II-625
Me
Me
Me
NH
Ph
C(Me)2CH2
cPr
(−)


II-626
Me
Et
Me
NH
Ph
C(Me)2CH2
cPr
racemic
















TABLE 22







(II)




embedded image




















Com-










pound







Con-


No.
R1
R2
R3
L2
R4
L3
R5
figuration





II-627
Me
Et
Me
NH
Ph
C(Me)2CH2
cPr
(+)


II-628
Me
Et
Me
NH
Ph
C(Me)2CH2
cPr
(−)


II-629
Me
Me
Me
NH
Ph
1,1-Cyclopropylene-CH2
H
racemic


II-630
Me
Me
Me
NH
Ph
1,1-Cyclopropylene-CH2
H
(+)


II-631
Me
Me
Me
NH
Ph
1,1-Cyclopropylene-CH2
H
(−)


II-632
Me
Et
Me
NH
Ph
1,1-Cyclopropylene-CH2
H
racemic


II-633
Me
Et
Me
NH
Ph
1,1-Cyclopropylene-CH2
H
(+)


II-634
Me
Et
Me
NH
Ph
1,1-Cyclopropylene-CH2
H
(−)


II-635
Me
Me
Me
NH
Ph
1,1-Cyclopropylene-CH2
Me
racemic


II-636
Me
Me
Me
NH
Ph
1,1-Cyclopropylene-CH2
Me
(+)


II-637
Me
Me
Me
NH
Ph
1,1-Cyclopropylene-CH2
Me
(−)


II-638
Me
Et
Me
NH
Ph
1,1-Cyclopropylene-CH2
Me
racemic


II-639
Me
Et
Me
NH
Ph
1,1-Cyclopropylene-CH2
Me
(+)


II-640
Me
Et
Me
NH
Ph
1,1-Cyclopropylene-CH2
Me
(−)


II-641
Me
Me
Me
NH
Ph
1,1-Cyclobutylene-CH2
H
racemic


II-642
Me
Me
Me
NH
Ph
1,1-Cyclobutylene-CH2
H
(+)


II-643
Me
Me
Me
NH
Ph
1,1-Cyclobutylene-CH2
H
(−)


II-644
Me
Et
Me
NH
Ph
1,1-Cyclobutylene-CH2
H
racemic


II-645
Me
Et
Me
NH
Ph
1,1-Cyclobutylene-CH2
H
(+)


II-646
Me
Et
Me
NH
Ph
1,1-Cyclobutylene-CH2
H
(−)


II-647
Me
Me
Me
NH
Ph
1,1-Cyclobutylene-CH2
Me
racemic


II-648
Me
Me
Me
NH
Ph
1,1-Cyclobutylene-CH2
Me
(+)


II-649
Me
Me
Me
NH
Ph
1,1-Cyclobutylene-CH2
Me
(−)


II-650
Me
Et
Me
NH
Ph
1,1-Cyclobutylene-CH2
Me
racemic


II-651
Me
Et
Me
NH
Ph
1,1-Cyclobutylene-CH2
Me
(+)


II-652
Me
Et
Me
NH
Ph
1,1-Cyclobutylene-CH2
Me
(−)


II-653
Me
Me
Me
NH
Ph
C(Et)2CH2
H
racemic


II-654
Me
Me
Me
NH
Ph
C(Et)2CH2
H
(+)


II-655
Me
Me
Me
NH
Ph
C(Et)2CH2
H
(−)


II-656
Me
Et
Me
NH
Ph
C(Et)2CH2
H
racemic


II-657
Me
Et
Me
NH
Ph
C(Et)2CH2
H
(+)


II-658
Me
Et
Me
NH
Ph
C(Et)2CH2
H
(−)


II-659
Me
Me
Me
NH
Ph
C(Et)2CH2
Me
racemic


II-660
Me
Me
Me
NH
Ph
C(Et)2CH2
Me
(+)


II-661
Me
Me
Me
NH
Ph
C(Et)2CH2
Me
(−)


II-662
Me
Et
Me
NH
Ph
C(Et)2CH2
Me
racemic


II-663
Me
Et
Me
NH
Ph
C(Et)2CH2
Me
(+)


II-664
Me
Et
Me
NH
Ph
C(Et)2CH2
Me
(−)


II-665
Me
Me
Me
NH
Ph
CH2-1,1-Cyclopropylene
H
racemic


II-666
Me
Me
Me
NH
Ph
CH2-1,1-Cyclopropylene
H
(R)-


II-667
Me
Et
Me
NH
Ph
CH2-1,1-Cyclopropylene
H
racemic


II-668
Me
Et
Me
NH
Ph
CH2-1,1-Cyclopropylene
H
(R)-


II-669
Me
Me
Me
NH
Ph
CH2-1,1-Cyclopropylene
Me
racemic


II-670
Me
Me
Me
NH
Ph
CH2-1,1-Cyclopropylene
Me
(R)-


II-671
Me
Et
Me
NH
Ph
CH2-1,1-Cyclopropylene
Me
racemic


II-672
Me
Et
Me
NH
Ph
CH2-1,1-Cyclopropylene
Me
(R)-


II-673
Me
Me
Me
NH
Ph
CH2-1,1-cyclobutylene
H
racemic


II-674
Me
Me
Me
NH
Ph
CH2-1,1-cyclobutylene
H
(R)-


II-675
Me
Et
Me
NH
Ph
CH2-1,1-cyclobutylene
H
racemic


II-676
Me
Et
Me
NH
Ph
CH2-1,1-cyclobutylene
H
(R)-
















TABLE 23







(II)




embedded image




















Compound







Con-


No.
R1
R2
R3
L2
R4
L3
R5
figuration





II-677
Me
Me
Me
NH
Ph
CH2-1,1-
Me
racemic








cyclobutylene




II-678
Me
Me
Me
NH
Ph
CH2-1,1-
Me
(R)-








cyclobutylene




II-679
Me
Et
Me
NH
Ph
CH2-1,1-
Me
racemic








cyclobutylene




II-680
Me
Et
Me
NH
Ph
CH2-1,1-
Me
(R)-








cyclobutylene




II-681
Me
Me
Me
NH
Ph
CH2C(Et)2
H
racemic


II-682
Me
Me
Me
NH
Ph
CH2C(Et)2
H
(R)-


II-683
Me
Et
Me
NH
Ph
CH2C(Et)2
H
racemic


II-684
Me
Et
Me
NH
Ph
CH2C(Et)2
H
(R)-


II-685
Me
Me
Me
NH
Ph
CH2C(Et)2
Me
racemic


II-686
Me
Me
Me
NH
Ph
CH2C(Et)2
Me
(R)-


II-687
Me
Et
Me
NH
Ph
CH2C(Et)2
Me
racemic


II-688
Me
Et
Me
NH
Ph
CH2C(Et)2
Me
(R)-


II-689
Me
Me
Me
NH
iPr
CH2
Me
racemic


II-690
Me
Me
Me
NH
iPr
CH2
Me
(S)-


II-691
Me
Et
Me
NH
iPr
CH2
Me
racemic


II-692
Me
Et
Me
NH
iPr
CH2
Me
(S)-


II-693
Me
Me
Me
NH
iPr
(CH2)2
H
racemic


II-694
Me
Me
Me
NH
iPr
(CH2)2
H
(R)-


II-695
Me
Et
Me
NH
iPr
(CH2)2
H
racemic


II-696
Me
Et
Me
NH
iPr
(CH2)2
H
(R)-


II-697
Me
Me
Me
NH
iPr
(CH2)2
Me
racemic


II-698
Me
Me
Me
NH
iPr
(CH2)2
Me
(R)-


II-699
Me
Et
Me
NH
iPr
(CH2)2
Me
racemic


II-700
Me
Et
Me
NH
iPr
(CH2)2
Me
(R)-


II-701
Me
Me
Me
NH
CF3
CH2
H
racemic


II-702
Me
Me
Me
NH
CF3
CH2
H
(S)-


II-703
Me
Et
Me
NH
CF3
CH2
H
racemic


II-704
Me
Et
Me
NH
CF3
CH2
H
(S)-


II-705
Me
Me
Me
NH
CH2OH
CH2
H



II-706
Me
Et
Me
NH
CH2OH
CH2
H



II-707
Me
Me
Me
NH
CH2OMe
CH2
H
racemic


II-708
Me
Me
Me
NH
CH2OMe
CH2
H
(R)-


II-709
Me
Et
Me
NH
CH2OMe
CH2
H
racemic


II-710
Me
Et
Me
NH
CH2OMe
CH2
H
(R)-


II-711
Me
Me
Me
NH
CH2Ph
CH2
H
racemic


II-712
Me
Me
Me
NH
CH2Ph
CH2
H
(R)-


II-713
Me
Me
Me
NH
CH2Ph
CH2
H
(S)-


II-714
Me
Et
Me
NH
CH2Ph
CH2
H
racemic


II-715
Me
Et
Me
NH
CH2Ph
CH2
H
(S)-


II-716
Me
Me
Me
NH
2-F—Ph
CH2
Me
racemic


II-717
Me
Me
Me
NH
2-F—Ph
CH2
Me
(S)-


II-718
Me
Et
Me
NH
2-F—Ph
CH2
Me
racemic


II-719
Me
Et
Me
NH
2-F—Ph
CH2
Me
(S)-


II-720
Me
Me
Me
NH
2-F—Ph
(CH2)2
H
racemic


II-721
Me
Me
Me
NH
2-F—Ph
(CH2)2
H
(R)-


II-722
Me
Et
Me
NH
2-F—Ph
(CH2)2
H
racemic


II-723
Me
Et
Me
NH
2-F—Ph
(CH2)2
H
(R)-


II-724
Me
Me
Me
NH
2-F—Ph
(CH2)2
Me
racemic


II-725
Me
Me
Me
NH
2-F—Ph
(CH2)2
Me
(R)-


II-726
Me
Et
Me
NH
2-F—Ph
(CH2)2
Me
racemic
















TABLE 24







(II)




embedded image




















Compound







Con-


No.
R1
R2
R3
L2
R4
L3
R5
figuration





II-727
Me
Et
Me
NH
2-F—Ph
(CH2)2
Me
(R)-


II-728
Me
Me
Me
NH
2-F—Ph
CH2C(Me)2
H
racemic


II-729
Me
Me
Me
NH
2-F—Ph
CH2C(Me)2
H
(R)-


II-730
Me
Et
Me
NH
2-F—Ph
CH2C(Me)2
H
racemic


II-731
Me
Et
Me
NH
2-F—Ph
CH2C(Me)2
H
(R)-


II-732
Me
Me
Me
NH
2-F—Ph
CH2C(Me)2
Me
racemic


II-733
Me
Me
Me
NH
2-F—Ph
CH2C(Me)2
Me
(R)-


II-734
Me
Et
Me
NH
2-F—Ph
CH2C(Me)2
Me
racemic


II-735
Me
Et
Me
NH
2-F—Ph
CH2C(Me)2
Me
(R)-


II-736
Me
Me
Me
NH
2-F—Ph
C(Me)2CH2
H
racemic


II-737
Me
Me
Me
NH
2-F—Ph
C(Me)2CH2
H
(+)


II-738
Me
Me
Me
NH
2-F—Ph
C(Me)2CH2
H
(−)


II-739
Me
Et
Me
NH
2-F—Ph
C(Me)2CH2
H
racemic


II-740
Me
Et
Me
NH
2-F—Ph
C(Me)2CH2
H
(+)


II-741
Me
Et
Me
NH
2-F—Ph
C(Me)2CH2
H
(−)


II-742
Me
Me
Me
NH
2-F—Ph
C(Me)2CH2
Me
racemic


II-743
Me
Me
Me
NH
2-F—Ph
C(Me)2CH2
Me
(+)


II-744
Me
Me
Me
NH
2-F—Ph
C(Me)2CH2
Me
(−)


II-745
Me
Et
Me
NH
2-F—Ph
C(Me)2CH2
Me
racemic


II-746
Me
Et
Me
NH
2-F—Ph
C(Me)2CH2
Me
(+)


II-747
Me
Et
Me
NH
2-F—Ph
C(Me)2CH2
Me
(−)


II-748
Me
Me
Me
NH
3-F—Ph
(CH2)2
H
racemic


II-749
Me
Me
Me
NH
3-F—Ph
(CH2)2
H
(R)-


II-750
Me
Et
Me
NH
3-F—Ph
(CH2)2
H
racemic


II-751
Me
Et
Me
NH
3-F—Ph
(CH2)2
H
(R)-


II-752
Me
Me
Me
NH
3-F—Ph
(CH2)2
Me
racemic


II-753
Me
Me
Me
NH
3-F—Ph
(CH2)2
Me
(R)-


II-754
Me
Et
Me
NH
3-F—Ph
(CH2)2
Me
racemic


II-755
Me
Et
Me
NH
3-F—Ph
(CH2)2
Me
(R)-


II-756
Me
Me
Me
NH
3-F—Ph
CH2C(Me)2
H
racemic


II-757
Me
Me
Me
NH
3-F—Ph
CH2C(Me)2
H
(R)-


II-758
Me
Et
Me
NH
3-F—Ph
CH2C(Me)2
H
racemic


II-759
Me
Et
Me
NH
3-F—Ph
CH2C(Me)2
H
(R)-


II-760
Me
Me
Me
NH
3-F—Ph
CH2C(Me)2
Me
racemic


II-761
Me
Me
Me
NH
3-F—Ph
CH2C(Me)2
Me
(R)-


II-762
Me
Et
Me
NH
3-F—Ph
CH2C(Me)2
Me
racemic


II-763
Me
Et
Me
NH
3-F—Ph
CH2C(Me)2
Me
(R)-


II-764
Me
Me
Me
NH
3-F—Ph
C(Me)2CH2
H
racemic


II-765
Me
Me
Me
NH
3-F—Ph
C(Me)2CH2
H
(+)


II-766
Me
Me
Me
NH
3-F—Ph
C(Me)2CH2
H
(−)


II-767
Me
Et
Me
NH
3-F—Ph
C(Me)2CH2
H
racemic


II-768
Me
Et
Me
NH
3-F—Ph
C(Me)2CH2
H
(+)


II-769
Me
Et
Me
NH
3-F—Ph
C(Me)2CH2
H
(−)


II-770
Me
Me
Me
NH
3-F—Ph
C(Me)2CH2
Me
racemic


II-771
Me
Me
Me
NH
3-F—Ph
C(Me)2CH2
Me
(+)


II-772
Me
Me
Me
NH
3-F—Ph
C(Me)2CH2
Me
(−)


II-773
Me
Et
Me
NH
3-F—Ph
C(Me)2CH2
Me
racemic


II-774
Me
Et
Me
NH
3-F—Ph
C(Me)2CH2
Me
(+)


II-775
Me
Et
Me
NH
3-F—Ph
C(Me)2CH2
Me
(−)


II-776
Me
Me
Me
NH
4-F—Ph
(CH2)2
H
racemic
















TABLE 25







(II)




embedded image




















Compound







Con-


No.
R1
R2
R3
L2
R4
L3
R5
figuration





II-777
Me
Me
Me
NH
4-F—Ph
(CH2)2
H
(R)-


II-778
Me
Et
Me
NH
4-F—Ph
(CH2)2
H
racemic


II-779
Me
Et
Me
NH
4-F—Ph
(CH2)2
H
(R)-


II-780
Me
Me
Me
NH
4-F—Ph
(CH2)2
Me
racemic


II-781
Me
Me
Me
NH
4-F—Ph
(CH2)2
Me
(R)-


II-782
Me
Et
Me
NH
4-F—Ph
(CH2)2
Me
racemic


II-783
Me
Et
Me
NH
4-F—Ph
(CH2)2
Me
(R)-


II-784
Me
Me
Me
NH
4-F—Ph
CH2C(Me)2
H
racemic


II-785
Me
Me
Me
NH
4-F—Ph
CH2C(Me)2
H
(R)-


II-786
Me
Et
Me
NH
4-F—Ph
CH2C(Me)2
H
racemic


II-787
Me
Et
Me
NH
4-F—Ph
CH2C(Me)2
H
(R)-


II-788
Me
Me
Me
NH
4-F—Ph
CH2C(Me)2
Me
racemic


II-789
Me
Me
Me
NH
4-F—Ph
CH2C(Me)2
Me
(R)-


II-790
Me
Et
Me
NH
4-F—Ph
CH2C(Me)2
Me
racemic


II-791
Me
Et
Me
NH
4-F—Ph
CH2C(Me)2
Me
(R)-


II-792
Me
Me
Me
NH
4-F—Ph
C(Me)2CH2
H
racemic


II-793
Me
Me
Me
NH
4-F—Ph
C(Me)2CH2
H
(+)


II-794
Me
Me
Me
NH
4-F—Ph
C(Me)2CH2
H
(−)


II-795
Me
Et
Me
NH
4-F—Ph
C(Me)2CH2
H
racemic


II-796
Me
Et
Me
NH
4-F—Ph
C(Me)2CH2
H
(+)


II-797
Me
Et
Me
NH
4-F—Ph
C(Me)2CH2
H
(−)


II-798
Me
Me
Me
NH
4-F—Ph
C(Me)2CH2
Me
racemic


II-799
Me
Me
Me
NH
4-F—Ph
C(Me)2CH2
Me
(+)


II-800
Me
Me
Me
NH
4-F—Ph
C(Me)2CH2
Me
(−)


II-801
Me
Et
Me
NH
4-F—Ph
C(Me)2CH2
Me
racemic


II-802
Me
Et
Me
NH
4-F—Ph
C(Me)2CH2
Me
(+)


II-803
Me
Et
Me
NH
4-F—Ph
C(Me)2CH2
Me
(−)


II-804
Me
Me
Me
NH
2-Cl—Ph
CH2
H
racemic


II-805
Me
Me
Me
NH
2-Cl—Ph
CH2
H
(S)-


II-806
Me
Et
Me
NH
2-Cl—Ph
CH2
H
racemic


II-807
Me
Et
Me
NH
2-Cl—Ph
CH2
H
(S)-


II-808
Me
Me
Me
NH
2-Cl—Ph
CH2
Me
racemic


II-809
Me
Me
Me
NH
2-Cl—Ph
CH2
Me
(S)-


II-810
Me
Et
Me
NH
2-Cl—Ph
CH2
Me
racemic


II-811
Me
Et
Me
NH
2-Cl—Ph
CH2
Me
(S)-


II-812
Me
Me
Me
NH
2-Cl—Ph
(CH2)2
H
racemic


II-813
Me
Me
Me
NH
2-Cl—Ph
(CH2)2
H
(R)-


II-814
Me
Et
Me
NH
2-Cl—Ph
(CH2)2
H
racemic


II-815
Me
Et
Me
NH
2-Cl—Ph
(CH2)2
H
(R)-


II-816
Me
Me
Me
NH
2-Cl—Ph
(CH2)2
Me
racemic


II-817
Me
Me
Me
NH
2-Cl—Ph
(CH2)2
Me
(R)-


II-818
Me
Et
Me
NH
2-Cl—Ph
(CH2)2
Me
racemic


II-819
Me
Et
Me
NH
2-Cl—Ph
(CH2)2
Me
(R)-


II-820
Me
Me
Me
NH
2-Cl—Ph
CH2C(Me)2
H
racemic


II-821
Me
Me
Me
NH
2-Cl—Ph
CH2C(Me)2
H
(R)-


II-822
Me
Et
Me
NH
2-Cl—Ph
CH2C(Me)2
H
racemic


II-823
Me
Et
Me
NH
2-Cl—Ph
CH2C(Me)2
H
(R)-


II-824
Me
Me
Me
NH
2-Cl—Ph
CH2C(Me)2
Me
racemic


II-825
Me
Me
Me
NH
2-Cl—Ph
CH2C(Me)2
Me
(R)-


II-826
Me
Et
Me
NH
2-Cl—Ph
CH2C(Me)2
Me
racemic
















TABLE 26







(II)




embedded image




















Compound







Con-


No.
R1
R2
R3
L2
R4
L3
R5
figuration





II-827
Me
Et
Me
NH
2-Cl—Ph
CH2C(Me)2
Me
(R)-


II-828
Me
Me
Me
NH
2-Cl—Ph
C(Me)2CH2
H
racemic


II-829
Me
Me
Me
NH
2-Cl—Ph
C(Me)2CH2
H
(+)


II-830
Me
Me
Me
NH
2-Cl—Ph
C(Me)2CH2
H
(−)


II-831
Me
Et
Me
NH
2-Cl—Ph
C(Me)2CH2
H
racemic


II-832
Me
Et
Me
NH
2-Cl—Ph
C(Me)2CH2
H
(+)


II-833
Me
Et
Me
NH
2-Cl—Ph
C(Me)2CH2
H
(−)


II-834
Me
Me
Me
NH
2-Cl—Ph
C(Me)2CH2
Me
racemic


II-835
Me
Me
Me
NH
2-Cl—Ph
C(Me)2CH2
Me
(+)


II-836
Me
Me
Me
NH
2-Cl—Ph
C(Me)2CH2
Me
(−)


II-837
Me
Et
Me
NH
2-Cl—Ph
C(Me)2CH2
Me
racemic


II-838
Me
Et
Me
NH
2-Cl—Ph
C(Me)2CH2
Me
(+)


II-839
Me
Et
Me
NH
2-Cl—Ph
C(Me)2CH2
Me
(−)


II-840
Me
Me
Me
NH
3-Cl—Ph
CH2
H
racemic


II-841
Me
Me
Me
NH
3-Cl—Ph
CH2
H
(S)-


II-842
Me
Et
Me
NH
3-Cl—Ph
CH2
H
racemic


II-843
Me
Et
Me
NH
3-Cl—Ph
CH2
H
(S)-


II-844
Me
Me
Me
NH
3-Cl—Ph
CH2
Me
racemic


II-845
Me
Me
Me
NH
3-Cl—Ph
CH2
Me
(S)-


II-846
Me
Et
Me
NH
3-Cl—Ph
CH2
Me
racemic


II-847
Me
Et
Me
NH
3-Cl—Ph
CH2
Me
(S)-


II-848
Me
Me
Me
NH
3-Cl—Ph
(CH2)2
H
racemic


II-849
Me
Me
Me
NH
3-Cl—Ph
(CH2)2
H
(R)-


II-850
Me
Et
Me
NH
3-Cl—Ph
(CH2)2
H
racemic


II-851
Me
Et
Me
NH
3-Cl—Ph
(CH2)2
H
(R)-


II-852
Me
Me
Me
NH
3-Cl—Ph
(CH2)2
Me
racemic


II-853
Me
Me
Me
NH
3-Cl—Ph
(CH2)2
Me
(R)-


II-854
Me
Et
Me
NH
3-Cl—Ph
(CH2)2
Me
racemic


II-855
Me
Et
Me
NH
3-Cl—Ph
(CH2)2
Me
(R)-


II-856
Me
Me
Me
NH
3-Cl—Ph
CH2C(Me)2
H
racemic


II-857
Me
Me
Me
NH
3-Cl—Ph
CH2C(Me)2
H
(R)-


II-858
Me
Et
Me
NH
3-Cl—Ph
CH2C(Me)2
H
racemic


II-859
Me
Et
Me
NH
3-Cl—Ph
CH2C(Me)2
H
(R)-


II-860
Me
Me
Me
NH
3-Cl—Ph
CH2C(Me)2
Me
racemic


II-861
Me
Me
Me
NH
3-Cl—Ph
CH2C(Me)2
Me
(R)-


II-862
Me
Et
Me
NH
3-Cl—Ph
CH2C(Me)2
Me
racemic


II-863
Me
Et
Me
NH
3-Cl—Ph
CH2C(Me)2
Me
(R)-


II-864
Me
Me
Me
NH
3-Cl—Ph
C(Me)2CH2
H
racemic


II-865
Me
Me
Me
NH
3-Cl—Ph
C(Me)2CH2
H
(+)


II-866
Me
Me
Me
NH
3-Cl—Ph
C(Me)2CH2
H
(−)


II-867
Me
Et
Me
NH
3-Cl—Ph
C(Me)2CH2
H
racemic


II-868
Me
Et
Me
NH
3-Cl—Ph
C(Me)2CH2
H
(+)


II-869
Me
Et
Me
NH
3-Cl—Ph
C(Me)2CH2
H
(−)


II-870
Me
Me
Me
NH
3-Cl—Ph
C(Me)2CH2
Me
racemic


II-871
Me
Me
Me
NH
3-Cl—Ph
C(Me)2CH2
Me
(+)


II-872
Me
Me
Me
NH
3-Cl—Ph
C(Me)2CH2
Me
(−)


II-873
Me
Et
Me
NH
3-Cl—Ph
C(Me)2CH2
Me
racemic


II-874
Me
Et
Me
NH
3-Cl—Ph
C(Me)2CH2
Me
(+)


II-875
Me
Et
Me
NH
3-Cl—Ph
C(Me)2CH2
Me
(−)


II-876
Me
Me
Me
NH
4-Cl—Ph
CH2
H
racemic
















TABLE 27







(II)




embedded image




















Compound







Con-


No.
R1
R2
R3
L2
R4
L3
R5
figuration





II-877
Me
Me
Me
NH
4-Cl—Ph
CH2
H
(S)-


II-878
Me
Et
Me
NH
4-Cl—Ph
CH2
H
racemic


II-879
Me
Et
Me
NH
4-Cl—Ph
CH2
H
(S)-


II-880
Me
Me
Me
NH
4-Cl—Ph
CH2
Me
racemic


II-881
Me
Me
Me
NH
4-Cl—Ph
CH2
Me
(S)-


II-882
Me
Et
Me
NH
4-Cl—Ph
CH2
Me
racemic


II-883
Me
Et
Me
NH
4-Cl—Ph
CH2
Me
(S)-


II-884
Me
Me
Me
NH
4-Cl—Ph
(CH2)2
H
racemic


II-885
Me
Me
Me
NH
4-Cl—Ph
(CH2)2
H
(R)-


II-886
Me
Et
Me
NH
4-Cl—Ph
(CH2)2
H
racemic


II-887
Me
Et
Me
NH
4-Cl—Ph
(CH2)2
H
(R)-


II-888
Me
Me
Me
NH
4-Cl—Ph
(CH2)2
Me
racemic


II-889
Me
Me
Me
NH
4-Cl—Ph
(CH2)2
Me
(R)-


II-890
Me
Et
Me
NH
4-Cl—Ph
(CH2)2
Me
racemic


II-891
Me
Et
Me
NH
4-Cl—Ph
(CH2)2
Me
(R)-


II-892
Me
Me
Me
NH
4-Cl—Ph
CH2C(Me)2
H
racemic


II-893
Me
Me
Me
NH
4-Cl—Ph
CH2C(Me)2
H
(R)-


II-894
Me
Et
Me
NH
4-Cl—Ph
CH2C(Me)2
H
racemic


II-895
Me
Et
Me
NH
4-Cl—Ph
CH2C(Me)2
H
(R)-


II-896
Me
Me
Me
NH
4-Cl—Ph
CH2C(Me)2
Me
racemic


II-897
Me
Me
Me
NH
4-Cl—Ph
CH2C(Me)2
Me
(R)-


II-898
Me
Et
Me
NH
4-Cl—Ph
CH2C(Me)2
Me
racemic


II-899
Me
Et
Me
NH
4-Cl—Ph
CH2C(Me)2
Me
(R)-


II-900
Me
Me
Me
NH
4-Cl—Ph
C(Me)2CH2
H
racemic


II-901
Me
Me
Me
NH
4-Cl—Ph
C(Me)2CH2
H
(+)


II-902
Me
Me
Me
NH
4-Cl—Ph
C(Me)2CH2
H
(−)


II-903
Me
Et
Me
NH
4-Cl—Ph
C(Me)2CH2
H
racemic


II-904
Me
Et
Me
NH
4-Cl—Ph
C(Me)2CH2
H
(+)


II-905
Me
Et
Me
NH
4-Cl—Ph
C(Me)2CH2
H
(−)


II-906
Me
Me
Me
NH
4-Cl—Ph
C(Me)2CH2
Me
racemic


II-907
Me
Me
Me
NH
4-Cl—Ph
C(Me)2CH2
Me
(+)


II-908
Me
Me
Me
NH
4-Cl—Ph
C(Me)2CH2
Me
(−)


II-909
Me
Et
Me
NH
4-Cl—Ph
C(Me)2CH2
Me
racemic


II-910
Me
Et
Me
NH
4-Cl—Ph
C(Me)2CH2
Me
(+)


II-911
Me
Et
Me
NH
4-Cl—Ph
C(Me)2CH2
Me
(−)


II-912
Me
Me
Me
NH
2-Me—Ph
CH2
H
racemic


II-913
Me
Me
Me
NH
2-Me—Ph
CH2
H
(S)-


II-914
Me
Et
Me
NH
2-Me—Ph
CH2
H
racemic


II-915
Me
Et
Me
NH
2-Me—Ph
CH2
H
(S)-


II-916
Me
Me
Me
NH
2-Me—Ph
CH2
Me
racemic


II-917
Me
Me
Me
NH
2-Me—Ph
CH2
Me
(S)-


II-918
Me
Et
Me
NH
2-Me—Ph
CH2
Me
racemic


II-919
Me
Et
Me
NH
2-Me—Ph
CH2
Me
(S)-


II-920
Me
Me
Me
NH
2-Me—Ph
(CH2)2
H
racemic


II-921
Me
Me
Me
NH
2-Me—Ph
(CH2)2
H
(R)-


II-922
Me
Et
Me
NH
2-Me—Ph
(CH2)2
H
racemic


II-923
Me
Et
Me
NH
2-Me—Ph
(CH2)2
H
(R)-


II-924
Me
Me
Me
NH
2-Me—Ph
(CH2)2
Me
racemic


II-925
Me
Me
Me
NH
2-Me—Ph
(CH2)2
Me
(R)-


II-926
Me
Et
Me
NH
2-Me—Ph
(CH2)2
Me
racemic
















TABLE 28







(II)




embedded image




















Compound







Con-


No.
R1
R2
R3
L2
R4
L3
R5
figuration





II-927
Me
Et
Me
NH
2-Me—Ph
(CH2)2
Me
(R)-


II-928
Me
Me
Me
NH
2-Me—Ph
CH2C(Me)2
H
racemic


II-929
Me
Me
Me
NH
2-Me—Ph
CH2C(Me)2
H
(R)-


II-930
Me
Et
Me
NH
2-Me—Ph
CH2C(Me)2
H
racemic


II-931
Me
Et
Me
NH
2-Me—Ph
CH2C(Me)2
H
(R)-


II-932
Me
Me
Me
NH
2-Me—Ph
CH2C(Me)2
Me
racemic


II-933
Me
Me
Me
NH
2-Me—Ph
CH2C(Me)2
Me
(R)-


II-934
Me
Et
Me
NH
2-Me—Ph
CH2C(Me)2
Me
racemic


II-935
Me
Et
Me
NH
2-Me—Ph
CH2C(Me)2
Me
(R)-


II-936
Me
Me
Me
NH
2-Me—Ph
C(Me)2CH2
H
racemic


II-937
Me
Me
Me
NH
2-Me—Ph
C(Me)2CH2
H
(+)


II-938
Me
Me
Me
NH
2-Me—Ph
C(Me)2CH2
H
(−)


II-939
Me
Et
Me
NH
2-Me—Ph
C(Me)2CH2
H
racemic


II-940
Me
Et
Me
NH
2-Me—Ph
C(Me)2CH2
H
(+)


II-941
Me
Et
Me
NH
2-Me—Ph
C(Me)2CH2
H
(−)


II-942
Me
Me
Me
NH
2-Me—Ph
C(Me)2CH2
Me
racemic


II-943
Me
Me
Me
NH
2-Me—Ph
C(Me)2CH2
Me
(+)


II-944
Me
Me
Me
NH
2-Me—Ph
C(Me)2CH2
Me
(−)


II-945
Me
Et
Me
NH
2-Me—Ph
C(Me)2CH2
Me
racemic


II-946
Me
Et
Me
NH
2-Me—Ph
C(Me)2CH2
Me
(+)


II-947
Me
Et
Me
NH
2-Me—Ph
C(Me)2CH2
Me
(−)


II-948
Me
Me
Me
NH
3-Me—Ph
CH2
H
racemic


II-949
Me
Me
Me
NH
3-Me—Ph
CH2
H
(S)-


II-950
Me
Et
Me
NH
3-Me—Ph
CH2
H
racemic


II-951
Me
Et
Me
NH
3-Me—Ph
CH2
H
(S)-


II-952
Me
Me
Me
NH
3-Me—Ph
CH2
Me
racemic


II-953
Me
Me
Me
NH
3-Me—Ph
CH2
Me
(S)-


II-954
Me
Et
Me
NH
3-Me—Ph
CH2
Me
racemic


II-955
Me
Et
Me
NH
3-Me—Ph
CH2
Me
(S)-


II-956
Me
Me
Me
NH
3-Me—Ph
(CH2)2
H
racemic


II-957
Me
Me
Me
NH
3-Me—Ph
(CH2)2
H
(R)-


II-958
Me
Et
Me
NH
3-Me—Ph
(CH2)2
H
racemic


II-959
Me
Et
Me
NH
3-Me—Ph
(CH2)2
H
(R)-


II-960
Me
Me
Me
NH
3-Me—Ph
(CH2)2
Me
racemic


II-961
Me
Me
Me
NH
3-Me—Ph
(CH2)2
Me
(R)-


II-962
Me
Et
Me
NH
3-Me—Ph
(CH2)2
Me
racemic


II-963
Me
Et
Me
NH
3-Me—Ph
(CH2)2
Me
(R)-


II-964
Me
Me
Me
NH
3-Me—Ph
CH2C(Me)2
H
racemic


II-965
Me
Me
Me
NH
3-Me—Ph
CH2C(Me)2
H
(R)-


II-966
Me
Et
Me
NH
3-Me—Ph
CH2C(Me)2
H
racemic


II-967
Me
Et
Me
NH
3-Me—Ph
CH2C(Me)2
H
(R)-


II-968
Me
Me
Me
NH
3-Me—Ph
CH2C(Me)2
Me
racemic


II-969
Me
Me
Me
NH
3-Me—Ph
CH2C(Me)2
Me
(R)-


II-970
Me
Et
Me
NH
3-Me—Ph
CH2C(Me)2
Me
racemic


II-971
Me
Et
Me
NH
3-Me—Ph
CH2C(Me)2
Me
(R)-


II-972
Me
Me
Me
NH
3-Me—Ph
C(Me)2CH2
H
racemic


II-973
Me
Me
Me
NH
3-Me—Ph
C(Me)2CH2
H
(+)


II-974
Me
Me
Me
NH
3-Me—Ph
C(Me)2CH2
H
(−)


II-975
Me
Et
Me
NH
3-Me—Ph
C(Me)2CH2
H
racemic


II-976
Me
Et
Me
NH
3-Me—Ph
C(Me)2CH2
H
(+)
















TABLE 29







(II)




embedded image




















Compound







Con-


No.
R1
R2
R3
L2
R4
L3
R5
figuration





II-977 
Me
Et
Me
NH
3-Me—Ph
C(Me)2CH2
H
(−)


II-978 
Me
Me
Me
NH
3-Me—Ph
C(Me)2CH2
Me
racemic


II-979 
Me
Me
Me
NH
3-Me—Ph
C(Me)2CH2
Me
(+)


II-980 
Me
Me
Me
NH
3-Me—Ph
C(Me)2CH2
Me
(−)


II-981 
Me
Et
Me
NH
3-Me—Ph
C(Me)2CH2
Me
racemic


II-982 
Me
Et
Me
NH
3-Me—Ph
C(Me)2CH2
Me
(+)


II-983 
Me
Et
Me
NH
3-Me—Ph
C(Me)2CH2
Me
(−)


II-984 
Me
Me
Me
NH
4-Me—Ph
CH2
H
racemic


II-985 
Me
Me
Me
NH
4-Me—Ph
CH2
H
(S)-


II-986 
Me
Et
Me
NH
4-Me—Ph
CH2
H
racemic


II-987 
Me
Et
Me
NH
4-Me—Ph
CH2
H
(S)-


II-988 
Me
Me
Me
NH
4-Me—Ph
CH2
Me
racemic


II-989 
Me
Me
Me
NH
4-Me—Ph
CH2
Me
(S)-


II-990 
Me
Et
Me
NH
4-Me—Ph
CH2
Me
racemic


II-991 
Me
Et
Me
NH
4-Me—Ph
CH2
Me
(S)-


II-992 
Me
Me
Me
NH
4-Me—Ph
(CH2)2
H
racemic


II-993 
Me
Me
Me
NH
4-Me—Ph
(CH2)2
H
(R)-


II-994 
Me
Et
Me
NH
4-Me—Ph
(CH2)2
H
racemic


II-995 
Me
Et
Me
NH
4-Me—Ph
(CH2)2
H
(R)-


II-996 
Me
Me
Me
NH
4-Me—Ph
(CH2)2
Me
racemic


II-997 
Me
Me
Me
NH
4-Me—Ph
(CH2)2
Me
(R)-


II-998 
Me
Et
Me
NH
4-Me—Ph
(CH2)2
Me
racemic


II-999 
Me
Et
Me
NH
4-Me—Ph
(CH2)2
Me
(R)-


II-1000
Me
Me
Me
NH
4-Me—Ph
CH2C(Me)2
H
racemic


II-1001
Me
Me
Me
NH
4-Me—Ph
CH2C(Me)2
H
(R)-


II-1002
Me
Et
Me
NH
4-Me—Ph
CH2C(Me)2
H
racemic


II-1003
Me
Et
Me
NH
4-Me—Ph
CH2C(Me)2
H
(R)-


II-1004
Me
Me
Me
NH
4-Me—Ph
CH2C(Me)2
Me
racemic


II-1005
Me
Me
Me
NH
4-Me—Ph
CH2C(Me)2
Me
(R)-


II-1006
Me
Et
Me
NH
4-Me—Ph
CH2C(Me)2
Me
racemic


II-1007
Me
Et
Me
NH
4-Me—Ph
CH2C(Me)2
Me
(R)-


II-1008
Me
Me
Me
NH
4-Me—Ph
C(Me)2CH2
H
racemic


II-1009
Me
Me
Me
NH
4-Me—Ph
C(Me)2CH2
H
(+)


II-1010
Me
Me
Me
NH
4-Me—Ph
C(Me)2CH2
H
(−)


II-1011
Me
Et
Me
NH
4-Me—Ph
C(Me)2CH2
H
racemic


II-1012
Me
Et
Me
NH
4-Me—Ph
C(Me)2CH2
H
(+)


II-1013
Me
Et
Me
NH
4-Me—Ph
C(Me)2CH2
H
(−)


II-1014
Me
Me
Me
NH
4-Me—Ph
C(Me)2CH2
Me
racemic


II-1015
Me
Me
Me
NH
4-Me—Ph
C(Me)2CH2
Me
(+)


II-1016
Me
Me
Me
NH
4-Me—Ph
C(Me)2CH2
Me
(−)


II-1017
Me
Et
Me
NH
4-Me—Ph
C(Me)2CH2
Me
racemic


II-1018
Me
Et
Me
NH
4-Me—Ph
C(Me)2CH2
Me
(+)


II-1019
Me
Et
Me
NH
4-Me—Ph
C(Me)2CH2
Me
(−)


II-1020
Me
Me
Me
—
Ph
—
H
racemic


II-1021
Me
Me
Me
—
Ph
—
H
(R)-


II-1022
Me
Et
Me
—
Ph
—
H
racemic


II-1023
Me
Et
Me
—
Ph
—
H
(R)-


II-1024
Me
Me
Me
—
Ph
—
Me
racemic


II-1025
Me
Me
Me
—
Ph
—
Me
(R)-


II-1026
Me
Et
Me
—
Ph
—
Me
racemic
















TABLE 30







(II)




embedded image




















Compound










No.
R1
R2
R3
L2
R4
L3
R5
Configuration





II-1027
Me
Et
Me
—
Ph
—
Me
(R)-


II-1028
Me
Me
Me
—
Ph
—
CHF2
racemic


II-1029
Me
Me
Me
—
Ph
—
CHF2
(R)-


II-1030
Me
Et
Me
—
Ph
—
CHF2
racemic


II-1031
Me
Et
Me
—
Ph
—
CHF2
(R)-


II-1032
Me
Me
Me
—
Ph
—
CF3
racemic


II-1033
Me
Me
Me
—
Ph
—
CF3
(R)-


II-1034
Me
Et
Me
—
Ph
—
CF3
racemic


II-1035
Me
Et
Me
—
Ph
—
CF3
(R)-


II-1036
Me
Me
Me
—
Ph
—
Et
racemic


II-1037
Me
Me
Me
—
Ph
—
Et
(R)-


II-1038
Me
Et
Me
—
Ph
—
Et
racemic


II-1039
Me
Et
Me
—
Ph
—
Et
(R)-


II-1040
Me
Me
Me
—
Ph
—
CF2CH3
racemic


II-1041
Me
Me
Me
—
Ph
—
CF2CH3
(R)-


II-1042
Me
Et
Me
—
Ph
—
CF2CH3
racemic


II-1043
Me
Et
Me
—
Ph
—
CF2CH3
(R)-


II-1044
Me
Me
Me
—
Ph
—
nPr
racemic


II-1045
Me
Me
Me
—
Ph
—
nPr
(R)-


II-1046
Me
Et
Me
—
Ph
—
nPr
racemic


II-1047
Me
Et
Me
—
Ph
—
nPr
(R)-


II-1048
Me
Me
Me
—
Ph
—
nBu
racemic


II-1049
Me
Me
Me
—
Ph
—
nBu
(R)-


II-1050
Me
Et
Me
—
Ph
—
nBu
racemic


II-1051
Me
Et
Me
—
Ph
—
nBu
(R)-


II-1052
Me
Me
Me
—
Ph
—
iPr
racemic


II-1053
Me
Me
Me
—
Ph
—
iPr
(R)-


II-1054
Me
Et
Me
—
Ph
—
iPr
racemic


II-1055
Me
Et
Me
—
Ph
—
iPr
(R)-


II-1056
Me
Me
Me
—
Ph
—
cPr
racemic


II-1057
Me
Me
Me
—
Ph
—
cPr
(R)-


II-1058
Me
Et
Me
—
Ph
—
cPr
racemic


II-1059
Me
Et
Me
—
Ph
—
cPr
(R)-


II-1060
Me
Me
Me
—
Ph
—
Ph
racemic


II-1061
Me
Me
Me
—
Ph
—
Ph
(R)-


II-1062
Me
Et
Me
—
Ph
—
Ph
racemic


II-1063
Me
Et
Me
—
Ph
—
Ph
(R)-


II-1064
Me
Me
Me
—
Ph
CH2
CHF2
racemic


II-1065
Me
Me
Me
—
Ph
CH2
CHF2
(S)-


II-1066
Me
Me
Me
—
Ph
CH2
Et
racemic


II-1067
Me
Me
Me
—
Ph
CH2
Et
(S)-


II-1068
Me
Me
Me
—
Ph
CH2
Ph
racemic


II-1069
Me
Me
Me
—
Ph
CH2
Ph
(R)-


II-1070
Me
Me
Me
—
Ph
(CH2)2
H
racemic


II-1071
Me
Me
Me
—
Ph
(CH2)2
H
(S)-


II-1072
Me
Me
Me
—
Ph
(CH2)2
Me
racemic


II-1073
Me
Me
Me
—
Ph
(CH2)2
Me
(S)-


II-1074
Me
Me
Me
—
Ph
(CH2)2
CHF2
racemic


II-1075
Me
Me
Me
—
Ph
(CH2)2
CHF2
(S)-


II-1076
Me
Me
Me
—
Ph
(CH2)2
Et
racemic
















TABLE 31







(II)




embedded image




















Compound










No.
R1
R2
R3
L2
R4
L3
R5
Configuration





II-1077
Me
Me
Me
—
Ph
(CH2)2
Et
(S)-


II-1078
Me
Me
Me
—
H
—
H



II-1079
Me
Me
Me
—
H
—
Me



II-1080
Me
Me
Me
—
H
—
CHF2



II-1081
Me
Me
Me
—
H
—
CF3



II-1082
Me
Me
Me
—
H
—
Et



II-1083
Me
Me
Me
—
H
—
nPr



II-1084
Me
Me
Me
—
H
—
iPr



II-1085
Me
Me
Me
—
H
—
cPr



II-1086
Me
Me
Me
—
H
—
Ph



II-1087
Me
Me
Me
—
Me
—
H
racemic


II-1088
Me
Me
Me
—
Me
—
H
(R)-


II-1089
Me
Me
Me
—
Me
—
Me
racemic


II-1090
Me
Me
Me
—
Me
—
Me
(R)-


II-1091
Me
Me
Me
—
Me
—
CHF2
racemic


II-1092
Me
Me
Me
—
Me
—
CHF2
(R)-


II-1093
Me
Me
Me
—
Me
—
CF3
racemic


II-1094
Me
Me
Me
—
Me
—
CF3
(R)-


II-1095
Me
Me
Me
—
Me
—
Et
racemic


II-1096
Me
Me
Me
—
Me
—
Et
(R)-


II-1097
Me
Me
Me
—
Me
—
nPr
racemic


II-1098
Me
Me
Me
—
Me
—
nPr
(R)-


II-1099
Me
Me
Me
—
Me
—
iPr
racemic


II-1100
Me
Me
Me
—
Me
—
iPr
(R)-


II-1101
Me
Me
Me
—
Me
—
cPr
racemic


II-1102
Me
Me
Me
—
Me
—
cPr
(R)-


II-1103
Me
Me
Me
—
Me
—
cHex
racemic


II-1104
Me
Me
Me
—
Me
—
cHex
(R)-


II-1105
Me
Me
Me
—
Me
—
Ph
racemic


II-1106
Me
Me
Me
—
Me
—
Ph
(R)-


II-1107
Me
Me
Me
—
Me
—
2-F—Ph
racemic


II-1108
Me
Me
Me
—
Me
—
2-F—Ph
(R)-


II-1109
Me
Me
Me
—
Me
—
3-F—Ph
racemic


II-1110
Me
Me
Me
—
Me
—
3-F—Ph
(R)-


II-1111
Me
Me
Me
—
Me
—
4-F—Ph
racemic


II-1112
Me
Me
Me
—
Me
—
4-F—Ph
(R)-


II-1113
Me
Me
Me
—
Me
—
2-Cl—Ph
racemic


II-1114
Me
Me
Me
—
Me
—
2-Cl—Ph
(R)-


II-1115
Me
Me
Me
—
Me
—
3-Cl—Ph
racemic


II-1116
Me
Me
Me
—
Me
—
3-Cl—Ph
(R)-


II-1117
Me
Me
Me
—
Me
—
4-Cl—Ph
racemic


II-1118
Me
Me
Me
—
Me
—
4-Cl—Ph
(R)-


II-1119
Me
Me
Me
—
Me
—
2-Py
racemic


II-1120
Me
Me
Me
—
Me
—
2-Py
(R)-


II-1121
Me
Me
Me
—
Me
—
3-Py
racemic


II-1122
Me
Me
Me
—
Me
—
3-Py
(R)-


II-1123
Me
Me
Me
—
Me
—
4-Py
racemic


II-1124
Me
Me
Me
—
Me
—
4-Py
(R)-


II-1125
Me
Me
Me
—
iPr
—
H
racemic


II-1126
Me
Me
Me
—
iPr
—
H
(R)-
















TABLE 32







(II)




embedded image




















Compound










No.
R1
R2
R3
L2
R4
L3
R5
Configuration





II-1127
Me
Me
Me
—
iPr
—
Me
racemic


II-1128
Me
Me
Me
—
iPr
—
Me
(R)-


II-1129
Me
Me
Me
—
iPr
—
CHF2
racemic


II-1130
Me
Me
Me
—
iPr
—
CHF2
(R)-


II-1131
Me
Me
Me
—
iPr
—
CF3
racemic


II-1132
Me
Me
Me
—
iPr
—
CF3
(R)-


II-1133
Me
Me
Me
—
iPr
—
Et
racemic


II-1134
Me
Me
Me
—
iPr
—
Et
(R)-


II-1135
Me
Me
Me
—
iPr
—
nPr
racemic


II-1136
Me
Me
Me
—
iPr
—
nPr
(R)-


II-1137
Me
Me
Me
—
iPr
—
iPr
racemic


II-1138
Me
Me
Me
—
iPr
—
iPr
(R)-


II-1139
Me
Me
Me
—
iPr
—
cPr
racemic


II-1140
Me
Me
Me
—
iPr
—
cPr
(R)-


II-1141
Me
Me
Me
—
iPr
—
Ph
racemic


II-1142
Me
Me
Me
—
iPr
—
Ph
(R)-


II-1143
Me
Me
Me
—
CF3
—
H
racemic


II-1144
Me
Me
Me
—
CF3
—
H
(R)-


II-1145
Me
Me
Me
—
CF3
—
Me
racemic


II-1146
Me
Me
Me
—
CF3
—
Me
(R)-


II-1147
Me
Me
Me
—
CF3
—
CHF2
racemic


II-1148
Me
Me
Me
—
CF3
—
CHF2
(R)-


II-1149
Me
Me
Me
—
CF3
—
CF3
racemic


II-1150
Me
Me
Me
—
CF3
—
CF3
(R)-


II-1151
Me
Me
Me
—
CF3
—
Et
racemic


II-1152
Me
Me
Me
—
CF3
—
Et
(R)-


II-1153
Me
Me
Me
—
CF3
—
nPr
racemic


II-1154
Me
Me
Me
—
CF3
—
nPr
(R)-


II-1155
Me
Me
Me
—
CF3
—
iPr
racemic


II-1156
Me
Me
Me
—
CF3
—
iPr
(R)-


II-1157
Me
Me
Me
—
CF3
—
cPr
racemic


II-1158
Me
Me
Me
—
CF3
—
cPr
(R)-


II-1159
Me
Me
Me
—
CF3
—
Ph
racemic


II-1160
Me
Me
Me
—
CF3
—
Ph
(R)-


II-1161
Me
Me
Me
—
CH2OH
—
H
racemic


II-1162
Me
Me
Me
—
CH2OH
—
H
(R)-


II-1163
Me
Me
Me
—
CH2OH
—
Me
racemic


II-1164
Me
Me
Me
—
CH2OH
—
Me
(R)-


II-1165
Me
Me
Me
—
CH2OH
—
CHF2
racemic


II-1166
Me
Me
Me
—
CH2OH
—
CHF2
(R)-


II-1167
Me
Me
Me
—
CH2OH
—
CF3
racemic


II-1168
Me
Me
Me
—
CH2OH
—
CF3
(R)-


II-1169
Me
Me
Me
—
CH2OH
—
Et
racemic


II-1170
Me
Me
Me
—
CH2OH
—
Et
(R)-


II-1171
Me
Me
Me
—
CH2OH
—
nPr
racemic


II-1172
Me
Me
Me
—
CH2OH
—
nPr
(R)-


II-1173
Me
Me
Me
—
CH2OH
—
iPr
racemic


II-1174
Me
Me
Me
—
CH2OH
—
iPr
(R)-


II-1175
Me
Me
Me
—
CH2OH
—
cPr
racemic


II-1176
Me
Me
Me
—
CH2OH
—
cPr
(R)-
















TABLE 33







(II)




embedded image




















Compound







Con-


No.
R1
R2
R3
L2
R4
L3
R5
figuration





II-1177
Me
Me
Me
—
CH2OH
—
Ph
racemic


II-1178
Me
Me
Me
—
CH2OH
—
Ph
(R)-


II-1179
Me
Me
Me
—
CH2OMe
—
H
racemic


II-1180
Me
Me
Me
—
CH2OMe
—
H
(R)-


II-1181
Me
Me
Me
—
CH2OMe
—
Me
racemic


II-1182
Me
Me
Me
—
CH2OMe
—
Me
(R)-


II-1183
Me
Me
Me
—
CH2OMe
—
CHF2
racemic


II-1184
Me
Me
Me
—
CH2OMe
—
CHF2
(R)-


II-1185
Me
Me
Me
—
CH2OMe
—
CF3
racemic


II-1186
Me
Me
Me
—
CH2OMe
—
CF3
(R)-


II-1187
Me
Me
Me
—
CH2OMe
—
Et
racemic


II-1188
Me
Me
Me
—
CH2OMe
—
Et
(R)-


II-1189
Me
Me
Me
—
CH2OMe
—
nPr
racemic


II-1190
Me
Me
Me
—
CH2OMe
—
nPr
(R)-


II-1191
Me
Me
Me
—
CH2OMe
—
iPr
racemic


II-1192
Me
Me
Me
—
CH2OMe
—
iPr
(R)-


II-1193
Me
Me
Me
—
CH2OMe
—
cPr
racemic


II-1194
Me
Me
Me
—
CH2OMe
—
cPr
(R)-


II-1195
Me
Me
Me
—
CH2OMe
—
Ph
racemic


II-1196
Me
Me
Me
—
CH2OMe
—
Ph
(R)-


II-1197
Me
Me
Me
—
CH2OBn
—
H
racemic


II-1198
Me
Me
Me
—
CH2OBn
—
H
(R)-


II-1199
Me
Me
Me
—
CH2OBn
—
Me
racemic


II-1200
Me
Me
Me
—
CH2OBn
—
Me
(R)-


II-1201
Me
Me
Me
—
CH2OBn
—
Ph
racemic


II-1202
Me
Me
Me
—
CH2OBn
—
Ph
(R)-


II-1203
Me
Me
Me
—
CH2NMe2
—
H
racemic


II-1204
Me
Me
Me
—
CH2NMe2
—
H
(R)-


II-1205
Me
Me
Me
—
CH2NMe2
—
Me
racemic


II-1206
Me
Me
Me
—
CH2NMe2
—
Me
(R)-


II-1207
Me
Me
Me
—
CH2NMe2
—
CHF2
racemic


II-1208
Me
Me
Me
—
CH2NMe2
—
CHF2
(R)-


II-1209
Me
Me
Me
—
CH2NMe2
—
CF3
racemic


II-1210
Me
Me
Me
—
CH2NMe2
—
CF3
(R)-


II-1211
Me
Me
Me
—
CH2NMe2
—
Et
racemic


II-1212
Me
Me
Me
—
CH2NMe2
—
Et
(R)-


II-1213
Me
Me
Me
—
CH2NMe2
—
nPr
racemic


II-1214
Me
Me
Me
—
CH2NMe2
—
nPr
(R)-


II-1215
Me
Me
Me
—
CH2NMe2
—
iPr
racemic


II-1216
Me
Me
Me
—
CH2NMe2
—
iPr
(R)-


II-1217
Me
Me
Me
—
CH2NMe2
—
cPr
racemic


II-1218
Me
Me
Me
—
CH2NMe2
—
cPr
(R)-


II-1219
Me
Me
Me
—
CH2NMe2
—
Ph
racemic


II-1220
Me
Me
Me
—
CH2NMe2
—
Ph
(R)-


II-1221
Me
Me
Me
—
CH2-(3,3-
—
H
racemic







difluoropyrrolidyl)





II-1222
Me
Me
Me
—
CH2-(3,3-
—
H
(R)-







difluoropyrrolidyl)





II-1223
Me
Me
Me
—
CH2-(3,3-
—
Me
racemic







difluoropyrrolidyl)





II-1224
Me
Me
Me
—
CH2-(3,3-
—
Me
(R)-







difluoropyrrolidyl)





II-1225
Me
Me
Me
—
CH2-(3,3-
—
Ph
racemic







difluoropyrrolidyl)





II-1226
Me
Me
Me
—
CH2-(3,3-
—
Ph
(R)-







difluoropyrrolidyl)
















TABLE 34







(II)




embedded image




















Compound










No.
R1
R2
R3
L2
R4
L3
R5
Configuration





II-1227
Me
Me
Me
—
2-F—Ph
—
H
racemic


II-1228
Me
Me
Me
—
2-F—Ph
—
H
(R)-


II-1229
Me
Me
Me
—
2-F—Ph
—
Me
racemic


II-1230
Me
Me
Me
—
2-F—Ph
—
Me
(R)-


II-1231
Me
Me
Me
—
2-F—Ph
—
CHF2
racemic


II-1232
Me
Me
Me
—
2-F—Ph
—
CHF2
(R)-


II-1233
Me
Me
Me
—
2-F—Ph
—
CF3
racemic


II-1234
Me
Me
Me
—
2-F—Ph
—
CF3
(R)-


II-1235
Me
Me
Me
—
2-F—Ph
—
Et
racemic


II-1236
Me
Me
Me
—
2-F—Ph
—
Et
(R)-


II-1237
Me
Me
Me
—
2-F—Ph
—
nPr
racemic


II-1238
Me
Me
Me
—
2-F—Ph
—
nPr
(R)-


II-1239
Me
Me
Me
—
2-F—Ph
—
iPr
racemic


II-1240
Me
Me
Me
—
2-F—Ph
—
iPr
(R)-


II-1241
Me
Me
Me
—
2-F—Ph
—
cPr
racemic


II-1242
Me
Me
Me
—
2-F—Ph
—
cPr
(R)-


II-1243
Me
Me
Me
—
3-F—Ph
—
H
racemic


II-1244
Me
Me
Me
—
3-F—Ph
—
H
(R)-


II-1245
Me
Me
Me
—
3-F—Ph
—
Me
racemic


II-1246
Me
Me
Me
—
3-F—Ph
—
Me
(R)-


II-1247
Me
Me
Me
—
3-F—Ph
—
CHF2
racemic


II-1248
Me
Me
Me
—
3-F—Ph
—
CHF2
(R)-


II-1249
Me
Me
Me
—
3-F—Ph
—
CF3
racemic


II-1250
Me
Me
Me
—
3-F—Ph
—
CF3
(R)-


II-1251
Me
Me
Me
—
3-F—Ph
—
Et
racemic


II-1252
Me
Me
Me
—
3-F—Ph
—
Et
(R)-


II-1253
Me
Me
Me
—
3-F—Ph
—
nPr
racemic


II-1254
Me
Me
Me
—
3-F—Ph
—
nPr
(R)-


II-1255
Me
Me
Me
—
3-F—Ph
—
iPr
racemic


II-1256
Me
Me
Me
—
3-F—Ph
—
iPr
(R)-


II-1257
Me
Me
Me
—
3-F—Ph
—
cPr
racemic


II-1258
Me
Me
Me
—
3-F—Ph
—
cPr
(R)-


II-1259
Me
Me
Me
—
4-F—Ph
—
H
racemic


II-1260
Me
Me
Me
—
4-F—Ph
—
H
(R)-


II-1261
Me
Me
Me
—
4-F—Ph
—
Me
racemic


II-1262
Me
Me
Me
—
4-F—Ph
—
Me
(R)-


II-1263
Me
Me
Me
—
4-F—Ph
—
CHF2
racemic


II-1264
Me
Me
Me
—
4-F—Ph
—
CHF2
(R)-


II-1265
Me
Me
Me
—
4-F—Ph
—
CF3
racemic


II-1266
Me
Me
Me
—
4-F—Ph
—
CF3
(R)-


II-1267
Me
Me
Me
—
4-F—Ph
—
Et
racemic


II-1268
Me
Me
Me
—
4-F—Ph
—
Et
(R)-


II-1269
Me
Me
Me
—
4-F—Ph
—
nPr
racemic


II-1270
Me
Me
Me
—
4-F—Ph
—
nPr
(R)-


II-1271
Me
Me
Me
—
4-F—Ph
—
iPr
racemic


II-1272
Me
Me
Me
—
4-F—Ph
—
iPr
(R)-


II-1273
Me
Me
Me
—
4-F—Ph
—
cPr
racemic


II-1274
Me
Me
Me
—
4-F—Ph
—
cPr
(R)-


II-1275
Me
Me
Me
—
2-thienyl
—
H
racemic


II-1276
Me
Me
Me
—
2-thienyl
—
H
(S)-
















TABLE 35







(II)




embedded image




















Com-










pound







Config-


No.
R1
R2
R3
L2
R4
L3
R5
uration





II-1277
Me
Me
Me
—
2-thienyl
—
Me
racemic


II-1278
Me
Me
Me
—
2-thienyl
—
Me
(S)-


II-1279
Me
Me
Me
—
2-thienyl
—
CHF2
racemic


II-1280
Me
Me
Me
—
2-thienyl
—
CHF2
(S)-


II-1281
Me
Me
Me
—
2-thienyl
—
CF3
racemic


II-1282
Me
Me
Me
—
2-thienyl
—
CF3
(S)-


II-1283
Me
Me
Me
—
2-thienyl
—
Et
racemic


II-1284
Me
Me
Me
—
2-thienyl
—
Et
(S)-


II-1285
Me
Me
Me
—
2-thienyl
—
nPr
racemic


II-1286
Me
Me
Me
—
2-thienyl
—
nPr
(S)-


II-1287
Me
Me
Me
—
2-thienyl
—
iPr
racemic


II-1288
Me
Me
Me
—
2-thienyl
—
iPr
(S)-


II-1289
Me
Me
Me
—
2-thienyl
—
cPr
racemic


II-1290
Me
Me
Me
—
2-thienyl
—
cPr
(S)-


II-1291
Me
Me
Me
—
3-thienyl
—
H
racemic


II-1292
Me
Me
Me
—
3-thienyl
—
H
(R)-


II-1293
Me
Me
Me
—
3-thienyl
—
Me
racemic


II-1294
Me
Me
Me
—
3-thienyl
—
Me
(R)-


II-1295
Me
Me
Me
—
3-thienyl
—
CHF2
racemic


II-1296
Me
Me
Me
—
3-thienyl
—
CHF2
(R)-


II-1297
Me
Me
Me
—
3-thienyl
—
CF3
racemic


II-1298
Me
Me
Me
—
3-thienyl
—
CF3
(R)-


II-1299
Me
Me
Me
—
3-thienyl
—
Et
racemic


II-1300
Me
Me
Me
—
3-thienyl
—
Et
(R)-


II-1301
Me
Me
Me
—
3-thienyl
—
nPr
racemic


II-1302
Me
Me
Me
—
3-thienyl
—
nPr
(R)-


II-1303
Me
Me
Me
—
3-thienyl
—
iPr
racemic


II-1304
Me
Me
Me
—
3-thienyl
—
iPr
(R)-


II-1305
Me
Me
Me
—
3-thienyl
—
cPr
racemic


II-1306
Me
Me
Me
—
3-thienyl
—
cPr
(R)-
















TABLE 36







(III)




embedded image




















Com-










pound







Config-


No.
R1
R2
R3
L2
R4
L3
R5
uration





III-1
Me
Me
Me
O
Ph
CH2
H
racemic


III-2
Me
Me
Me
O
Ph
CH2
H
(S)-


III-3
Me
Et
Me
O
Ph
CH2
H
racemic


III-4
Me
Et
Me
O
Ph
CH2
H
(S)-


III-5
Me
Me
Me
O
Ph
CH2
Me
racemic


III-6
Me
Me
Me
O
Ph
CH2
Me
(S)-


III-7
Me
Et
Me
O
Ph
CH2
Me
racemic


III-8
Me
Et
Me
O
Ph
CH2
Me
(S)-


III-9
Me
Me
Me
O
Ph
CH2
CHF2
racemic


III-10
Me
Me
Me
O
Ph
CH2
CHF2
(S)-


III-11
Me
Et
Me
O
Ph
CH2
CHF2
racemic


III-12
Me
Et
Me
O
Ph
CH2
CHF2
(S)-


III-13
Me
Me
Me
O
Ph
CH2
Et
racemic


III-14
Me
Me
Me
O
Ph
CH2
Et
(S)-


III-15
Me
Et
Me
O
Ph
CH2
Et
racemic


III-16
Me
Et
Me
O
Ph
CH2
Et
(S)-


III-17
Me
Me
Me
O
Ph
CH2
iPr
racemic


III-18
Me
Me
Me
O
Ph
CH2
iPr
(S)-


III-19
Me
Et
Me
O
Ph
CH2
iPr
racemic


III-20
Me
Et
Me
O
Ph
CH2
iPr
(S)-


III-21
Me
Me
Me
O
Ph
CH2
cPr
racemic


III-22
Me
Me
Me
O
Ph
CH2
cPr
(S)-


III-23
Me
Et
Me
O
Ph
CH2
cPr
racemic


III-24
Me
Et
Me
O
Ph
CH2
cPr
(S)-


III-25
Me
Me
Me
O
Ph
CH2
Ph
racemic


III-26
Me
Me
Me
O
Ph
CH2
Ph
(S)-


III-27
Me
Et
Me
O
Ph
CH2
Ph
racemic


III-28
Me
Et
Me
O
Ph
CH2
Ph
(S)-


III-29
Me
Me
Me
O
Ph
C(Me)2
H
racemic


III-30
Me
Me
Me
O
Ph
C(Me)2
H
(S)-


III-31
Me
Et
Me
O
Ph
C(Me)2
H
racemic


III-32
Me
Et
Me
O
Ph
C(Me)2
H
(S)-


III-33
Me
Me
Me
O
Ph
C(Me)2
Me
racemic


III-34
Me
Me
Me
O
Ph
C(Me)2
Me
(S)-


III-35
Me
Et
Me
O
Ph
C(Me)2
Me
racemic


III-36
Me
Et
Me
O
Ph
C(Me)2
Me
(S)-


III-37
Me
Me
Me
O
Ph
C(Me)2
CHF2
racemic


III-38
Me
Me
Me
O
Ph
C(Me)2
CHF2
(S)-


III-39
Me
Et
Me
O
Ph
C(Me)2
CHF2
racemic


III-40
Me
Et
Me
O
Ph
C(Me)2
CHF2
(S)-


III-41
Me
Me
Me
O
Ph
C(Me)2
Et
racemic


III-42
Me
Me
Me
O
Ph
C(Me)2
Et
(S)-


III-43
Me
Et
Me
O
Ph
C(Me)2
Et
racemic


III-44
Me
Et
Me
O
Ph
C(Me)2
Et
(S)-


III-45
Me
Me
Me
O
Ph
C(Me)2
iPr
racemic


III-46
Me
Me
Me
O
Ph
C(Me)2
iPr
(S)-


III-47
Me
Et
Me
O
Ph
C(Me)2
iPr
racemic


III-48
Me
Et
Me
O
Ph
C(Me)2
iPr
(S)-


III-49
Me
Me
Me
O
Ph
C(Me)2
cPr
racemic


III-50
Me
Me
Me
O
Ph
C(Me)2
cPr
(S)-
















TABLE 37







(III)




embedded image




















Com-










pound







Config-


No.
R1
R2
R3
L2
R4
L3
R5
uration





III-51
Me
Et
Me
O
Ph
C(Me)2
cPr
racemic


III-52
Me
Et
Me
O
Ph
C(Me)2
cPr
(S)-


III-53
Me
Me
Me
O
Ph
C(Me)2
Ph
racemic


III-54
Me
Me
Me
O
Ph
C(Me)2
Ph
(S)-


III-55
Me
Et
Me
O
Ph
C(Me)2
Ph
racemic


III-56
Me
Et
Me
O
Ph
C(Me)2
Ph
(S)-


III-57
Me
Me
Me
O
Ph
(CH2)2
H
racemic


III-58
Me
Me
Me
O
Ph
(CH2)2
H
(R)-


III-59
Me
Et
Me
O
Ph
(CH2)2
H
racemic


III-60
Me
Et
Me
O
Ph
(CH2)2
H
(R)-


III-61
Me
Me
Me
O
Ph
(CH2)2
Me
racemic


III-62
Me
Me
Me
O
Ph
(CH2)2
Me
(R)-


III-63
Me
Et
Me
O
Ph
(CH2)2
Me
racemic


III-64
Me
Et
Me
O
Ph
(CH2)2
Me
(R)-


III-65
Me
Me
Me
O
Ph
(CH2)2
CHF2
racemic


III-66
Me
Me
Me
O
Ph
(CH2)2
CHF2
(R)-


III-67
Me
Et
Me
O
Ph
(CH2)2
CHF2
racemic


III-68
Me
Et
Me
O
Ph
(CH2)2
CHF2
(R)-


III-69
Me
Me
Me
O
Ph
(CH2)2
Et
racemic


III-70
Me
Me
Me
O
Ph
(CH2)2
Et
(R)-


III-71
Me
Et
Me
O
Ph
(CH2)2
Et
racemic


III-72
Me
Et
Me
O
Ph
(CH2)2
Et
(R)-


III-73
Me
Me
Me
O
Ph
(CH2)2
iPr
racemic


III-74
Me
Me
Me
O
Ph
(CH2)2
iPr
(R)-


III-75
Me
Et
Me
O
Ph
(CH2)2
iPr
racemic


III-76
Me
Et
Me
O
Ph
(CH2)2
iPr
(R)-


III-77
Me
Me
Me
O
Ph
(CH2)2
cPr
racemic


III-78
Me
Me
Me
O
Ph
(CH2)2
cPr
(R)-


III-79
Me
Et
Me
O
Ph
(CH2)2
cPr
racemic


III-80
Me
Et
Me
O
Ph
(CH2)2
cPr
(R)-


III-81
Me
Me
Me
O
Ph
(CH2)2
Ph
racemic


III-82
Me
Me
Me
O
Ph
(CH2)2
Ph
(R)-


III-83
Me
Et
Me
O
Ph
(CH2)2
Ph
racemic


III-84
Me
Et
Me
O
Ph
(CH2)2
Ph
(R)-


III-85
Me
Me
Me
O
Ph
CH2C(Me)2
H
racemic


III-86
Me
Me
Me
O
Ph
CH2C(Me)2
H
(R)-


III-87
Me
Et
Me
O
Ph
CH2C(Me)2
H
racemic


III-88
Me
Et
Me
O
Ph
CH2C(Me)2
H
(R)-


III-89
Me
Me
Me
O
Ph
CH2C(Me)2
Me
racemic


III-90
Me
Me
Me
O
Ph
CH2C(Me)2
Me
(R)-


III-91
Me
Et
Me
O
Ph
CH2C(Me)2
Me
racemic


III-92
Me
Et
Me
O
Ph
CH2C(Me)2
Me
(R)-


III-93
Me
Me
Me
O
Ph
CH2C(Me)2
CHF2
racemic


III-94
Me
Me
Me
O
Ph
CH2C(Me)2
CHF2
(R)-


III-95
Me
Et
Me
O
Ph
CH2C(Me)2
CHF2
racemic


III-96
Me
Et
Me
O
Ph
CH2C(Me)2
CHF2
(R)-


III-97
Me
Me
Me
O
Ph
CH2C(Me)2
Et
racemic


III-98
Me
Me
Me
O
Ph
CH2C(Me)2
Et
(R)-


III-99
Me
Et
Me
O
Ph
CH2C(Me)2
Et
racemic


III-100
Me
Et
Me
O
Ph
CH2C(Me)2
Et
(R)-
















TABLE 38







(III)




embedded image




















Com-










pound







Config-


No.
R1
R2
R3
L2
R4
L3
R5
uration





III-101
Me
Me
Me
O
Ph
CH2C(Me)2
iPr
racemic


III-102
Me
Me
Me
O
Ph
CH2C(Me)2
iPr
(R)-


III-103
Me
Et
Me
O
Ph
CH2C(Me)2
iPr
racemic


III-104
Me
Et
Me
O
Ph
CH2C(Me)2
iPr
(R)-


III-105
Me
Me
Me
O
Ph
CH2C(Me)2
cPr
racemic


III-106
Me
Me
Me
O
Ph
CH2C(Me)2
cPr
(R)-


III-107
Me
Et
Me
O
Ph
CH2C(Me)2
cPr
racemic


III-108
Me
Et
Me
O
Ph
CH2C(Me)2
cPr
(R)-


III-109
Me
Me
Me
O
Ph
CH2C(Me)2
Ph
racemic


III-110
Me
Me
Me
O
Ph
CH2C(Me)2
Ph
(R)-


III-111
Me
Et
Me
O
Ph
CH2C(Me)2
Ph
racemic


III-112
Me
Et
Me
O
Ph
CH2C(Me)2
Ph
(R)-


III-113
Me
Me
Me
NH
Ph
CH2
H
racemic


III-114
Me
Me
Me
NH
Ph
CH2
H
(S)-


III-115
Me
Et
Me
NH
Ph
CH2
H
racemic


III-116
Me
Et
Me
NH
Ph
CH2
H
(S)-


III-117
Me
Me
Me
N(Me)
Ph
CH2
H
racemic


III-118
Me
Me
Me
N(Me)
Ph
CH2
H
(S)-


III-119
Me
Et
Me
N(Me)
Ph
CH2
H
racemic


III-120
Me
Et
Me
N(Me)
Ph
CH2
H
(S)-


III-121
Me
Me
Me
NH
Ph
CH2
Me
racemic


III-122
Me
Me
Me
NH
Ph
CH2
Me
(S)-


III-123
Me
Et
Me
NH
Ph
CH2
Me
racemic


III-124
Me
Et
Me
NH
Ph
CH2
Me
(S)-


III-125
Me
Me
Me
N(Me)
Ph
CH2
Me
racemic


III-126
Me
Me
Me
N(Me)
Ph
CH2
Me
(S)-


III-127
Me
Et
Me
N(Me)
Ph
CH2
Me
racemic


III-128
Me
Et
Me
N(Me)
Ph
CH2
Me
(S)-


III-129
Me
Me
Me
NH
Ph
CH2
CHF2
racemic


III-130
Me
Me
Me
NH
Ph
CH2
CHF2
(S)-


III-131
Me
Et
Me
NH
Ph
CH2
CHF2
racemic


III-132
Me
Et
Me
NH
Ph
CH2
CHF2
(S)-


III-133
Me
Me
Me
N(Me)
Ph
CH2
CHF2
racemic


III-134
Me
Me
Me
N(Me)
Ph
CH2
CHF2
(S)-


III-135
Me
Et
Me
N(Me)
Ph
CH2
CHF2
racemic


III-136
Me
Et
Me
N(Me)
Ph
CH2
CHF2
(S)-


III-137
Me
Me
Me
NH
Ph
CH2
Et
racemic


III-138
Me
Me
Me
NH
Ph
CH2
Et
(S)-


III-139
Me
Et
Me
NH
Ph
CH2
Et
racemic


III-140
Me
Et
Me
NH
Ph
CH2
Et
(S)-


III-141
Me
Me
Me
N(Me)
Ph
CH2
Et
racemic


III-142
Me
Me
Me
N(Me)
Ph
CH2
Et
(S)-


III-143
Me
Et
Me
N(Me)
Ph
CH2
Et
racemic


III-144
Me
Et
Me
N(Me)
Ph
CH2
Et
(S)-


III-145
Me
Me
Me
NH
Ph
CH2
iPr
racemic


III-146
Me
Me
Me
NH
Ph
CH2
iPr
(S)-


III-147
Me
Et
Me
NH
Ph
CH2
iPr
racemic


III-148
Me
Et
Me
NH
Ph
CH2
iPr
(S)-


III-149
Me
Me
Me
N(Me)
Ph
CH2
iPr
racemic


III-150
Me
Me
Me
N(Me)
Ph
CH2
iPr
(S)-
















TABLE 39







(III)




embedded image




















Com-










pound







Config-


No.
R1
R2
R3
L2
R4
L3
R5
guration





III-151
Me
Et
Me
N(Me)
Ph
CH2
iPr
racemic


III-152
Me
Et
Me
N(Me)
Ph
CH2
iPr
(S)-


III-153
Me
Me
Me
NH
Ph
CH2
cPr
racemic


III-154
Me
Me
Me
NH
Ph
CH2
cPr
(S)-


III-155
Me
Et
Me
NH
Ph
CH2
cPr
racemic


III-156
Me
Et
Me
NH
Ph
CH2
cPr
(S)-


III-157
Me
Me
Me
N(Me)
Ph
CH2
cPr
racemic


III-158
Me
Me
Me
N(Me)
Ph
CH2
cPr
(S)-


III-159
Me
Et
Me
N(Me)
Ph
CH2
cPr
racemic


III-160
Me
Et
Me
N(Me)
Ph
CH2
cPr
(S)-


III-161
Me
Me
Me
NH
Ph
CH2
Ph
racemic


III-162
Me
Me
Me
NH
Ph
CH2
Ph
(S)-


III-163
Me
Et
Me
NH
Ph
CH2
Ph
racemic


III-164
Me
Et
Me
NH
Ph
CH2
Ph
(S)-


III-165
Me
Me
Me
N(Me)
Ph
CH2
Ph
racemic


III-166
Me
Me
Me
N(Me)
Ph
CH2
Ph
(S)-


III-167
Me
Et
Me
N(Me)
Ph
CH2
Ph
racemic


III-168
Me
Et
Me
N(Me)
Ph
CH2
Ph
(S)-


III-169
Me
Me
Me
NH
Ph
C(Me)2
H
racemic


III-170
Me
Me
Me
NH
Ph
C(Me)2
H
(S)-


III-171
Me
Et
Me
NH
Ph
C(Me)2
H
racemic


III-172
Me
Et
Me
NH
Ph
C(Me)2
H
(S)-


III-173
Me
Me
Me
N(Me)
Ph
C(Me)2
H
racemic


III-174
Me
Me
Me
N(Me)
Ph
C(Me)2
H
(S)-


III-175
Me
Et
Me
N(Me)
Ph
C(Me)2
H
racemic


III-176
Me
Et
Me
N(Me)
Ph
C(Me)2
H
(S)-


III-177
Me
Me
Me
NH
Ph
C(Me)2
Me
racemic


III-178
Me
Me
Me
NH
Ph
C(Me)2
Me
(S)-


III-179
Me
Et
Me
NH
Ph
C(Me)2
Me
racemic


III-180
Me
Et
Me
NH
Ph
C(Me)2
Me
(S)-


III-181
Me
Me
Me
N(Me)
Ph
C(Me)2
Me
racemic


III-182
Me
Me
Me
N(Me)
Ph
C(Me)2
Me
(S)-


III-183
Me
Et
Me
N(Me)
Ph
C(Me)2
Me
racemic


III-184
Me
Et
Me
N(Me)
Ph
C(Me)2
Me
(S)-


III-185
Me
Me
Me
NH
Ph
C(Me)2
CHF2
racemic


III-186
Me
Me
Me
NH
Ph
C(Me)2
CHF2
(S)-


III-187
Me
Et
Me
NH
Ph
C(Me)2
CHF2
racemic


III-188
Me
Et
Me
NH
Ph
C(Me)2
CHF2
(S)-


III-189
Me
Me
Me
N(Me)
Ph
C(Me)2
CHF2
racemic


III-190
Me
Me
Me
N(Me)
Ph
C(Me)2
CHF2
(S)-


III-191
Me
Et
Me
N(Me)
Ph
C(Me)2
CHF2
racemic


III-192
Me
Et
Me
N(Me)
Ph
C(Me)2
CHF2
(S)-


III-193
Me
Me
Me
NH
Ph
C(Me)2
Et
racemic


III-194
Me
Me
Me
NH
Ph
C(Me)2
Et
(S)-


III-195
Me
Et
Me
NH
Ph
C(Me)2
Et
racemic


III-196
Me
Et
Me
NH
Ph
C(Me)2
Et
(S)-


III-197
Me
Me
Me
N(Me)
Ph
C(Me)2
Et
racemic


III-198
Me
Me
Me
N(Me)
Ph
C(Me)2
Et
(S)-


III-199
Me
Et
Me
N(Me)
Ph
C(Me)2
Et
racemic


III-200
Me
Et
Me
N(Me)
Ph
C(Me)2
Et
(S)-
















TABLE 40







(III)




embedded image




















Com-










pound







Config-


No.
R1
R2
R3
L2
R4
L3
R5
uration





III-201
Me
Me
Me
NH
Ph
C(Me)2
iPr
racemic


III-202
Me
Me
Me
NH
Ph
C(Me)2
iPr
(S)-


III-203
Me
Et
Me
NH
Ph
C(Me)2
iPr
racemic


III-204
Me
Et
Me
NH
Ph
C(Me)2
iPr
(S)-


III-205
Me
Me
Me
N(Me)
Ph
C(Me)2
iPr
racemic


III-206
Me
Me
Me
N(Me)
Ph
C(Me)2
iPr
(S)-


III-207
Me
Et
Me
N(Me)
Ph
C(Me)2
iPr
racemic


III-208
Me
Et
Me
N(Me)
Ph
C(Me)2
iPr
(S)-


III-209
Me
Me
Me
NH
Ph
C(Me)2
cPr
racemic


III-210
Me
Me
Me
NH
Ph
C(Me)2
cPr
(S)-


III-211
Me
Et
Me
NH
Ph
C(Me)2
cPr
racemic


III-212
Me
Et
Me
NH
Ph
C(Me)2
cPr
(S)-


III-213
Me
Me
Me
N(Me)
Ph
C(Me)2
cPr
racemic


III-214
Me
Me
Me
N(Me)
Ph
C(Me)2
cPr
(S)-


III-215
Me
Et
Me
N(Me)
Ph
C(Me)2
cPr
racemic


III-216
Me
Et
Me
N(Me)
Ph
C(Me)2
cPr
(S)-


III-217
Me
Me
Me
NH
Ph
C(Me)2
Ph
racemic


III-218
Me
Me
Me
NH
Ph
C(Me)2
Ph
(S)-


III-219
Me
Et
Me
NH
Ph
C(Me)2
Ph
racemic


III-220
Me
Et
Me
NH
Ph
C(Me)2
Ph
(S)-


III-221
Me
Me
Me
N(Me)
Ph
C(Me)2
Ph
racemic


III-222
Me
Me
Me
N(Me)
Ph
C(Me)2
Ph
(S)-


III-223
Me
Et
Me
N(Me)
Ph
C(Me)2
Ph
racemic


III-224
Me
Et
Me
N(Me)
Ph
C(Me)2
Ph
(S)-


III-225
Me
Me
Me
NH
Ph
C(Me)2
H
racemic


III-226
Me
Me
Me
NH
Ph
C(Me)2
H
(R)-


III-227
Me
Et
Me
NH
Ph
C(Me)2
H
racemic


III-228
Me
Et
Me
NH
Ph
C(Me)2
H
(R)-


III-229
Me
Me
Me
N(Me)
Ph
C(Me)2
H
racemic


III-230
Me
Me
Me
N(Me)
Ph
C(Me)2
H
(R)-


III-231
Me
Et
Me
N(Me)
Ph
C(Me)2
H
racemic


III-232
Me
Et
Me
N(Me)
Ph
C(Me)2
H
(R)-


III-233
Me
Me
Me
NH
Ph
C(Me)2
Me
racemic


III-234
Me
Me
Me
NH
Ph
C(Me)2
Me
(R)-


III-235
Me
Et
Me
NH
Ph
C(Me)2
Me
racemic


III-236
Me
Et
Me
NH
Ph
C(Me)2
Me
(R)-


III-237
Me
Me
Me
N(Me)
Ph
C(Me)2
Me
racemic


III-238
Me
Me
Me
N(Me)
Ph
C(Me)2
Me
(R)-


III-239
Me
Et
Me
N(Me)
Ph
C(Me)2
Me
racemic


III-240
Me
Et
Me
N(Me)
Ph
C(Me)2
Me
(R)-


III-241
Me
Me
Me
NH
Ph
C(Me)2
CHF2
racemic


III-242
Me
Me
Me
NH
Ph
C(Me)2
CHF2
(R)-


III-243
Me
Et
Me
NH
Ph
C(Me)2
CHF2
racemic


III-244
Me
Et
Me
NH
Ph
C(Me)2
CHF2
(R)-


III-245
Me
Me
Me
N(Me)
Ph
C(Me)2
CHF2
racemic


III-246
Me
Me
Me
N(Me)
Ph
C(Me)2
CHF2
(R)-


III-247
Me
Et
Me
N(Me)
Ph
C(Me)2
CHF2
racemic


III-248
Me
Et
Me
N(Me)
Ph
C(Me)2
CHF2
(R)-


III-249
Me
Me
Me
NH
Ph
C(Me)2
Et
racemic


III-250
Me
Me
Me
NH
Ph
C(Me)2
Et
(R)-
















TABLE 41







(III)




embedded image




















Com-










pound







Config-


No.
R1
R2
R3
L2
R4
L3
R5
uration





III-251
Me
Et
Me
NH
Ph
(CH2)2
Et
racemic


III-252
Me
Et
Me
NH
Ph
(CH2)2
Et
(R)-


III-253
Me
Me
Me
N(Me)
Ph
(CH2)2
Et
racemic


III-254
Me
Me
Me
N(Me)
Ph
(CH2)2
Et
(R)-


III-255
Me
Et
Me
N(Me)
Ph
(CH2)2
Et
racemic


III-256
Me
Et
Me
N(Me)
Ph
(CH2)2
Et
(R)-


III-257
Me
Me
Me
NH
Ph
(CH2)2
iPr
racemic


III-258
Me
Me
Me
NH
Ph
(CH2)2
iPr
(R)-


III-259
Me
Et
Me
NH
Ph
(CH2)2
iPr
racemic


III-260
Me
Et
Me
NH
Ph
(CH2)2
iPr
(R)-


III-261
Me
Me
Me
N(Me)
Ph
(CH2)2
iPr
racemic


III-262
Me
Me
Me
N(Me)
Ph
(CH2)2
iPr
(R)-


III-263
Me
Et
Me
N(Me)
Ph
(CH2)2
iPr
racemic


III-264
Me
Et
Me
N(Me)
Ph
(CH2)2
iPr
(R)-


III-265
Me
Me
Me
NH
Ph
(CH2)2
cPr
racemic


III-266
Me
Me
Me
NH
Ph
(CH2)2
cPr
(R)-


III-267
Me
Et
Me
NH
Ph
(CH2)2
cPr
racemic


III-268
Me
Et
Me
NH
Ph
(CH2)2
cPr
(R)-


III-269
Me
Me
Me
N(Me)
Ph
(CH2)2
cPr
racemic


III-270
Me
Me
Me
N(Me)
Ph
(CH2)2
cPr
(R)-


III-271
Me
Et
Me
N(Me)
Ph
(CH2)2
cPr
racemic


III-272
Me
Et
Me
N(Me)
Ph
(CH2)2
cPr
(R)-


III-273
Me
Me
Me
NH
Ph
(CH2)2
Ph
racemic


III-274
Me
Me
Me
NH
Ph
(CH2)2
Ph
(R)-


III-275
Me
Et
Me
NH
Ph
(CH2)2
Ph
racemic


III-276
Me
Et
Me
NH
Ph
(CH2)2
Ph
(R)-


III-277
Me
Me
Me
N(Me)
Ph
(CH2)2
Ph
racemic


III-278
Me
Me
Me
N(Me)
Ph
(CH2)2
Ph
(R)-


III-279
Me
Et
Me
N(Me)
Ph
(CH2)2
Ph
racemic


III-280
Me
Et
Me
N(Me)
Ph
(CH2)2
Ph
(R)-


III-281
Me
Me
Me
NH
Ph
(CH2)3
H
racemic


III-282
Me
Me
Me
NH
Ph
(CH2)3
H
(R)-


III-283
Me
Et
Me
NH
Ph
(CH2)3
H
racemic


III-284
Me
Et
Me
NH
Ph
(CH2)3
H
(R)-


III-285
Me
Me
Me
N(Me)
Ph
(CH2)3
H
racemic


III-286
Me
Me
Me
N(Me)
Ph
(CH2)3
H
(R)-


III-287
Me
Et
Me
N(Me)
Ph
(CH2)3
H
racemic


III-288
Me
Et
Me
N(Me)
Ph
(CH2)3
H
(R)-


III-289
Me
Me
Me
NH
Ph
(CH2)4
H
racemic


III-290
Me
Me
Me
NH
Ph
(CH2)4
H
(R)-


III-291
Me
Et
Me
NH
Ph
(CH2)4
H
racemic


III-292
Me
Et
Me
NH
Ph
(CH2)4
H
(R)-


III-293
Me
Me
Me
N(Me)
Ph
(CH2)4
H
racemic


III-294
Me
Me
Me
N(Me)
Ph
(CH2)4
H
(R)-


III-295
Me
Et
Me
N(Me)
Ph
(CH2)4
H
racemic


III-296
Me
Et
Me
N(Me)
Ph
(CH2)4
H
(R)-


III-297
Me
Me
Me
NH
Ph
CH2C(Me)2
H
racemic


III-298
Me
Me
Me
NH
Ph
CH2C(Me)2
H
(R)-


III-299
Me
Et
Me
NH
Ph
CH2C(Me)2
H
racemic


III-300
Me
Et
Me
NH
Ph
CH2C(Me)2
H
(R)-
















TABLE 42







(III)




embedded image




















Com-










pound







Config-


No.
R1
R2
R3
L2
R4
L3
R5
uration





III-301
Me
Me
Me
N(Me)
Ph
CH2C(Me)2
H
racemic


III-302
Me
Me
Me
N(Me)
Ph
CH2C(Me)2
H
(R)-


III-303
Me
Et
Me
N(Me)
Ph
CH2C(Me)2
H
racemic


III-304
Me
Et
Me
N(Me)
Ph
CH2C(Me)2
H
(R)-


III-305
Me
Me
Me
NH
Ph
CH2C(Me)2
Me
racemic


III-306
Me
Me
Me
NH
Ph
CH2C(Me)2
Me
(R)-


III-3 07
Me
Et
Me
NH
Ph
CH2C(Me)2
Me
racemic


III-308
Me
Et
Me
NH
Ph
CH2C(Me)2
Me
(R)-


III-309
Me
Me
Me
N(Me)
Ph
CH2C(Me)2
Me
racemic


III-310
Me
Me
Me
N(Me)
Ph
CH2C(Me)2
Me
(R)-


III-311
Me
Et
Me
N(Me)
Ph
CH2C(Me)2
Me
racemic


III-312
Me
Et
Me
N(Me)
Ph
CH2C(Me)2
Me
(R)-


III-313
Me
Me
Me
NH
Ph
CH2C(Me)2
CHF2
racemic


III-314
Me
Me
Me
NH
Ph
CH2C(Me)2
CHF2
(R)-


III-315
Me
Et
Me
NH
Ph
CH2C(Me)2
CHF2
racemic


III-316
Me
Et
Me
NH
Ph
CH2C(Me)2
CHF2
(R)-


III-317
Me
Me
Me
N(Me)
Ph
CH2C(Me)2
CHF2
racemic


III-318
Me
Me
Me
N(Me)
Ph
CH2C(Me)2
CHF2
(R)-


III-319
Me
Et
Me
N(Me)
Ph
CH2C(Me)2
CHF2
racemic


III-320
Me
Et
Me
N(Me)
Ph
CH2C(Me)2
CHF2
(R)-


III-321
Me
Me
Me
NH
Ph
CH2C(Me)2
Et
racemic


III-322
Me
Me
Me
NH
Ph
CH2C(Me)2
Et
(R)-


III-323
Me
Et
Me
NH
Ph
CH2C(Me)2
Et
racemic


III-324
Me
Et
Me
NH
Ph
CH2C(Me)2
Et
(R)-


III-325
Me
Me
Me
N(Me)
Ph
CH2C(Me)2
Et
racemic


III-326
Me
Me
Me
N(Me)
Ph
CH2C(Me)2
Et
(R)-


III-327
Me
Et
Me
N(Me)
Ph
CH2C(Me)2
Et
racemic


III-328
Me
Et
Me
N(Me)
Ph
CH2C(Me)2
Et
(R)-


III-329
Me
Me
Me
NH
Ph
CH2C(Me)2
iPr
racemic


III-330
Me
Me
Me
NH
Ph
CH2C(Me)2
iPr
(R)-


III-331
Me
Et
Me
NH
Ph
CH2C(Me)2
iPr
racemic


III-332
Me
Et
Me
NH
Ph
CH2C(Me)2
iPr
(R)-


III-333
Me
Me
Me
N(Me)
Ph
CH2C(Me)2
iPr
racemic


III-334
Me
Me
Me
N(Me)
Ph
CH2C(Me)2
iPr
(R)-


III-335
Me
Et
Me
N(Me)
Ph
CH2C(Me)2
iPr
racemic


III-336
Me
Et
Me
N(Me)
Ph
CH2C(Me)2
iPr
(R)-


III-337
Me
Me
Me
NH
Ph
CH2C(Me)2
cPr
racemic


III-338
Me
Me
Me
NH
Ph
CH2C(Me)2
cPr
(R)-


III-339
Me
Et
Me
NH
Ph
CH2C(Me)2
cPr
racemic


III-340
Me
Et
Me
NH
Ph
CH2C(Me)2
cPr
(R)-


III-341
Me
Me
Me
N(Me)
Ph
CH2C(Me)2
cPr
racemic


III-342
Me
Me
Me
N(Me)
Ph
CH2C(Me)2
cPr
(R)-


III-343
Me
Et
Me
N(Me)
Ph
CH2C(Me)2
cPr
racemic


III-344
Me
Et
Me
N(Me)
Ph
CH2C(Me)2
cPr
(R)-


III-345
Me
Me
Me
NH
Ph
CH2C(Me)2
Ph
racemic


III-346
Me
Me
Me
NH
Ph
CH2C(Me)2
Ph
(R)-


III-347
Me
Et
Me
NH
Ph
CH2C(Me)2
Ph
racemic


III-348
Me
Et
Me
NH
Ph
CH2C(Me)2
Ph
(R)-


III-349
Me
Me
Me
N(Me)
Ph
CH2C(Me)2
Ph
racemic


III-350
Me
Me
Me
N(Me)
Ph
CH2C(Me)2
Ph
(R)-
















TABLE 43







(III)




embedded image




















Com-










pound







Config-


No.
R1
R2
R3
L2
R4
L3
R5
uration





III-351
Me
Et
Me
N(Me)
Ph
CH2C(Me)2
Ph
racemic


III-352
Me
Et
Me
N(Me)
Ph
CH2C(Me)2
Ph
(R)-


III-353
Me
Me
Me
NH
Ph
CH2C(Me)2
H
racemic


III-354
Me
Me
Me
NH
Ph
CH2C(Me)2
H
(S)-


III-355
Me
Et
Me
NH
Ph
CH2C(Me)2
H
racemic


III-356
Me
Et
Me
NH
Ph
CH2C(Me)2
H
(S)-


III-357
Me
Me
Me
N(Me)
Ph
CH2C(Me)2
H
racemic


III-358
Me
Me
Me
N(Me)
Ph
CH2C(Me)2
H
(S)-


III-359
Me
Et
Me
N(Me)
Ph
CH2C(Me)2
H
racemic


III-360
Me
Et
Me
N(Me)
Ph
CH2C(Me)2
H
(S)-


III-361
Me
Me
Me
NH
Ph
CF2CH2
H
racemic


III-362
Me
Me
Me
NH
Ph
CF2CH2
H
(S)-


III-363
Me
Et
Me
NH
Ph
CF2CH2
H
racemic


III-364
Me
Et
Me
NH
Ph
CF2CH2
H
(S)-


III-365
Me
Me
Me
N(Me)
Ph
CF2CH2
H
racemic


III-366
Me
Me
Me
N(Me)
Ph
CF2CH2
H
(S)-


III-367
Me
Et
Me
N(Me)
Ph
CF2CH2
H
racemic


III-368
Me
Et
Me
N(Me)
Ph
CF2CH2
H
(S)-


III-369
Me
Me
Me
NH
Ph
CH═CHCH2
H
racemic


III-370
Me
Me
Me
NH
Ph
CH═CHCH2
H
(S)-


III-371
Me
Et
Me
NH
Ph
CH═CHCH2
H
racemic


III-372
Me
Et
Me
NH
Ph
CH═CHCH2
H
(S)-


III-373
Me
Me
Me
N(Me)
Ph
CH═CHCH2
H
racemic


III-374
Me
Me
Me
N(Me)
Ph
CH═CHCH2
H
(S)-


III-375
Me
Et
Me
N(Me)
Ph
CH═CHCH2
H
racemic


III-376
Me
Et
Me
N(Me)
Ph
CH═CHCH2
H
(S)-


III-377
Me
Me
Me
NH
Ph
C≡CH2
H
racemic


III-378
Me
Me
Me
NH
Ph
C≡CH2
H
(S)-


III-379
Me
Et
Me
NH
Ph
C≡CH2
H
racemic


III-380
Me
Et
Me
NH
Ph
C≡CH2
H
(S)-


III-381
Me
Me
Me
N(Me)
Ph
C≡CH2
H
racemic


III-382
Me
Me
Me
N(Me)
Ph
C≡CH2
H
(S)-


III-383
Me
Et
Me
N(Me)
Ph
C≡CH2
H
racemic


III-384
Me
Et
Me
N(Me)
Ph
C≡CH2
H
(S)-


III-385
Me
Me
Me
NH
Ph
1,1 -Cyclopro
H
racemic








pylene




III-386
Me
Me
Me
NH
Ph
1,1-Cyclopro
H
(S)-








pylene




III-387
Me
Et
Me
NH
Ph
1,1-Cyclopro
H
racemic








pylene




III-388
Me
Et
Me
NH
Ph
1,1-Cyclopro
H
(S)-








pylene




III-389
Me
Me
Me
N(Me)
Ph
1,1-Cyclopro
H
racemic








pylene




III-390
Me
Me
Me
N(Me)
Ph
1,1-Cyclopro
H
(S)-








pylene




III-391
Me
Et
Me
N(Me)
Ph
1,1-Cyclopro
H
racemic








pylene




III-392
Me
Et
Me
N(Me)
Ph
1,1-Cyclopro
H
(S)-








pylene




III-393
Me
Me
Me
NH
Ph
1,2-Cyclopro
H
racemic








pynylene




III-394
Me
Me
Me
NH
Ph
1,2-Cyclopro
H
(S)-








pynylene




III-395
Me
Et
Me
NH
Ph
1 ,2-Cyclopro
H
racemic








pynylene




III-396
Me
Et
Me
NH
Ph
1,2-Cyclopro
H
(S)-








pynylene




III-397
Me
Me
Me
N(Me)
Ph
1,2-Cyclopro
H
racemic








pynylene




III-398
Me
Me
Me
N(Me)
Ph
1,2-Cyclopro
H
(S)-








pynylene




III-399
Me
Et
Me
N(Me)
Ph
1,2-Cyclopro
H
racemic








pynylene




III-400
Me
Et
Me
N(Me)
Ph
1 ,2-Cyclopro
H
(S)-








pynylene
















TABLE 44







(III)




embedded image




















Com-










pound







Config-


No.
R1
R2
R3
L2
R4
L3
R5
uration





III-401
Me
Me
Me
NH
Ph
C(═O)
H
racemic


III-402
Me
Me
Me
NH
Ph
C(═O)
H
(S)-


III-403
Me
Et
Me
NH
Ph
C(═O)
H
racemic


III-404
Me
Et
Me
NH
Ph
C(═O)
H
(S)-


III-405
Me
Me
Me
N(Me)
Ph
C(═O)
H
racemic


III-406
Me
Me
Me
N(Me)
Ph
C(═O)
H
(S)-


III-407
Me
Et
Me
N(Me)
Ph
C(═O)
H
racemic


III-408
Me
Et
Me
N(Me)
Ph
C(═O)
H
(S)-


III-409
Me
Me
Me
NH
Ph
C(═O)
Bn
racemic


III-410
Me
Me
Me
NH
Ph
C(═O)
Bn
(S)-


III-411
Me
Et
Me
NH
Ph
C(═O)
Bn
racemic


III-412
Me
Et
Me
NH
Ph
C(═O)
Bn
(S)-


III-413
Me
Me
Me
N(Me)
Ph
C(═O)
Bn
racemic


III-414
Me
Me
Me
N(Me)
Ph
C(═O)
Bn
(S)-


III-415
Me
Et
Me
N(Me)
Ph
C(═O)
Bn
racemic


III-416
Me
Et
Me
N(Me)
Ph
C(═O)
Bn
(S)-


III-417
Me
Me
Me
NH
Ph
C(═O)
Me
racemic


III-418
Me
Me
Me
NH
Ph
C(═O)
Me
(S)-


III-419
Me
Et
Me
NH
Ph
C(═O)
Me
racemic


III-420
Me
Et
Me
NH
Ph
C(═O)
Me
(S)-


III-421
Me
Me
Me
N(Me)
Ph
C(═O)
Me
racemic


III-422
Me
Me
Me
N(Me)
Ph
C(═O)
Me
(S)-


III-423
Me
Et
Me
N(Me)
Ph
C(═O)
Me
racemic


III-424
Me
Et
Me
N(Me)
Ph
C(═O)
Me
(S)-


III-425
Me
Me
Me
NH
H
CH2
H



III-426
Me
Et
Me
NH
H
CH2
H



III-427
Me
Me
Me
N(Me)
H
CH2
H



III-428
Me
Et
Me
N(Me)
H
CH2
H



III-429
Me
Me
Me
NH
H
CH(Me)
H



III-430
Me
Et
Me
NH
H
CH(Me)
H



III-431
Me
Me
Me
N(Me)
H
CH(Me)
H



III-432
Me
Et
Me
N(Me)
H
CH(Me)
H



III-433
Me
Me
Me
NH
H
CH(iPr)
H



III-434
Me
Et
Me
NH
H
CH(iPr)
H



III-435
Me
Me
Me
N(Me)
H
CH(iPr)
H



III-436
Me
Et
Me
N(Me)
H
CH(iPr)
H



III-437
Me
Me
Me
NH
H
CH(Ph)
H



III-438
Me
Et
Me
NH
H
CH(Ph)
H



III-439
Me
Me
Me
N(Me)
H
CH(Ph)
H



III-440
Me
Et
Me
N(Me)
H
CH(Ph)
H



III-441
Me
Me
Me
NH
Me
CH2
H
racemic


III-442
Me
Me
Me
NH
Me
CH2
H
(S)-


III-443
Me
Et
Me
NH
Me
CH2
H
racemic


III-444
Me
Et
Me
NH
Me
CH2
H
(S)-


III-445
Me
Me
Me
N(Me)
Me
CH2
H
racemic


III-446
Me
Me
Me
N(Me)
Me
CH2
H
(S)-


III-447
Me
Et
Me
N(Me)
Me
CH2
H
racemic


III-448
Me
Et
Me
N(Me)
Me
CH2
H
(S)-


III-449
Me
Me
Me
NH
iPr
CH2
H
racemic


III-450
Me
Me
Me
NH
iPr
CH2
H
(S)-

















TABLE 45








(III)




embedded image





















Compound







Configura-


No.
R1
R2
R3
L2
R4
L3
R5
tion





III-451
Me
Et
Me
NH
iPr
CH2
H
racemic


III-452
Me
Et
Me
NH
iPr
CH2
H
(S)-


III-453
Me
Me
Me
N(Me)
iPr
CH2
H
racemic


III-454
Me
Me
Me
N(Me)
iPr
CH2
H
(S)-


III-455
Me
Et
Me
N(Me)
iPr
CH2
H
racemic


III-456
Me
Et
Me
N(Me)
iPr
CH2
H
(S)-


III-457
Me
Me
Me
NH
cHex
CH2
H
racemic


III-458
Me
Me
Me
NH
cHex
CH2
H
(S)-


III-459
Me
Et
Me
NH
cHex
CH2
H
racemic


III-460
Me
Et
Me
NH
cHex
CH2
H
(S)-


III-461
Me
Me
Me
N(Me)
cHex
CH2
H
racemic


III-462
Me
Me
Me
N(Me)
cHex
CH2
H
(S)-


III-463
Me
Et
Me
N(Me)
cHex
CH2
H
racemic


III-464
Me
Et
Me
N(Me)
cHex
CH2
H
(S)-


III-465
Me
Me
Me
NH
1,3-Benzo-
CH2
H
racemic







dioxol-4-yl





III-466
Me
Me
Me
NH
1,3-Benzo-
CH2
H
(S)-







dioxol-4-yl





III-467
Me
Et
Me
NH
1,3-Benzo-
CH2
H
racemic







dioxol-4-yl





III-468
Me
Et
Me
NH
1,3-Benzo-
CH2
H
(S)-







dioxol-4-yl





III-469
Me
Me
Me
N(Me)
1,3-Benzo-
CH2
H
racemic







dioxol-4-yl





III-470
Me
Me
Me
N(Me)
1,3-Benzo-
CH2
H
(S)-







dioxol-4-yl





III-471
Me
Et
Me
N(Me)
1,3-Benzo-
CH2
H
racemic







diox-4-yl





III-472
Me
Et
Me
N(Me)
1,3-Benzo-
CH2
H
(S)-







dioxol





III-473
Me
Me
Me
NH
2-F—Ph
CH2
H
racemic


III-474
Me
Me
Me
NH
2-F—Ph
CH2
H
(S)-


III-475
Me
Et
Me
NH
2-F—Ph
CH2
H
racemic


III-476
Me
Et
Me
NH
2-F—Ph
CH2
H
(S)-


III-477
Me
Me
Me
N(Me)
2-F—Ph
CH2
H
racemic


III-478
Me
Me
Me
N(Me)
2-F—Ph
CH2
H
(S)-


III-479
Me
Et
Me
N(Me)
2-F—Ph
CH2
H
racemic


III-480
Me
Et
Me
N(Me)
2-F—Ph
CH2
H
(S)-


III-481
Me
Me
Me
NH
3-F—Ph
CH2
H
racemic


III-482
Me
Me
Me
NH
3-F—Ph
CH2
H
(S)-


III-483
Me
Et
Me
NH
3-F—Ph
CH2
H
racemic


III-484
Me
Et
Me
NH
3-F—Ph
CH2
H
(S)-


III-485
Me
Me
Me
N(Me)
3-F—Ph
CH2
H
racemic


III-486
Me
Me
Me
N(Me)
3-F—Ph
CH2
H
(S)-


III-487
Me
Et
Me
N(Me)
3-F—Ph
CH2
H
racemic


III-488
Me
Et
Me
N(Me)
3-F—Ph
CH2
H
(S)-


III-489
Me
Me
Me
NH
4-F—Ph
CH2
H
racemic


III-490
Me
Me
Me
NH
4-F—Ph
CH2
H
(S)-


III-491
Me
Et
Me
NH
4-F—Ph
CH2
H
racemic


III-492
Me
Et
Me
NH
4-F—Ph
CH2
H
(S)-


III-493
Me
Me
Me
N(Me)
4-F—Ph
CH2
H
racemic


III-494
Me
Me
Me
N(Me)
4-F—Ph
CH2
H
(S)-


III-495
Me
Et
Me
N(Me)
4-F—Ph
CH2
H
racemic


III-496
Me
Et
Me
N(Me)
4-F—Ph
CH2
H
(S)-


III-497
Me
Me
Me
NH
2-Py
CH2
H
racemic


III-498
Me
Me
Me
NH
2-Py
CH2
H
(S)-


III-499
Me
Et
Me
NH
2-Py
CH2
H
racemic


III-500
Me
Et
Me
NH
2-Py
CH2
H
(S)-

















TABLE 46








(III)




embedded image





















Compound







Configura-


No.
R1
R2
R3
L2
R4
L3
R5
tion





III-501
Me
Me
Me
N(Me)
2-Py
CH2
H
racemic


III-502
Me
Me
Me
N(Me)
2-Py
CH2
H
(S)-


III-503
Me
Et
Me
N(Me)
2-Py
CH2
H
racemic


III-504
Me
Et
Me
N(Me)
2-Py
CH2
H
(S)-


III-505
Me
Me
Me
NH
3-Py
CH2
H
racemic


III-506
Me
Me
Me
NH
3-Py
CH2
H
(S)-


III-507
Me
Et
Me
NH
3-Py
CH2
H
racemic


III-508
Me
Et
Me
NH
3-Py
CH2
H
(S)-


III-509
Me
Me
Me
N(Me)
3-Py
CH2
H
racemic


III-510
Me
Me
Me
N(Me)
3-Py
CH2
H
(S)-


III-511
Me
Et
Me
N(Me)
3-Py
CH2
H
racemic


III-512
Me
Et
Me
N(Me)
3-Py
CH2
H
(S)-


III-513
Me
Me
Me
NH
4-Py
CH2
H
racemic


III-514
Me
Me
Me
NH
4-Py
CH2
H
(S)-


III-515
Me
Et
Me
NH
4-Py
CH2
H
racemic


III-516
Me
Et
Me
NH
4-Py
CH2
H
(S)-


III-517
Me
Me
Me
N(Me)
4-Py
CH2
H
racemic


III-518
Me
Me
Me
N(Me)
4-Py
CH2
H
(S)-


III-519
Me
Et
Me
N(Me)
4-Py
CH2
H
racemic


III-520
Me
Et
Me
N(Me)
4-Py
CH2
H
(S)-


III-521
Me
Me
Me
CH2
Ph
CH2
H
racemic


III-522
Me
Me
Me
CH2
Ph
CH2
H
(S)-


III-523
Me
Et
Me
CH2
Ph
CH2
H
racemic


III-524
Me
Et
Me
CH2
Ph
CH2
H
(S)-


III-525
Me
Me
Me
CH2
Ph
—
H
racemic


III-526
Me
Me
Me
CH2
Ph
—
H
(S)-


III-527
Me
Et
Me
CH2
Ph
—
H
racemic


III-528
Me
Et
Me
CH2
Ph
—
H
(S)-


III-529
Me
Me
Me
CH2
Ph
CH2
Me
racemic


III-530
Me
Me
Me
CH2
Ph
CH2
Me
(S)-


III-531
Me
Et
Me
CH2
Ph
CH2
Me
racemic


III-532
Me
Et
Me
CH2
Ph
CH2
Me
(S)-


III-533
Me
Me
Me
CH2
Ph
CH2
CHF2
racemic


III-534
Me
Me
Me
CH2
Ph
CH2
CHF2
(S)-


III-535
Me
Et
Me
CH2
Ph
CH2
CHF2
racemic


III-536
Me
Et
Me
CH2
Ph
CH2
CHF2
(S)-


III-537
Me
Me
Me
CH2
Ph
CH2
Et
racemic


III-538
Me
Me
Me
CH2
Ph
CH2
Et
(S)-


III-539
Me
Et
Me
CH2
Ph
CH2
Et
racemic


III-540
Me
Et
Me
CH2
Ph
CH2
Et
(S)-


III-541
Me
Me
Me
CH2
Ph
CH2
cPr
racemic


III-542
Me
Me
Me
CH2
Ph
CH2
cPr
(S)-


III-543
Me
Me
Me
CH2
Ph
CH2
Ph
racemic


III-544
Me
Me
Me
CH2
Ph
CH2
Ph
(S)-


III-545
Me
Me
Me
CH2
Ph
C(Me)2
H
racemic


III-546
Me
Me
Me
CH2
Ph
C(Me)2
H
(S)-


III-547
Me
Et
Me
CH2
Ph
C(Me)2
H
racemic


III-548
Me
Et
Me
CH2
Ph
C(Me)2
H
(S)-


III-549
Me
Me
Me
CH2
Ph
C(Me)2
Me
racemic


III-550
Me
Me
Me
CH2
Ph
C(Me)2
Me
(S)-

















TABLE 47








(III)




embedded image





















Compound







Configura-


No.
R1
R2
R3
L2
R4
L3
R5
tion





III-551
Me
Et
Me
CH2
Ph
C(Me)2
Me
racemic


III-552
Me
Et
Me
CH2
Ph
C(Me)2
Me
(S)-


III-553
Me
Me
Me
CH2
Ph
C(Me)2
CHF2
racemic


III-554
Me
Me
Me
CH2
Ph
C(Me)2
CHF2
(S)-


III-555
Me
Me
Me
CH2
Ph
C(Me)2
Et
racemic


III-556
Me
Me
Me
CH2
Ph
C(Me)2
Et
(S)-


III-557
Me
Me
Me
CH2
Ph
C(Me)2
cPr
racemic


III-558
Me
Me
Me
CH2
Ph
C(Me)2
cPr
(S)-


III-559
Me
Me
Me
CH2
Ph
C(Me)2
Ph
racemic


III-560
Me
Me
Me
CH2
Ph
C(Me)2
Ph
(S)-


III-561
Me
Me
Me
CH2
Ph
(CH2)2
H
racemic


III-562
Me
Me
Me
CH2
Ph
(CH2)2
H
(S)-


III-563
Me
Et
Me
CH2
Ph
(CH2)2
H
racemic


III-564
Me
Et
Me
CH2
Ph
(CH2)2
H
(S)-


III-565
Me
Me
Me
CH2
Ph
(CH2)2
Me
racemic


III-566
Me
Me
Me
CH2
Ph
(CH2)2
Me
(S)-


III-567
Me
Me
Me
CH2
Ph
(CH2)2
CHF2
racemic


III-568
Me
Me
Me
CH2
Ph
(CH2)2
CHF2
(S)-


III-569
Me
Me
Me
CH2
Ph
(CH2)2
Et
racemic


III-570
Me
Me
Me
CH2
Ph
(CH2)2
Et
(S)-


III-571
Me
Me
Me
CH2
Ph
(CH2)2
cPr
racemic


III-572
Me
Me
Me
CH2
Ph
(CH2)2
cPr
(S)-


III-573
Me
Me
Me
CH2
Ph
(CH2)2
Ph
racemic


III-574
Me
Me
Me
CH2
Ph
(CH2)2
Ph
(S)-


III-575
Me
Me
Me
CH2
Ph
CH2C(Me)2
H
racemic


III-576
Me
Me
Me
CH2
Ph
CH2C(Me)2
H
(S)-


III-577
Me
Et
Me
CH2
Ph
CH2C(Me)2
H
racemic


III-578
Me
Et
Me
CH2
Ph
CH2C(Me)2
H
(S)-


III-579
Me
Me
Me
CH2
Ph
CH2C(Me)2
Me
racemic


III-580
Me
Me
Me
CH2
Ph
CH2C(Me)2
Me
(S)-


III-581
Me
Et
Me
CH2
Ph
CH2C(Me)2
Me
racemic


III-582
Me
Et
Me
CH2
Ph
CH2C(Me)2
Me
(S)-


III-583
Me
Me
Me
CH2
Ph
CH2C(Me)2
CHF2
racemic


III-584
Me
Me
Me
CH2
Ph
CH2C(Me)2
CHF2
(S)-


III-585
Me
Me
Me
CH2
Ph
CH2C(Me)2
Et
racemic


III-586
Me
Me
Me
CH2
Ph
CH2C(Me)2
Et
(S)-


III-587
Me
Me
Me
CH2
Ph
CH2C(Me)2
cPr
racemic


III-588
Me
Me
Me
CH2
Ph
CH2C(Me)2
cPr
(S)-


III-589
Me
Me
Me
CH2
Ph
CH2C(Me)2
Ph
racemic


III-590
Me
Me
Me
CH2
Ph
CH2C(Me)2
Ph
(S)-


III-591
Me
Me
Me
—
Ph
CH2
H
racemic


III-592
Me
Me
Me
—
Ph
CH2
H
(S)-


III-593
Me
Me
Me
—
Ph
CH2
Me
racemic


III-594
Me
Me
Me
—
Ph
CH2
Me
(S)-


III-595
Me
Me
Me
CH═CH
Ph
CH2
H
racemic


III-596
Me
Me
Me
CH═CH
Ph
CH2
H
(S)-


III-597
Me
Me
Me
CH═CH
Ph
CH2
Me
racemic


III-598
Me
Me
Me
CH═CH
Ph
CH2
Me
(S)-


III-599
Me
Me
Me
C≡C
Ph
CH2
H
racemic


III-600
Me
Me
Me
C≡C
Ph
CH2
H
(S)-

















TABLE 48








(III)




embedded image





















Com-







Con-


pound







figura-


No.
R1
R2
R3
L2
R4
L3
R5
tion





III-601
Me
Me
Me
C≡C
Ph
CH2
Me
racemic


III-602
Me
Me
Me
C≡C
Ph
CH2
Me
(S)-


III-603
Me
Me
Me
1,2-Cyclopropylene
Ph
CH2
H
racemic


III-604
Me
Me
Me
1,2-Cyclopropylene
Ph
CH2
H
(S)-


III-605
Me
Me
Me
1,2-Cyclopropylene
Ph
CH2
Me
racemic


III-606
Me
Me
Me
1,2-Cyclopropylene
Ph
CH2
Me
(S)-


III-607
Me
Me
Me
1,2-Cyclopropynylene
Ph
CH2
H
racemic


III-608
Me
Me
Me
1,2-Cyclopropynylene
Ph
CH2
H
(S)-


III-609
Me
Me
Me
1,2-Cyclopropynylene
Ph
CH2
Me
racemic


III-610
Me
Me
Me
1,2-Cyclopropynylene
Ph
CH2
Me
(S)-

















TABLE 49








(III)




embedded image





















Compound







Configura-


No.
R1
R2
R3
L2
R4
L3
R5
tion





III-611
Me
Me
Me
O
Ph
C(Me)2CH2
H
racemic


III-612
Me
Me
Me
O
Ph
C(Me)2CH2
H
(+)


III-613
Me
Me
Me
O
Ph
C(Me)2CH2
H
(−)


III-614
Me
Et
Me
O
Ph
C(Me)2CH2
H
racemic


III-615
Me
Et
Me
O
Ph
C(Me)2CH2
H
(+)


III-616
Me
Et
Me
O
Ph
C(Me)2CH2
H
(−)


III-617
Me
Me
Me
O
Ph
C(Me)2CH2
Me
racemic


III-618
Me
Me
Me
O
Ph
C(Me)2CH2
Me
(+)


III-619
Me
Me
Me
O
Ph
C(Me)2CH2
Me
(−)


III-620
Me
Et
Me
O
Ph
C(Me)2CH2
Me
racemic


III-621
Me
Et
Me
O
Ph
C(Me)2CH2
Me
(+)


III-622
Me
Et
Me
O
Ph
C(Me)2CH2
Me
(−)


III-623
Me
Me
Me
O
Ph
C(Me)2CH2
CHF2
racemic


III-624
Me
Me
Me
O
Ph
C(Me)2CH2
CHF2
(+)


III-625
Me
Me
Me
O
Ph
C(Me)2CH2
CHF2
(−)


III-626
Me
Me
Me
O
Ph
C(Me)2CH2
Et
racemic


III-627
Me
Me
Me
O
Ph
C(Me)2CH2
Et
(+)


III-628
Me
Me
Me
O
Ph
C(Me)2CH2
Et
(−)


III-629
Me
Me
Me
NH
Ph
C(Me)2CH2
H
(+)


III-630
Me
Me
Me
NH
Ph
C(Me)2CH2
H
(−)


III-631
Me
Et
Me
NH
Ph
C(Me)2CH2
H
(+)


III-632
Me
Et
Me
NH
Ph
C(Me)2CH2
H
(−)


III-633
Me
Me
Me
NH
Ph
C(Me)2CH2
Me
racemic


III-634
Me
Me
Me
NH
Ph
C(Me)2CH2
Me
(+)


III-635
Me
Me
Me
NH
Ph
C(Me)2CH2
Me
(−)


III-636
Me
Et
Me
NH
Ph
C(Me)2CH2
Me
racemic


III-637
Me
Et
Me
NH
Ph
C(Me)2CH2
Me
(+)


III-638
Me
Et
Me
NH
Ph
C(Me)2CH2
Me
(−)


III-639
Me
Me
Me
NH
Ph
C(Me)2CH2
CHF2
racemic


III-640
Me
Me
Me
NH
Ph
C(Me)2CH2
CHF2
(+)


III-641
Me
Me
Me
NH
Ph
C(Me)2CH2
CHF2
(−)


III-642
Me
Et
Me
NH
Ph
C(Me)2CH2
CHF2
racemic


III-643
Me
Et
Me
NH
Ph
C(Me)2CH2
CHF2
(+)


III-644
Me
Et
Me
NH
Ph
C(Me)2CH2
CHF2
(−)


III-645
Me
Me
Me
NH
Ph
C(Me)2CH2
Et
racemic


III-646
Me
Me
Me
NH
Ph
C(Me)2CH2
Et
(+)


III-647
Me
Me
Me
NH
Ph
C(Me)2CH2
Et
(−)


III-648
Me
Et
Me
NH
Ph
C(Me)2CH2
Et
racemic


III-649
Me
Et
Me
NH
Ph
C(Me)2CH2
Et
(+)


III-650
Me
Et
Me
NH
Ph
C(Me)2CH2
Et
(−)

















TABLE 50








(III)




embedded image





















Compound







Configura-


No.
R1
R2
R3
L2
R4
L3
R5
tion





III-651
Me
Me
Me
NH
Ph
C(Me)2CH2
iPr
racemic


III-652
Me
Me
Me
NH
Ph
C(Me)2CH2
iPr
(+)


III-653
Me
Me
Me
NH
Ph
C(Me)2CH2
iPr
(−)


III-654
Me
Et
Me
NH
Ph
C(Me)2CH2
iPr
racemic


III-655
Me
Et
Me
NH
Ph
C(Me)2CH2
iPr
(+)


III-656
Me
Et
Me
NH
Ph
C(Me)2CH2
iPr
(−)


III-657
Me
Me
Me
NH
Ph
C(Me)2CH2
cPr
racemic


III-658
Me
Me
Me
NH
Ph
C(Me)2CH2
cPr
(+)


III-659
Me
Me
Me
NH
Ph
C(Me)2CH2
cPr
(−)


III-660
Me
Et
Me
NH
Ph
C(Me)2CH2
cPr
racemic


III-661
Me
Et
Me
NH
Ph
C(Me)2CH2
cPr
(+)


III-662
Me
Et
Me
NH
Ph
C(Me)2CH2
cPr
(−)


III-663
Me
Me
Me
NH
Ph
1,1-Cyclo-
H
racemic








propylene-CH2




III-664
Me
Me
Me
NH
Ph
1,1-Cyclo-
H
(+)








propylene-CH2




III-665
Me
Me
Me
NH
Ph
1,1-Cyclo-
H
(−)








propylene-CH2




III-666
Me
Et
Me
NH
Ph
1,1-Cyclo-
H
racemic








propylene-CH2




III-667
Me
Et
Me
NH
Ph
1,1-Cyclo-
H
(+)








propylene-CH2




III-668
Me
Et
Me
NH
Ph
1,1-Cyclo-
H
(−)








propylene-CH2




III-669
Me
Me
Me
NH
Ph
1,1-Cyclo-
Me
racemic








propylene-CH2




III-670
Me
Me
Me
NH
Ph
1,1-Cyclo-
Me
(+)








propylene-CH2




III-671
Me
Me
Me
NH
Ph
1,1-Cyclo-
Me
(−)








propylene-CH2




III-672
Me
Et
Me
NH
Ph
1,1-Cyclo-
Me
racemic








propylene-CH2




III-673
Me
Et
Me
NH
Ph
1,1-Cyclo-
Me
(+)








propylene-CH2




III-674
Me
Et
Me
NH
Ph
1,1-Cyclo-
Me
(−)








propylene-CH2




III-675
Me
Me
Me
NH
Ph
1,1-Cyclo-
H
racemic








butylene-CH2




III-676
Me
Me
Me
NH
Ph
1,1-Cyclo-
H
(+)








butylene-CH2




III-677
Me
Me
Me
NH
Ph
1,1-Cyclo-
H
(−)








butylene-CH2




III-678
Me
Et
Me
NH
Ph
1,1-Cyclo-
H
racemic








butylene-CH2




III-679
Me
Et
Me
NH
Ph
1,1-Cyclo-
H
(+)








butylene-CH2




III-680
Me
Et
Me
NH
Ph
1,1-Cyclo-
H
(−)








butylene-CH2




III-681
Me
Me
Me
NH
Ph
1,1-Cyclo-
Me
racemic








butylene-CH2




III-682
Me
Me
Me
NH
Ph
1,1-Cyclo-
Me
(+)








butylene-CH2




III-683
Me
Me
Me
NH
Ph
1,1-Cyclo-
Me
(−)








butylene-CH2




III-684
Me
Et
Me
NH
Ph
1,1-Cyclo-
Me
racemic








butylene-CH2




III-685
Me
Et
Me
NH
Ph
1,1-Cyclo-
Me
(+)








butylene-CH2




III-686
Me
Et
Me
NH
Ph
1,1-Cyclo-
Me
(−)








butylene-CH2




III-687
Me
Me
Me
NH
Ph
C(Et)2CH2
H
racemic


III-688
Me
Me
Me
NH
Ph
C(Et)2CH2
H
(+)


III-689
Me
Me
Me
NH
Ph
C(Et)2CH2
H
(−)


III-690
Me
Et
Me
NH
Ph
C(Et)2CH2
H
racemic


III-691
Me
Et
Me
NH
Ph
C(Et)2CH2
H
(+)


III-692
Me
Et
Me
NH
Ph
C(Et)2CH2
H
(−)


III-693
Me
Me
Me
NH
Ph
C(Et)2CH2
Me
racemic


III-694
Me
Me
Me
NH
Ph
C(Et)2CH2
Me
(+)


III-695
Me
Me
Me
NH
Ph
C(Et)2CH2
Me
(−)


III-696
Me
Et
Me
NH
Ph
C(Et)2CH2
Me
racemic


III-697
Me
Et
Me
NH
Ph
C(Et)2CH2
Me
(+)


III-698
Me
Et
Me
NH
Ph
C(Et)2CH2
Me
(−)


III-699
Me
Me
Me
NH
Ph
CH2-1,1-Cyclo-
H
racemic








propylene




III-700
Me
Me
Me
NH
Ph
CH2-1,1-Cyclo-
H
(R)-








propylene

















TABLE 51








(III)




embedded image





















Com-







Con-


pound







figura-


No.
R1
R2
R3
L2
R4
L3
R5
tion





III-701
Me
Et
Me
NH
Ph
CH2-1,1-Cyclo-
H
racemic








propylene




III-702
Me
Et
Me
NH
Ph
CH2-1,1-Cyclo-
H
(R)-








propylene




III-703
Me
Me
Me
NH
Ph
CH2-1,1-Cyclo-
Me
racemic








propylene




III-704
Me
Me
Me
NH
Ph
CH2-1,1-Cyclo-
Me
(R)-








propylene




III-705
Me
Et
Me
NH
Ph
CH2-1,1-Cyclo-
Me
racemic








propylene




III-706
Me
Et
Me
NH
Ph
CH2-1,1-Cyclo-
Me
(R)-








propylene




III-707
Me
Me
Me
NH
Ph
CH2-1,1-cyclo-
H
racemic








butylene




III-708
Me
Me
Me
NH
Ph
CH2-1,1-cyclo-
H
(R)-








butylene




III-709
Me
Et
Me
NH
Ph
CH2-1,1-cyclo-
H
racemic








butylene




III-710
Me
Et
Me
NH
Ph
CH2-1,1-cyclo-
H
(R)-








butylene




III-711
Me
Me
Me
NH
Ph
CH2-1,1-cyclo-
Me
racemic








butylene




III-712
Me
Me
Me
NH
Ph
CH2-1,1-cyclo-
Me
(R)-








butylene




III-713
Me
Et
Me
NH
Ph
CH2-1,1-cyclo-
Me
racemic








butylene




III-714
Me
Et
Me
NH
Ph
CH2-1,1-cyclo-
Me
(R)-








butylene




III-715
Me
Me
Me
NH
Ph
CH2C(Et)2
H
racemic


III-716
Me
Me
Me
NH
Ph
CH2C(Et)2
H
(R)-


III-717
Me
Et
Me
NH
Ph
CH2C(Et)2
H
racemic


III-718
Me
Et
Me
NH
Ph
CH2C(Et)2
H
(R)-


III-719
Me
Me
Me
NH
Ph
CH2C(Et)2
Me
racemic


III-720
Me
Me
Me
NH
Ph
CH2C(Et)2
Me
(R)-


III-721
Me
Et
Me
NH
Ph
CH2C(Et)2
Me
racemic


III-722
Me
Et
Me
NH
Ph
CH2C(Et)2
Me
(R)-


III-723
Me
Me
Me
NH
iPr
CH2
Me
racemic


III-724
Me
Me
Me
NH
iPr
CH2
Me
(S)-


III-725
Me
Et
Me
NH
iPr
CH2
Me
racemic


III-726
Me
Et
Me
NH
iPr
CH2
Me
(S)-


III-727
Me
Me
Me
NH
iPr
(CH2)2
H
racemic


III-728
Me
Me
Me
NH
iPr
(CH2)2
H
(R)-


III-729
Me
Et
Me
NH
iPr
(CH2)2
H
racemic


III-730
Me
Et
Me
NH
iPr
(CH2)2
H
(R)-


III-731
Me
Me
Me
NH
iPr
(CH2)2
Me
racemic


III-732
Me
Me
Me
NH
iPr
(CH2)2
Me
(R)-


III-733
Me
Et
Me
NH
iPr
(CH2)2
Me
racemic


III-734
Me
Et
Me
NH
iPr
(CH2)2
Me
(R)-


III-735
Me
Me
Me
NH
CF3
CH2
H
racemic


III-736
Me
Me
Me
NH
CF3
CH2
H
(S)-


III-737
Me
Et
Me
NH
CF3
CH2
H
racemic


III-738
Me
Et
Me
NH
CF3
CH2
H
(S)-


III-739
Me
Me
Me
NH
CH2OH
CH2
H



III-740
Me
Et
Me
NH
CH2OH
CH2
H



III-741
Me
Me
Me
NH
CH2OMe
CH2
H
racemic


III-742
Me
Me
Me
NH
CH2OMe
CH2
H
(R)-


III-743
Me
Et
Me
NH
CH2OMe
CH2
H
racemic


III-744
Me
Et
Me
NH
CH2OMe
CH2
H
(R)-


III-745
Me
Me
Me
NH
CH2Ph
CH2
H
racemic


III-746
Me
Me
Me
NH
CH2Ph
CH2
H
(R)-


III-747
Me
Me
Me
NH
CH2Ph
CH2
H
(S)-


III-748
Me
Et
Me
NH
CH2Ph
CH2
H
racemic


III-749
Me
Et
Me
NH
CH2Ph
CH2
H
(S)-


III-750
Me
Me
Me
NH
2-F—Ph
CH2
Me
racemic

















TABLE 52








(III)




embedded image





















Compound







Configura-


No.
R1
R2
R3
L2
R4
L3
R5
tion





III-751
Me
Me
Me
NH
2-F—Ph
CH2
Me
(S)-


III-752
Me
Et
Me
NH
2-F—Ph
CH2
Me
racemic


III-753
Me
Et
Me
NH
2-F—Ph
CH2
Me
(S)-


III-754
Me
Me
Me
NH
2-F—Ph
(CH2)2
H
racemic


III-755
Me
Me
Me
NH
2-F—Ph
(CH2)2
H
(R)-


III-756
Me
Et
Me
NH
2-F—Ph
(CH2)2
H
racemic


III-757
Me
Et
Me
NH
2-F—Ph
(CH2)2
H
(R)-


III-758
Me
Me
Me
NH
2-F—Ph
(CH2)2
Me
racemic


III-759
Me
Me
Me
NH
2-F—Ph
(CH2)2
Me
(R)-


III-760
Me
Et
Me
NH
2-F—Ph
(CH2)2
Me
racemic


III-761
Me
Et
Me
NH
2-F—Ph
(CH2)2
Me
(R)-


III-762
Me
Me
Me
NH
2-F—Ph
CH2C(Me)2
H
racemic


III-763
Me
Me
Me
NH
2-F—Ph
CH2C(Me)2
H
(R)-


III-764
Me
Et
Me
NH
2-F—Ph
CH2C(Me)2
H
racemic


III-765
Me
Et
Me
NH
2-F—Ph
CH2C(Me)2
H
(R)-


III-766
Me
Me
Me
NH
2-F—Ph
CH2C(Me)2
Me
racemic


III-767
Me
Me
Me
NH
2-F—Ph
CH2C(Me)2
Me
(R)-


III-768
Me
Et
Me
NH
2-F—Ph
CH2C(Me)2
Me
racemic


III-769
Me
Et
Me
NH
2-F—Ph
CH2C(Me)2
Me
(R)-


III-770
Me
Me
Me
NH
2-F—Ph
C(Me)2CH2
H
racemic


III-771
Me
Me
Me
NH
2-F—Ph
C(Me)2CH2
H
(+)


III-772
Me
Me
Me
NH
2-F—Ph
C(Me)2CH2
H
(−)


III-773
Me
Et
Me
NH
2-F—Ph
C(Me)2CH2
H
racemic


III-774
Me
Et
Me
NH
2-F—Ph
C(Me)2CH2
H
(+)


III-775
Me
Et
Me
NH
2-F—Ph
C(Me)2CH2
H
(−)


III-776
Me
Me
Me
NH
2-F—Ph
C(Me)2CH2
Me
racemic


III-777
Me
Me
Me
NH
2-F—Ph
C(Me)2CH2
Me
(+)


III-778
Me
Me
Me
NH
2-F—Ph
C(Me)2CH2
Me
(−)


III-779
Me
Et
Me
NH
2-F—Ph
C(Me)2CH2
Me
racemic


III-780
Me
Et
Me
NH
2-F—Ph
C(Me)2CH2
Me
(+)


III-781
Me
Et
Me
NH
2-F—Ph
C(Me)2CH2
Me
(−)


III-782
Me
Me
Me
NH
3-F—Ph
(CH2)2
H
racemic


III-783
Me
Me
Me
NH
3-F—Ph
(CH2)2
H
(R)-


III-784
Me
Et
Me
NH
3-F—Ph
(CH2)2
H
racemic


III-785
Me
Et
Me
NH
3-F—Ph
(CH2)2
H
(R)-


III-786
Me
Me
Me
NH
3-F—Ph
(CH2)2
Me
racemic


III-787
Me
Me
Me
NH
3-F—Ph
(CH2)2
Me
(R)-


III-788
Me
Et
Me
NH
3-F—Ph
(CH2)2
Me
racemic


III-789
Me
Et
Me
NH
3-F—Ph
(CH2)2
Me
(R)-


III-790
Me
Me
Me
NH
3-F—Ph
CH2C(Me)2
H
racemic


III-791
Me
Me
Me
NH
3-F—Ph
CH2C(Me)2
H
(R)-


III-792
Me
Et
Me
NH
3-F—Ph
CH2C(Me)2
H
racemic


III-793
Me
Et
Me
NH
3-F—Ph
CH2C(Me)2
H
(R)-


III-794
Me
Me
Me
NH
3-F—Ph
CH2C(Me)2
Me
racemic


III-795
Me
Me
Me
NH
3-F—Ph
CH2C(Me)2
Me
(R)-


III-796
Me
Et
Me
NH
3-F—Ph
CH2C(Me)2
Me
racemic


III-797
Me
Et
Me
NH
3-F—Ph
CH2C(Me)2
Me
(R)-


III-798
Me
Me
Me
NH
3-F—Ph
C(Me)2CH2
H
racemic


III-799
Me
Me
Me
NH
3-F—Ph
C(Me)2CH2
H
(+)


III-800
Me
Me
Me
NH
3-F—Ph
C(Me)2CH2
H
(−)

















TABLE 53








(III)




embedded image





















Compound







Configura-


No.
R1
R2
R3
L2
R4
L3
R5
tion





III-801
Me
Et
Me
NH
3-F—Ph
C(Me)2CH2
H
racemic


III-802
Me
Et
Me
NH
3-F—Ph
C(Me)2CH2
H
(+)


III-803
Me
Et
Me
NH
3-F—Ph
C(Me)2CH2
H
(−)


III-804
Me
Me
Me
NH
3-F—Ph
C(Me)2CH2
Me
racemic


III-805
Me
Me
Me
NH
3-F—Ph
C(Me)2CH2
Me
(+)


III-806
Me
Me
Me
NH
3-F—Ph
C(Me)2CH2
Me
(−)


III-807
Me
Et
Me
NH
3-F—Ph
C(Me)2CH2
Me
racemic


III-808
Me
Et
Me
NH
3-F—Ph
C(Me)2CH2
Me
(+)


III-809
Me
Et
Me
NH
3-F—Ph
C(Me)2CH2
Me
(−)


III-810
Me
Me
Me
NH
4-F—Ph
(CH2)2
H
racemic


III-811
Me
Me
Me
NH
4-F—Ph
(CH2)2
H
(R)-


III-812
Me
Et
Me
NH
4-F—Ph
(CH2)2
H
racemic


III-813
Me
Et
Me
NH
4-F—Ph
(CH2)2
H
(R)-


III-814
Me
Me
Me
NH
4-F—Ph
(CH2)2
Me
racemic


III-815
Me
Me
Me
NH
4-F—Ph
(CH2)2
Me
(R)-


III-816
Me
Et
Me
NH
4-F—Ph
(CH2)2
Me
racemic


III-817
Me
Et
Me
NH
4-F—Ph
(CH2)2
Me
(R)-


III-818
Me
Me
Me
NH
4-F—Ph
CH2C(Me)2
H
racemic


III-819
Me
Me
Me
NH
4-F—Ph
CH2C(Me)2
H
(R)-


III-820
Me
Et
Me
NH
4-F—Ph
CH2C(Me)2
H
racemic


III-821
Me
Et
Me
NH
4-F—Ph
CH2C(Me)2
H
(R)-


III-822
Me
Me
Me
NH
4-F—Ph
CH2C(Me)2
Me
racemic


III-823
Me
Me
Me
NH
4-F—Ph
CH2C(Me)2
Me
(R)-


III-824
Me
Et
Me
NH
4-F—Ph
CH2C(Me)2
Me
racemic


III-825
Me
Et
Me
NH
4-F—Ph
CH2C(Me)2
Me
(R)-


III-826
Me
Me
Me
NH
4-F—Ph
C(Me)2CH2
H
racemic


III-827
Me
Me
Me
NH
4-F—Ph
C(Me)2CH2
H
(+)


III-828
Me
Me
Me
NH
4-F—Ph
C(Me)2CH2
H
(−)


III-829
Me
Et
Me
NH
4-F—Ph
C(Me)2CH2
H
racemic


III-830
Me
Et
Me
NH
4-F—Ph
C(Me)2CH2
H
(+)


III-831
Me
Et
Me
NH
4-F—Ph
C(Me)2CH2
H
(−)


III-832
Me
Me
Me
NH
4-F—Ph
C(Me)2CH2
Me
racemic


III-833
Me
Me
Me
NH
4-F—Ph
C(Me)2CH2
Me
(+)


III-834
Me
Me
Me
NH
4-F—Ph
C(Me)2CH2
Me
(−)


III-835
Me
Et
Me
NH
4-F—Ph
C(Me)2CH2
Me
racemic


III-836
Me
Et
Me
NH
4-F—Ph
C(Me)2CH2
Me
(+)


III-837
Me
Et
Me
NH
4-F—Ph
C(Me)2CH2
Me
(−)


III-838
Me
Me
Me
NH
2-Cl—Ph
CH2
H
racemic


III-839
Me
Me
Me
NH
2-Cl—Ph
CH2
H
(S)-


III-840
Me
Et
Me
NH
2-Cl—Ph
CH2
H
racemic


III-841
Me
Et
Me
NH
2-Cl—Ph
CH2
H
(S)-


III-842
Me
Me
Me
NH
2-Cl—Ph
CH2
Me
racemic


III-843
Me
Me
Me
NH
2-Cl—Ph
CH2
Me
(S)-


III-844
Me
Et
Me
NH
2-Cl—Ph
CH2
Me
racemic


III-845
Me
Et
Me
NH
2-Cl—Ph
CH2
Me
(S)-


III-846
Me
Me
Me
NH
2-Cl—Ph
(CH2)2
H
racemic


III-847
Me
Me
Me
NH
2-Cl—Ph
(CH2)2
H
(R)-


III-848
Me
Et
Me
NH
2-Cl—Ph
(CH2)2
H
racemic


III-849
Me
Et
Me
NH
2-Cl—Ph
(CH2)2
H
(R)-


III-850
Me
Me
Me
NH
2-Cl—Ph
(CH2)2
Me
racemic

















TABLE 54








(III)




embedded image





















Compound







Configura-


No.
R1
R2
R3
L2
R4
L3
R5
tion





III-851
Me
Me
Me
NH
2-Cl—Ph
(CH2)2
Me
(R)-


III-852
Me
Et
Me
NH
2-Cl—Ph
(CH2)2
Me
racemic


III-853
Me
Et
Me
NH
2-Cl—Ph
(CH2)2
Me
(R)-


III-854
Me
Me
Me
NH
2-Cl—Ph
CH2C(Me)2
H
racemic


III-855
Me
Me
Me
NH
2-Cl—Ph
CH2C(Me)2
H
(R)-


III-856
Me
Et
Me
NH
2-Cl—Ph
CH2C(Me)2
H
racemic


III-857
Me
Et
Me
NH
2-Cl—Ph
CH2C(Me)2
H
(R)-


III-858
Me
Me
Me
NH
2-Cl—Ph
CH2C(Me)2
Me
racemic


III-859
Me
Me
Me
NH
2-Cl—Ph
CH2C(Me)2
Me
(R)-


III-860
Me
Et
Me
NH
2-Cl—Ph
CH2C(Me)2
Me
racemic


III-861
Me
Et
Me
NH
2-Cl—Ph
CH2C(Me)2
Me
(R)-


III-862
Me
Me
Me
NH
2-Cl—Ph
C(Me)2CH2
H
racemic


III-863
Me
Me
Me
NH
2-Cl—Ph
C(Me)2CH2
H
(+)


III-864
Me
Me
Me
NH
2-Cl—Ph
C(Me)2CH2
H
(−)


III-865
Me
Et
Me
NH
2-Cl—Ph
C(Me)2CH2
H
racemic


III-866
Me
Et
Me
NH
2-Cl—Ph
C(Me)2CH2
H
(+)


III-867
Me
Et
Me
NH
2-Cl—Ph
C(Me)2CH2
H
(−)


III-868
Me
Me
Me
NH
2-Cl—Ph
C(Me)2CH2
Me
racemic


III-869
Me
Me
Me
NH
2-Cl—Ph
C(Me)2CH2
Me
(+)


III-870
Me
Me
Me
NH
2-Cl—Ph
C(Me)2CH2
Me
(−)


III-871
Me
Et
Me
NH
2-Cl—Ph
C(Me)2CH2
Me
racemic


III-872
Me
Et
Me
NH
2-Cl—Ph
C(Me)2CH2
Me
(+)


III-873
Me
Et
Me
NH
2-Cl—Ph
C(Me)2CH2
Me
(−)


III-874
Me
Me
Me
NH
3-Cl—Ph
CH2
H
racemic


III-875
Me
Me
Me
NH
3-Cl—Ph
CH2
H
(S)-


III-876
Me
Et
Me
NH
3-Cl—Ph
CH2
H
racemic


III-877
Me
Et
Me
NH
3-Cl—Ph
CH2
H
(S)-


III-878
Me
Me
Me
NH
3-Cl—Ph
CH2
Me
racemic


III-879
Me
Me
Me
NH
3-Cl—Ph
CH2
Me
(S)-


III-880
Me
Et
Me
NH
3-Cl—Ph
CH2
Me
racemic


III-881
Me
Et
Me
NH
3-Cl—Ph
CH2
Me
(S)-


III-882
Me
Me
Me
NH
3-Cl—Ph
(CH2)2
H
racemic


III-883
Me
Me
Me
NH
3-Cl—Ph
(CH2)2
H
(R)-


III-884
Me
Et
Me
NH
3-Cl—Ph
(CH2)2
H
racemic


III-885
Me
Et
Me
NH
3-Cl—Ph
(CH2)2
H
(R)-


III-886
Me
Me
Me
NH
3-Cl—Ph
(CH2)2
Me
racemic


III-887
Me
Me
Me
NH
3-Cl—Ph
(CH2)2
Me
(R)-


III-888
Me
Et
Me
NH
3-Cl—Ph
(CH2)2
Me
racemic


III-889
Me
Et
Me
NH
3-Cl—Ph
(CH2)2
Me
(R)-


III-890
Me
Me
Me
NH
3-Cl—Ph
CH2C(Me)2
H
racemic


III-891
Me
Me
Me
NH
3-Cl—Ph
CH2C(Me)2
H
(R)-


III-892
Me
Et
Me
NH
3-Cl—Ph
CH2C(Me)2
H
racemic


III-893
Me
Et
Me
NH
3-Cl—Ph
CH2C(Me)2
H
(R)-


III-894
Me
Me
Me
NH
3-Cl—Ph
CH2C(Me)2
Me
racemic


III-895
Me
Me
Me
NH
3-Cl—Ph
CH2C(Me)2
Me
(R)-


III-896
Me
Et
Me
NH
3-Cl—Ph
CH2C(Me)2
Me
racemic


III-897
Me
Et
Me
NH
3-Cl—Ph
CH2C(Me)2
Me
(R)-


III-898
Me
Me
Me
NH
3-Cl—Ph
C(Me)2CH2
H
racemic


III-899
Me
Me
Me
NH
3-Cl—Ph
C(Me)2CH2
H
(+)


III-900
Me
Me
Me
NH
3-Cl—Ph
C(Me)2CH2
H
(−)
















TABLE 55







(III)




embedded image




















Com-







Con-


pound







figu-


No.
R1
R2
R3
L2
R4
L3
R5
ration





III-901
Me
Et
Me
NH
3-Cl—Ph
C(Me)2CH2
H
racemic


III-902
Me
Et
Me
NH
3-Cl—Ph
C(Me)2CH2
H
(+)


III-903
Me
Et
Me
NH
3-Cl—Ph
C(Me)2CH2
H
(−)


III-904
Me
Me
Me
NH
3-Cl—Ph
C(Me)2CH2
Me
racemic


III-905
Me
Me
Me
NH
3-Cl—Ph
C(Me)2CH2
Me
(+)


III-906
Me
Me
Me
NH
3-Cl—Ph
C(Me)2CH2
Me
(−)


III-907
Me
Et
Me
NH
3-Cl—Ph
C(Me)2CH2
Me
racemic


III-908
Me
Et
Me
NH
3-Cl—Ph
C(Me)2CH2
Me
(+)


III-909
Me
Et
Me
NH
3-Cl—Ph
C(Me)2CH2
Me
(−)


III-910
Me
Me
Me
NH
4-Cl—Ph
CH2
H
racemic


III-911
Me
Me
Me
NH
4-Cl—Ph
CH2
H
(S)-


III-912
Me
Et
Me
NH
4-Cl—Ph
CH2
H
racemic


III-913
Me
Et
Me
NH
4-Cl—Ph
CH2
H
(S)-


III-914
Me
Me
Me
NH
4-Cl—Ph
CH2
Me
racemic


III-915
Me
Me
Me
NH
4-Cl—Ph
CH2
Me
(S)-


III-916
Me
Et
Me
NH
4-Cl—Ph
CH2
Me
racemic


III-917
Me
Et
Me
NH
4-Cl—Ph
CH2
Me
(S)-


III-918
Me
Me
Me
NH
4-Cl—Ph
(CH2)2
H
racemic


III-919
Me
Me
Me
NH
4-Cl—Ph
(CH2)2
H
(R)-


III-920
Me
Et
Me
NH
4-Cl—Ph
(CH2)2
H
racemic


III-921
Me
Et
Me
NH
4-Cl—Ph
(CH2)2
H
(R)-


III-922
Me
Me
Me
NH
4-Cl—Ph
(CH2)2
Me
racemic


III-923
Me
Me
Me
NH
4-Cl—Ph
(CH2)2
Me
(R)-


III-924
Me
Et
Me
NH
4-Cl—Ph
(CH2)2
Me
racemic


III-925
Me
Et
Me
NH
4-Cl—Ph
(CH2)2
Me
(R)-


III-926
Me
Me
Me
NH
4-Cl—Ph
CH2C(Me)2
H
racemic


III-927
Me
Me
Me
NH
4-Cl—Ph
CH2C(Me)2
H
(R)-


III-928
Me
Et
Me
NH
4-Cl—Ph
CH2C(Me)2
H
racemic


III-929
Me
Et
Me
NH
4-Cl—Ph
CH2C(Me)2
H
(R)-


III-930
Me
Me
Me
NH
4-Cl—Ph
CH2C(Me)2
Me
racemic


III-931
Me
Me
Me
NH
4-Cl—Ph
CH2C(Me)2
Me
(R)-


III-932
Me
Et
Me
NH
4-Cl—Ph
CH2C(Me)2
Me
racemic


III-933
Me
Et
Me
NH
4-Cl—Ph
CH2C(Me)2
Me
(R)-


III-934
Me
Me
Me
NH
4-Cl—Ph
C(Me)2CH2
H
racemic


III-935
Me
Me
Me
NH
4-Cl—Ph
C(Me)2CH2
H
(+)


III-936
Me
Me
Me
NH
4-Cl—Ph
C(Me)2CH2
H
(−)


III-937
Me
Et
Me
NH
4-Cl—Ph
C(Me)2CH2
H
racemic


III-938
Me
Et
Me
NH
4-Cl—Ph
C(Me)2CH2
H
(+)


III-939
Me
Et
Me
NH
4-Cl—Ph
C(Me)2CH2
H
(−)


III-940
Me
Me
Me
NH
4-Cl—Ph
C(Me)2CH2
Me
racemic


III-941
Me
Me
Me
NH
4-Cl—Ph
C(Me)2CH2
Me
(+)


III-942
Me
Me
Me
NH
4-Cl—Ph
C(Me)2CH2
Me
(−)


III-943
Me
Et
Me
NH
4-Cl—Ph
C(Me)2CH2
Me
racemic


III-944
Me
Et
Me
NH
4-Cl—Ph
C(Me)2CH2
Me
(+)


III-945
Me
Et
Me
NH
4-Cl—Ph
C(Me)2CH2
Me
(−)


III-946
Me
Me
Me
NH
2-Me—Ph
CH2
H
racemic


III-947
Me
Me
Me
NH
2-Me—Ph
CH2
H
(S)-


III-948
Me
Et
Me
NH
2-Me—Ph
CH2
H
racemic


III-949
Me
Et
Me
NH
2-Me—Ph
CH2
H
(S)-


III-950
Me
Me
Me
NH
2-Me—Ph
CH2
Me
racemic
















TABLE 56







(III)




embedded image




















Com-







Con-


pound







figu-


No.
R1
R2
R3
L2
R4
L3
R5
ration





III-951
Me
Me
Me
NH
2-Me—Ph
CH2
Me
(S)-


III-952
Me
Et
Me
NH
2-Me—Ph
CH2
Me
racemic


III-953
Me
Et
Me
NH
2-Me—Ph
CH2
Me
(S)-


III-954
Me
Me
Me
NH
2-Me—Ph
(CH2)2
H
racemic


III-955
Me
Me
Me
NH
2-Me—Ph
(CH2)2
H
(R)-


III-956
Me
Et
Me
NH
2-Me—Ph
(CH2)2
H
racemic


III-957
Me
Et
Me
NH
2-Me—Ph
(CH2)2
H
(R)-


III-958
Me
Me
Me
NH
2-Me—Ph
(CH2)2
Me
racemic


III-959
Me
Me
Me
NH
2-Me—Ph
(CH2)2
Me
(R)-


III-960
Me
Et
Me
NH
2-Me—Ph
(CH2)2
Me
racemic


III-961
Me
Et
Me
NH
2-Me—Ph
(CH2)2
Me
(R)-


III-962
Me
Me
Me
NH
2-Me—Ph
CH2C(Me)2
H
racemic


III-963
Me
Me
Me
NH
2-Me—Ph
CH2C(Me)2
H
(R)-


III-964
Me
Et
Me
NH
2-Me—Ph
CH2C(Me)2
H
racemic


III-965
Me
Et
Me
NH
2-Me—Ph
CH2C(Me)2
H
(R)-


III-966
Me
Me
Me
NH
2-Me—Ph
CH2C(Me)2
Me
racemic


III-967
Me
Me
Me
NH
2-Me—Ph
CH2C(Me)2
Me
(R)-


III-968
Me
Et
Me
NH
2-Me—Ph
CH2C(Me)2
Me
racemic


III-969
Me
Et
Me
NH
2-Me—Ph
CH2C(Me)2
Me
(R)-


III-970
Me
Me
Me
NH
2-Me—Ph
C(Me)2CH2
H
racemic


III-971
Me
Me
Me
NH
2-Me—Ph
C(Me)2CH2
H
(+)


III-972
Me
Me
Me
NH
2-Me—Ph
C(Me)2CH2
H
(−)


III-973
Me
Et
Me
NH
2-Me—Ph
C(Me)2CH2
H
racemic


III-974
Me
Et
Me
NH
2-Me—Ph
C(Me)2CH2
H
(+)


III-975
Me
Et
Me
NH
2-Me—Ph
C(Me)2CH2
H
(−)


III-976
Me
Me
Me
NH
2-Me—Ph
C(Me)2CH2
Me
racemic


III-977
Me
Me
Me
NH
2-Me—Ph
C(Me)2CH2
Me
(+)


III-978
Me
Me
Me
NH
2-Me—Ph
C(Me)2CH2
Me
(−)


III-979
Me
Et
Me
NH
2-Me—Ph
C(Me)2CH2
Me
racemic


III-980
Me
Et
Me
NH
2-Me—Ph
C(Me)2CH2
Me
(+)


III-981
Me
Et
Me
NH
2-Me—Ph
C(Me)2CH2
Me
(−)


III-982
Me
Me
Me
NH
3-Me—Ph
CH2
H
racemic


III-983
Me
Me
Me
NH
3-Me—Ph
CH2
H
(S)-


III-984
Me
Et
Me
NH
3-Me—Ph
CH2
H
racemic


III-985
Me
Et
Me
NH
3-Me—Ph
CH2
H
(S)-


III-986
Me
Me
Me
NH
3-Me—Ph
CH2
Me
racemic


III-987
Me
Me
Me
NH
3-Me—Ph
CH2
Me
(S)-


III-988
Me
Et
Me
NH
3-Me—Ph
CH2
Me
racemic


III-989
Me
Et
Me
NH
3-Me—Ph
CH2
Me
(S)-


III-990
Me
Me
Me
NH
3-Me—Ph
(CH2)2
H
racemic


III-991
Me
Me
Me
NH
3-Me—Ph
(CH2)2
H
(R)-


III-992
Me
Et
Me
NH
3-Me—Ph
(CH2)2
H
racemic


III-993
Me
Et
Me
NH
3-Me—Ph
(CH2)2
H
(R)-


III-994
Me
Me
Me
NH
3-Me—Ph
(CH2)2
Me
racemic


III-995
Me
Me
Me
NH
3-Me—Ph
(CH2)2
Me
(R)-


III-996
Me
Et
Me
NH
3-Me—Ph
(CH2)2
Me
racemic


III-997
Me
Et
Me
NH
3-Me—Ph
(CH2)2
Me
(R)-


III-998
Me
Me
Me
NH
3-Me—Ph
CH2C(Me)2
H
racemic


III-999
Me
Me
Me
NH
3-Me—Ph
CH2C(Me)2
H
(R)-


 III-1000
Me
Et
Me
NH
3-Me—Ph
CH2C(Me)2
H
racemic
















TABLE 57







(III)




embedded image




















Com-







Con-


pound







figu-


No.
R1
R2
R3
L2
R4
L3
R5
ration





III-1001
Me
Et
Me
NH
3-Me—Ph
CH2C(Me)2
H
(R)-


III-1002
Me
Me
Me
NH
3-Me—Ph
CH2C(Me)2
Me
racemic


III-1003
Me
Me
Me
NH
3-Me—Ph
CH2C(Me)2
Me
(R)-


III-1004
Me
Et
Me
NH
3-Me—Ph
CH2C(Me)2
Me
racemic


III-1005
Me
Et
Me
NH
3-Me—Ph
CH2C(Me)2
Me
(R)-


III-1006
Me
Me
Me
NH
3-Me—Ph
C(Me)2CH2
H
racemic


III-1007
Me
Me
Me
NH
3-Me—Ph
C(Me)2CH2
H
(+)


III-1008
Me
Me
Me
NH
3-Me—Ph
C(Me)2CH2
H
(−)


III-1009
Me
Et
Me
NH
3-Me—Ph
C(Me)2CH2
H
racemic


III-1010
Me
Et
Me
NH
3-Me—Ph
C(Me)2CH2
H
(+)


III-1011
Me
Et
Me
NH
3-Me—Ph
C(Me)2CH2
H
(−)


III-1012
Me
Me
Me
NH
3-Me—Ph
C(Me)2CH2
Me
racemic


III-1013
Me
Me
Me
NH
3-Me—Ph
C(Me)2CH2
Me
(+)


III-1014
Me
Me
Me
NH
3-Me—Ph
C(Me)2CH2
Me
(−)


III-1015
Me
Et
Me
NH
3-Me—Ph
C(Me)2CH2
Me
racemic


III-1016
Me
Et
Me
NH
3-Me—Ph
C(Me)2CH2
Me
(+)


III-1017
Me
Et
Me
NH
3-Me—Ph
C(Me)2CH2
Me
(−)


III-1018
Me
Me
Me
NH
4-Me—Ph
CH2
H
racemic


III-1019
Me
Me
Me
NH
4-Me—Ph
CH2
H
(S)-


III-1020
Me
Et
Me
NH
4-Me—Ph
CH2
H
racemic


III-1021
Me
Et
Me
NH
4-Me—Ph
CH2
H
(S)-


III-1022
Me
Me
Me
NH
4-Me—Ph
CH2
Me
racemic


III-1023
Me
Me
Me
NH
4-Me—Ph
CH2
Me
(S)-


III-1024
Me
Et
Me
NH
4-Me—Ph
CH2
Me
racemic


III-1025
Me
Et
Me
NH
4-Me—Ph
CH2
Me
(S)-


III-1026
Me
Me
Me
NH
4-Me—Ph
(CH2)2
H
racemic


III-1027
Me
Me
Me
NH
4-Me—Ph
(CH2)2
H
(R)-


III-1028
Me
Et
Me
NH
4-Me—Ph
(CH2)2
H
racemic


III-1029
Me
Et
Me
NH
4-Me—Ph
(CH2)2
H
(R)-


III-1030
Me
Me
Me
NH
4-Me—Ph
(CH2)2
Me
racemic


III-1031
Me
Me
Me
NH
4-Me—Ph
(CH2)2
Me
(R)-


III-1032
Me
Et
Me
NH
4-Me—Ph
(CH2)2
Me
racemic


III-1033
Me
Et
Me
NH
4-Me—Ph
(CH2)2
Me
(R)-


III-1034
Me
Me
Me
NH
4-Me—Ph
CH2C(Me)2
H
racemic


III-1035
Me
Me
Me
NH
4-Me—Ph
CH2C(Me)2
H
(R)-


III-1036
Me
Et
Me
NH
4-Me—Ph
CH2C(Me)2
H
racemic


III-1037
Me
Et
Me
NH
4-Me—Ph
CH2C(Me)2
H
(R)-


III-1038
Me
Me
Me
NH
4-Me—Ph
CH2C(Me)2
Me
racemic


III-1039
Me
Me
Me
NH
4-Me—Ph
CH2C(Me)2
Me
(R)-


III-1040
Me
Et
Me
NH
4-Me—Ph
CH2C(Me)2
Me
racemic


III-1041
Me
Et
Me
NH
4-Me—Ph
CH2C(Me)2
Me
(R)-


III-1042
Me
Me
Me
NH
4-Me—Ph
C(Me)2CH2
H
racemic


III-1043
Me
Me
Me
NH
4-Me—Ph
C(Me)2CH2
H
(+)


III-1044
Me
Me
Me
NH
4-Me—Ph
C(Me)2CH2
H
(−)


III-1045
Me
Et
Me
NH
4-Me—Ph
C(Me)2CH2
H
racemic


III-1046
Me
Et
Me
NH
4-Me—Ph
C(Me)2CH2
H
(+)


III-1047
Me
Et
Me
NH
4-Me—Ph
C(Me)2CH2
H
(−)


III-1048
Me
Me
Me
NH
4-Me—Ph
C(Me)2CH2
Me
racemic


III-1049
Me
Me
Me
NH
4-Me—Ph
C(Me)2CH2
Me
(+)


III-1050
Me
Me
Me
NH
4-Me—Ph
C(Me)2CH2
Me
(−)
















TABLE 58







(III)




embedded image




















Com-







Con-


pound







figu-


No.
R1
R2
R3
L2
R4
L3
R5
ration





III-1051
Me
Et
Me
NH
4-Me—Ph
C(Me)2CH2
Me
racemic


III-1052
Me
Et
Me
NH
4-Me—Ph
C(Me)2CH2
Me
(+)


III-1053
Me
Et
Me
NH
4-Me—Ph
C(Me)2CH2
Me
(−)


III-1054
Me
Me
Me
—
Ph
—
H
racemic


III-1055
Me
Me
Me
—
Ph
—
H
(R)-


III-1056
Me
Et
Me
—
Ph
—
H
racemic


III-1057
Me
Et
Me
—
Ph
—
H
(R)-


III-1058
Me
Me
Me
—
Ph
—
Me
racemic


III-1059
Me
Me
Me
—
Ph
—
Me
(R)-


III-1060
Me
Et
Me
—
Ph
—
Me
racemic


III-1061
Me
Et
Me
—
Ph
—
Me
(R)-


III-1062
Me
Me
Me
—
Ph
—
CHF2
racemic


III-1063
Me
Me
Me
—
Ph
—
CHF2
(R)-


III-1064
Me
Et
Me
—
Ph
—
CHF2
racemic


III-1065
Me
Et
Me
—
Ph
—
CHF2
(R)-


III-1066
Me
Me
Me
—
Ph
—
CF3
racemic


III-1067
Me
Me
Me
—
Ph
—
CF3
(R)-


III-1068
Me
Et
Me
—
Ph
—
CF3
racemic


III-1069
Me
Et
Me
—
Ph
—
CF3
(R)-


III-1070
Me
Me
Me
—
Ph
—
Et
racemic


III-1071
Me
Me
Me
—
Ph
—
Et
(R)-


III-1072
Me
Et
Me
—
Ph
—
Et
racemic


III-1073
Me
Et
Me
—
Ph
—
Et
(R)-


III-1074
Me
Me
Me
—
Ph
—
CF2CH3
racemic


III-1075
Me
Me
Me
—
Ph
—
CF2CH3
(R)-


III-1076
Me
Et
Me
—
Ph
—
CF2CH3
racemic


III-1077
Me
Et
Me
—
Ph
—
CF2CH3
(R)-


III-1078
Me
Me
Me
—
Ph
—
nPr
racemic


III-1079
Me
Me
Me
—
Ph
—
nPr
(R)-


III-1080
Me
Et
Me
—
Ph
—
nPr
racemic


III-1081
Me
Et
Me
—
Ph
—
nPr
(R)-


III-1082
Me
Me
Me
—
Ph
—
nBu
racemic


III-1083
Me
Me
Me
—
Ph
—
nBu
(R)-


III-1084
Me
Et
Me
—
Ph
—
nBu
racemic


III-1085
Me
Et
Me
—
Ph
—
nBu
(R)-


III-1086
Me
Me
Me
—
Ph
—
iPr
racemic


III-1087
Me
Me
Me
—
Ph
—
iPr
(R)-


III-1088
Me
Et
Me
—
Ph
—
iPr
racemic


III-1089
Me
Et
Me
—
Ph
—
iPr
(R)-


III-1090
Me
Me
Me
—
Ph
—
cPr
racemic


III-1091
Me
Me
Me
—
Ph
—
cPr
(R)-


III-1092
Me
Et
Me
—
Ph
—
cPr
racemic


III-1093
Me
Et
Me
—
Ph
—
cPr
(R)-


III-1094
Me
Me
Me
—
Ph
—
Ph
racemic


III-1095
Me
Me
Me
—
Ph
—
Ph
(R)-


III-1096
Me
Et
Me
—
Ph
—
Ph
racemic


III-1097
Me
Et
Me
—
Ph
—
Ph
(R)-


III-1098
Me
Me
Me
—
Ph
CH2
CHF2
racemic


III-1099
Me
Me
Me
—
Ph
CH2
CHF2
(S)-


III-1100
Me
Me
Me
—
Ph
CH2
Et
racemic
















TABLE 59







(III)




embedded image




















Compound










No.
R1
R2
R3
L2
R4
L3
R5
Configuration





III-1101
Me
Me
Me
—
Ph
CH2
Et
(S)-


III-1102
Me
Me
Me
—
Ph
CH2
Ph
racemic


III-1103
Me
Me
Me
—
Ph
CH2
Ph
(R)-


III-1104
Me
Me
Me
—
Ph
(CH2)2
H
racemic


III-1105
Me
Me
Me
—
Ph
(CH2)2
H
(S)-


III-1106
Me
Me
Me
—
Ph
(CH2)2
Me
racemic


III-1107
Me
Me
Me
—
Ph
(CH2)2
Me
(S)-


III-1108
Me
Me
Me
—
Ph
(CH2)2
CHF2
racemic


III-1109
Me
Me
Me
—
Ph
(CH2)2
CHF2
(S)-


III-1110
Me
Me
Me
—
Ph
(CH2)2
Et
racemic


III-1111
Me
Me
Me
—
Ph
(CH2)2
Et
(S)-


III-1112
Me
Me
Me
—
H
—
H



III-1113
Me
Me
Me
—
H
—
Me



III-1114
Me
Me
Me
—
H
—
CHF2



III-1115
Me
Me
Me
—
H
—
CF3



III-1116
Me
Me
Me
—
H
—
Et



III-1117
Me
Me
Me
—
H
—
nPr



III-1118
Me
Me
Me
—
H
—
iPr



III-1119
Me
Me
Me
—
H
—
cPr



III-1120
Me
Me
Me
—
H
—
Ph



III-1121
Me
Me
Me
—
Me
—
H
racemic


III-1122
Me
Me
Me
—
Me
—
H
(R)-


III-1123
Me
Me
Me
—
Me
—
Me
racemic


III-1124
Me
Me
Me
—
Me
—
Me
(R)-


III-1125
Me
Me
Me
—
Me
—
CHF2
racemic


III-1126
Me
Me
Me
—
Me
—
CHF2
(R)-


III-1127
Me
Me
Me
—
Me
—
CF3
racemic


III-1128
Me
Me
Me
—
Me
—
CF3
(R)-


III-1129
Me
Me
Me
—
Me
—
Et
racemic


III-1130
Me
Me
Me
—
Me
—
Et
(R)-


III-1131
Me
Me
Me
—
Me
—
nPr
racemic


III-1132
Me
Me
Me
—
Me
—
nPr
(R)-


III-1133
Me
Me
Me
—
Me
—
iPr
racemic


III-1134
Me
Me
Me
—
Me
—
iPr
(R)-


III-1135
Me
Me
Me
—
Me
—
cPr
racemic


III-1136
Me
Me
Me
—
Me
—
cPr
(R)-


III-1137
Me
Me
Me
—
Me
—
cHex
racemic


III-1138
Me
Me
Me
—
Me
—
cHex
(R)-


III-1139
Me
Me
Me
—
Me
—
Ph
racemic


III-1140
Me
Me
Me
—
Me
—
Ph
(R)-


III-1141
Me
Me
Me
—
Me
—
2-F—Ph
racemic


III-1142
Me
Me
Me
—
Me
—
2-F—Ph
(R)-


III-1143
Me
Me
Me
—
Me
—
3-F—Ph
racemic


III-1144
Me
Me
Me
—
Me
—
3-F—Ph
(R)-


III-1145
Me
Me
Me
—
Me
—
4-F—Ph
racemic


III-1146
Me
Me
Me
—
Me
—
4-F—Ph
(R)-


III-1147
Me
Me
Me
—
Me
—
2-Cl—Ph
racemic


III-1148
Me
Me
Me
—
Me
—
2-Cl—Ph
(R)-


III-1149
Me
Me
Me
—
Me
—
3-Cl—Ph
racemic


III-1150
Me
Me
Me
—
Me
—
3-Cl—Ph
(R)-
















TABLE 60







(III)




embedded image




















Compound










No.
R1
R2
R3
L2
R4
L3
R5
Configuration





III-1151
Me
Me
Me
—
Me
—
4-Cl—Ph
racemic


III-1152
Me
Me
Me
—
Me
—
4-Cl—Ph
(R)-


III-1153
Me
Me
Me
—
Me
—
2-Py
racemic


III-1154
Me
Me
Me
—
Me
—
2-Py
(R)-


III-1155
Me
Me
Me
—
Me
—
3-Py
racemic


III-1156
Me
Me
Me
—
Me
—
3-Py
(R)-


III-1157
Me
Me
Me
—
Me
—
4-Py
racemic


III-1158
Me
Me
Me
—
Me
—
4-Py
(R)-


III-1159
Me
Me
Me
—
iPr
—
H
racemic


III-1160
Me
Me
Me
—
iPr
—
H
(R)-


III-1161
Me
Me
Me
—
iPr
—
Me
racemic


III-1162
Me
Me
Me
—
iPr
—
Me
(R)-


III-1163
Me
Me
Me
—
iPr
—
CHF2
racemic


III-1164
Me
Me
Me
—
iPr
—
CHF2
(R)-


III-1165
Me
Me
Me
—
iPr
—
CF3
racemic


III-1166
Me
Me
Me
—
iPr
—
CF3
(R)-


III-1167
Me
Me
Me
—
iPr
—
Et
racemic


III-1168
Me
Me
Me
—
iPr
—
Et
(R)-


III-1169
Me
Me
Me
—
iPr
—
nPr
racemic


III-1170
Me
Me
Me
—
iPr
—
nPr
(R)-


III-1171
Me
Me
Me
—
iPr
—
iPr
racemic


III-1172
Me
Me
Me
—
iPr
—
iPr
(R)-


III-1173
Me
Me
Me
—
iPr
—
cPr
racemic


III-1174
Me
Me
Me
—
iPr
—
cPr
(R)-


III-1175
Me
Me
Me
—
iPr
—
Ph
racemic


III-1176
Me
Me
Me
—
iPr
—
Ph
(R)-


III-1177
Me
Me
Me
—
CF3
—
H
racemic


III-1178
Me
Me
Me
—
CF3
—
H
(R)-


III-1179
Me
Me
Me
—
CF3
—
Me
racemic


III-1180
Me
Me
Me
—
CF3
—
Me
(R)-


III-1181
Me
Me
Me
—
CF3
—
CHF2
racemic


III-1182
Me
Me
Me
—
CF3
—
CHF2
(R)-


III-1183
Me
Me
Me
—
CF3
—
CF3
racemic


III-1184
Me
Me
Me
—
CF3
—
CF3
(R)-


III-1185
Me
Me
Me
—
CF3
—
Et
racemic


III-1186
Me
Me
Me
—
CF3
—
Et
(R)-


III-1187
Me
Me
Me
—
CF3
—
nPr
racemic


III-1188
Me
Me
Me
—
CF3
—
nPr
(R)-


III-1189
Me
Me
Me
—
CF3
—
iPr
racemic


III-1190
Me
Me
Me
—
CF3
—
iPr
(R)-


III-1191
Me
Me
Me
—
CF3
—
cPr
racemic


III-1192
Me
Me
Me
—
CF3
—
cPr
(R)-


III-1193
Me
Me
Me
—
CF3
—
Ph
racemic


III-1194
Me
Me
Me
—
CF3
—
Ph
(R)-


III-1195
Me
Me
Me
—
CH2OH
—
H
racemic


III-1196
Me
Me
Me
—
CH2OH
—
H
(R)-


III-1197
Me
Me
Me
—
CH2OH
—
Me
racemic


III-1198
Me
Me
Me
—
CH2OH
—
Me
(R)-


III-1199
Me
Me
Me
—
CH2OH
—
CHF2
racemic


III-1200
Me
Me
Me
—
CH2OH
—
CHF2
(R)-
















TABLE 61







(III)




embedded image




















Compound










No.
R1
R2
R3
L2
R4
L3
R5
Configuration





III-1201
Me
Me
Me
—
CH2OH
—
CF3
racemic


III-1202
Me
Me
Me
—
CH2OH
—
CF3
(R)-


III-1203
Me
Me
Me
—
CH2OH
—
Et
racemic


III-1204
Me
Me
Me
—
CH2OH
—
Et
(R)-


III-1205
Me
Me
Me
—
CH2OH
—
nPr
racemic


III-1206
Me
Me
Me
—
CH2OH
—
nPr
(R)-


III-1207
Me
Me
Me
—
CH2OH
—
iPr
racemic


III-1208
Me
Me
Me
—
CH2OH
—
iPr
(R)-


III-1209
Me
Me
Me
—
CH2OH
—
cPr
racemic


III-1210
Me
Me
Me
—
CH2OH
—
cPr
(R)-


III-1211
Me
Me
Me
—
CH2OH
—
Ph
racemic


III-1212
Me
Me
Me
—
CH2OH
—
Ph
(R)-


III-1213
Me
Me
Me
—
CH2OMe
—
H
racemic


III-1214
Me
Me
Me
—
CH2OMe
—
H
(R)-


III-1215
Me
Me
Me
—
CH2OMe
—
Me
racemic


III-1216
Me
Me
Me
—
CH2OMe
—
Me
(R)-


III-1217
Me
Me
Me
—
CH2OMe
—
CHF2
racemic


III-1218
Me
Me
Me
—
CH2OMe
—
CHF2
(R)-


III-1219
Me
Me
Me
—
CH2OMe
—
CF3
racemic


III-1220
Me
Me
Me
—
CH2OMe
—
CF3
(R)-


III-1221
Me
Me
Me
—
CH2OMe
—
Et
racemic


III-1222
Me
Me
Me
—
CH2OMe
—
Et
(R)-


III-1223
Me
Me
Me
—
CH2OMe
—
nPr
racemic


III-1224
Me
Me
Me
—
CH2OMe
—
nPr
(R)-


III-1225
Me
Me
Me
—
CH2OMe
—
iPr
racemic


III-1226
Me
Me
Me
—
CH2OMe
—
iPr
(R)-


III-1227
Me
Me
Me
—
CH2OMe
—
cPr
racemic


III-1228
Me
Me
Me
—
CH2OMe
—
cPr
(R)-


III-1229
Me
Me
Me
—
CH2OMe
—
Ph
racemic


III-1230
Me
Me
Me
—
CH2OMe
—
Ph
(R)-


III-1231
Me
Me
Me
—
CH2OBn
—
H
racemic


III-1232
Me
Me
Me
—
CH2OBn
—
H
(R)-


III-1233
Me
Me
Me
—
CH2OBn
—
Me
racemic


III-1234
Me
Me
Me
—
CH2OBn
—
Me
(R)-


III-1235
Me
Me
Me
—
CH2OBn
—
Ph
racemic


III-1236
Me
Me
Me
—
CH2OBn
—
Ph
(R)-


III-1237
Me
Me
Me
—
CH2NMe2
—
H
racemic


III-1238
Me
Me
Me
—
CH2NMe2
—
H
(R)-


III-1239
Me
Me
Me
—
CH2NMe2
—
Me
racemic


III-1240
Me
Me
Me
—
CH2NMe2
—
Me
(R)-


III-1241
Me
Me
Me
—
CH2NMe2
—
CHF2
racemic


III-1242
Me
Me
Me
—
CH2NMe2
—
CHF2
(R)-


III-1243
Me
Me
Me
—
CH2NMe2
—
CF3
racemic


III-1244
Me
Me
Me
—
CH2NMe2
—
CF3
(R)-


III-1245
Me
Me
Me
—
CH2NMe2
—
Et
racemic


III-1246
Me
Me
Me
—
CH2NMe2
—
Et
(R)-


III-1247
Me
Me
Me
—
CH2NMe2
—
nPr
racemic


III-1248
Me
Me
Me
—
CH2NMe2
—
nPr
(R)-


III-1249
Me
Me
Me
—
CH2NMe2
—
iPr
racemic


III-1250
Me
Me
Me
—
CH2NMe2
—
iPr
(R)-
















TABLE 62







(III)




embedded image




















Com-







Con-


pound







figu-


No.
R1
R2
R3
L2
R4
L3
R5
ration





III-1251
Me
Me
Me
—
CH2NMe2
—
cPr
racemic


III-1252
Me
Me
Me
—
CH2NMe2
—
cPr
(R)-


III-1253
Me
Me
Me
—
CH2NMe2
—
Ph
racemic


III-1254
Me
Me
Me
—
CH2NMe2
—
Ph
(R)-


III-1255
Me
Me
Me
—
CH2-(3,3-difluoro-
—
H
racemic







pyrrolidyl)





III-1256
Me
Me
Me
—
CH2-(3,3-difluoro-
—
H
(R)-







pyrrolidyl)





III-1257
Me
Me
Me
—
CH2-(3,3-difluoro-
—
Me
racemic







pyrrolidyl)





III-1258
Me
Me
Me
—
CH2-(3,3-difluoro-
—
Me
(R)-







pyrrolidyl)





III-1259
Me
Me
Me
—
CH2-(3,3-difluoro-
—
Ph
racemic







pyrrolidyl)





III-1260
Me
Me
Me
—
CH2-(3,3-difluoro-
—
Ph
(R)-







pyrrolidyl)





III-1261
Me
Me
Me
—
2-F—Ph
—
H
racemic


III-1262
Me
Me
Me
—
2-F—Ph
—
H
(R)-


III-1263
Me
Me
Me
—
2-F—Ph
—
Me
racemic


III-1264
Me
Me
Me
—
2-F—Ph
—
Me
(R)-


III-1265
Me
Me
Me
—
2-F—Ph
—
CHF2
racemic


III-1266
Me
Me
Me
—
2-F—Ph
—
CHF2
(R)-


III-1267
Me
Me
Me
—
2-F—Ph
—
CF3
racemic


III-1268
Me
Me
Me
—
2-F—Ph
—
CF3
(R)-


III-1269
Me
Me
Me
—
2-F—Ph
—
Et
racemic


III-1270
Me
Me
Me
—
2-F—Ph
—
Et
(R)-


III-1271
Me
Me
Me
—
2-F—Ph
—
nPr
racemic


III-1272
Me
Me
Me
—
2-F—Ph
—
nPr
(R)-


III-1273
Me
Me
Me
—
2-F—Ph
—
iPr
racemic


III-1274
Me
Me
Me
—
2-F—Ph
—
iPr
(R)-


III-1275
Me
Me
Me
—
2-F—Ph
—
cPr
racemic


III-1276
Me
Me
Me
—
2-F—Ph
—
cPr
(R)-


III-1277
Me
Me
Me
—
3-F—Ph
—
H
racemic


III-1278
Me
Me
Me
—
3-F—Ph
—
H
(R)-


III-1279
Me
Me
Me
—
3-F—Ph
—
Me
racemic


III-1280
Me
Me
Me
—
3-F—Ph
—
Me
(R)-


III-1281
Me
Me
Me
—
3-F—Ph
—
CHF2
racemic


III-1282
Me
Me
Me
—
3-F—Ph
—
CHF2
(R)-


III-1283
Me
Me
Me
—
3-F—Ph
—
CF3
racemic


III-1284
Me
Me
Me
—
3-F—Ph
—
CF3
(R)-


III-1285
Me
Me
Me
—
3-F—Ph
—
Et
racemic


III-1286
Me
Me
Me
—
3-F—Ph
—
Et
(R)-


III-1287
Me
Me
Me
—
3-F—Ph
—
nPr
racemic


III-1288
Me
Me
Me
—
3-F—Ph
—
nPr
(R)-


III-1289
Me
Me
Me
—
3-F—Ph
—
iPr
racemic


III-1290
Me
Me
Me
—
3-F—Ph
—
iPr
(R)-


III-1291
Me
Me
Me
—
3-F—Ph
—
cPr
racemic


III-1292
Me
Me
Me
—
3-F—Ph
—
cPr
(R)-


III-1293
Me
Me
Me
—
4-F—Ph
—
H
racemic


III-1294
Me
Me
Me
—
4-F—Ph
—
H
(R)-


III-1295
Me
Me
Me
—
4-F—Ph
—
Me
racemic


III-1296
Me
Me
Me
—
4-F—Ph
—
Me
(R)-


III-1297
Me
Me
Me
—
4-F—Ph
—
CHF2
racemic


III-1298
Me
Me
Me
—
4-F—Ph
—
CHF2
(R)-


III-1299
Me
Me
Me
—
4-F—Ph
—
CF3
racemic


III-1300
Me
Me
Me
—
4-F—Ph
—
CF3
(R)-
















TABLE 63







(III)




embedded image




















Compound










No.
R1
R2
R3
L2
R4
L3
R5
Configuration





III-1301
Me
Me
Me
—
4-F—Ph
—
Et
racemic


III-1302
Me
Me
Me
—
4-F—Ph
—
Et
(R)-


III-1303
Me
Me
Me
—
4-F—Ph
—
nPr
racemic


III-1304
Me
Me
Me
—
4-F—Ph
—
nPr
(R)-


III-1305
Me
Me
Me
—
4-F—Ph
—
iPr
racemic


III-1306
Me
Me
Me
—
4-F—Ph
—
iPr
(R)-


III-1307
Me
Me
Me
—
4-F—Ph
—
cPr
racemic


III-1308
Me
Me
Me
—
4-F—Ph
—
cPr
(R)-


III-1309
Me
Me
Me
—
2-thienyl
—
H
racemic


III-1310
Me
Me
Me
—
2-thienyl
—
H
(S)-


III-1311
Me
Me
Me
—
2-thienyl
—
Me
racemic


III-1312
Me
Me
Me
—
2-thienyl
—
Me
(S)-


III-1313
Me
Me
Me
—
2-thienyl
—
CHF2
racemic


III-1314
Me
Me
Me
—
2-thienyl
—
CHF2
(S)-


III-1315
Me
Me
Me
—
2-thienyl
—
CF3
racemic


III-1316
Me
Me
Me
—
2-thienyl
—
CF3
(S)-


III-1317
Me
Me
Me
—
2-thienyl
—
Et
racemic


III-1318
Me
Me
Me
—
2-thienyl
—
Et
(S)-


III-1319
Me
Me
Me
—
2-thienyl
—
nPr
racemic


III-1320
Me
Me
Me
—
2-thienyl
—
nPr
(S)-


III-1321
Me
Me
Me
—
2-thienyl
—
iPr
racemic


III-1322
Me
Me
Me
—
2-thienyl
—
iPr
(S)-


III-1323
Me
Me
Me
—
2-thienyl
—
cPr
racemic


III-1324
Me
Me
Me
—
2-thienyl
—
cPr
(S)-


III-1325
Me
Me
Me
—
3-thienyl
—
H
racemic


III-1326
Me
Me
Me
—
3-thienyl
—
H
(R)-


III-1327
Me
Me
Me
—
3-thienyl
—
Me
racemic


III-1328
Me
Me
Me
—
3-thienyl
—
Me
(R)-


III-1329
Me
Me
Me
—
3-thienyl
—
CHF2
racemic


III-1330
Me
Me
Me
—
3-thienyl
—
CHF2
(R)-


III-1331
Me
Me
Me
—
3-thienyl
—
CF3
racemic


III-1332
Me
Me
Me
—
3-thienyl
—
CF3
(R)-


III-1333
Me
Me
Me
—
3-thienyl
—
Et
racemic


III-1334
Me
Me
Me
—
3-thienyl
—
Et
(R)-


III-1335
Me
Me
Me
—
3-thienyl
—
nPr
racemic


III-1336
Me
Me
Me
—
3-thienyl
—
nPr
(R)-


III-1337
Me
Me
Me
—
3-thienyl
—
iPr
racemic


III-1338
Me
Me
Me
—
3-thienyl
—
iPr
(R)-


III-1339
Me
Me
Me
—
3-thienyl
—
cPr
racemic


III-1340
Me
Me
Me
—
3-thienyl
—
cPr
(R)-
















TABLE 64







(IV)




embedded image




















Compound










No.
R1
R2
R3
L2
R4
L3
R5
Configuration





IV-1 
Me
Me
Me
O
Ph
CH2
H
racemic


IV-2 
Me
Me
Me
O
Ph
CH2
H
(S)-


IV-3 
Me
Et
Me
O
Ph
CH2
H
racemic


IV-4 
Me
Et
Me
O
Ph
CH2
H
(S)-


IV-5 
Me
Me
Me
O
Ph
CH2
Me
racemic


IV-6 
Me
Me
Me
O
Ph
CH2
Me
(S)-


IV-7 
Me
Et
Me
O
Ph
CH2
Me
racemic


IV-8 
Me
Et
Me
O
Ph
CH2
Me
(S)-


IV-9 
Me
Me
Me
O
Ph
CH2
CHF2
racemic


IV-10
Me
Me
Me
O
Ph
CH2
CHF2
(S)-


IV-11
Me
Et
Me
O
Ph
CH2
CHF2
racemic


IV-12
Me
Et
Me
O
Ph
CH2
CHF2
(S)-


IV-13
Me
Me
Me
O
Ph
CH2
Et
racemic


IV-14
Me
Me
Me
O
Ph
CH2
Et
(S)-


IV-15
Me
Et
Me
O
Ph
CH2
Et
racemic


IV-16
Me
Et
Me
O
Ph
CH2
Et
(S)-


IV-17
Me
Me
Me
O
Ph
CH2
iPr
racemic


IV-18
Me
Me
Me
O
Ph
CH2
iPr
(S)-


IV-19
Me
Et
Me
O
Ph
CH2
iPr
racemic


IV-20
Me
Et
Me
O
Ph
CH2
iPr
(S)-


IV-21
Me
Me
Me
O
Ph
CH2
cPr
racemic


IV-22
Me
Me
Me
O
Ph
CH2
cPr
(S)-


IV-23
Me
Et
Me
O
Ph
CH2
cPr
racemic


IV-24
Me
Et
Me
O
Ph
CH2
cPr
(S)-


IV-25
Me
Me
Me
O
Ph
CH2
Ph
racemic


IV-26
Me
Me
Me
O
Ph
CH2
Ph
(S)-


IV-27
Me
Et
Me
O
Ph
CH2
Ph
racemic


IV-28
Me
Et
Me
O
Ph
CH2
Ph
(S)-


IV-29
Me
Me
Me
O
Ph
C(Me)2
H
racemic


IV-30
Me
Me
Me
O
Ph
C(Me)2
H
(S)-


IV-31
Me
Et
Me
O
Ph
C(Me)2
H
racemic


IV-32
Me
Et
Me
O
Ph
C(Me)2
H
(S)-


IV-33
Me
Me
Me
O
Ph
C(Me)2
Me
racemic


IV-34
Me
Me
Me
O
Ph
C(Me)2
Me
(S)-


IV-35
Me
Et
Me
O
Ph
C(Me)2
Me
racemic


IV-36
Me
Et
Me
O
Ph
C(Me)2
Me
(S)-


IV-37
Me
Me
Me
O
Ph
C(Me)2
CHF2
racemic


IV-38
Me
Me
Me
O
Ph
C(Me)2
CHF2
(S)-


IV-39
Me
Et
Me
O
Ph
C(Me)2
CHF2
racemic


IV-40
Me
Et
Me
O
Ph
C(Me)2
CHF2
(S)-


IV-41
Me
Me
Me
O
Ph
C(Me)2
Et
racemic


IV-42
Me
Me
Me
O
Ph
C(Me)2
Et
(S)-


IV-43
Me
Et
Me
O
Ph
C(Me)2
Et
racemic


IV-44
Me
Et
Me
O
Ph
C(Me)2
Et
(S)-


IV-45
Me
Me
Me
O
Ph
C(Me)2
iPr
racemic


IV-46
Me
Me
Me
O
Ph
C(Me)2
iPr
(S)-


IV-47
Me
Et
Me
O
Ph
C(Me)2
iPr
racemic


IV-48
Me
Et
Me
O
Ph
C(Me)2
iPr
(S)-


IV-49
Me
Me
Me
O
Ph
C(Me)2
cPr
racemic


IV-50
Me
Me
Me
O
Ph
C(Me)2
cPr
(S)-
















TABLE 65







(IV)




embedded image




















Com-










pound







Con-


No.
R1
R2
R3
L2
R4
L3
R5
figuration





IV-51
Me
Et
Me
O
Ph
C(Me)2
cPr
racemic


IV-52
Me
Et
Me
O
Ph
C(Me)2
cPr
(S)-


IV-53
Me
Me
Me
O
Ph
C(Me)2
Ph
racemic


IV-54
Me
Me
Me
O
Ph
C(Me)2
Ph
(S)-


IV-55
Me
Et
Me
O
Ph
C(Me)2
Ph
racemic


IV-56
Me
Et
Me
O
Ph
C(Me)2
Ph
(S)-


IV-57
Me
Me
Me
O
Ph
(CH2)2
H
racemic


IV-58
Me
Me
Me
O
Ph
(CH2)2
H
(R)-


IV-59
Me
Et
Me
O
Ph
(CH2)2
H
racemic


IV-60
Me
Et
Me
O
Ph
(CH2)2
H
(R)-


IV-61
Me
Me
Me
O
Ph
(CH2)2
Me
racemic


IV-62
Me
Me
Me
O
Ph
(CH2)2
Me
(R)-


IV-63
Me
Et
Me
O
Ph
(CH2)2
Me
racemic


IV-64
Me
Et
Me
O
Ph
(CH2)2
Me
(R)-


IV-65
Me
Me
Me
O
Ph
(CH2)2
CHF2
racemic


IV-66
Me
Me
Me
O
Ph
(CH2)2
CHF2
(R)-


IV-67
Me
Et
Me
O
Ph
(CH2)2
CHF2
racemic


IV-68
Me
Et
Me
O
Ph
(CH2)2
CHF2
(R)-


IV-69
Me
Me
Me
O
Ph
(CH2)2
Et
racemic


IV-70
Me
Me
Me
O
Ph
(CH2)2
Et
(R)-


IV-71
Me
Et
Me
O
Ph
(CH2)2
Et
racemic


IV-72
Me
Et
Me
O
Ph
(CH2)2
Et
(R)-


IV-73
Me
Me
Me
O
Ph
(CH2)2
iPr
racemic


IV-74
Me
Me
Me
O
Ph
(CH2)2
iPr
(R)-


IV-75
Me
Et
Me
O
Ph
(CH2)2
iPr
racemic


IV-76
Me
Et
Me
O
Ph
(CH2)2
iPr
(R)-


IV-77
Me
Me
Me
O
Ph
(CH2)2
cPr
racemic


IV-78
Me
Me
Me
O
Ph
(CH2)2
cPr
(R)-


IV-79
Me
Et
Me
O
Ph
(CH2)2
cPr
racemic


IV-80
Me
Et
Me
O
Ph
(CH2)2
cPr
(R)-


IV-81
Me
Me
Me
O
Ph
(CH2)2
Ph
racemic


IV-82
Me
Me
Me
O
Ph
(CH2)2
Ph
(R)-


IV-83
Me
Et
Me
O
Ph
(CH2)2
Ph
racemic


IV-84
Me
Et
Me
O
Ph
(CH2)2
Ph
(R)-


IV-85
Me
Me
Me
O
Ph
CH2C(Me)2
H
racemic


IV-86
Me
Me
Me
O
Ph
CH2C(Me)2
H
(R)-


IV-87
Me
Et
Me
O
Ph
CH2C(Me)2
H
racemic


IV-88
Me
Et
Me
O
Ph
CH2C(Me)2
H
(R)-


IV-89
Me
Me
Me
O
Ph
CH2C(Me)2
Me
racemic


IV-90
Me
Me
Me
O
Ph
CH2C(Me)2
Me
(R)-


IV-91
Me
Et
Me
O
Ph
CH2C(Me)2
Me
racemic


IV-92
Me
Et
Me
O
Ph
CH2C(Me)2
Me
(R)-


IV-93
Me
Me
Me
O
Ph
CH2C(Me)2
CHF2
racemic


IV-94
Me
Me
Me
O
Ph
CH2C(Me)2
CHF2
(R)-


IV-95
Me
Et
Me
O
Ph
CH2C(Me)2
CHF2
racemic


IV-96
Me
Et
Me
O
Ph
CH2C(Me)2
CHF2
(R)-


IV-97
Me
Me
Me
O
Ph
CH2C(Me)2
Et
racemic


IV-98
Me
Me
Me
O
Ph
CH2C(Me)2
Et
(R)-


IV-99
Me
Et
Me
O
Ph
CH2C(Me)2
Et
racemic


 IV-100
Me
Et
Me
O
Ph
CH2C(Me)2
Et
(R)-
















TABLE 66







(IV)




embedded image




















Compound







Con-


No.
R1
R2
R3
L2
R4
L3
R5
figuration





IV-101
Me
Me
Me
O
Ph
CH2C(Me)2
iPr
racemic


IV-102
Me
Me
Me
O
Ph
CH2C(Me)2
iPr
(R)-


IV-103
Me
Et
Me
O
Ph
CH2C(Me)2
iPr
racemic


IV-104
Me
Et
Me
O
Ph
CH2C(Me)2
iPr
(R)-


IV-105
Me
Me
Me
O
Ph
CH2C(Me)2
cPr
racemic


IV-106
Me
Me
Me
O
Ph
CH2C(Me)2
cPr
(R)-


IV-107
Me
Et
Me
O
Ph
CH2C(Me)2
cPr
racemic


IV-108
Me
Et
Me
O
Ph
CH2C(Me)2
cPr
(R)-


IV-109
Me
Me
Me
O
Ph
CH2C(Me)2
Ph
racemic


IV-110
Me
Me
Me
O
Ph
CH2C(Me)2
Ph
(R)-


IV-111
Me
Et
Me
O
Ph
CH2C(Me)2
Ph
racemic


IV-112
Me
Et
Me
O
Ph
CH2C(Me)2
Ph
(R)-


IV-113
Me
Me
Me
NH
Ph
CH2
H
racemic


IV-114
Me
Me
Me
NH
Ph
CH2
H
(S)-


IV-115
Me
Me
Me
NH
Ph
CH2
H
(R)-


IV-116
Me
Et
Me
NH
Ph
CH2
H
racemic


IV-117
Me
Et
Me
NH
Ph
CH2
H
(S)-


IV-118
Me
Me
Me
N(Me)
Ph
CH2
H
racemic


IV-119
Me
Me
Me
N(Me)
Ph
CH2
H
(S)-


IV-120
Me
Et
Me
N(Me)
Ph
CH2
H
racemic


IV-121
Me
Et
Me
N(Me)
Ph
CH2
H
(S)-


IV-122
Me
Me
Me
NH
Ph
CH2
Me
racemic


IV-123
Me
Me
Me
NH
Ph
CH2
Me
(S)-


IV-124
Me
Et
Me
NH
Ph
CH2
Me
racemic


IV-125
Me
Et
Me
NH
Ph
CH2
Me
(S)-


IV-126
Me
Me
Me
N(Me)
Ph
CH2
Me
racemic


IV-127
Me
Me
Me
N(Me)
Ph
CH2
Me
(S)-


IV-128
Me
Et
Me
N(Me)
Ph
CH2
Me
racemic


IV-129
Me
Et
Me
N(Me)
Ph
CH2
Me
(S)-


IV-130
Me
Me
Me
NH
Ph
CH2
CHF2
racemic


IV-131
Me
Me
Me
NH
Ph
CH2
CHF2
(S)-


IV-132
Me
Et
Me
NH
Ph
CH2
CHF2
racemic


IV-133
Me
Et
Me
NH
Ph
CH2
CHF2
(S)-


IV-134
Me
Me
Me
N(Me)
Ph
CH2
CHF2
racemic


IV-135
Me
Me
Me
N(Me)
Ph
CH2
CHF2
(S)-


IV-136
Me
Et
Me
N(Me)
Ph
CH2
CHF2
racemic


IV-137
Me
Et
Me
N(Me)
Ph
CH2
CHF2
(S)-


IV-138
Me
Me
Me
NH
Ph
CH2
Et
racemic


IV-139
Me
Me
Me
NH
Ph
CH2
Et
(S)-


IV-140
Me
Et
Me
NH
Ph
CH2
Et
racemic


IV-141
Me
Et
Me
NH
Ph
CH2
Et
(S)-


IV-142
Me
Me
Me
N(Me)
Ph
CH2
Et
racemic


IV-143
Me
Me
Me
N(Me)
Ph
CH2
Et
(S)-


IV-144
Me
Et
Me
N(Me)
Ph
CH2
Et
racemic


IV-145
Me
Et
Me
N(Me)
Ph
CH2
Et
(S)-


IV-146
Me
Me
Me
NH
Ph
CH2
iPr
racemic


IV-147
Me
Me
Me
NH
Ph
CH2
iPr
(S)-


IV-148
Me
Et
Me
NH
Ph
CH2
iPr
racemic


IV-149
Me
Et
Me
NH
Ph
CH2
iPr
(S)-


IV-150
Me
Me
Me
N(Me)
Ph
CH2
iPr
racemic
















TABLE 67







(IV)




embedded image




















Compound










No.
R1
R2
R3
L2
R4
L3
R5
Configuration





IV-151
Me
Me
Me
N(Me)
Ph
CH2
iPr
(S)-


IV-152
Me
Et
Me
N(Me)
Ph
CH2
iPr
racemic


IV-153
Me
Et
Me
N(Me)
Ph
CH2
iPr
(S)-


IV-154
Me
Me
Me
NH
Ph
CH2
cPr
racemic


IV-155
Me
Me
Me
NH
Ph
CH2
cPr
(S)-


IV-156
Me
Et
Me
NH
Ph
CH2
cPr
racemic


IV-157
Me
Et
Me
NH
Ph
CH2
cPr
(S)-


IV-158
Me
Me
Me
N(Me)
Ph
CH2
cPr
racemic


IV-159
Me
Me
Me
N(Me)
Ph
CH2
cPr
(S)-


IV-160
Me
Et
Me
N(Me)
Ph
CH2
cPr
racemic


IV-161
Me
Et
Me
N(Me)
Ph
CH2
cPr
(S)-


IV-162
Me
Me
Me
NH
Ph
CH2
Ph
racemic


IV-163
Me
Me
Me
NH
Ph
CH2
Ph
(S)-


IV-164
Me
Et
Me
NH
Ph
CH2
Ph
racemic


IV-165
Me
Et
Me
NH
Ph
CH2
Ph
(S)-


IV-166
Me
Me
Me
N(Me)
Ph
CH2
Ph
racemic


IV-167
Me
Me
Me
N(Me)
Ph
CH2
Ph
(S)-


IV-168
Me
Et
Me
N(Me)
Ph
CH2
Ph
racemic


IV-169
Me
Et
Me
N(Me)
Ph
CH2
Ph
(S)-


IV-170
Me
Me
Me
NH
Ph
C(Me)2
H
racemic


IV-171
Me
Me
Me
NH
Ph
C(Me)2
H
(S)-


IV-172
Me
Et
Me
NH
Ph
C(Me)2
H
racemic


IV-173
Me
Et
Me
NH
Ph
C(Me)2
H
(S)-


IV-174
Me
Me
Me
N(Me)
Ph
C(Me)2
H
racemic


IV-175
Me
Me
Me
N(Me)
Ph
C(Me)2
H
(S)-


IV-176
Me
Et
Me
N(Me)
Ph
C(Me)2
H
racemic


IV-177
Me
Et
Me
N(Me)
Ph
C(Me)2
H
(S)-


IV-178
Me
Me
Me
NH
Ph
C(Me)2
Me
racemic


IV-179
Me
Me
Me
NH
Ph
C(Me)2
Me
(S)-


IV-180
Me
Et
Me
NH
Ph
C(Me)2
Me
racemic


IV-181
Me
Et
Me
NH
Ph
C(Me)2
Me
(S)-


IV-182
Me
Me
Me
N(Me)
Ph
C(Me)2
Me
racemic


IV-183
Me
Me
Me
N(Me)
Ph
C(Me)2
Me
(S)-


IV-184
Me
Et
Me
N(Me)
Ph
C(Me)2
Me
racemic


IV-185
Me
Et
Me
N(Me)
Ph
C(Me)2
Me
(S)-


IV-186
Me
Me
Me
NH
Ph
C(Me)2
CHF2
racemic


IV-187
Me
Me
Me
NH
Ph
C(Me)2
CHF2
(S)-


IV-188
Me
Et
Me
NH
Ph
C(Me)2
CHF2
racemic


IV-189
Me
Et
Me
NH
Ph
C(Me)2
CHF2
(S)-


IV-190
Me
Me
Me
N(Me)
Ph
C(Me)2
CHF2
racemic


IV-191
Me
Me
Me
N(Me)
Ph
C(Me)2
CHF2
(S)-


IV-192
Me
Et
Me
N(Me)
Ph
C(Me)2
CHF2
racemic


IV-193
Me
Et
Me
N(Me)
Ph
C(Me)2
CHF2
(S)-


IV-194
Me
Me
Me
NH
Ph
C(Me)2
Et
racemic


IV-195
Me
Me
Me
NH
Ph
C(Me)2
Et
(S)-


IV-196
Me
Et
Me
NH
Ph
C(Me)2
Et
racemic


IV-197
Me
Et
Me
NH
Ph
C(Me)2
Et
(S)-


IV-198
Me
Me
Me
N(Me)
Ph
C(Me)2
Et
racemic


IV-199
Me
Me
Me
N(Me)
Ph
C(Me)2
Et
(S)-


IV-200
Me
Et
Me
N(Me)
Ph
C(Me)2
Et
racemic
















TABLE 68







(IV)




embedded image




















Compound










No.
R1
R2
R3
L2
R4
L3
R5
Configuration





IV-201
Me
Et
Me
N(Me)
Ph
C(Me)2
Et
(S)-


IV-202
Me
Me
Me
NH
Ph
C(Me)2
iPr
racemic


IV-203
Me
Me
Me
NH
Ph
C(Me)2
iPr
(S)-


IV-204
Me
Et
Me
NH
Ph
C(Me)2
iPr
racemic


IV-205
Me
Et
Me
NH
Ph
C(Me)2
iPr
(S)-


IV-206
Me
Me
Me
N(Me)
Ph
C(Me)2
iPr
racemic


IV-207
Me
Me
Me
N(Me)
Ph
C(Me)2
iPr
(S)-


IV-208
Me
Et
Me
N(Me)
Ph
C(Me)2
iPr
racemic


IV-209
Me
Et
Me
N(Me)
Ph
C(Me)2
iPr
(S)-


IV-210
Me
Me
Me
NH
Ph
C(Me)2
cPr
racemic


IV-211
Me
Me
Me
NH
Ph
C(Me)2
cPr
(S)-


IV-212
Me
Et
Me
NH
Ph
C(Me)2
cPr
racemic


IV-213
Me
Et
Me
NH
Ph
C(Me)2
cPr
(S)-


IV-214
Me
Me
Me
N(Me)
Ph
C(Me)2
cPr
racemic


IV-215
Me
Me
Me
N(Me)
Ph
C(Me)2
cPr
(S)-


IV-216
Me
Et
Me
N(Me)
Ph
C(Me)2
cPr
racemic


IV-217
Me
Et
Me
N(Me)
Ph
C(Me)2
cPr
(S)-


IV-218
Me
Me
Me
NH
Ph
C(Me)2
Ph
racemic


IV-219
Me
Me
Me
NH
Ph
C(Me)2
Ph
(S)-


IV-220
Me
Et
Me
NH
Ph
C(Me)2
Ph
racemic


IV-221
Me
Et
Me
NH
Ph
C(Me)2
Ph
(S)-


IV-222
Me
Me
Me
N(Me)
Ph
C(Me)2
Ph
racemic


IV-223
Me
Me
Me
N(Me)
Ph
C(Me)2
Ph
(S)-


IV-224
Me
Et
Me
N(Me)
Ph
C(Me)2
Ph
racemic


IV-225
Me
Et
Me
N(Me)
Ph
C(Me)2
Ph
(S)-


IV-226
Me
Me
Me
NH
Ph
(CH2)2
H
racemic


IV-227
Me
Me
Me
NH
Ph
(CH2)2
H
(R)-


IV-228
Me
Et
Me
NH
Ph
(CH2)2
H
racemic


IV-229
Me
Et
Me
NH
Ph
(CH2)2
H
(R)-


IV-230
Me
Me
Me
N(Me)
Ph
(CH2)2
H
racemic


IV-231
Me
Me
Me
N(Me)
Ph
(CH2)2
H
(R)-


IV-232
Me
Et
Me
N(Me)
Ph
(CH2)2
H
racemic


IV-233
Me
Et
Me
N(Me)
Ph
(CH2)2
H
(R)-


IV-234
Me
Me
Me
NH
Ph
(CH2)2
Me
racemic


IV-235
Me
Me
Me
NH
Ph
(CH2)2
Me
(R)-


IV-236
Me
Et
Me
NH
Ph
(CH2)2
Me
racemic


IV-237
Me
Et
Me
NH
Ph
(CH2)2
Me
(R)-


IV-238
Me
Me
Me
N(Me)
Ph
(CH2)2
Me
racemic


IV-239
Me
Me
Me
N(Me)
Ph
(CH2)2
Me
(R)-


IV-240
Me
Et
Me
N(Me)
Ph
(CH2)2
Me
racemic


IV-241
Me
Et
Me
N(Me)
Ph
(CH2)2
Me
(R)-


IV-242
Me
Me
Me
NH
Ph
(CH2)2
CHF2
racemic


IV-243
Me
Me
Me
NH
Ph
(CH2)2
CHF2
(R)-


IV-244
Me
Et
Me
NH
Ph
(CH2)2
CHF2
racemic


IV-245
Me
Et
Me
NH
Ph
(CH2)2
CHF2
(R)-


IV-246
Me
Me
Me
N(Me)
Ph
(CH2)2
CHF2
racemic


IV-247
Me
Me
Me
N(Me)
Ph
(CH2)2
CHF2
(R)-


IV-248
Me
Et
Me
N(Me)
Ph
(CH2)2
CHF2
racemic


IV-249
Me
Et
Me
N(Me)
Ph
(CH2)2
CHF2
(R)-


IV-250
Me
Me
Me
NH
Ph
(CH2)2
Et
racemic
















TABLE 69







(IV)




embedded image




















Compound










No.
R1
R2
R3
L2
R4
L3
R5
Configuration





IV-251
Me
Me
Me
NH
Ph
(CH2)2
Et
(R)-


IV-252
Me
Et
Me
NH
Ph
(CH2)2
Et
racemic


IV-253
Me
Et
Me
NH
Ph
(CH2)2
Et
(R)-


IV-254
Me
Me
Me
N(Me)
Ph
(CH2)2
Et
racemic


IV-255
Me
Me
Me
N(Me)
Ph
(CH2)2
Et
(R)-


IV-256
Me
Et
Me
N(Me)
Ph
(CH2)2
Et
racemic


IV-257
Me
Et
Me
N(Me)
Ph
(CH2)2
Et
(R)-


IV-258
Me
Me
Me
NH
Ph
(CH2)2
iPr
racemic


IV-259
Me
Me
Me
NH
Ph
(CH2)2
iPr
(R)-


IV-260
Me
Et
Me
NH
Ph
(CH2)2
iPr
racemic


IV-261
Me
Et
Me
NH
Ph
(CH2)2
iPr
(R)-


IV-262
Me
Me
Me
N(Me)
Ph
(CH2)2
iPr
racemic


IV-263
Me
Me
Me
N(Me)
Ph
(CH2)2
iPr
(R)-


IV-264
Me
Et
Me
N(Me)
Ph
(CH2)2
iPr
racemic


IV-265
Me
Et
Me
N(Me)
Ph
(CH2)2
iPr
(R)-


IV-266
Me
Me
Me
NH
Ph
(CH2)2
cPr
racemic


IV-267
Me
Me
Me
NH
Ph
(CH2)2
cPr
(R)-


IV-268
Me
Et
Me
NH
Ph
(CH2)2
cPr
racemic


IV-269
Me
Et
Me
NH
Ph
(CH2)2
cPr
(R)-


IV-270
Me
Me
Me
N(Me)
Ph
(CH2)2
cPr
racemic


IV-271
Me
Me
Me
N(Me)
Ph
(CH2)2
cPr
(R)-


IV-272
Me
Et
Me
N(Me)
Ph
(CH2)2
cPr
racemic


IV-273
Me
Et
Me
N(Me)
Ph
(CH2)2
cPr
(R)-


IV-274
Me
Me
Me
NH
Ph
(CH2)2
Ph
racemic


IV-275
Me
Me
Me
NH
Ph
(CH2)2
Ph
(R)-


IV-276
Me
Et
Me
NH
Ph
(CH2)2
Ph
racemic


IV-277
Me
Et
Me
NH
Ph
(CH2)2
Ph
(R)-


IV-278
Me
Me
Me
N(Me)
Ph
(CH2)2
Ph
racemic


IV-279
Me
Me
Me
N(Me)
Ph
(CH2)2
Ph
(R)-


IV-280
Me
Et
Me
N(Me)
Ph
(CH2)2
Ph
racemic


IV-281
Me
Et
Me
N(Me)
Ph
(CH2)2
Ph
(R)-


IV-282
Me
Me
Me
NH
Ph
(CH2)3
H
racemic


IV-283
Me
Me
Me
NH
Ph
(CH2)3
H
(R)-


IV-284
Me
Et
Me
NH
Ph
(CH2)3
H
racemic


IV-285
Me
Et
Me
NH
Ph
(CH2)3
H
(R)-


IV-286
Me
Me
Me
N(Me)
Ph
(CH2)3
H
racemic


IV-287
Me
Me
Me
N(Me)
Ph
(CH2)3
H
(R)-


IV-288
Me
Et
Me
N(Me)
Ph
(CH2)3
H
racemic


IV-289
Me
Et
Me
N(Me)
Ph
(CH2)3
H
(R)-


IV-290
Me
Me
Me
NH
Ph
(CH2)4
H
racemic


IV-291
Me
Me
Me
NH
Ph
(CH2)4
H
(R)-


IV-292
Me
Et
Me
NH
Ph
(CH2)4
H
racemic


IV-293
Me
Et
Me
NH
Ph
(CH2)4
H
(R)-


IV-294
Me
Me
Me
N(Me)
Ph
(CH2)4
H
racemic


IV-295
Me
Me
Me
N(Me)
Ph
(CH2)4
H
(R)-


IV-296
Me
Et
Me
N(Me)
Ph
(CH2)4
H
racemic


IV-297
Me
Et
Me
N(Me)
Ph
(CH2)4
H
(R)-


IV-298
Me
Me
Me
NH
Ph
CH2C(Me)2
H
racemic


IV-299
Me
Me
Me
NH
Ph
CH2C(Me)2
H
(R)-


IV-300
Me
Et
Me
NH
Ph
CH2C(Me)2
H
racemic
















TABLE 70







(IV)




embedded image




















Com-










pound










No.
R1
R2
R3
L2
R4
L3
R5
Configuration





IV-301
Me
Et
Me
NH
Ph
CH2C(Me)2
H
(R)-


IV-302
Me
Me
Me
N(Me)
Ph
CH2C(Me)2
H
racemic


IV-303
Me
Me
Me
N(Me)
Ph
CH2C(Me)2
H
(R)-


IV-304
Me
Et
Me
N(Me)
Ph
CH2C(Me)2
H
racemic


IV-305
Me
Et
Me
N(Me)
Ph
CH2C(Me)2
H
(R)-


IV-306
Me
Me
Me
NH
Ph
CH2C(Me)2
Me
racemic


IV-307
Me
Me
Me
NH
Ph
CH2C(Me)2
Me
(R)-


IV-308
Me
Et
Me
NH
Ph
CH2C(Me)2
Me
racemic


IV-309
Me
Et
Me
NH
Ph
CH2C(Me)2
Me
(R)-


IV-310
Me
Me
Me
N(Me)
Ph
CH2C(Me)2
Me
racemic


IV-311
Me
Me
Me
N(Me)
Ph
CH2C(Me)2
Me
(R)-


IV-312
Me
Et
Me
N(Me)
Ph
CH2C(Me)2
Me
racemic


IV-313
Me
Et
Me
N(Me)
Ph
CH2C(Me)2
Me
(R)-


IV-314
Me
Me
Me
NH
Ph
CH2C(Me)2
CHF2
racemic


IV-315
Me
Me
Me
NH
Ph
CH2C(Me)2
CHF2
(R)-


IV-316
Me
Et
Me
NH
Ph
CH2C(Me)2
CHF2
racemic


IV-317
Me
Et
Me
NH
Ph
CH2C(Me)2
CHF2
(R)-


IV-318
Me
Me
Me
N(Me)
Ph
CH2C(Me)2
CHF2
racemic


IV-319
Me
Me
Me
N(Me)
Ph
CH2C(Me)2
CHF2
(R)-


IV-320
Me
Et
Me
N(Me)
Ph
CH2C(Me)2
CHF2
racemic


IV-321
Me
Et
Me
N(Me)
Ph
CH2C(Me)2
CHF2
(R)-


IV-322
Me
Me
Me
NH
Ph
CH2C(Me)2
Et
racemic


IV-323
Me
Me
Me
NH
Ph
CH2C(Me)2
Et
(R)-


IV-324
Me
Et
Me
NH
Ph
CH2C(Me)2
Et
racemic


IV-325
Me
Et
Me
NH
Ph
CH2C(Me)2
Et
(R)-


IV-326
Me
Me
Me
N(Me)
Ph
CH2C(Me)2
Et
racemic


IV-327
Me
Me
Me
N(Me)
Ph
CH2C(Me)2
Et
(R)-


IV-328
Me
Et
Me
N(Me)
Ph
CH2C(Me)2
Et
racemic


IV-329
Me
Et
Me
N(Me)
Ph
CH2C(Me)2
Et
(R)-


IV-330
Me
Me
Me
NH
Ph
CH2C(Me)2
iPr
racemic


IV-331
Me
Me
Me
NH
Ph
CH2C(Me)2
iPr
(R)-


IV-332
Me
Et
Me
NH
Ph
CH2C(Me)2
iPr
racemic


IV-333
Me
Et
Me
NH
Ph
CH2C(Me)2
iPr
(R)-


IV-334
Me
Me
Me
N(Me)
Ph
CH2C(Me)2
iPr
racemic


IV-335
Me
Me
Me
N(Me)
Ph
CH2C(Me)2
iPr
(R)-


IV-336
Me
Et
Me
N(Me)
Ph
CH2C(Me)2
iPr
racemic


IV-337
Me
Et
Me
N(Me)
Ph
CH2C(Me)2
iPr
(R)-


IV-338
Me
Me
Me
NH
Ph
CH2C(Me)2
cPr
racemic


IV-339
Me
Me
Me
NH
Ph
CH2C(Me)2
cPr
(R)-


IV-340
Me
Et
Me
NH
Ph
CH2C(Me)2
cPr
racemic


IV-341
Me
Et
Me
NH
Ph
CH2C(Me)2
cPr
(R)-


IV-342
Me
Me
Me
N(Me)
Ph
CH2C(Me)2
cPr
racemic


IV-343
Me
Me
Me
N(Me)
Ph
CH2C(Me)2
cPr
(R)-


IV-344
Me
Et
Me
N(Me)
Ph
CH2C(Me)2
cPr
racemic


IV-345
Me
Et
Me
N(Me)
Ph
CH2C(Me)2
cPr
(R)-


IV-346
Me
Me
Me
NH
Ph
CH2C(Me)2
Ph
racemic


IV-347
Me
Me
Me
NH
Ph
CH2C(Me)2
Ph
(R)-


IV-348
Me
Et
Me
NH
Ph
CH2C(Me)2
Ph
racemic


IV-349
Me
Et
Me
NH
Ph
CH2C(Me)2
Ph
(R)-


IV-350
Me
Me
Me
N(Me)
Ph
CH2C(Me)2
Ph
racemic
















TABLE 71







(IV)




embedded image




















Com-







Con-


pound







figu-


No.
R1
R2
R3
L2
R4
L3
R5
ration





IV-351
Me
Me
Me
N(Me)
Ph
CH2C(Me)2
Ph
(R)-


IV-352
Me
Et
Me
N(Me)
Ph
CH2C(Me)2
Ph
racemic


IV-353
Me
Et
Me
N(Me)
Ph
CH2C(Me)2
Ph
(R)-


IV-354
Me
Me
Me
NH
Ph
C(Me)2CH2
H
racemic


IV-355
Me
Me
Me
NH
Ph
C(Me)2CH2
H
(S)-


IV-356
Me
Et
Me
NH
Ph
C(Me)2CH2
H
racemic


IV-357
Me
Et
Me
NH
Ph
C(Me)2CH2
H
(S)-


IV-358
Me
Me
Me
N(Me)
Ph
C(Me)2CH2
H
racemic


IV-359
Me
Me
Me
N(Me)
Ph
C(Me)2CH2
H
(S)-


IV-360
Me
Et
Me
N(Me)
Ph
C(Me)2CH2
H
racemic


IV-361
Me
Et
Me
N(Me)
Ph
C(Me)2CH2
H
(S)-


IV-362
Me
Me
Me
NH
Ph
CF2CH2
H
racemic


IV-363
Me
Me
Me
NH
Ph
CF2CH2
H
(S)-


IV-364
Me
Et
Me
NH
Ph
CF2CH2
H
racemic


IV-365
Me
Et
Me
NH
Ph
CF2CH2
H
(S)-


IV-366
Me
Me
Me
N(Me)
Ph
CF2CH2
H
racemic


IV-367
Me
Me
Me
N(Me)
Ph
CF2CH2
H
(S)-


IV-368
Me
Et
Me
N(Me)
Ph
CF2CH2
H
racemic


IV-369
Me
Et
Me
N(Me)
Ph
CF2CH2
H
(S)-


IV-370
Me
Me
Me
NH
Ph
CH═CHCH2
H
racemic


IV-371
Me
Me
Me
NH
Ph
CH═CHCH2
H
(S)-


IV-372
Me
Et
Me
NH
Ph
CH═CHCH2
H
racemic


IV-373
Me
Et
Me
NH
Ph
CH═CHCH2
H
(S)-


IV-374
Me
Me
Me
N(Me)
Ph
CH═CHCH2
H
racemic


IV-375
Me
Me
Me
N(Me)
Ph
CH═CHCH2
H
(S)-


IV-376
Me
Et
Me
N(Me)
Ph
CH═CHCH2
H
racemic


IV-377
Me
Et
Me
N(Me)
Ph
CH═CHCH2
H
(S)-


IV-378
Me
Me
Me
NH
Ph
C≡CCH2
H
racemic


IV-379
Me
Me
Me
NH
Ph
C≡CCH2
H
(S)-


IV-380
Me
Et
Me
NH
Ph
C≡CCH2
H
racemic


IV-381
Me
Et
Me
NH
Ph
C≡CCH2
H
(S)-


IV-382
Me
Me
Me
N(Me)
Ph
C≡CCH2
H
racemic


IV-383
Me
Me
Me
N(Me)
Ph
C≡CCH2
H
(S)-


IV-384
Me
Et
Me
N(Me)
Ph
C≡CCH2
H
racemic


IV-385
Me
Et
Me
N(Me)
Ph
C≡CCH2
H
(S)-


IV-386
Me
Me
Me
NH
Ph
1,1-Cyclopropylene
H
racemic


IV-387
Me
Me
Me
NH
Ph
1,1-Cyclopropylene
H
(S)-


IV-388
Me
Et
Me
NH
Ph
1,1-Cyclopropylene
H
racemic


IV-389
Me
Et
Me
NH
Ph
1,1-Cyclopropylene
H
(S)-


IV-390
Me
Me
Me
N(Me)
Ph
1,1-Cyclopropylene
H
racemic


IV-391
Me
Me
Me
N(Me)
Ph
1,1-Cyclopropylene
H
(S)-


IV-392
Me
Et
Me
N(Me)
Ph
1,1-Cyclopropylene
H
racemic


IV-393
Me
Et
Me
N(Me)
Ph
1,1-Cyclopropylene
H
(S)-


IV-394
Me
Me
Me
NH
Ph
1,2-Cyclo-
H
racemic








propynylene




IV-395
Me
Me
Me
NH
Ph
1,2-Cyclo-
H
(S)-








propynylene




IV-396
Me
Et
Me
NH
Ph
1,2-Cyclo-
H
racemic








propynylene




IV-397
Me
Et
Me
NH
Ph
1,2-Cyclo-
H
(S)-








propynylene




IV-398
Me
Me
Me
N(Me)
Ph
1,2-Cyclo-
H
racemic








propynylene




IV-399
Me
Me
Me
N(Me)
Ph
1,2-Cyclo-
H
(S)-








propynylene




IV-400
Me
Et
Me
N(Me)
Ph
1,2-Cyclo-
H
racemic








propynylene
















TABLE 72







(IV)




embedded image




















Compound







Con-


No.
R1
R2
R3
L2
R4
L3
R5
figuration





IV-401
Me
Et
Me
N(Me)
Ph
1,2-Cyclo-
H
(S)-








propynylene




IV-402
Me
Me
Me
NH
Ph
C(═O)
H
racemic


IV-403
Me
Me
Me
NH
Ph
C(═O)
H
(S)-


IV-404
Me
Et
Me
NH
Ph
C(═O)
H
racemic


IV-405
Me
Et
Me
NH
Ph
C(═O)
H
(S)-


IV-406
Me
Me
Me
N(Me)
Ph
C(═O)
H
racemic


IV-407
Me
Me
Me
N(Me)
Ph
C(═O)
H
(S)-


IV-408
Me
Et
Me
N(Me)
Ph
C(═O)
H
racemic


IV-409
Me
Et
Me
N(Me)
Ph
C(═O)
H
(S)-


IV-410
Me
Me
Me
NH
Ph
C(═O)
Bn
racemic


IV-411
Me
Me
Me
NH
Ph
C(═O)
Bn
(S)-


IV-412
Me
Et
Me
NH
Ph
C(═O)
Bn
racemic


IV-413
Me
Et
Me
NH
Ph
C(═O)
Bn
(S)-


IV-414
Me
Me
Me
N(Me)
Ph
C(═O)
Bn
racemic


IV-415
Me
Me
Me
N(Me)
Ph
C(═O)
Bn
(S)-


IV-416
Me
Et
Me
N(Me)
Ph
C(═O)
Bn
racemic


IV-417
Me
Et
Me
N(Me)
Ph
C(═O)
Bn
(S)-


IV-418
Me
Me
Me
NH
Ph
C(═O)
Me
racemic


IV-419
Me
Me
Me
NH
Ph
C(═O)
Me
(S)-


IV-420
Me
Et
Me
NH
Ph
C(═O)
Me
racemic


IV-421
Me
Et
Me
NH
Ph
C(═O)
Me
(S)-


IV-422
Me
Me
Me
N(Me)
Ph
C(═O)
Me
racemic


IV-423
Me
Me
Me
N(Me)
Ph
C(═O)
Me
(S)-


IV-424
Me
Et
Me
N(Me)
Ph
C(═O)
Me
racemic


IV-425
Me
Et
Me
N(Me)
Ph
C(═O)
Me
(S)-


IV-426
Me
Me
Me
NH
Ph
CH(Me)
H
racemic


IV-427
Me
Me
Me
NH
Ph
CH(Me)
H
(S)-


IV-428
Me
Et
Me
NH
Ph
CH(Me)
H
racemic


IV-429
Me
Et
Me
NH
Ph
CH(Me)
H
(S)-


IV-430
Me
Me
Me
NH
Ph
CH(iPr)
H
racemic


IV-431
Me
Me
Me
NH
Ph
CH(iPr)
H
(S)-


IV-432
Me
Et
Me
NH
Ph
CH(iPr)
H
racemic


IV-433
Me
Et
Me
NH
Ph
CH(iPr)
H
(S)-


IV-434
Me
Me
Me
NH
Ph
CH(Ph)
H
racemic


IV-435
Me
Me
Me
NH
Ph
CH(Ph)
H
(S)-


IV-436
Me
Et
Me
NH
Ph
CH(Ph)
H
racemic


IV-437
Me
Et
Me
NH
Ph
CH(Ph)
H
(S)-


IV-438
Me
Me
Me
NH
H
CH2
H



IV-439
Me
Et
Me
NH
H
CH2
H



IV-440
Me
Me
Me
N(Me)
H
CH2
H



IV-441
Me
Et
Me
N(Me)
H
CH2
H



IV-442
Me
Me
Me
NH
H
CH(Me)
H



IV-443
Me
Et
Me
NH
H
CH(Me)
H



IV-444
Me
Me
Me
N(Me)
H
CH(Me)
H



IV-445
Me
Et
Me
N(Me)
H
CH(Me)
H



IV-446
Me
Me
Me
NH
H
CH(iPr)
H



IV-447
Me
Et
Me
NH
H
CH(iPr)
H



IV-448
Me
Me
Me
N(Me)
H
CH(iPr)
H



IV-449
Me
Et
Me
N(Me)
H
CH(iPr)
H



IV-450
Me
Me
Me
NH
H
CH(Ph)
H
















TABLE 73







(IV)




embedded image




















Compound










No.
R1
R2
R3
L2
R4
L3
R5
Configuration





IV-451
Me
Et
Me
NH
H
CH(Ph)
H



IV-452
Me
Me
Me
N(Me)
H
CH(Ph)
H



IV-453
Me
Et
Me
N(Me)
H
CH(Ph)
H



IV-454
Me
Me
Me
NH
Me
CH2
H
racemic


IV-455
Me
Me
Me
NH
Me
CH2
H
(S)-


IV-456
Me
Et
Me
NH
Me
CH2
H
racemic


IV-457
Me
Et
Me
NH
Me
CH2
H
(S)-


IV-458
Me
Me
Me
NH
Me
CH(Me)
H
racemic


IV-459
Me
Me
Me
NH
Me
CH(Me)
H
(S)-


IV-460
Me
Et
Me
NH
Me
CH(Me)
H
racemic


IV-461
Me
Et
Me
NH
Me
CH(Me)
H
(S)-


IV-462
Me
Me
Me
NH
Me
CH(iPr)
H
racemic


IV-463
Me
Me
Me
NH
Me
CH(iPr)
H
(S)-


IV-464
Me
Et
Me
NH
Me
CH(iPr)
H
racemic


IV-465
Me
Et
Me
NH
Me
CH(iPr)
H
(S)-


IV-466
Me
Me
Me
NH
Me
CH(Ph)
H
racemic


IV-467
Me
Me
Me
NH
Me
CH(Ph)
H
(S)-


IV-468
Me
Et
Me
NH
Me
CH(Ph)
H
racemic


IV-469
Me
Et
Me
NH
Me
CH(Ph)
H
(S)-


IV-470
Me
Me
Me
N(Me)
Me
CH2
H
racemic


IV-471
Me
Me
Me
N(Me)
Me
CH2
H
(S)-


IV-472
Me
Et
Me
N(Me)
Me
CH2
H
racemic


IV-473
Me
Et
Me
N(Me)
Me
CH2
H
(S)-


IV-474
Me
Me
Me
NH
iPr
CH2
H
racemic


IV-475
Me
Me
Me
NH
iPr
CH2
H
(S)-


IV-476
Me
Et
Me
NH
iPr
CH2
H
racemic


IV-477
Me
Et
Me
NH
iPr
CH2
H
(S)-


IV-478
Me
Me
Me
NH
iPr
CH(Me)
H
racemic


IV-479
Me
Me
Me
NH
iPr
CH(Me)
H
(S)-


IV-480
Me
Et
Me
NH
iPr
CH(Me)
H
racemic


IV-481
Me
Et
Me
NH
iPr
CH(Me)
H
(S)-


IV-482
Me
Me
Me
NH
iPr
CH(iPr)
H
racemic


IV-483
Me
Me
Me
NH
iPr
CH(iPr)
H
(S)-


IV-484
Me
Et
Me
NH
iPr
CH(iPr)
H
racemic


IV-485
Me
Et
Me
NH
iPr
CH(iPr)
H
(S)-


IV-486
Me
Me
Me
NH
iPr
CH(Ph)
H
racemic


IV-487
Me
Me
Me
NH
iPr
CH(Ph)
H
(S)-


IV-488
Me
Et
Me
NH
iPr
CH(Ph)
H
racemic


IV-489
Me
Et
Me
NH
iPr
CH(Ph)
H
(S)-


IV-490
Me
Me
Me
N(Me)
iPr
CH2
H
racemic


IV-491
Me
Me
Me
N(Me)
iPr
CH2
H
(S)-


IV-492
Me
Et
Me
N(Me)
iPr
CH2
H
racemic


IV-493
Me
Et
Me
N(Me)
iPr
CH2
H
(S)-


IV-494
Me
Me
Me
NH
cHex
CH2
H
racemic


IV-495
Me
Me
Me
NH
cHex
CH2
H
(S)-


IV-496
Me
Et
Me
NH
cHex
CH2
H
racemic


IV-497
Me
Et
Me
NH
cHex
CH2
H
(S)-


IV-498
Me
Me
Me
N(Me)
cHex
CH2
H
racemic


IV-499
Me
Me
Me
N(Me)
cHex
CH2
H
(S)-


IV-500
Me
Et
Me
N(Me)
cHex
CH2
H
racemic
















TABLE 74







(IV)




embedded image




















Com-










pound







Con-


No.
R1
R2
R3
L2
R4
L3
R5
figuration





IV-501
Me
Et
Me
N(Me)
cHex
CH2
H
(S)-


IV-502
Me
Me
Me
NH
1,3-Benzo-
CH2
H
racemic







dioxol-4-yl





IV-503
Me
Me
Me
NH
1,3-Benzo-
CH2
H
(S)-







dioxol-4-yl





IV-504
Me
Et
Me
NH
1,3-Benzo-
CH2
H
racemic







dioxol-4-yl





IV-505
Me
Et
Me
NH
1,3-Benzo-
CH2
H
(S)-







dioxol-4-yl





IV-506
Me
Me
Me
N(Me)
1,3-Benzo-
CH2
H
racemic







dioxol-4-yl





IV-507
Me
Me
Me
N(Me)
1,3-Benzo-
CH2
H
(S)-







dioxol-4-yl





IV-508
Me
Et
Me
N(Me)
1,3-Benzo-
CH2
H
racemic







dioxol-4-yl





IV-509
Me
Et
Me
N(Me)
1,3-Benzo-
CH2
H
(S)-







dioxol-4-yl





IV-510
Me
Me
Me
NH
2-F—Ph
CH2
H
racemic


IV-511
Me
Me
Me
NH
2-F—Ph
CH2
H
(S)-


IV-512
Me
Et
Me
NH
2-F—Ph
CH2
H
racemic


IV-513
Me
Et
Me
NH
2-F—Ph
CH2
H
(S)-


IV-514
Me
Me
Me
N(Me)
2-F—Ph
CH2
H
racemic


IV-515
Me
Me
Me
N(Me)
2-F—Ph
CH2
H
(S)-


IV-516
Me
Et
Me
N(Me)
2-F—Ph
CH2
H
racemic


IV-517
Me
Et
Me
N(Me)
2-F—Ph
CH2
H
(S)-


IV-518
Me
Me
Me
NH
3-F—Ph
CH2
H
racemic


IV-519
Me
Me
Me
NH
3-F—Ph
CH2
H
(S)-


IV-520
Me
Et
Me
NH
3-F—Ph
CH2
H
racemic


IV-521
Me
Et
Me
NH
3-F—Ph
CH2
H
(S)-


IV-522
Me
Me
Me
N(Me)
3-F—Ph
CH2
H
racemic


IV-523
Me
Me
Me
N(Me)
3-F—Ph
CH2
H
(S)-


IV-524
Me
Et
Me
N(Me)
3-F—Ph
CH2
H
racemic


IV-525
Me
Et
Me
N(Me)
3-F—Ph
CH2
H
(S)-


IV-526
Me
Me
Me
NH
4-F—Ph
CH2
H
racemic


IV-527
Me
Me
Me
NH
4-F—Ph
CH2
H
(S)-


IV-528
Me
Et
Me
NH
4-F—Ph
CH2
H
racemic


IV-529
Me
Et
Me
NH
4-F—Ph
CH2
H
(S)-


IV-530
Me
Me
Me
N(Me)
4-F—Ph
CH2
H
racemic


IV-531
Me
Me
Me
N(Me)
4-F—Ph
CH2
H
(S)-


IV-532
Me
Et
Me
N(Me)
4-F—Ph
CH2
H
racemic


IV-533
Me
Et
Me
N(Me)
4-F—Ph
CH2
H
(S)-


IV-534
Me
Me
Me
NH
2-Py
CH2
H
racemic


IV-535
Me
Me
Me
NH
2-Py
CH2
H
(S)-


IV-536
Me
Et
Me
NH
2-Py
CH2
H
racemic


IV-537
Me
Et
Me
NH
2-Py
CH2
H
(S)-


IV-538
Me
Me
Me
N(Me)
2-Py
CH2
H
racemic


IV-539
Me
Me
Me
N(Me)
2-Py
CH2
H
(S)-


IV-540
Me
Et
Me
N(Me)
2-Py
CH2
H
racemic


IV-541
Me
Et
Me
N(Me)
2-Py
CH2
H
(S)-


IV-542
Me
Me
Me
NH
3-Py
CH2
H
racemic


IV-543
Me
Me
Me
NH
3-Py
CH2
H
(S)-


IV-544
Me
Et
Me
NH
3-Py
CH2
H
racemic


IV-545
Me
Et
Me
NH
3-Py
CH2
H
(S)-


IV-546
Me
Me
Me
N(Me)
3-Py
CH2
H
racemic


IV-547
Me
Me
Me
N(Me)
3-Py
CH2
H
(S)-


IV-548
Me
Et
Me
N(Me)
3-Py
CH2
H
racemic


IV-549
Me
Et
Me
N(Me)
3-Py
CH2
H
(S)-


IV-550
Me
Me
Me
NH
4-Py
CH2
H
racemic

















TABLE 75








(IV)




embedded image





















Com-







Con-


pound







figura-


No.
R1
R2
R3
L2
R4
L3
R5
tion





IV-551
Me
Me
Me
NH
4-Py
CH2
H
(S)-


IV-552
Me
Et
Me
NH
4-Py
CH2
H
racemic


IV-553
Me
Et
Me
NH
4-Py
CH2
H
(S)-


IV-554
Me
Me
Me
N(Me)
4-Py
CH2
H
racemic


IV-555
Me
Me
Me
N(Me)
4-Py
CH2
H
(S)-


IV-556
Me
Et
Me
N(Me)
4-Py
CH2
H
racemic


IV-557
Me
Et
Me
N(Me)
4-Py
CH2
H
(S)-


IV-558
Me
Me
Me
CH2
Ph
CH2
H
racemic


IV-559
Me
Me
Me
CH2
Ph
CH2
H
(S)-


IV-560
Me
Et
Me
CH2
Ph
CH2
H
racemic


IV-561
Me
Et
Me
CH2
Ph
CH2
H
(S)-


IV-562
Me
Me
Me
CH2
Ph
—
H
racemic


IV-563
Me
Me
Me
CH2
Ph
—
H
(S)-


IV-564
Me
Et
Me
CH2
Ph
—
H
racemic


IV-565
Me
Et
Me
CH2
Ph
—
H
(S)-


IV-566
Me
Me
Me
CH2
Ph
CH2
Me
racemic


IV-567
Me
Me
Me
CH2
Ph
CH2
Me
(S)-


IV-568
Me
Et
Me
CH2
Ph
CH2
Me
racemic


IV-569
Me
Et
Me
CH2
Ph
CH2
Me
(S)-


IV-570
Me
Me
Me
CH2
Ph
CH2
CHF2
racemic


IV-571
Me
Me
Me
CH2
Ph
CH2
CHF2
(S)-


IV-572
Me
Me
Me
CH2
Ph
CH2
Et
racemic


IV-573
Me
Me
Me
CH2
Ph
CH2
Et
(S)-


IV-574
Me
Et
Me
CH2
Ph
CH2
Et
racemic


IV-575
Me
Et
Me
CH2
Ph
CH2
Et
(S)-


IV-576
Me
Me
Me
CH2
Ph
CH2
cPr
racemic


IV-577
Me
Me
Me
CH2
Ph
CH2
cPr
(S)-


IV-578
Me
Et
Me
CH2
Ph
CH2
cPr
racemic


IV-579
Me
Et
Me
CH2
Ph
CH2
cPr
(S)-


IV-580
Me
Me
Me
CH2
Ph
CH2
Ph
racemic


IV-581
Me
Me
Me
CH2
Ph
CH2
Ph
(S)-


IV-582
Me
Et
Me
CH2
Ph
CH2
Ph
racemic


IV-583
Me
Et
Me
CH2
Ph
CH2
Ph
(S)-


IV-584
Me
Me
Me
CH2
Ph
C(Me)2
H
racemic


IV-585
Me
Me
Me
CH2
Ph
C(Me)2
H
(S)-


IV-586
Me
Et
Me
CH2
Ph
C(Me)2
H
racemic


IV-587
Me
Et
Me
CH2
Ph
C(Me)2
H
(S)-


IV-588
Me
Me
Me
CH2
Ph
C(Me)2
Me
racemic


IV-589
Me
Me
Me
CH2
Ph
C(Me)2
Me
(S)-


IV-590
Me
Et
Me
CH2
Ph
C(Me)2
Me
racemic


IV-591
Me
Et
Me
CH2
Ph
C(Me)2
Me
(S)-


IV-592
Me
Me
Me
CH2
Ph
C(Me)2
CHF2
racemic


IV-593
Me
Me
Me
CH2
Ph
C(Me)2
CHF2
(S)-


IV-594
Me
Me
Me
CH2
Ph
C(Me)2
Et
racemic


IV-595
Me
Me
Me
CH2
Ph
C(Me)2
Et
(S)-


IV-596
Me
Me
Me
CH2
Ph
C(Me)2
cPr
racemic


IV-597
Me
Me
Me
CH2
Ph
C(Me)2
cPr
(S)-


IV-598
Me
Me
Me
CH2
Ph
C(Me)2
Ph
racemic


IV-599
Me
Me
Me
CH2
Ph
C(Me)2
Ph
(S)-


IV-600
Me
Me
Me
CH2
Ph
(CH2)2
H
racemic

















TABLE 76








(IV)




embedded image





















Com-







Con-


pound







figura-


No.
R1
R2
R3
L2
R4
L3
R5
tion





IV-601
Me
Me
Me
CH2
Ph
(CH2)2
H
(S)-


IV-602
Me
Et
Me
CH2
Ph
(CH2)2
H
racemic


IV-603
Me
Et
Me
CH2
Ph
(CH2)2
H
(S)-


IV-604
Me
Me
Me
CH2
Ph
(CH2)2
Me
racemic


IV-605
Me
Me
Me
CH2
Ph
(CH2)2
Me
(S)-


IV-606
Me
Et
Me
CH2
Ph
(CH2)2
Me
racemic


IV-607
Me
Et
Me
CH2
Ph
(CH2)2
Me
(S)-


IV-608
Me
Me
Me
CH2
Ph
(CH2)2
CHF2
racemic


IV-609
Me
Me
Me
CH2
Ph
(CH2)2
CHF2
(S)-


IV-610
Me
Me
Me
CH2
Ph
(CH2)2
Et
racemic


IV-611
Me
Me
Me
CH2
Ph
(CH2)2
Et
(S)-


IV-612
Me
Me
Me
CH2
Ph
(CH2)2
cPr
racemic


IV-613
Me
Me
Me
CH2
Ph
(CH2)2
cPr
(S)-


IV-614
Me
Me
Me
CH2
Ph
(CH2)2
Ph
racemic


IV-615
Me
Me
Me
CH2
Ph
(CH2)2
Ph
(S)-


IV-616
Me
Me
Me
CH2
Ph
CH2C(Me)2
H
racemic


IV-617
Me
Me
Me
CH2
Ph
CH2C(Me)2
H
(S)-


IV-618
Me
Et
Me
CH2
Ph
CH2C(Me)2
H
racemic


IV-619
Me
Et
Me
CH2
Ph
CH2C(Me)2
H
(S)-


IV-620
Me
Me
Me
CH2
Ph
CH2C(Me)2
Me
racemic


IV-621
Me
Me
Me
CH2
Ph
CH2C(Me)2
Me
(S)-


IV-622
Me
Et
Me
CH2
Ph
CH2C(Me)2
Me
racemic


IV-623
Me
Et
Me
CH2
Ph
CH2C(Me)2
Me
(S)-


IV-624
Me
Me
Me
CH2
Ph
CH2C(Me)2
CHF2
racemic


IV-625
Me
Me
Me
CH2
Ph
CH2C(Me)2
CHF2
(S)-


IV-626
Me
Me
Me
CH2
Ph
CH2C(Me)2
Et
racemic


IV-627
Me
Me
Me
CH2
Ph
CH2C(Me)2
Et
(S)-


IV-628
Me
Me
Me
CH2
Ph
CH2C(Me)2
cPr
racemic


IV-629
Me
Me
Me
CH2
Ph
CH2C(Me)2
cPr
(S)-


IV-630
Me
Me
Me
CH2
Ph
CH2C(Me)2
Ph
racemic


IV-631
Me
Me
Me
CH2
Ph
CH2C(Me)2
Ph
(S)-


IV-632
Me
Me
Me
—
Ph
CH2
H
racemic


IV-633
Me
Me
Me
—
Ph
CH2
H
(S)-


IV-634
Me
Me
Me
—
Ph
CH2
Me
racemic


IV-635
Me
Me
Me
—
Ph
CH2
Me
(S)-


IV-636
Me
Me
Me
CH═CH
Ph
CH2
H
racemic


IV-637
Me
Me
Me
CH═CH
Ph
CH2
H
(S)-


IV-638
Me
Me
Me
CH═CH
Ph
CH2
Me
racemic


IV-639
Me
Me
Me
CH═CH
Ph
CH2
Me
(S)-


IV-640
Me
Me
Me
C≡C
Ph
CH2
H
racemic


IV-641
Me
Me
Me
C≡C
Ph
CH2
H
(S)-


IV-642
Me
Me
Me
C≡C
Ph
CH2
Me
racemic


IV-643
Me
Me
Me
C≡C
Ph
CH2
Me
(S)-


IV-644
Me
Me
Me
1,2-Cyclo-
Ph
CH2
H
racemic






propylene






IV-645
Me
Me
Me
1,2-Cyclo-
Ph
CH2
H
(S)-






propylene






IV-646
Me
Me
Me
1,2-Cyclo-
Ph
CH2
Me
racemic






propylene






IV-647
Me
Me
Me
1,2-Cyclo-
Ph
CH2
Me
(S)-






propylene






IV-648
Me
Me
Me
1,2-Cyclo
Ph
CH2
H
racemic






propynylene






IV-649
Me
Me
Me
1,2-Cyclo-
Ph
CH2
H
(S)-






propynylene






IV-650
Me
Me
Me
1,2-Cyclo-
Ph
CH2
Me
racemic






propynylene






IV-651
Me
Me
Me
1,2-Cyclo-
Ph
CH2
Me
(S)-






propynylene

















TABLE 77








(IV)




embedded image





















Com-







Con-


pound







figura-


No.
R1
R2
R3
L2
R4
L3
R5
tion





IV-652
Me
Me
Me
O
Ph
C(Me)2CH2
H
racemic


IV-653
Me
Me
Me
O
Ph
C(Me)2CH2
H
(+)


IV-654
Me
Me
Me
O
Ph
C(Me)2CH2
H
(−)


IV-655
Me
Et
Me
O
Ph
C(Me)2CH2
H
racemic


IV-656
Me
Et
Me
O
Ph
C(Me)2CH2
H
(+)


IV-657
Me
Et
Me
O
Ph
C(Me)2CH2
H
(−)


IV-658
Me
Me
Me
O
Ph
C(Me)2CH2
Me
racemic


IV-659
Me
Me
Me
O
Ph
C(Me)2CH2
Me
(+)


IV-660
Me
Me
Me
O
Ph
C(Me)2CH2
Me
(−)


IV-661
Me
Et
Me
O
Ph
C(Me)2CH2
Me
racemic


IV-662
Me
Et
Me
O
Ph
C(Me)2CH2
Me
(+)


IV-663
Me
Et
Me
O
Ph
C(Me)2CH2
Me
(−)


IV-664
Me
Me
Me
O
Ph
C(Me)2CH2
CHF2
racemic


IV-665
Me
Me
Me
O
Ph
C(Me)2CH2
CHF2
(+)


IV-666
Me
Me
Me
O
Ph
C(Me)2CH2
CHF2
(−)


IV-667
Me
Me
Me
O
Ph
C(Me)2CH2
Et
racemic


IV-668
Me
Me
Me
O
Ph
C(Me)2CH2
Et
(+)


IV-669
Me
Me
Me
O
Ph
C(Me)2CH2
Et
(−)


IV-670
Me
Me
Me
O
H
CH(Ph)
H



IV-671
Me
Et
Me
O
H
CH(Ph)
H



IV-672
Me
Me
Me
NH
Ph
C(Me)2CH2
H
(+)


IV-673
Me
Me
Me
NH
Ph
C(Me)2CH2
H
(−)


IV-674
Me
Et
Me
NH
Ph
C(Me)2CH2
H
(+)


IV-675
Me
Et
Me
NH
Ph
C(Me)2CH2
H
(−)


IV-676
Me
Me
Me
NH
Ph
C(Me)2CH2
Me
racemic


IV-677
Me
Me
Me
NH
Ph
C(Me)2CH2
Me
(+)


IV-678
Me
Me
Me
NH
Ph
C(Me)2CH2
Me
(−)


IV-679
Me
Et
Me
NH
Ph
C(Me)2CH2
Me
racemic


IV-680
Me
Et
Me
NH
Ph
C(Me)2CH2
Me
(+)


IV-681
Me
Et
Me
NH
Ph
C(Me)2CH2
Me
(−)


IV-682
Me
Me
Me
NH
Ph
C(Me)2CH2
CHF2
racemic


IV-683
Me
Me
Me
NH
Ph
C(Me)2CH2
CHF2
(+)


IV-684
Me
Me
Me
NH
Ph
C(Me)2CH2
CHF2
(−)


IV-685
Me
Et
Me
NH
Ph
C(Me)2CH2
CHF2
racemic


IV-686
Me
Et
Me
NH
Ph
C(Me)2CH2
CHF2
(+)


IV-687
Me
Et
Me
NH
Ph
C(Me)2CH2
CHF2
(−)


IV-688
Me
Me
Me
NH
Ph
C(Me)2CH2
Et
racemic


IV-689
Me
Me
Me
NH
Ph
C(Me)2CH2
Et
(+)


IV-690
Me
Me
Me
NH
Ph
C(Me)2CH2
Et
(−)


IV-691
Me
Et
Me
NH
Ph
C(Me)2CH2
Et
racemic


IV-692
Me
Et
Me
NH
Ph
C(Me)2CH2
Et
(+)


IV-693
Me
Et
Me
NH
Ph
C(Me)2CH2
Et
(−)


IV-694
Me
Me
Me
NH
Ph
C(Me)2CH2
iPr
racemic


IV-695
Me
Me
Me
NH
Ph
C(Me)2CH2
iPr
(+)


IV-696
Me
Me
Me
NH
Ph
C(Me)2CH2
iPr
(−)


IV-697
Me
Et
Me
NH
Ph
C(Me)2CH2
iPr
racemic


IV-698
Me
Et
Me
NH
Ph
C(Me)2CH2
iPr
(+)


IV-699
Me
Et
Me
NH
Ph
C(Me)2CH2
iPr
(−)


IV-700
Me
Me
Me
NH
Ph
C(Me)2CH2
cPr
racemic


IV-701
Me
Me
Me
NH
Ph
C(Me)2CH2
cPr
(+)

















TABLE 78








(IV)




embedded image





















Com-







Con-


pound







figura-


No.
R1
R2
R3
L2
R4
L3
R5
tion





IV-702
Me
Me
Me
NH
Ph
C(Me)2CH2
cPr
(−)


IV-703
Me
Et
Me
NH
Ph
C(Me)2CH2
cPr
racemic


IV-704
Me
Et
Me
NH
Ph
C(Me)2CH2
cPr
(+)


IV-705
Me
Et
Me
NH
Ph
C(Me)2CH2
cPr
(−)


IV-706
Me
Me
Me
NH
Ph
1,1-Cyclo-
H
racemic








propylene-










CH2




IV-707
Me
Me
Me
NH
Ph
1,1-Cyclo-
H
(+)








propylene-










CH2




IV-708
Me
Me
Me
NH
Ph
1,1-Cyclo-
H
(+)








propylene-










CH2




IV-709
Me
Et
Me
NH
Ph
1,1-Cyclo-
H
racemic








propylene-










CH2




IV-710
Me
Et
Me
NH
Ph
1,1-Cyclo-
H
(+)








propylene-










CH2




IV-711
Me
Et
Me
NH
Ph
1,1-Cyclo-
H
(−)








propylene-










CH2




IV-712
Me
Me
Me
NH
Ph
1,1-Cyclo-
Me
racemic








propylene-










CH2




IV-713
Me
Me
Me
NH
Ph
1,1-Cyclo-
Me
(+)








propylene-










CH2




IV-714
Me
Me
Me
NH
Ph
1,1-Cyclo-
Me
(−)








propylene-










CH2




IV-715
Me
Et
Me
NH
Ph
1,1-Cyclo-
Me
racemic








propylene-










CH2




IV-716
Me
Et
Me
NH
Ph
1,1-Cyclo-
Me
(+)








propylene-










CH2




IV-717
Me
Et
Me
NH
Ph
1,1-Cyclo-
Me
(−)








propylene-










CH2




IV-718
Me
Me
Me
NH
Ph
1,1-Cyclo-
H
racemic








butylene-










CH2




IV-719
Me
Me
Me
NH
Ph
1,1-Cyclo-
H
(+)








butylene-










CH2




IV-720
Me
Me
Me
NH
Ph
1,1-Cyclo-
H
(−)








butylene-










CH2




IV-721
Me
Et
Me
NH
Ph
1,1-Cyclo-
H
racemic








butylene-










CH2




IV-722
Me
Et
Me
NH
Ph
1,1-Cyclo-
H
(+)








butylene-










CH2




IV-723
Me
Et
Me
NH
Ph
1,1-Cyclo-
H
(−)








butylene-










CH2




IV-724
Me
Me
Me
NH
Ph
1,1-Cyclo-
Me
racemic








butylene-










CH2




IV-725
Me
Me
Me
NH
Ph
1,1-Cyclo-
Me
(+)








butylene-










CH2




IV-726
Me
Me
Me
NH
Ph
1,1-Cyclo-
Me
(−)








butylene-










CH2




IV-727
Me
Et
Me
NH
Ph
1,1-Cyclo-
Me
racemic








butylene-










CH2




IV-728
Me
Et
Me
NH
Ph
1,1-Cyclo-
Me
(+)








butylene-










CH2




IV-729
Me
Et
Me
NH
Ph
1,1-Cyclo-
Me
(−)








butylene-










CH2




IV-730
Me
Me
Me
NH
Ph
C(Et)2CH2
H
racemic


IV-731
Me
Me
Me
NH
Ph
C(Et)2CH2
H
(+)


IV-732
Me
Me
Me
NH
Ph
C(Et)2CH2
H
(−)


IV-733
Me
Et
Me
NH
Ph
C(Et)2CH2
H
racemic


IV-734
Me
Et
Me
NH
Ph
C(Et)2CH2
H
(+)


IV-735
Me
Et
Me
NH
Ph
C(Et)2CH2
H
(−)


IV-736
Me
Me
Me
NH
Ph
C(Et)2CH2
Me
racemic


IV-737
Me
Me
Me
NH
Ph
C(Et)2CH2
Me
(+)


IV-738
Me
Me
Me
NH
Ph
C(Et)2CH2
Me
(−)


IV-739
Me
Et
Me
NH
Ph
C(Et)2CH2
Me
racemic


IV-740
Me
Et
Me
NH
Ph
C(Et)2CH2
Me
(+)


IV-741
Me
Et
Me
NH
Ph
C(Et)2CH2
Me
(−)


IV-742
Me
Me
Me
NH
Ph
CH2-1,1-
H
racemic








Cyclo-










propylene




IV-743
Me
Me
Me
NH
Ph
CH2-1,1-
H
(R)-








Cyclo-










propylene




IV-744
Me
Et
Me
NH
Ph
CH2-1,1-
H
racemic








Cyclo-










propylene




IV-745
Me
Et
Me
NH
Ph
CH2-1,1-
H
(R)-








Cyclo-










propylene




IV-746
Me
Me
Me
NH
Ph
CH2-1,1-
Me
racemic








Cyclo-










propylene




IV-747
Me
Me
Me
NH
Ph
CH2-1,1-
Me
(R)-








Cyclo-










propylene




IV-748
Me
Et
Me
NH
Ph
CH2-1,1-
Me
racemic








Cyclo-










propylene




IV-749
Me
Et
Me
NH
Ph
CH2-1,1-
Me
(R)-








Cyclo-










propylene




IV-750
Me
Me
Me
NH
Ph
CH2-1,1-
H
racemic








cyclo-










butylene




IV-751
Me
Me
Me
NH
Ph
CH2-1,1-
H
(R)-








cyclo-










butylene

















TABLE 79








(IV)




embedded image





















Com-







Con-


pound







figura-


No.
R1
R2
R3
L2
R4
L3
R5
tion





IV-752
Me
Et
Me
NH
Ph
CH2-1,1-
H
racemic








cyclo-










butylene




IV-753
Me
Et
Me
NH
Ph
CH2-1,1-
H
(R)-








cyclo-










butylene




IV-754
Me
Me
Me
NH
Ph
CH2-1,1-
Me
racemic








cyclo-










butylene




IV-755
Me
Me
Me
NH
Ph
CH2-1,1-
Me
(R)-








cyclo-










butylene




IV-756
Me
Et
Me
NH
Ph
CH2-1,1-
Me
racemic








cyclo-










butylene




IV-757
Me
Et
Me
NH
Ph
CH2-1,1-
Me
(R)-








cyclo-










butylene




IV-758
Me
Me
Me
NH
Ph
CH2C(Et)2
H
racemic


IV-759
Me
Me
Me
NH
Ph
CH2C(Et)2
H
(R)-


IV-760
Me
Et
Me
NH
Ph
CH2C(Et)2
H
racemic


IV-761
Me
Et
Me
NH
Ph
CH2C(Et)2
H
(R)-


IV-762
Me
Me
Me
NH
Ph
CH2C(Et)2
Me
racemic


IV-763
Me
Me
Me
NH
Ph
CH2C(Et)2
Me
(R)-


IV-764
Me
Et
Me
NH
Ph
CH2C(Et)2
Me
racemic


IV-765
Me
Et
Me
NH
Ph
CH2C(Et)2
Me
(R)-


IV-766
Me
Me
Me
NH
Ph
(R)-CH(Me)
H
(S)-


IV-767
Me
Me
Me
NH
Ph
(S)-CH(Me)
H
(S)-


IV-768
Me
Et
Me
NH
Ph
(R)-CH(Me)
H
(S)-


IV-769
Me
Et
Me
NH
Ph
(S)-CH(Me)
H
(S)-


IV-770
Me
Me
Me
NH
Ph
(R)-CH(iPr)
H
(S)-


IV-771
Me
Me
Me
NH
Ph
(S)-CH(iPr)
H
(S)-


IV-772
Me
Et
Me
NH
Ph
(R)-CH(iPr)
H
(S)-


IV-773
Me
Et
Me
NH
Ph
(S)-CH(iPr)
H
(S)-


IV-774
Me
Me
Me
NH
Ph
(R)-CH(Ph)
H
(S)-


IV-775
Me
Me
Me
NH
Ph
(S)-CH(Ph)
H
(S)-


IV-776
Me
Et
Me
NH
Ph
(R)-CH(Ph)
H
(S)-


IV-777
Me
Et
Me
NH
Ph
(S)-CH(Ph)
H
(S)-


IV-778
Me
Me
Me
NH
H
(R)-CH(Me)
H



IV-779
Me
Me
Me
NH
H
(S)-CH(Me)
H



IV-780
Me
Et
Me
NH
H
(R)-CH(Me)
H



IV-781
Me
Et
Me
NH
H
(S)-CH(Me)
H



IV-782
Me
Me
Me
NH
H
(R)-CH(iPr)
H



IV-783
Me
Me
Me
NH
H
(S)-CH(iPr)
H



IV-784
Me
Et
Me
NH
H
(R)-CH(iPr)
H



IV-785
Me
Et
Me
NH
H
(S)-CH(iPr)
H



IV-786
Me
Me
Me
NH
H
(R)-CH(Ph)
H



IV-787
Me
Me
Me
NH
H
(S)-CH(Ph)
H



IV-788
Me
Et
Me
NH
H
(R)-CH(Ph)
H



IV-789
Me
Et
Me
NH
H
(S)-CH(Ph)
H



IV-790
Me
Me
Me
NH
Me
(R)-CH(Me)
H
(S)-


IV-791
Me
Me
Me
NH
Me
(S)-CH(Me)
H
(S)-


IV-792
Me
Et
Me
NH
Me
(R)-CH(Me)
H
(S)-


IV-793
Me
Et
Me
NH
Me
(S)-CH(Me)
H
(S)-


IV-794
Me
Me
Me
NH
Me
(R)-CH(iPr)
H
(S)-


IV-795
Me
Me
Me
NH
Me
(S)-CH(iPr)
H
(S)-


IV-796
Me
Et
Me
NH
Me
(R)-CH(iPr)
H
(S)-


IV-797
Me
Et
Me
NH
Me
(S)-CH(iPr)
H
(S)-


IV-798
Me
Me
Me
NH
Me
(R)-CH(Ph)
H
(S)-


IV-799
Me
Me
Me
NH
Me
(S)-CH(Ph)
H
(S)-


IV-800
Me
Et
Me
NH
Me
(R)-CH(Ph)
H
(S)-


IV-801
Me
Et
Me
NH
Me
(S)-CH(Ph)
H
(S)-

















TABLE 80








(IV)




embedded image


















Com-







Con-


pound







figura-


No.
R1
R2
R3
L2
R4
L3
R5
tion





IV-802
Me
Me
Me
NH
iPr
CH2
Me
racemic


IV-803
Me
Me
Me
NH
iPr
CH2
Me
(S)-


IV-804
Me
Et
Me
NH
iPr
CH2
Me
racemic


IV-805
Me
Et
Me
NH
iPr
CH2
Me
(S)-


IV-806
Me
Me
Me
NH
iPr
(CH2)2
H
racemic


IV-807
Me
Me
Me
NH
iPr
(CH2)2
H
(R)-


IV-808
Me
Et
Me
NH
iPr
(CH2)2
H
racemic


IV-809
Me
Et
Me
NH
iPr
(CH2)2
H
(R)-


IV-810
Me
Me
Me
NH
iPr
(CH2)2
Me
racemic


IV-811
Me
Me
Me
NH
iPr
(CH2)2
Me
(R)-


IV-812
Me
Et
Me
NH
iPr
(CH2)2
Me
racemic


IV-813
Me
Et
Me
NH
iPr
(CH2)2
Me
(R)-


IV-814
Me
Me
Me
NH
iPr
CH2C(Me)2
H
racemic


IV-815
Me
Me
Me
NH
iPr
CH2C(Me)2
H
(R)-


IV-816
Me
Et
Me
NH
iPr
CH2C(Me)2
H
racemic


IV-817
Me
Et
Me
NH
iPr
CH2C(Me)2
H
(R)-


IV-818
Me
Me
Me
NH
iPr
CH2C(Me)2
Me
racemic


IV-819
Me
Me
Me
NH
iPr
CH2C(Me)2
Me
(R)-


IV-820
Me
Et
Me
NH
iPr
CH2C(Me)2
Me
racemic


IV-821
Me
Et
Me
NH
iPr
CH2C(Me)2
Me
(R)-


IV-822
Me
Me
Me
NH
iPr
C(Me)2CH2
H
racemic


IV-823
Me
Me
Me
NH
iPr
C(Me)2CH2
H
(+)


IV-824
Me
Me
Me
NH
iPr
C(Me)2CH2
H
(−)


IV-825
Me
Et
Me
NH
iPr
C(Me)2CH2
H
racemic


IV-826
Me
Et
Me
NH
iPr
C(Me)2CH2
H
(+)


IV-827
Me
Et
Me
NH
iPr
C(Me)2CH2
H
(−)


IV-828
Me
Me
Me
NH
iPr
C(Me)2CH2
Me
racemic


IV-829
Me
Me
Me
NH
iPr
C(Me)2CH2
Me
(+)


IV-830
Me
Me
Me
NH
iPr
C(Me)2CH2
Me
(−)


IV-831
Me
Et
Me
NH
iPr
C(Me)2CH2
Me
racemic


IV-832
Me
Et
Me
NH
iPr
C(Me)2CH2
Me
(+)


IV-833
Me
Et
Me
NH
iPr
C(Me)2CH2
Me
(−)


IV-834
Me
Me
Me
NH
iPr
(R)-CH(Me)
H
(S)-


IV-835
Me
Me
Me
NH
iPr
(S)-CH(Me)
H
(S)-


IV-836
Me
Et
Me
NH
iPr
(R)-CH(Me)
H
(S)-


IV-837
Me
Et
Me
NH
iPr
(S)-CH(Me)
H
(S)-


IV-838
Me
Me
Me
NH
iPr
(R)-CH(iPr)
H
(S)-


IV-839
Me
Me
Me
NH
iPr
(S)-CH(iPr)
H
(S)-


IV-840
Me
Et
Me
NH
iPr
(R)-CH(iPr)
H
(S)-


IV-841
Me
Et
Me
NH
iPr
(S)-CH(iPr)
H
(S)-


IV-842
Me
Me
Me
NH
iPr
(R)-CH(Ph)
H
(S)-


IV-843
Me
Me
Me
NH
iPr
(S)-CH(Ph)
H
(S)-


IV-844
Me
Et
Me
NH
iPr
(R)-CH(Ph)
H
(S)-


IV-845
Me
Et
Me
NH
iPr
(S)-CH(Ph)
H
(S)-


IV-846
Me
Me
Me
NH
CF3
CH2
H
racemic


IV-847
Me
Me
Me
NH
CF3
CH2
H
(S)-


IV-848
Me
Et
Me
NH
CF3
CH2
H
racemic


IV-849
Me
Et
Me
NH
CF3
CH2
H
(S)-


IV-850
Me
Me
Me
N(Me)
CF3
CH2
H
racemic


IV-851
Me
Me
Me
N(Me)
CF3
CH2
H
(S)-

















TABLE 81








(IV)




embedded image





















Com-







Con-


pound







figura-


No.
R1
R2
R3
L2
R4
L3
R5
tion





IV-852
Me
Et
Me
N(Me)
CF3
CH2
H
racemic


IV-853
Me
Et
Me
N(Me)
CF3
CH2
H
(S)-


IV-854
Me
Me
Me
NH
CH2OH
CH2
H



IV-855
Me
Et
Me
NH
CH2OH
CH2
H



IV-856
Me
Me
Me
NH
CH2OMe
CH2
H
racemic


IV-857
Me
Me
Me
NH
CH2OMe
CH2
H
(R)-


IV-858
Me
Et
Me
NH
CH2OMe
CH2
H
racemic


IV-859
Me
Et
Me
NH
CH2OMe
CH2
H
(R)-


IV-860
Me
Me
Me
NH
CH2Ph
CH2
H
racemic


IV-861
Me
Me
Me
NH
CH2Ph
CH2
H
(R)-


IV-862
Me
Me
Me
NH
CH2Ph
CH2
H
(S)-


IV-863
Me
Et
Me
NH
CH2Ph
CH2
H
racemic


IV-864
Me
Et
Me
NH
CH2Ph
CH2
H
(S)-


IV-865
Me
Me
Me
N(Me)
CH2Ph
CH2
H
racemic


IV-866
Me
Me
Me
N(Me)
CH2Ph
CH2
H
(S)-


IV-867
Me
Et
Me
N(Me)
CH2Ph
CH2
H
racemic


IV-868
Me
Et
Me
N(Me)
CH2Ph
CH2
H
(S)-


IV-869
Me
Me
Me
NH
2-F—Ph
CH2
Me
racemic


IV-870
Me
Me
Me
NH
2-F—Ph
CH2
Me
(S)-


IV-871
Me
Et
Me
NH
2-F—Ph
CH2
Me
racemic


IV-872
Me
Et
Me
NH
2-F—Ph
CH2
Me
(S)-


IV-873
Me
Me
Me
NH
2-F—Ph
(CH2)2
H
racemic


IV-874
Me
Me
Me
NH
2-F—Ph
(CH2)2
H
(+)-


IV-875
Me
Me
Me
NH
2-F—Ph
(CH2)2
H
(−)-


IV-876
Me
Et
Me
NH
2-F—Ph
(CH2)2
H
racemic


IV-877
Me
Et
Me
NH
2-F—Ph
(CH2)2
H
(R)-


IV-878
Me
Me
Me
NH
2-F—Ph
(CH2)2
Me
racemic


IV-879
Me
Me
Me
NH
2-F—Ph
(CH2)2
Me
(R)-


IV-880
Me
Et
Me
NH
2-F—Ph
(CH2)2
Me
racemic


IV-881
Me
Et
Me
NH
2-F—Ph
(CH2)2
Me
(R)-


IV-882
Me
Me
Me
NH
2-F—Ph
CH2C(Me)2
H
racemic


IV-883
Me
Me
Me
NH
2-F—Ph
CH2C(Me)2
H
(R)-


IV-884
Me
Et
Me
NH
2-F—Ph
CH2C(Me)2
H
racemic


IV-885
Me
Et
Me
NH
2-F—Ph
CH2C(Me)2
H
(R)-


IV-886
Me
Me
Me
NH
2-F—Ph
CH2C(Me)2
Me
racemic


IV-887
Me
Me
Me
NH
2-F—Ph
CH2C(Me)2
Me
(R)-


IV-888
Me
Et
Me
NH
2-F—Ph
CH2C(Me)2
Me
racemic


IV-889
Me
Et
Me
NH
2-F—Ph
CH2C(Me)2
Me
(R)-


IV-890
Me
Me
Me
NH
2-F—Ph
C(Me)2CH2
H
racemic


IV-891
Me
Me
Me
NH
2-F—Ph
C(Me)2CH2
H
(+)


IV-892
Me
Me
Me
NH
2-F—Ph
C(Me)2CH2
H
(−)


IV-893
Me
Et
Me
NH
2-F—Ph
C(Me)2CH2
H
racemic


IV-894
Me
Et
Me
NH
2-F—Ph
C(Me)2CH2
H
(+)


IV-895
Me
Et
Me
NH
2-F—Ph
C(Me)2CH2
H
(−)


IV-896
Me
Me
Me
NH
2-F—Ph
C(Me)2CH2
Me
racemic


IV-897
Me
Me
Me
NH
2-F—Ph
C(Me)2CH2
Me
(+)


IV-898
Me
Me
Me
NH
2-F—Ph
C(Me)2CH2
Me
(−)


IV-899
Me
Et
Me
NH
2-F—Ph
C(Me)2CH2
Me
racemic


IV-900
Me
Et
Me
NH
2-F—Ph
C(Me)2CH2
Me
(+)


IV-901
Me
Et
Me
NH
2-F—Ph
C(Me)2CH2
Me
(−)

















TABLE 82








(IV)




embedded image





















Com-







Con-


pound







figura-


No.
R1
R2
R3
L2
R4
L3
R5
tion





IV-902
Me
Me
Me
NH
3-F—Ph
(CH2)2
H
racemic


IV-903
Me
Me
Me
NH
3-F—Ph
(CH2)2
H
(R)-


IV-904
Me
Et
Me
NH
3-F—Ph
(CH2)2
H
racemic


IV-905
Me
Et
Me
NH
3-F—Ph
(CH2)2
H
(R)-


IV-906
Me
Me
Me
NH
3-F—Ph
(CH2)2
Me
racemic


IV-907
Me
Me
Me
NH
3-F—Ph
(CH2)2
Me
(R)-


IV-908
Me
Et
Me
NH
3-F—Ph
(CH2)2
Me
racemic


IV-909
Me
Et
Me
NH
3-F—Ph
(CH2)2
Me
(R)-


IV-910
Me
Me
Me
NH
3-F—Ph
CH2C(Me)2
H
racemic


IV-911
Me
Me
Me
NH
3-F—Ph
CH2C(Me)2
H
(R)-


IV-912
Me
Et
Me
NH
3-F—Ph
CH2C(Me)2
H
racemic


IV-913
Me
Et
Me
NH
3-F—Ph
CH2C(Me)2
H
(R)-


IV-914
Me
Me
Me
NH
3-F—Ph
CH2C(Me)2
Me
racemic


IV-915
Me
Me
Me
NH
3-F—Ph
CH2C(Me)2
Me
(R)-


IV-916
Me
Et
Me
NH
3-F—Ph
CH2C(Me)2
Me
racemic


IV-917
Me
Et
Me
NH
3-F—Ph
CH2C(Me)2
Me
(R)-


IV-918
Me
Me
Me
NH
3-F—Ph
C(Me)2CH2
H
racemic


IV-919
Me
Me
Me
NH
3-F—Ph
C(Me)2CH2
H
(+)


IV-920
Me
Me
Me
NH
3-F—Ph
C(Me)2CH2
H
(−)


IV-921
Me
Et
Me
NH
3-F—Ph
C(Me)2CH2
H
racemic


IV-922
Me
Et
Me
NH
3-F—Ph
C(Me)2CH2
H
(+)


IV-923
Me
Et
Me
NH
3-F—Ph
C(Me)2CH2
H
(−)


IV-924
Me
Me
Me
NH
3-F—Ph
C(Me)2CH2
Me
racemic


IV-925
Me
Me
Me
NH
3-F—Ph
C(Me)2CH2
Me
(+)


IV-926
Me
Me
Me
NH
3-F—Ph
C(Me)2CH2
Me
(−)


IV-927
Me
Et
Me
NH
3-F—Ph
C(Me)2CH2
Me
racemic


IV-928
Me
Et
Me
NH
3-F—Ph
C(Me)2CH2
Me
(+)


IV-929
Me
Et
Me
NH
3-F—Ph
C(Me)2CH2
Me
(−)


IV-930
Me
Me
Me
NH
4-F—Ph
(CH2)2
H
racemic


IV-931
Me
Me
Me
NH
4-F—Ph
(CH2)2
H
(R)-


IV-932
Me
Et
Me
NH
4-F—Ph
(CH2)2
H
racemic


IV-933
Me
Et
Me
NH
4-F—Ph
(CH2)2
H
(R)-


IV-934
Me
Me
Me
NH
4-F—Ph
(CH2)2
Me
racemic


IV-935
Me
Me
Me
NH
4-F—Ph
(CH2)2
Me
(R)-


IV-936
Me
Et
Me
NH
4-F—Ph
(CH2)2
Me
racemic


IV-937
Me
Et
Me
NH
4-F—Ph
(CH2)2
Me
(R)-


IV-938
Me
Me
Me
NH
4-F—Ph
CH2C(Me)2
H
racemic


IV-939
Me
Me
Me
NH
4-F—Ph
CH2C(Me)2
H
(R)-


IV-940
Me
Et
Me
NH
4-F—Ph
CH2C(Me)2
H
racemic


IV-941
Me
Et
Me
NH
4-F—Ph
CH2C(Me)2
H
(R)-


IV-942
Me
Me
Me
NH
4-F—Ph
CH2C(Me)2
Me
racemic


IV-943
Me
Me
Me
NH
4-F—Ph
CH2C(Me)2
Me
(R)-


IV-944
Me
Et
Me
NH
4-F—Ph
CH2C(Me)2
Me
racemic


IV-945
Me
Et
Me
NH
4-F—Ph
CH2C(Me)2
Me
(R)-


IV-946
Me
Me
Me
NH
4-F—Ph
C(Me)2CH2
H
racemic


IV-947
Me
Me
Me
NH
4-F—Ph
C(Me)2CH2
H
(+)


IV-948
Me
Me
Me
NH
4-F—Ph
C(Me)2CH2
H
(−)


IV-949
Me
Et
Me
NH
4-F—Ph
C(Me)2CH2
H
racemic


IV-950
Me
Et
Me
NH
4-F—Ph
C(Me)2CH2
H
(+)


IV-951
Me
Et
Me
NH
4-F—Ph
C(Me)2CH2
H
(−)

















TABLE 83








(IV)




embedded image





















Com-







Con-


pound







figura-


No.
R1
R2
R3
L2
R4
L3
R5
tion





IV-952
Me
Me
Me
NH
4-F—Ph
C(Me)2CH2
Me
racemic


IV-953
Me
Me
Me
NH
4-F—Ph
C(Me)2CH2
Me
(+)


IV-954
Me
Me
Me
NH
4-F—Ph
C(Me)2CH2
Me
(−)


IV-955
Me
Et
Me
NH
4-F—Ph
C(Me)2CH2
Me
racemic


IV-956
Me
Et
Me
NH
4-F—Ph
C(Me)2CH2
Me
(+)


IV-957
Me
Et
Me
NH
4-F—Ph
C(Me)2CH2
Me
(−)


IV-958
Me
Me
Me
NH
2-Cl—Ph
CH2
H
racemic


IV-959
Me
Me
Me
NH
2-Cl—Ph
CH2
H
(S)-


IV-960
Me
Et
Me
NH
2-Cl—Ph
CH2
H
racemic


IV-961
Me
Et
Me
NH
2-Cl—Ph
CH2
H
(S)-


IV-962
Me
Me
Me
NH
2-Cl—Ph
CH2
Me
racemic


IV-963
Me
Me
Me
NH
2-Cl—Ph
CH2
Me
(S)-


IV-964
Me
Et
Me
NH
2-Cl—Ph
CH2
Me
racemic


IV-965
Me
Et
Me
NH
2-Cl—Ph
CH2
Me
(S)-


IV-966
Me
Me
Me
NH
2-Cl—Ph
(CH2)2
H
racemic


IV-967
Me
Me
Me
NH
2-Cl—Ph
(CH2)2
H
(R)-


IV-968
Me
Et
Me
NH
2-Cl—Ph
(CH2)2
H
racemic


IV-969
Me
Et
Me
NH
2-Cl—Ph
(CH2)2
H
(R)-


IV-970
Me
Me
Me
NH
2-Cl—Ph
(CH2)2
Me
racemic


IV-971
Me
Me
Me
NH
2-Cl—Ph
(CH2)2
Me
(R)-


IV-972
Me
Et
Me
NH
2-Cl—Ph
(CH2)2
Me
racemic


IV-973
Me
Et
Me
NH
2-Cl—Ph
(CH2)2
Me
(R)-


IV-974
Me
Me
Me
NH
2-Cl—Ph
CH2C(Me)2
H
racemic


IV-975
Me
Me
Me
NH
2-Cl—Ph
CH2C(Me)2
H
(R)-


IV-976
Me
Et
Me
NH
2-Cl—Ph
CH2C(Me)2
H
racemic


IV-977
Me
Et
Me
NH
2-Cl—Ph
CH2C(Me)2
H
(R)-


IV-978
Me
Me
Me
NH
2-Cl—Ph
CH2C(Me)2
Me
racemic


IV-979
Me
Me
Me
NH
2-Cl—Ph
CH2C(Me)2
Me
(R)-


IV-980
Me
Et
Me
NH
2-Cl—Ph
CH2C(Me)2
Me
racemic


IV-981
Me
Et
Me
NH
2-Cl—Ph
CH2C(Me)2
Me
(R)-


IV-982
Me
Me
Me
NH
2-Cl—Ph
C(Me)2CH2
H
racemic


IV-983
Me
Me
Me
NH
2-Cl—Ph
C(Me)2CH2
H
(+)


IV-984
Me
Me
Me
NH
2-Cl—Ph
C(Me)2CH2
H
(−)


IV-985
Me
Et
Me
NH
2-Cl—Ph
C(Me)2CH2
H
racemic


IV-986
Me
Et
Me
NH
2-Cl—Ph
C(Me)2CH2
H
(+)


IV-987
Me
Et
Me
NH
2-Cl—Ph
C(Me)2CH2
H
(−)


IV-988
Me
Me
Me
NH
2-Cl—Ph
C(Me)2CH2
Me
racemic


IV-989
Me
Me
Me
NH
2-Cl—Ph
C(Me)2CH2
Me
(+)


IV-990
Me
Me
Me
NH
2-Cl—Ph
C(Me)2CH2
Me
(−)


IV-991
Me
Et
Me
NH
2-Cl—Ph
C(Me)2CH2
Me
racemic


IV-992
Me
Et
Me
NH
2-Cl—Ph
C(Me)2CH2
Me
(+)


IV-993
Me
Et
Me
NH
2-Cl—Ph
C(Me)2CH2
Me
(−)


IV-994
Me
Me
Me
NH
3-Cl—Ph
CH2
H
racemic


IV-995
Me
Me
Me
NH
3-Cl—Ph
CH2
H
(S)-


IV-996
Me
Et
Me
NH
3-Cl—Ph
CH2
H
racemic


IV-997
Me
Et
Me
NH
3-Cl—Ph
CH2
H
(S)-


IV-998
Me
Me
Me
NH
3-Cl—Ph
CH2
Me
racemic


IV-999
Me
Me
Me
NH
3-Cl—Ph
CH2
Me
(S)-


IV-1000
Me
Et
Me
NH
3-Cl—Ph
CH2
Me
racemic


IV-1001
Me
Et
Me
NH
3-Cl—Ph
CH2
Me
(S)-
















TABLE 84







(IV)




embedded image




















Com-










pound







Config-


No.
R1
R2
R3
L2
R4
L3
R5
uration





IV-1002
Me
Me
Me
NH
3-Cl—Ph
(CH2)2
H
racemic


IV-1003
Me
Me
Me
NH
3-Cl—Ph
(CH2)2
H
(R)-


IV-1004
Me
Et
Me
NH
3-Cl—Ph
(CH2)2
H
racemic


IV-1005
Me
Et
Me
NH
3-Cl—Ph
(CH2)2
H
(R)-


IV-1006
Me
Me
Me
NH
3-Cl—Ph
(CH2)2
Me
racemic


IV-1007
Me
Me
Me
NH
3-Cl—Ph
(CH2)2
Me
(R)-


IV-1008
Me
Et
Me
NH
3-Cl—Ph
(CH2)2
Me
racemic


IV-1009
Me
Et
Me
NH
3-Cl—Ph
(CH2)2
Me
(R)-


IV-1010
Me
Me
Me
NH
3-Cl—Ph
CH2C(Me)2
H
racemic


IV-1011
Me
Me
Me
NH
3-Cl—Ph
CH2C(Me)2
H
(R)-


IV-1012
Me
Et
Me
NH
3-Cl—Ph
CH2C(Me)2
H
racemic


IV-1013
Me
Et
Me
NH
3-Cl—Ph
CH2C(Me)2
H
(R)-


IV-1014
Me
Me
Me
NH
3-Cl—Ph
CH2C(Me)2
Me
racemic


IV-1015
Me
Me
Me
NH
3-Cl—Ph
CH2C(Me)2
Me
(R)-


IV-1016
Me
Et
Me
NH
3-Cl—Ph
CH2C(Me)2
Me
racemic


IV-1017
Me
Et
Me
NH
3-Cl—Ph
CH2C(Me)2
Me
(R)-


IV-1018
Me
Me
Me
NH
3-Cl—Ph
C(Me)2CH2
H
racemic


IV-1019
Me
Me
Me
NH
3-Cl—Ph
C(Me)2CH2
H
(+)


IV-1020
Me
Me
Me
NH
3-Cl—Ph
C(Me)2CH2
H
(−)


IV-1021
Me
Et
Me
NH
3-Cl—Ph
C(Me)2CH2
H
racemic


IV-1022
Me
Et
Me
NH
3-Cl—Ph
C(Me)2CH2
H
(+30)


IV-1023
Me
Et
Me
NH
3-Cl—Ph
C(Me)2CH2
H
(-)


IV-1024
Me
Me
Me
NH
3-Cl—Ph
C(Me)2CH2
Me
racemic


IV-1025
Me
Me
Me
NH
3-Cl—Ph
C(Me)2CH2
Me
(+)


IV-1026
Me
Me
Me
NH
3-Cl—Ph
C(Me)2CH2
Me
(−)


IV-1027
Me
Et
Me
NH
3-Cl—Ph
C(Me)2CH2
Me
racemic


IV-1028
Me
Et
Me
NH
3-Cl—Ph
C(Me)2CH2
Me
(+)


IV-1029
Me
Et
Me
NH
3-Cl—Ph
C(Me)2CH2
Me
(−)


IV-1030
Me
Me
Me
NH
3-Cl—Ph
CH2
H
racemic


IV-1031
Me
Me
Me
NH
3-Cl—Ph
CH2
H
(S)-


IV-1032
Me
Et
Me
NH
3-Cl—Ph
CH2
H
racemic


IV-1033
Me
Et
Me
NH
3-Cl—Ph
CH2
H
(S)-


IV-1034
Me
Me
Me
NH
3-Cl—Ph
CH2
Me
racemic


IV-1035
Me
Me
Me
NH
3-Cl—Ph
CH2
Me
(S)-


IV-1036
Me
Et
Me
NH
3-Cl—Ph
CH2
Me
racemic


IV-1037
Me
Et
Me
NH
3-Cl—Ph
CH2
Me
(S)-


IV-1038
Me
Me
Me
NH
3-Cl—Ph
(CH2)2
H
racemic


IV-1039
Me
Me
Me
NH
3-Cl—Ph
(CH2)2
H
(R)-


IV-1040
Me
Et
Me
NH
3-Cl—Ph
(CH2)2
H
racemic


IV-1041
Me
Et
Me
NH
3-Cl—Ph
(CH2)2
H
(R)-


IV-1042
Me
Me
Me
NH
3-Cl—Ph
(CH2)2
Me
racemic


IV-1043
Me
Me
Me
NH
3-Cl—Ph
(CH2)2
Me
(R)-


IV-1044
Me
Et
Me
NH
3-Cl—Ph
(CH2)2
Me
racemic


IV-1045
Me
Et
Me
NH
3-Cl—Ph
(CH2)2
Me
(R)-


IV-1046
Me
Me
Me
NH
3-Cl—Ph
CH2C(Me)2
H
racemic


IV-1047
Me
Me
Me
NH
3-Cl—Ph
CH2C(Me)2
H
(R)-


IV-1048
Me
Et
Me
NH
3-Cl—Ph
CH2C(Me)2
H
racemic


IV-1049
Me
Et
Me
NH
3-Cl—Ph
CH2C(Me)2
H
(R)-


IV-1050
Me
Me
Me
NH
3-Cl—Ph
CH2C(Me)2
Me
racemic


IV-1051
Me
Me
Me
NH
3-Cl—Ph
CH2C(Me)2
Me
(R)-
















TABLE 85







(IV)




embedded image




















Com-










pound







Config-


No.
R1
R2
R3
L2
R4
L3
R5
uration





IV-1052
Me
Et
Me
NH
4-Cl—Ph
CH2C(Me)2
Me
racemic


IV-1053
Me
Et
Me
NH
4-Cl—Ph
CH2C(Me)2
Me
(R)-


IV-1054
Me
Me
Me
NH
4-Cl—Ph
CH2C(Me)2
H
racemic


IV-1055
Me
Me
Me
NH
4-Cl—Ph
CH2C(Me)2
H
(+)


IV-1056
Me
Me
Me
NH
4-Cl—Ph
CH2C(Me)2
H
(−)


IV-1057
Me
Et
Me
NH
4-Cl—Ph
CH2C(Me)2
H
racemic


IV-1058
Me
Et
Me
NH
4-Cl—Ph
CH2C(Me)2
H
(+)


IV-1059
Me
Et
Me
NH
4-Cl—Ph
CH2C(Me)2
H
(−)


IV-1060
Me
Me
Me
NH
4-Cl—Ph
CH2C(Me)2
Me
racemic


IV-1061
Me
Me
Me
NH
4-Cl—Ph
CH2C(Me)2
Me
(+)


IV-1062
Me
Me
Me
NH
4-Cl—Ph
CH2C(Me)2
Me
(−)


IV-1063
Me
Et
Me
NH
4-Cl—Ph
CH2C(Me)2
Me
racemic


IV-1064
Me
Et
Me
NH
4-Cl—Ph
CH2C(Me)2
Me
(+)


IV-1065
Me
Et
Me
NH
4-Cl—Ph
CH2C(Me)2
Me
(−)


IV-1066
Me
Me
Me
NH
2-Me—Ph
CH2
H
racemic


IV-1067
Me
Me
Me
NH
2-Me—Ph
CH2
H
(S)-


IV-1068
Me
Et
Me
NH
2-Me—Ph
CH2
H
racemic


IV-1069
Me
Et
Me
NH
2-Me—Ph
CH2
H
(S)-


IV-1070
Me
Me
Me
NH
2-Me—Ph
CH2
Me
racemic


IV-1071
Me
Me
Me
NH
2-Me—Ph
CH2
Me
(S)-


IV-1072
Me
Et
Me
NH
2-Me—Ph
CH2
Me
racemic


IV-1073
Me
Et
Me
NH
2-Me—Ph
CH2
Me
(S)-


IV-1074
Me
Me
Me
NH
2-Me—Ph
(CH2)2
H
racemic


IV-1075
Me
Me
Me
NH
2-Me—Ph
(CH2)2
H
(R)-


IV-1076
Me
Et
Me
NH
2-Me—Ph
(CH2)2
H
racemic


IV-1077
Me
Et
Me
NH
2-Me—Ph
(CH2)2
H
(R)-


IV-1078
Me
Me
Me
NH
2-Me—Ph
(CH2)2
Me
racemic


IV-1079
Me
Me
Me
NH
2-Me—Ph
(CH2)2
Me
(R)-


IV-1080
Me
Et
Me
NH
2-Me—Ph
(CH2)2
Me
racemic


IV-1081
Me
Et
Me
NH
2-Me—Ph
(CH2)2
Me
(R)-


IV-1082
Me
Me
Me
NH
2-Me—Ph
CH2C(Me)2
H
racemic


IV-1083
Me
Me
Me
NH
2-Me—Ph
CH2C(Me)2
H
(R)-


IV-1084
Me
Et
Me
NH
2-Me—Ph
CH2C(Me)2
H
racemic


IV-1085
Me
Et
Me
NH
2-Me—Ph
CH2C(Me)2
H
(R)-


IV-1086
Me
Me
Me
NH
2-Me—Ph
CH2C(Me)2
Me
racemic


IV-1087
Me
Me
Me
NH
2-Me—Ph
CH2C(Me)2
Me
(R)-


IV-1088
Me
Et
Me
NH
2-Me—Ph
CH2C(Me)2
Me
racemic


IV-1089
Me
Et
Me
NH
2-Me—Ph
CH2C(Me)2
Me
(R)-


IV-1090
Me
Me
Me
NH
2-Me—Ph
CH2C(Me)2
H
racemic


IV-1091
Me
Me
Me
NH
2-Me—Ph
CH2C(Me)2
H
(+)


IV-1092
Me
Me
Me
NH
2-Me—Ph
CH2C(Me)2
H
(−)


IV-1093
Me
Et
Me
NH
2-Me—Ph
CH2C(Me)2
H
racemic


IV-1094
Me
Et
Me
NH
2-Me—Ph
CH2C(Me)2
H
(+)


IV-1095
Me
Et
Me
NH
2-Me—Ph
CH2C(Me)2
H
(−)


IV-1096
Me
Me
Me
NH
2-Me—Ph
CH2C(Me)2
Me
racemic


IV-1097
Me
Me
Me
NH
2-Me—Ph
CH2C(Me)2
Me
(+)


IV-1098
Me
Me
Me
NH
2-Me—Ph
CH2C(Me)2
Me
(−)


IV-1099
Me
Et
Me
NH
2-Me—Ph
CH2C(Me)2
Me
racemic


IV-1100
Me
Et
Me
NH
2-Me—Ph
CH2C(Me)2
Me
(+)


IV-1101
Me
Et
Me
NH
2-Me—Ph
CH2C(Me)2
Me
(−)
















TABLE 86







(IV)




embedded image




















Com-










pound







Config-


No.
R1
R2
R3
L2
R4
L3
R5
uration





IV-1102
Me
Me
Me
NH
3-Me—Ph
CH2
H
racemic


IV-1103
Me
Me
Me
NH
3-Me—Ph
CH2
H
(S)-


IV-1104
Me
Et
Me
NH
3-Me—Ph
CH2
H
racemic


IV-1105
Me
Et
Me
NH
3-Me—Ph
CH2
H
(S)-


IV-1106
Me
Me
Me
NH
3-Me—Ph
CH2
Me
racemic


IV-1107
Me
Me
Me
NH
3-Me—Ph
CH2
Me
(S)-


IV-1108
Me
Et
Me
NH
3-Me—Ph
CH2
Me
racemic


IV-1109
Me
Et
Me
NH
3-Me—Ph
CH2
Me
(S)-


IV-1110
Me
Me
Me
NH
3-Me—Ph
(CH2)2
H
racemic


IV-1111
Me
Me
Me
NH
3-Me—Ph
(CH2)2
H
(R)-


IV-1112
Me
Et
Me
NH
3-Me—Ph
(CH2)2
H
racemic


IV-1113
Me
Et
Me
NH
3-Me—Ph
(CH2)2
H
(R)-


IV-1114
Me
Me
Me
NH
3-Me—Ph
(CH2)2
Me
racemic


IV-1115
Me
Me
Me
NH
3-Me—Ph
(CH2)2
Me
(R)-


IV-1116
Me
Et
Me
NH
3-Me—Ph
(CH2)2
Me
racemic


IV-1117
Me
Et
Me
NH
3-Me—Ph
(CH2)2
Me
(R)-


IV-1118
Me
Me
Me
NH
3-Me—Ph
CH2C(Me)2
H
racemic


IV-1119
Me
Me
Me
NH
3-Me—Ph
CH2C(Me)2
H
(R)-


IV-1120
Me
Et
Me
NH
3-Me—Ph
CH2C(Me)2
H
racemic


IV-1121
Me
Et
Me
NH
3-Me—Ph
CH2C(Me)2
H
(R)-


IV-1122
Me
Me
Me
NH
3-Me—Ph
CH2C(Me)2
Me
racemic


IV-1123
Me
Me
Me
NH
3-Me—Ph
CH2C(Me)2
Me
(R)-


IV-1124
Me
Et
Me
NH
3-Me—Ph
CH2C(Me)2
Me
racemic


IV-1125
Me
Et
Me
NH
3-Me—Ph
CH2C(Me)2
Me
(R)-


IV-1126
Me
Me
Me
NH
3-Me—Ph
C(Me)2CH2
H
racemic


IV-1127
Me
Me
Me
NH
3-Me—Ph
C(Me)2CH2
H
(+)


IV-1128
Me
Me
Me
NH
3-Me—Ph
C(Me)2CH2
H
(−)


IV-1129
Me
Et
Me
NH
3-Me—Ph
C(Me)2CH2
H
racemic


IV-1130
Me
Et
Me
NH
3-Me—Ph
C(Me)2CH2
H
(+)


IV-1131
Me
Et
Me
NH
3-Me—Ph
C(Me)2CH2
H
(−)


IV-1132
Me
Me
Me
NH
3-Me—Ph
C(Me)2CH2
Me
racemic


IV-1133
Me
Me
Me
NH
3-Me—Ph
C(Me)2CH2
Me
(+)


IV-1134
Me
Me
Me
NH
3-Me—Ph
C(Me)2CH2
Me
(−)


IV-1135
Me
Et
Me
NH
3-Me—Ph
C(Me)2CH2
Me
racemic


IV-1136
Me
Et
Me
NH
3-Me—Ph
C(Me)2CH2
Me
(+)


IV-1137
Me
Et
Me
NH
3-Me—Ph
C(Me)2CH2
Me
(−)


IV-1138
Me
Me
Me
NH
3-Me—Ph
CH2
H
racemic


IV-1139
Me
Me
Me
NH
3-Me—Ph
CH2
H
(S)-


IV-1140
Me
Et
Me
NH
3-Me—Ph
CH2
H
racemic


IV-1141
Me
Et
Me
NH
3-Me—Ph
CH2
H
(S)-


IV-1142
Me
Me
Me
NH
3-Me—Ph
CH2
Me
racemic


IV-1143
Me
Me
Me
NH
3-Me—Ph
CH2
Me
(S)-


IV-1144
Me
Et
Me
NH
3-Me—Ph
CH2
Me
racemic


IV-1145
Me
Et
Me
NH
3-Me—Ph
CH2
Me
(S)-


IV-1146
Me
Me
Me
NH
3-Me—Ph
(CH2)2
H
racemic


IV-1147
Me
Me
Me
NH
3-Me—Ph
(CH2)2
H
(R)-


IV-1148
Me
Me
Me
NH
3-Me—Ph
(CH2)2
Me
racemic


IV-1149
Me
Me
Me
NH
3-Me—Ph
(CH2)2
Me
(R)-


IV-1150
Me
Me
Me
NH
3-Me—Ph
CH2C(Me)2
H
racemic


IV-1151
Me
Me
Me
NH
3-Me—Ph
CH2C(Me)2
H
(R)-
















TABLE 87







(IV)




embedded image




















Com-










pound







Config-


No.
R1
R2
R3
L2
R4
L3
R5
uration





IV-1152
Me
Et
Me
NH
4-Me—Ph
CH2C(Me)2
H
racemic


IV-1153
Me
Et
Me
NH
4-Me—Ph
CH2C(Me)2
H
(R)-


IV-1154
Me
Me
Me
NH
4-Me—Ph
CH2C(Me)2
Me
racemic


IV-1155
Me
Me
Me
NH
4-Me—Ph
CH2C(Me)2
Me
(R)-


IV-1156
Me
Et
Me
NH
4-Me—Ph
CH2C(Me)2
Me
racemic


IV-1157
Me
Et
Me
NH
4-Me—Ph
CH2C(Me)2
Me
(R)-


IV-1158
Me
Me
Me
NH
4-Me—Ph
C(Me)2CH2
H
racemic


IV-1159
Me
Me
Me
NH
4-Me—Ph
C(Me)2CH2
H
(+)


IV-1160
Me
Me
Me
NH
4-Me—Ph
C(Me)2CH2
H
(−)


IV-1161
Me
Et
Me
NH
4-Me—Ph
C(Me)2CH2
H
racemic


IV-1162
Me
Et
Me
NH
4-Me—Ph
C(Me)2CH2
H
(+)


IV-1163
Me
Et
Me
NH
4-Me—Ph
C(Me)2CH2
H
(−)


IV-1164
Me
Me
Me
NH
4-Me—Ph
C(Me)2CH2
Me
racemic


IV-1165
Me
Me
Me
NH
4-Me—Ph
C(Me)2CH2
Me
(+)


IV-1166
Me
Me
Me
NH
4-Me—Ph
C(Me)2CH2
Me
(−)


IV-1167
Me
Et
Me
NH
4-Me—Ph
C(Me)2CH2
Me
racemic


IV-1168
Me
Et
Me
NH
4-Me—Ph
C(Me)2CH2
Me
(+)


IV-1169
Me
Et
Me
NH
4-Me—Ph
C(Me)2CH2
Me
(−)


IV-1170
Me
Me
Me
—
Ph
—
H
racemic


IV-1171
Me
Me
Me
—
Ph
—
H
(R)-


IV-1172
Me
Et
Me
—
Ph
—
H
racemic


IV-1173
Me
Et
Me
—
Ph
—
H
(R)-


IV-1174
Me
Me
Me
—
Ph
—
Me
racemic


IV-1175
Me
Me
Me
—
Ph
—
Me
(R)-


IV-1176
Me
Me
Me
—
Ph
—
Me
(S)-


IV-1177
Me
Et
Me
—
Ph
—
Me
racemic


IV-1178
Me
Et
Me
—
Ph
—
Me
(R)-


IV-1179
Me
Me
Me
—
Ph
—
CHF2
racemic


IV-1180
Me
Me
Me
—
Ph
—
CHF2
(R)-


IV-1181
Me
Et
Me
—
Ph
—
CHF2
racemic


IV-1182
Me
Et
Me
—
Ph
—
CHF2
(R)-


IV-1183
Me
Me
Me
—
Ph
—
CF3
racemic


IV-1184
Me
Me
Me
—
Ph
—
CF3
(R)-


IV-1185
Me
Et
Me
—
Ph
—
CF3
racemic


IV-1186
Me
Et
Me
—
Ph
—
CF3
(R)-


IV-1187
Me
Me
Me
—
Ph
—
Et
racemic


IV-1188
Me
Me
Me
—
Ph
—
Et
(R)-


IV-1189
Me
Et
Me
—
Ph
—
Et
racemic


IV-1190
Me
Et
Me
—
Ph
—
Et
(R)-


IV-1191
Me
Me
Me
—
Ph
—
CF2CH3
racemic


IV-1192
Me
Me
Me
—
Ph
—
CF2CH3
(R)-


IV-1193
Me
Et
Me
—
Ph
—
CF2CH3
racemic


IV-1194
Me
Et
Me
—
Ph
—
CF2CH3
(R)-


IV-1195
Me
Me
Me
—
Ph
—
nPr
racemic


IV-1196
Me
Me
Me
—
Ph
—
nPr
(R)-


IV-1197
Me
Et
Me
—
Ph
—
nPr
racemic


IV-1198
Me
Et
Me
—
Ph
—
nPr
(R)-


IV-1199
Me
Me
Me
—
Ph
—
nBu
racemic


IV-1200
Me
Me
Me
—
Ph
—
nBu
(R)-


IV-1201
Me
Et
Me
—
Ph
—
nBu
racemic
















TABLE 88







(IV)




embedded image




















Com-










pound







Config-


No.
R1
R2
R3
L2
R4
L3
R5
uration





IV-1202
Me
Et
Me
—
Ph
—
nBu
(R)-


IV-1203
Me
Me
Me
—
Ph
—
iPr
racemic


IV-1204
Me
Me
Me
—
Ph
—
iPr
(R)-


IV-1205
Me
Et
Me
—
Ph
—
iPr
racemic


IV-1206
Me
Et
Me
—
Ph
—
iPr
(R)-


IV-1207
Me
Me
Me
—
Ph
—
cPr
racemic


IV-1208
Me
Me
Me
—
Ph
—
cPr
(R)-


IV-1209
Me
Et
Me
—
Ph
—
cPr
racemic


IV-1210
Me
Et
Me
—
Ph
—
cPr
(R)-


IV-1211
Me
Me
Me
—
Ph
—
Ph
racemic


IV-1212
Me
Me
Me
—
Ph
—
Ph
(R)-


IV-1213
Me
Me
Me
—
Ph
—
2,2-diF-cPr
racemic


IV-1214
Me
Me
Me
—
Ph
—
2,2-diF-cPr
(R)-


IV-1215
Me
Me
Me
—
Ph
CH2
H
(R)-


IV-1216
Me
Me
Me
—
Ph
CH2
CHF2
racemic


IV-1217
Me
Me
Me
—
Ph
CH2
CHF2
(S)-


IV-1218
Me
Me
Me
—
Ph
CH2
Et
racemic


IV-1219
Me
Me
Me
—
Ph
CH2
Et
(S)-


IV-1220
Me
Me
Me
—
Ph
CH2
Bn
racemic


IV-1221
Me
Me
Me
—
Ph
CH2
Bn
(R)-


IV-1222
Me
Me
Me
—
Ph
(CH2)2
H
racemic


IV-1223
Me
Me
Me
—
Ph
(CH2)2
H
(S)-


IV-1224
Me
Me
Me
—
Ph
(CH2)2
Me
racemic


IV-1225
Me
Me
Me
—
Ph
(CH2)2
Me
(S)-


IV-1226
Me
Me
Me
—
Ph
(CH2)2
CHF2
racemic


IV-1227
Me
Me
Me
—
Ph
(CH2)2
CHF2
(S)-


IV-1228
Me
Me
Me
—
Ph
(CH2)2
Et
racemic


IV-1229
Me
Me
Me
—
Ph
(CH2)2
Et
(S)-


IV-1230
Me
Me
Me
—
H
—
H



IV-1231
Me
Me
Me
—
H
—
Me



IV-1232
Me
Me
Me
—
H
—
CHF2



IV-1233
Me
Me
Me
—
H
—
CF3



IV-1234
Me
Me
Me
—
H
—
Et



IV-1235
Me
Me
Me
—
H
—
nPr



IV-1236
Me
Me
Me
—
H
—
iPr



IV-1237
Me
Me
Me
—
H
—
cPr



IV-1238
Me
Me
Me
—
H
—
Ph



IV-1239
Me
Me
Me
—
Me
—
H
racemic


IV-1240
Me
Me
Me
—
Me
—
H
(R)-


IV-1241
Me
Me
Me
—
Me
—
Me
racemic


IV-1242
Me
Me
Me
—
Me
—
Me
(R)-


IV-1243
Me
Me
Me
—
Me
—
CHF2
racemic


IV-1244
Me
Me
Me
—
Me
—
CHF2
(R)-


IV-1245
Me
Me
Me
—
Me
—
CF3
racemic


IV-1246
Me
Me
Me
—
Me
—
CF3
(R)-


IV-1247
Me
Me
Me
—
Me
—
Et
racemic


IV-1248
Me
Me
Me
—
Me
—
Et
(R)-


IV-1249
Me
Me
Me
—
Me
—
nPr
racemic


IV-1250
Me
Me
Me
—
Me
—
nPr
(R)-


IV-1251
Me
Me
Me
—
Me
—
iPr
racemic
















TABLE 89







(IV)




embedded image




















Com-










pound







Config-


No.
R1
R2
R3
L2
R4
L3
R5
uration





IV-1252
Me
Me
Me
—
Me
—
iPr
(R)-


IV-1253
Me
Me
Me
—
Me
—
cPr
racemic


IV-1254
Me
Me
Me
—
Me
—
cPr
(R)-


IV-1255
Me
Me
Me
—
Me
—
cHex
racemic


IV-1256
Me
Me
Me
—
Me
—
cHex
(R)-


IV-1257
Me
Me
Me
—
Me
—
Ph
racemic


IV-1258
Me
Me
Me
—
Me
—
Ph
(R)-


IV-1259
Me
Me
Me
—
Me
—
Ph
(S)-


IV-1260
Me
Me
Me
—
Me
—
2-F—Ph
racemic


IV-1261
Me
Me
Me
—
Me
—
2-F—Ph
(R)-


IV-1262
Me
Me
Me
—
Me
—
2-F—Ph
racemic


IV-1263
Me
Me
Me
—
Me
—
2-F—Ph
(R)-


IV-1264
Me
Me
Me
—
Me
—
2-F—Ph
racemic


IV-1265
Me
Me
Me
—
Me
—
2-F—Ph
(R)-


IV-1266
Me
Me
Me
—
Me
—
2-Cl—Ph
racemic


IV-1267
Me
Me
Me
—
Me
—
2-Cl—Ph
(R)-


IV-1268
Me
Me
Me
—
Me
—
2-Cl—Ph
racemic


IV-1269
Me
Me
Me
—
Me
—
2-Cl—Ph
(R)-


IV-1270
Me
Me
Me
—
Me
—
2-Cl—Ph
racemic


IV-1271
Me
Me
Me
—
Me
—
2-Cl—Ph
(R)-


IV-1272
Me
Me
Me
—
Me
—
2-Py
racemic


IV-1273
Me
Me
Me
—
Me
—
2-Py
(R)-


IV-1274
Me
Me
Me
—
Me
—
3-Py
racemic


IV-1275
Me
Me
Me
—
Me
—
3-Py
(R)-


IV-1276
Me
Me
Me
—
Me
—
4-Py
racemic


IV-1277
Me
Me
Me
—
Me
—
4-Py
(R)-


IV-1278
Me
Me
Me
—
iPr
—
H
racemic


IV-1279
Me
Me
Me
—
iPr
—
H
(R)-


IV-1280
Me
Me
Me
—
iPr
—
Me
racemic


IV-1281
Me
Me
Me
—
iPr
—
Me
(R)-


IV-1282
Me
Me
Me
—
iPr
—
CHF2
racemic


IV-1283
Me
Me
Me
—
iPr
—
CHF2
(R)-


IV-1284
Me
Me
Me
—
iPr
—
CF3
racemic


IV-1285
Me
Me
Me
—
iPr
—
CF3
(R)-


IV-1286
Me
Me
Me
—
iPr
—
Et
racemic


IV-1287
Me
Me
Me
—
iPr
—
Et
(R)-


IV-1288
Me
Me
Me
—
iPr
—
nPr
racemic


IV-1289
Me
Me
Me
—
iPr
—
nPr
(R)-


IV-1290
Me
Me
Me
—
iPr
—
iPr
racemic


IV-1291
Me
Me
Me
—
iPr
—
iPr
(R)-


IV-1292
Me
Me
Me
—
iPr
—
cPr
racemic


IV-1293
Me
Me
Me
—
iPr
—
cPr
(R)-


IV-1294
Me
Me
Me
—
iPr
—
Ph
racemic


IV-1295
Me
Me
Me
—
iPr
—
Ph
(R)-


IV-1296
Me
Me
Me
—
CF3
—
H
racemic


IV-1297
Me
Me
Me
—
CF3
—
H
(R)-


IV-1298
Me
Me
Me
—
CF3
—
Me
racemic


IV-1299
Me
Me
Me
—
CF3
—
Me
(R)-


IV-1300
Me
Me
Me
—
CF3
—
CHF2
racemic


IV-1301
Me
Me
Me
—
CF3
—
CHF2
(R)-
















TABLE 90







(IV)




embedded image




















Com-










pound







Config-


No.
R1
R2
R3
L2
R4
L3
R5
uration





IV-1302
Me
Me
Me
—
CF3
—
CF3
racemic


IV-1303
Me
Me
Me
—
CF3
—
CF3
(R)-


IV-1304
Me
Me
Me
—
CF3
—
Et
racemic


IV-1305
Me
Me
Me
—
CF3
—
Et
(R)-


IV-1306
Me
Me
Me
—
CF3
—
nPr
racemic


IV-1307
Me
Me
Me
—
CF3
—
nPr
(R)-


IV-1308
Me
Me
Me
—
CF3
—
iPr
racemic


IV-1309
Me
Me
Me
—
CF3
—
iPr
(R)-


IV-1310
Me
Me
Me
—
CF3
—
cPr
racemic


IV-1311
Me
Me
Me
—
CF3
—
cPr
(R)-


IV-1312
Me
Me
Me
—
CF3
—
Ph
racemic


IV-1313
Me
Me
Me
—
CF3
—
Ph
(R)-


IV-1314
Me
Me
Me
—
CH2OH
—
H
racemic


IV-1315
Me
Me
Me
—
CH2OH
—
H
(R)-


IV-1316
Me
Me
Me
—
CH2OH
—
Me
racemic


IV-1317
Me
Me
Me
—
CH2OH
—
Me
(R)-


IV-1318
Me
Me
Me
—
CH2OH
—
CHF2
racemic


IV-1319
Me
Me
Me
—
CH2OH
—
CHF2
(R)-


IV-1320
Me
Me
Me
—
CH2OH
—
CF3
racemic


IV-1321
Me
Me
Me
—
CH2OH
—
CF3
(R)-


IV-1322
Me
Me
Me
—
CH2OH
—
Et
racemic


IV-1323
Me
Me
Me
—
CH2OH
—
Et
(R)-


IV-1324
Me
Me
Me
—
CH2OH
—
nPr
racemic


IV-1325
Me
Me
Me
—
CH2OH
—
nPr
(R)-


IV-1326
Me
Me
Me
—
CH2OH
—
iPr
racemic


IV-1327
Me
Me
Me
—
CH2OH
—
iPr
(R)-


IV-1328
Me
Me
Me
—
CH2OH
—
cPr
racemic


IV-1329
Me
Me
Me
—
CH2OH
—
cPr
(R)-


IV-1330
Me
Me
Me
—
CH2OH
—
Ph
racemic


IV-1331
Me
Me
Me
—
CH2OH
—
Ph
(R)-


IV-1332
Me
Me
Me
—
CH2OMe
—
H
racemic


IV-1333
Me
Me
Me
—
CH2OMe
—
H
(R)-


IV-1334
Me
Me
Me
—
CH2OMe
—
Me
racemic


IV-1335
Me
Me
Me
—
CH2OMe
—
Me
(R)-


IV-1336
Me
Me
Me
—
CH2OMe
—
CHF2
racemic


IV-1337
Me
Me
Me
—
CH2OMe
—
CHF2
(R)-


IV-1338
Me
Me
Me
—
CH2OMe
—
CF3
racemic


IV-1339
Me
Me
Me
—
CH2OMe
—
CF3
(R)-


IV-1340
Me
Me
Me
—
CH2OMe
—
Et
racemic


IV-1341
Me
Me
Me
—
CH2OMe
—
Et
(R)-


IV-1342
Me
Me
Me
—
CH2OMe
—
nPr
racemic


IV-1343
Me
Me
Me
—
CH2OMe
—
nPr
(R)-


IV-1344
Me
Me
Me
—
CH2OMe
—
iPr
racemic


IV-1345
Me
Me
Me
—
CH2OMe
—
iPr
(R)-


IV-1346
Me
Me
Me
—
CH2OMe
—
cPr
racemic


IV-1347
Me
Me
Me
—
CH2OMe
—
cPr
(R)-


IV-1348
Me
Me
Me
—
CH2OMe
—
Ph
racemic


IV-1349
Me
Me
Me
—
CH2OMe
—
Ph
(R)-


IV-1350
Me
Me
Me
—
CH2OBn
—
H
racemic


IV-1351
Me
Me
Me
—
CH2OBn
—
H
(R)-
















TABLE 91







(IV)




embedded image




















Com-










pound







Config-


No.
R1
R2
R3
L2
R4
L3
R5
uration


















IV-1352
Me
Me
Me
—
CH2OBn
—
Me
racemic


IV-1353
Me
Me
Me
—
CH2OBn
—
Me
(R)-


IV-1354
Me
Me
Me
—
CH2OBn
—
Ph
racemic


IV-1355
Me
Me
Me
—
CH2OBn
—
Ph
(R)-


IV-1356
Me
Me
Me
—
CH2NMe2
—
H
racemic


IV-1357
Me
Me
Me
—
CH2NMe2
—
H
(R)-


IV-1358
Me
Me
Me
—
CH2NMe2
—
Me
racemic


IV-1359
Me
Me
Me
—
CH2NMe2
—
Me
(R)-


IV-1360
Me
Me
Me
—
CH2NMe2
—
CHF2
racemic


IV-1361
Me
Me
Me
—
CH2NMe2
—
CHF2
(R)-


IV-1362
Me
Me
Me
—
CH2NMe2
—
CF3
racemic


IV-1363
Me
Me
Me
—
CH2NMe2
—
CF3
(R)-


IV-1364
Me
Me
Me
—
CH2NMe2
—
Et
racemic


IV-1365
Me
Me
Me
—
CH2NMe2
—
Et
(R)-


IV-1366
Me
Me
Me
—
CH2NMe2
—
nPr
racemic


IV-1367
Me
Me
Me
—
CH2NMe2
—
nPr
(R)-


IV-1368
Me
Me
Me
—
CH2NMe2
—
iPr
racemic


IV-1369
Me
Me
Me
—
CH2NMe2
—
iPr
(R)-


IV-1370
Me
Me
Me
—
CH2NMe2
—
cPr
racemic


IV-1371
Me
Me
Me
—
CH2NMe2
—
cPr
(R)-


IV-1372
Me
Me
Me
—
CH2NMe2
—
Ph
racemic


IV-1373
Me
Me
Me
—
CH2NMe2
—
Ph
(R)-


IV-1374
Me
Me
Me
—
CH2-3-(3,3-(3,
—
H
racemic






—
pyrrolidyl)
—




IV-1375
Me
Me
Me
—
CH2-3-(3,3-(3,
—
H
(R)-






—
pyrrolidyl)
—




IV-1376
Me
Me
Me
—
CH2-3-(3,3-(3,
—
Me
racemic






—
pyrrolidyl)
—




IV-1377
Me
Me
Me
—
CH2-3-(3,3-(3,
—
Me
(R)-






—
pyrrolidyl)
—




IV-1378
Me
Me
Me
—
CH2-3-(3,3-(3,
—
Ph
racemic






—
pyrrolidyl)
—




IV-1379
Me
Me
Me
—
CH2-3-(3,3-(3,
—
Ph
(R)-






—
pyrrolidyl)
—




IV-1380
Me
Me
Me
—
2-F—Ph
—
H
racemic


IV-1381
Me
Me
Me
—
2-F—Ph
—
H
(R)-


IV-1382
Me
Me
Me
—
2-F—Ph
—
Me
racemic


IV-1383
Me
Me
Me
—
2-F—Ph
—
Me
(R)-


IV-1384
Me
Me
Me
—
2-F—Ph
—
Me
(S)-


IV-1385
Me
Me
Me
—
2-F—Ph
—
CHF2
racemic


IV-1386
Me
Me
Me
—
2-F—Ph
—
CHF2
(R)-


IV-1387
Me
Me
Me
—
2-F—Ph
—
CHF2
(S)-


IV-1388
Me
Me
Me
—
2-F—Ph
—
CF3
racemic


IV-1389
Me
Me
Me
—
2-F—Ph
—
CF3
(R)-


IV-1390
Me
Me
Me
—
2-F—Ph
—
CF3
(S)-


IV-1391
Me
Me
Me
—
2-F—Ph
—
Et
racemic


IV-1392
Me
Me
Me
—
2-F—Ph
—
Et
(R)-


IV-1393
Me
Me
Me
—
2-F—Ph
—
Et
(S)-


IV-1394
Me
Me
Me
—
2-F—Ph
—
nPr
racemic


IV-1395
Me
Me
Me
—
2-F—Ph
—
nPr
(R)-


IV-1396
Me
Me
Me
—
2-F—Ph
—
iPr
racemic


IV-1397
Me
Me
Me
—
2-F—Ph
—
iPr
(R)-


IV-1398
Me
Me
Me
—
2-F—Ph
—
iPr
(S)-


IV-1399
Me
Me
Me
—
2-F—Ph
—
cPr
racemic


IV-1400
Me
Me
Me
—
2-F—Ph
—
cPr
(R)-


IV-1401
Me
Me
Me
—
2-F—Ph
—
cPr
(S)-
















TABLE 92







(IV)




embedded image




















Com-










pound







Config-


No.
R1
R2
R3
L2
R4
L3
R5
uration





IV-1402
Me
Me
Me
—
3-F—Ph
—
H
racemic


IV-1403
Me
Me
Me
—
3-F—Ph
—
H
(R)-


IV-1404
Me
Me
Me
—
3-F—Ph
—
Me
racemic


IV-1405
Me
Me
Me
—
3-F—Ph
—
Me
(R)-


IV-1406
Me
Me
Me
—
3-F—Ph
—
Me
(S)-


IV-1407
Me
Me
Me
—
3-F—Ph
—
CHF2
racemic


IV-1408
Me
Me
Me
—
3-F—Ph
—
CHF2
(R)-


IV-1409
Me
Me
Me
—
3-F—Ph
—
CHF2
(S)-


IV-1410
Me
Me
Me
—
3-F—Ph
—
CF3
racemic


IV-1411
Me
Me
Me
—
3-F—Ph
—
CF3
(R)-


IV-1412
Me
Me
Me
—
3-F—Ph
—
CF3
(S)-


IV-1413
Me
Me
Me
—
3-F—Ph
—
Et
racemic


IV-1414
Me
Me
Me
—
3-F—Ph
—
Et
(R)-


IV-1415
Me
Me
Me
—
3-F—Ph
—
Et
(S)-


IV-1416
Me
Me
Me
—
3-F—Ph
—
nPr
racemic


IV-1417
Me
Me
Me
—
3-F—Ph
—
nPr
(R)-


IV-1418
Me
Me
Me
—
3-F—Ph
—
nPr
(S)-


IV-1419
Me
Me
Me
—
3-F—Ph
—
iPr
racemic


IV-1420
Me
Me
Me
—
3-F—Ph
—
iPr
(R)-


IV-1421
Me
Me
Me
—
3-F—Ph
—
iPr
(S)-


IV-1422
Me
Me
Me
—
3-F—Ph
—
cPr
racemic


IV-1423
Me
Me
Me
—
3-F—Ph
—
cPr
(R)-


IV-1424
Me
Me
Me
—
3-F—Ph
—
cPr
(S)-


IV-1425
Me
Me
Me
—
4-F—Ph
—
H
racemic


IV-1426
Me
Me
Me
—
4-F—Ph
—
H
(R)-


IV-1427
Me
Me
Me
—
4-F—Ph
—
Me
racemic


IV-1428
Me
Me
Me
—
4-F—Ph
—
Me
(R)-


IV-1429
Me
Me
Me
—
4-F—Ph
—
Me
(S)-


IV-1430
Me
Me
Me
—
4-F—Ph
—
CHF2
racemic


IV-1431
Me
Me
Me
—
4-F—Ph
—
CHF2
(R)-


IV-1432
Me
Me
Me
—
4-F—Ph
—
CHF2
(S)-


IV-1433
Me
Me
Me
—
4-F—Ph
—
CF3
racemic


IV-1434
Me
Me
Me
—
4-F—Ph
—
CF3
(R)-


IV-1435
Me
Me
Me
—
4-F—Ph
—
CF3
(S)-


IV-1436
Me
Me
Me
—
4-F—Ph
—
Et
racemic


IV-1437
Me
Me
Me
—
4-F—Ph
—
Et
(R)-


IV-1438
Me
Me
Me
—
4-F—Ph
—
Et
(S)-


IV-1439
Me
Me
Me
—
4-F—Ph
—
nPr
racemic


IV-1440
Me
Me
Me
—
4-F—Ph
—
nPr
(R)-


IV-1441
Me
Me
Me
—
4-F—Ph
—
nPr
(S)-


IV-1442
Me
Me
Me
—
4-F—Ph
—
iPr
racemic


IV-1443
Me
Me
Me
—
4-F—Ph
—
iPr
(R)-


IV-1444
Me
Me
Me
—
4-F—Ph
—
iPr
(S)-


IV-1445
Me
Me
Me
—
4-F—Ph
—
cPr
racemic


IV-1446
Me
Me
Me
—
4-F—Ph
—
cPr
(R)-


IV-1447
Me
Me
Me
—
4-F—Ph
—
cPr
(S)-


IV-1448
Me
Me
Me
—
2-Cl—Ph
—
H
racemic


IV-1449
Me
Me
Me
—
2-Cl—Ph
—
H
(R)-


IV-1450
Me
Me
Me
—
2-Cl—Ph
—
Me
racemic


IV-1451
Me
Me
Me
—
2-Cl—Ph
—
Me
(R)-
















TABLE 93







(IV)




embedded image




















Com-










pound







Config-


No.
R1
R2
R3
L2
R4
L3
R5
uration





IV-1452
Me
Me
Me
—
2-Cl—Ph
—
CHF2
racemic


IV-1453
Me
Me
Me
—
2-Cl—Ph
—
CHF2
(R)-


IV-1454
Me
Me
Me
—
2-Cl—Ph
—
CF3
racemic


IV-1455
Me
Me
Me
—
2-Cl—Ph
—
CF3
(R)-


IV-1456
Me
Me
Me
—
2-Cl—Ph
—
Et
racemic


IV-1457
Me
Me
Me
—
2-Cl—Ph
—
Et
(R)-


IV-1458
Me
Me
Me
—
2-Cl—Ph
—
nPr
racemic


IV-1459
Me
Me
Me
—
2-Cl—Ph
—
nPr
(R)-


IV-1460
Me
Me
Me
—
2-Cl—Ph
—
iPr
racemic


IV-1461
Me
Me
Me
—
2-Cl—Ph
—
iPr
(R)-


IV-1462
Me
Me
Me
—
2-Cl—Ph
—
cPr
racemic


IV-1463
Me
Me
Me
—
2-Cl—Ph
—
cPr
(R)-


IV-1464
Me
Me
Me
—
2-Cl—Ph
—
H
racemic


IV-1465
Me
Me
Me
—
2-Cl—Ph
—
H
(R)-


IV-1466
Me
Me
Me
—
2-Cl—Ph
—
Me
racemic


IV-1467
Me
Me
Me
—
2-Cl—Ph
—
Me
(R)-


IV-1468
Me
Me
Me
—
2-Cl—Ph
—
CHF2
racemic


IV-1469
Me
Me
Me
—
2-Cl—Ph
—
CHF2
(R)-


IV-1470
Me
Me
Me
—
2-Cl—Ph
—
CF3
racemic


IV-1471
Me
Me
Me
—
2-Cl—Ph
—
CF3
(R)-


IV-1472
Me
Me
Me
—
2-Cl—Ph
—
Et
racemic


IV-1473
Me
Me
Me
—
2-Cl—Ph
—
Et
(R)-


IV-1474
Me
Me
Me
—
2-Cl—Ph
—
nPr
racemic


IV-1475
Me
Me
Me
—
2-Cl—Ph
—
nPr
(R)-


IV-1476
Me
Me
Me
—
2-Cl—Ph
—
iPr
racemic


IV-1477
Me
Me
Me
—
2-Cl—Ph
—
iPr
(R)-


IV-1478
Me
Me
Me
—
2-Cl—Ph
—
cPr
racemic


IV-1479
Me
Me
Me
—
2-Cl—Ph
—
cPr
(R)-


IV-1480
Me
Me
Me
—
4-Cl—Ph
—
H
racemic


IV-1481
Me
Me
Me
—
4-Cl—Ph
—
H
(R)-


IV-1482
Me
Me
Me
—
4-Cl—Ph
—
Me
racemic


IV-1483
Me
Me
Me
—
4-Cl—Ph
—
Me
(R)-


IV-1484
Me
Me
Me
—
4-Cl—Ph
—
CHF2
racemic


IV-1485
Me
Me
Me
—
4-Cl—Ph
—
CHF2
(R)-


IV-1486
Me
Me
Me
—
4-Cl—Ph
—
CF3
racemic


IV-1487
Me
Me
Me
—
4-Cl—Ph
—
CF3
(R)-


IV-1488
Me
Me
Me
—
4-Cl—Ph
—
Et
racemic


IV-1489
Me
Me
Me
—
4-Cl—Ph
—
Et
(R)-


IV-1490
Me
Me
Me
—
4-Cl—Ph
—
nPr
racemic


IV-1491
Me
Me
Me
—
4-Cl—Ph
—
nPr
(R)-


IV-1492
Me
Me
Me
—
4-Cl—Ph
—
iPr
racemic


IV-1493
Me
Me
Me
—
4-Cl—Ph
—
iPr
(R)-


IV-1494
Me
Me
Me
—
4-Cl—Ph
—
cPr
racemic


IV-1495
Me
Me
Me
—
4-Cl—Ph
—
cPr
(R)-


IV-1496
Me
Me
Me
—
2-Me—Ph
—
H
racemic


IV-1497
Me
Me
Me
—
2-Me—Ph
—
H
(R)-


IV-1498
Me
Me
Me
—
2-Me—Ph
—
Me
racemic


IV-1499
Me
Me
Me
—
2-Me—Ph
—
Me
(R)-


IV-1500
Me
Me
Me
—
2-Me—Ph
—
CHF2
racemic


IV-1501
Me
Me
Me
—
2-Me—Ph
—
CHF2
(R)-

















TABLE 94








(IV)




embedded image





















Com-










pound







Config-


No.
R1
R2
R3
L2
R4
L3
R5
uration





IV-1502
Me
Me
Me
—
2-Me—Ph
—
CF3
racemic


IV-1503
Me
Me
Me
—
2-Me—Ph
—
CF3
(R)-


IV-1504
Me
Me
Me
—
2-Me—Ph
—
Et
racemic


IV-1505
Me
Me
Me
—
2-Me—Ph
—
Et
(R)-


IV-1506
Me
Me
Me
—
2-Me—Ph
—
nPr
racemic


IV-1507
Me
Me
Me
—
2-Me—Ph
—
nPr
(R)-


IV-1508
Me
Me
Me
—
2-Me—Ph
—
iPr
racemic


IV-1509
Me
Me
Me
—
2-Me—Ph
—
iPr
(R)-


IV-1510
Me
Me
Me
—
2-Me—Ph
—
cPr
racemic


IV-1511
Me
Me
Me
—
2-Me—Ph
—
cPr
(R)-


IV-1512
Me
Me
Me
—
3-Me—Ph
—
H
racemic


IV-1513
Me
Me
Me
—
3-Me—Ph
—
H
(R)-


IV-1514
Me
Me
Me
—
3-Me—Ph
—
Me
racemic


IV-1515
Me
Me
Me
—
3-Me—Ph
—
Me
(R)-


IV-1516
Me
Me
Me
—
3-Me—Ph
—
CHF2
racemic


IV-1517
Me
Me
Me
—
3-Me—Ph
—
CHF2
(R)-


IV-1518
Me
Me
Me
—
3-Me—Ph
—
CF3
racemic


IV-1519
Me
Me
Me
—
3-Me—Ph
—
CF3
(R)-


IV-1520
Me
Me
Me
—
3-Me—Ph
—
Et
racemic


IV-1521
Me
Me
Me
—
3-Me—Ph
—
Et
(R)-


IV-1522
Me
Me
Me
—
3-Me—Ph
—
nPr
racemic


IV-1523
Me
Me
Me
—
3-Me—Ph
—
nPr
(R)-


IV-1524
Me
Me
Me
—
3-Me—Ph
—
iPr
racemic


IV-1525
Me
Me
Me
—
3-Me—Ph
—
iPr
(R)-


IV-1526
Me
Me
Me
—
3-Me—Ph
—
cPr
racemic


IV-1527
Me
Me
Me
—
3-Me—Ph
—
cPr
(R)-


IV-1528
Me
Me
Me
—
4-Me—Ph
—
H
racemic


IV-1529
Me
Me
Me
—
4-Me—Ph
—
H
(R)-


IV-1530
Me
Me
Me
—
4-Me—Ph
—
Me
racemic


IV-1531
Me
Me
Me
—
4-Me—Ph
—
Me
(R)-


IV-1532
Me
Me
Me
—
4-Me—Ph
—
CHF2
racemic


IV-1533
Me
Me
Me
—
4-Me—Ph
—
CHF2
(R)-


IV-1534
Me
Me
Me
—
4-Me—Ph
—
CF3
racemic


IV-1535
Me
Me
Me
—
4-Me—Ph
—
CF3
(R)-


IV-1536
Me
Me
Me
—
4-Me—Ph
—
Et
racemic


IV-1537
Me
Me
Me
—
4-Me—Ph
—
Et
(R)-


IV-1538
Me
Me
Me
—
4-Me—Ph
—
nPr
racemic


IV-1539
Me
Me
Me
—
4-Me—Ph
—
nPr
(R)-


IV-1540
Me
Me
Me
—
4-Me—Ph
—
iPr
racemic


IV-1541
Me
Me
Me
—
4-Me—Ph
—
iPr
(R)-


IV-1542
Me
Me
Me
—
4-Me—Ph
—
cPr
racemic


IV-1543
Me
Me
Me
—
4-Me—Ph
—
cPr
(R)-


IV-1544
Me
Me
Me
—
2-thienyl
—
H
racemic


IV-1545
Me
Me
Me
—
2-thienyl
—
H
(S)-


IV-1546
Me
Me
Me
—
2-thienyl
—
Me
racemic


IV-1547
Me
Me
Me
—
2-thienyl
—
Me
(+)-


IV-1548
Me
Me
Me
—
2-thienyl
—
Me
(−)-


IV-1549
Me
Me
Me
—
2-thienyl
—
CHF2
racemic


IV-1550
Me
Me
Me
—
2-thienyl
—
CHF2
(+)-


IV-1551
Me
Me
Me
—
2-thienyl
—
CHF2
(−)-

















TABLE 95








(IV)




embedded image





















Com-










pound







Config-


No.
R1
R2
R3
L2
R4
L3
R5
uration





IV-1552
Me
Me
Me
—
2-thienyl
—
CF3
racemic


IV-1553
Me
Me
Me
—
2-thienyl
—
CF3
(+)-


IV-1554
Me
Me
Me
—
2-thienyl
—
CF3
(−)-


IV-1555
Me
Me
Me
—
2-thienyl
—
Et
racemic


IV-1556
Me
Me
Me
—
2-thienyl
—
Et
(+)-


IV-1557
Me
Me
Me
—
2-thienyl
—
Et
(−)-


IV-1558
Me
Me
Me
—
2-thienyl
—
nPr
racemic


IV-1559
Me
Me
Me
—
2-thienyl
—
nPr
(+)-


IV-1560
Me
Me
Me
—
2-thienyl
—
nPr
(−)-


IV-1561
Me
Me
Me
—
2-thienyl
—
iPr
racemic


IV-1562
Me
Me
Me
—
2-thienyl
—
iPr
(+)-


IV-1563
Me
Me
Me
—
2-thienyl
—
iPr
(−)-


IV-1564
Me
Me
Me
—
2-thienyl
—
cPr
racemic


IV-1565
Me
Me
Me
—
2-thienyl
—
cPr
(+)-


IV-1566
Me
Me
Me
—
2-thienyl
—
cPr
(−)-


IV-1567
Me
Me
Me
—
3-F-2-thienyl
—
H
racemic


IV-1568
Me
Me
Me
—
3-F-2-thienyl
—
H
(S)-


IV-1569
Me
Me
Me
—
3-F-2-thienyl
—
Me
racemic


IV-1570
Me
Me
Me
—
3-F-2-thienyl
—
Me
(S)-


IV-1571
Me
Me
Me
—
3-F-2-thienyl
—
CHF2
racemic


IV-1572
Me
Me
Me
—
3-F-2-thienyl
—
CHF2
(S)-


IV-1573
Me
Me
Me
—
3-F-2-thienyl
—
CF3
racemic


IV-1574
Me
Me
Me
—
3-F-2-thienyl
—
CF3
(S)-


IV-1575
Me
Me
Me
—
3-F-2-thienyl
—
Et
racemic


IV-1576
Me
Me
Me
—
3-F-2-thienyl
—
Et
(S)-


IV-1577
Me
Me
Me
—
3-F-2-thienyl
—
nPr
racemic


IV-1578
Me
Me
Me
—
3-F-2-thienyl
—
nPr
(S)-


IV-1579
Me
Me
Me
—
3-F-2-thienyl
—
iPr
racemic


IV-1580
Me
Me
Me
—
3-F-2-thienyl
—
iPr
(S)-


IV-1581
Me
Me
Me
—
3-F-2-thienyl
—
cPr
racemic


IV-1582
Me
Me
Me
—
3-F-2-thienyl
—
cPr
(S)-


IV-1583
Me
Me
Me
—
4-F-2-thienyl
—
H
racemic


IV-1584
Me
Me
Me
—
4-F-2-thienyl
—
H
(S)-


IV-1585
Me
Me
Me
—
4-F-2-thienyl
—
Me
racemic


IV-1586
Me
Me
Me
—
4-F-2-thienyl
—
Me
(S)-


IV-1587
Me
Me
Me
—
4-F-2-thienyl
—
CHF2
racemic


IV-1588
Me
Me
Me
—
4-F-2-thienyl
—
CHF2
(S)-


IV-1589
Me
Me
Me
—
4-F-2-thienyl
—
CF3
racemic


IV-1590
Me
Me
Me
—
4-F-2-thienyl
—
CF3
(S)-


IV-1591
Me
Me
Me
—
4-F-2-thienyl
—
Et
racemic


IV-1592
Me
Me
Me
—
4-F-2-thienyl
—
Et
(S)-


IV-1593
Me
Me
Me
—
4-F-2-thienyl
—
nPr
racemic


IV-1594
Me
Me
Me
—
4-F-2-thienyl
—
nPr
(S)-


IV-1595
Me
Me
Me
—
4-F-2-thienyl
—
iPr
racemic


IV-1596
Me
Me
Me
—
4-F-2-thienyl
—
iPr
(S)-


IV-1597
Me
Me
Me
—
4-F-2-thienyl
—
cPr
racemic


IV-1598
Me
Me
Me
—
4-F-2-thienyl
—
cPr
(S)-


IV-1599
Me
Me
Me
—
4-F-2-thienyl
—
H
racemic


IV-1600
Me
Me
Me
—
4-F-2-thienyl
—
H
(S)-


IV-1601
Me
Me
Me
—
4-F-2-thienyl
—
Me
racemic

















TABLE 96








(IV)




embedded image





















Com-










pound







Config-


No.
R1
R2
R3
L2
R4
L3
R5
uration





IV-1602
Me
Me
Me
—
5-F-2-thienyl
—
Me
(S)-


IV-1603
Me
Me
Me
—
5-F-2-thienyl
—
CHF2
racemic


IV-1604
Me
Me
Me
—
5-F-2-thienyl
—
CHF2
(S)-


IV-1605
Me
Me
Me
—
5-F-2-thienyl
—
CF3
racemic


IV-1606
Me
Me
Me
—
5-F-2-thienyl
—
CF3
(S)-


IV-1607
Me
Me
Me
—
5-F-2-thienyl
—
Et
racemic


IV-1608
Me
Me
Me
—
5-F-2-thienyl
—
Et
(S)-


IV-1609
Me
Me
Me
—
5-F-2-thienyl
—
nPr
racemic


IV-1610
Me
Me
Me
—
5-F-2-thienyl
—
nPr
(S)-


IV-1611
Me
Me
Me
—
5-F-2-thienyl
—
iPr
racemic


IV-1612
Me
Me
Me
—
5-F-2-thienyl
—
iPr
(S)-


IV-1613
Me
Me
Me
—
5-F-2-thienyl
—
cPr
racemic


IV-1614
Me
Me
Me
—
5-F-2-thienyl
—
cPr
(S)-


IV-1615
Me
Me
Me
—
3-Cl-2-thienyl
—
H
racemic


IV-1616
Me
Me
Me
—
3-Cl-2-thienyl
—
H
(S)-


IV-1617
Me
Me
Me
—
3-Cl-2-thienyl
—
Me
racemic


IV-1618
Me
Me
Me
—
3-Cl-2-thienyl
—
Me
(S)-


IV-1619
Me
Me
Me
—
3-Cl-2-thienyl
—
CHF2
racemic


IV-1620
Me
Me
Me
—
3-Cl-2-thienyl
—
CHF2
(S)-


IV-1621
Me
Me
Me
—
3-Cl-2-thienyl
—
CF3
racemic


IV-1622
Me
Me
Me
—
3-Cl-2-thienyl
—
CF3
(S)-


IV-1623
Me
Me
Me
—
3-Cl-2-thienyl
—
Et
racemic


IV-1624
Me
Me
Me
—
3-Cl-2-thienyl
—
Et
(S)-


IV-1625
Me
Me
Me
—
3-Cl-2-thienyl
—
nPr
racemic


IV-1626
Me
Me
Me
—
3-Cl-2-thienyl
—
nPr
(S)-


IV-1627
Me
Me
Me
—
3-Cl-2-thienyl
—
iPr
racemic


IV-1628
Me
Me
Me
—
3-Cl-2-thienyl
—
iPr
(S)-


IV-1629
Me
Me
Me
—
3-Cl-2-thienyl
—
cPr
racemic


IV-1630
Me
Me
Me
—
3-Cl-2-thienyl
—
cPr
(S)-


IV-1631
Me
Me
Me
—
4-Cl-2-thienyl
—
H
racemic


IV-1632
Me
Me
Me
—
4-Cl-2-thienyl
—
H
(S)-


IV-1633
Me
Me
Me
—
4-Cl-2-thienyl
—
Me
racemic


IV-1634
Me
Me
Me
—
4-Cl-2-thienyl
—
Me
(S)-


IV-1635
Me
Me
Me
—
4-Cl-2-thienyl
—
CHF2
racemic


IV-1636
Me
Me
Me
—
4-Cl-2-thienyl
—
CHF2
(S)-


IV-1637
Me
Me
Me
—
4-Cl-2-thienyl
—
CF3
racemic


IV-1638
Me
Me
Me
—
4-Cl-2-thienyl
—
CF3
(S)-


IV-1639
Me
Me
Me
—
4-Cl-2-thienyl
—
Et
racemic


IV-1640
Me
Me
Me
—
4-Cl-2-thienyl
—
Et
(S)-


IV-1641
Me
Me
Me
—
4-Cl-2-thienyl
—
nPr
racemic


IV-1642
Me
Me
Me
—
4-Cl-2-thienyl
—
nPr
(S)-


IV-1643
Me
Me
Me
—
4-Cl-2-thienyl
—
iPr
racemic


IV-1644
Me
Me
Me
—
4-Cl-2-thienyl
—
iPr
(S)-


IV-1645
Me
Me
Me
—
4-Cl-2-thienyl
—
cPr
racemic


IV-1646
Me
Me
Me
—
4-Cl-2-thienyl
—
cPr
(S)-


IV-1647
Me
Me
Me
—
5-Cl-2-thienyl
—
H
racemic


IV-1648
Me
Me
Me
—
5-Cl-2-thienyl
—
H
(S)-


IV-1649
Me
Me
Me
—
5-Cl-2-thienyl
—
Me
racemic


IV-1650
Me
Me
Me
—
5-Cl-2-thienyl
—
Me
(S)-


IV-1651
Me
Me
Me
—
5-Cl-2-thienyl
—
CHF2
racemic

















TABLE 97








(IV)




embedded image





















Com-










pound







Config-


No.
R1
R2
R3
L2
R4
L3
R5
uration





IV-1652
Me
Me
Me
—
5-Cl-2-thienyl
—
CHF2
(S)-


IV-1653
Me
Me
Me
—
5-Cl-2-thienyl
—
CF3
racemic


IV-1654
Me
Me
Me
—
5-Cl-2-thienyl
—
CF3
(S)-


IV-1655
Me
Me
Me
—
5-Cl-2-thienyl
—
Et
racemic


IV-1656
Me
Me
Me
—
5-Cl-2-thienyl
—
Et
(S)-


IV-1657
Me
Me
Me
—
5-Cl-2-thienyl
—
nPr
racemic


IV-1658
Me
Me
Me
—
5-Cl-2-thienyl
—
nPr
(S)-


IV-1659
Me
Me
Me
—
5-Cl-2-thienyl
—
iPr
racemic


IV-1660
Me
Me
Me
—
5-Cl-2-thienyl
—
iPr
(S)-


IV-1661
Me
Me
Me
—
5-Cl-2-thienyl
—
cPr
racemic


IV-1662
Me
Me
Me
—
5-Cl-2-thienyl
—
cPr
(S)-


IV-1663
Me
Me
Me
—
3-Me-2-thienyl
—
H
racemic


IV-1664
Me
Me
Me
—
3-Me-2-thienyl
—
H
(S)-


IV-1665
Me
Me
Me
—
3-Me-2-thienyl
—
Me
racemic


IV-1666
Me
Me
Me
—
3-Me-2-thienyl
—
Me
(S)-


IV-1667
Me
Me
Me
—
3-Me-2-thienyl
—
CHF2
racemic


IV-1668
Me
Me
Me
—
3-Me-2-thienyl
—
CHF2
(S)-


IV-1669
Me
Me
Me
—
3-Me-2-thienyl
—
CF3
racemic


IV-1670
Me
Me
Me
—
3-Me-2-thienyl
—
CF3
(S)-


IV-1671
Me
Me
Me
—
3-Me-2-thienyl
—
Et
racemic


IV-1672
Me
Me
Me
—
3-Me-2-thienyl
—
Et
(S)-


IV-1673
Me
Me
Me
—
3-Me-2-thienyl
—
nPr
racemic


IV-1674
Me
Me
Me
—
3-Me-2-thienyl
—
nPr
(S)-


IV-1675
Me
Me
Me
—
3-Me-2-thienyl
—
iPr
racemic


IV-1676
Me
Me
Me
—
3-Me-2-thienyl
—
iPr
(S)-


IV-1677
Me
Me
Me
—
3-Me-2-thienyl
—
cPr
racemic


IV-1678
Me
Me
Me
—
3-Me-2-thienyl
—
cPr
(S)-


IV-1679
Me
Me
Me
—
4-Me-2-thienyl
—
H
racemic


IV-1680
Me
Me
Me
—
4-Me-2-thienyl
—
H
(S)-


IV-1681
Me
Me
Me
—
4-Me-2-thienyl
—
Me
racemic


IV-1682
Me
Me
Me
—
4-Me-2-thienyl
—
Me
(S)-


IV-1683
Me
Me
Me
—
4-Me-2-thienyl
—
CHF2
racemic


IV-1684
Me
Me
Me
—
4-Me-2-thienyl
—
CHF2
(S)-


IV-1685
Me
Me
Me
—
4-Me-2-thienyl
—
CF3
racemic


IV-1686
Me
Me
Me
—
4-Me-2-thienyl
—
CF3
(S)-


IV-1687
Me
Me
Me
—
4-Me-2-thienyl
—
Et
racemic


IV-1688
Me
Me
Me
—
4-Me-2-thienyl
—
Et
(S)-


IV-1689
Me
Me
Me
—
4-Me-2-thienyl
—
nPr
racemic


IV-1690
Me
Me
Me
—
4-Me-2-thienyl
—
nPr
(S)-


IV-1691
Me
Me
Me
—
4-Me-2-thienyl
—
iPr
racemic


IV-1692
Me
Me
Me
—
4-Me-2-thienyl
—
iPr
(S)-


IV-1693
Me
Me
Me
—
4-Me-2-thienyl
—
cPr
racemic


IV-1694
Me
Me
Me
—
4-Me-2-thienyl
—
cPr
(S)-


IV-1695
Me
Me
Me
—
5-Me-2-thienyl
—
H
racemic


IV-1696
Me
Me
Me
—
5-Me-2-thienyl
—
H
(S)-


IV-1697
Me
Me
Me
—
5-Me-2-thienyl
—
Me
racemic


IV-1698
Me
Me
Me
—
5-Me-2-thienyl
—
Me
(S)-


IV-1699
Me
Me
Me
—
5-Me-2-thienyl
—
CHF2
racemic


IV-1700
Me
Me
Me
—
5-Me-2-thienyl
—
CHF2
(S)-


IV-1701
Me
Me
Me
—
5-Me-2-thienyl
—
CF3
racemic

















TABLE 98








(IV)




embedded image





















Com-










pound







Config-


No.
R1
R2
R3
L2
R4
L3
R5
uration





IV-1702
Me
Me
Me
—
5-Me-2-thienyl
—
CF3
(S)-


IV-1703
Me
Me
Me
—
5-Me-2-thienyl
—
Et
racemic


IV-1704
Me
Me
Me
—
5-Me-2-thienyl
—
Et
(S)-


IV-1705
Me
Me
Me
—
5-Me-2-thienyl
—
nPr
racemic


IV-1706
Me
Me
Me
—
5-Me-2-thienyl
—
nPr
(S)-


IV-1707
Me
Me
Me
—
5-Me-2-thienyl
—
iPr
racemic


IV-1708
Me
Me
Me
—
5-Me-2-thienyl
—
iPr
(S)-


IV-1709
Me
Me
Me
—
5-Me-2-thienyl
—
cPr
racemic


IV-1710
Me
Me
Me
—
5-Me-2-thienyl
—
cPr
(S)-


IV-1711
Me
Me
Me
—
3-thienyl
—
H
racemic


IV-1712
Me
Me
Me
—
3-thienyl
—
H
(R)-


IV-1713
Me
Me
Me
—
3-thienyl
—
Me
racemic


IV-1714
Me
Me
Me
—
3-thienyl
—
Me
(R)-


IV-1715
Me
Me
Me
—
3-thienyl
—
CHF2
racemic


IV-1716
Me
Me
Me
—
3-thienyl
—
CHF2
(R)-


IV-1717
Me
Me
Me
—
3-thienyl
—
CF3
racemic


IV-1718
Me
Me
Me
—
3-thienyl
—
CF3
(R)-


IV-1719
Me
Me
Me
—
3-thienyl
—
Et
racemic


IV-1720
Me
Me
Me
—
3-thienyl
—
Et
(R)-


IV-1721
Me
Me
Me
—
3-thienyl
—
nPr
racemic


IV-1722
Me
Me
Me
—
3-thienyl
—
nPr
(R)-


IV-1723
Me
Me
Me
—
3-thienyl
—
iPr
racemic


IV-1724
Me
Me
Me
—
3-thienyl
—
iPr
(R)-


IV-1725
Me
Me
Me
—
3-thienyl
—
cPr
racemic


IV-1726
Me
Me
Me
—
3-thienyl
—
cPr
(R)-

















TABLE 99








(Va)




embedded image





















Com-










pound







Config-


No.
R1
R2
R3
L2
R4
L3
R5
uration





V-1 
Me
Me
Me
O
Ph
CH2
Me
racemic


V-2 
Me
Me
Me
O
Ph
CH2
Me
(S)-


V-3 
Me
Et
Me
O
Ph
CH2
Me
racemic


V-4 
Me
Et
Me
O
Ph
CH2
Me
(S)-


V-5 
Me
Me
Me
O
Ph
CH2
Et
racemic


V-6 
Me
Me
Me
O
Ph
CH2
Et
(S)-


V-7 
Me
Et
Me
O
Ph
CH2
Et
racemic


V-8 
Me
Et
Me
O
Ph
CH2
Et
(S)-


V-9 
Me
Me
Me
O
Ph
CH2
nPr
racemic


V-10
Me
Me
Me
O
Ph
CH2
nPr
(S)-


V-11
Me
Et
Me
O
Ph
CH2
nPr
racemic


V-12
Me
Et
Me
O
Ph
CH2
nPr
(S)-


V-13
Me
Me
Me
O
Ph
CH2
iPr
racemic


V-14
Me
Me
Me
O
Ph
CH2
iPr
(S)-


V-15
Me
Et
Me
O
Ph
CH2
iPr
racemic


V-16
Me
Et
Me
O
Ph
CH2
iPr
(S)-


V-17
Me
Me
Me
O
Ph
CH2
nBu
racemic


V-18
Me
Me
Me
O
Ph
CH2
nBu
(S)-


V-19
Me
Et
Me
O
Ph
CH2
nBu
racemic


V-20
Me
Et
Me
O
Ph
CH2
nBu
(S)-


V-21
Me
Me
Me
O
Ph
CH2
tBu
racemic


V-22
Me
Me
Me
O
Ph
CH2
tBu
(S)-


V-23
Me
Et
Me
O
Ph
CH2
tBu
racemic


V-24
Me
Et
Me
O
Ph
CH2
tBu
(S)-


V-25
Me
Me
Me
O
Ph
CH2
iBu
racemic


V-26
Me
Me
Me
O
Ph
CH2
iBu
(S)-


V-27
Me
Et
Me
O
Ph
CH2
iBu
racemic


V-28
Me
Et
Me
O
Ph
CH2
iBu
(S)-


V-29
Me
Me
Me
O
Ph
CH2
n-Heptyl
racemic


V-30
Me
Me
Me
O
Ph
CH2
n-Heptyl
(S)-


V-31
Me
Et
Me
O
Ph
CH2
n-Heptyl
racemic


V-32
Me
Et
Me
O
Ph
CH2
n-Heptyl
(S)-


V-33
Me
Me
Me
O
Ph
CH2
n-Undecyl
racemic


V-34
Me
Me
Me
O
Ph
CH2
n-Undecyl
(S)-


V-35
Me
Et
Me
O
Ph
CH2
n-Undecyl
racemic


V-36
Me
Et
Me
O
Ph
CH2
n-Undecyl
(S)-


V-37
Me
Me
Me
O
Ph
CH2
Ph
racemic


V-38
Me
Me
Me
O
Ph
CH2
Ph
(S)-


V-39
Me
Et
Me
O
Ph
CH2
Ph
racemic


V-40
Me
Et
Me
O
Ph
CH2
Ph
(S)-


V-41
Me
Me
Me
O
Ph
CH2
OEt
racemic


V-42
Me
Me
Me
O
Ph
CH2
OEt
(S)-


V-43
Me
Et
Me
O
Ph
CH2
OEt
racemic


V-44
Me
Et
Me
O
Ph
CH2
OEt
(S)-


V-45
Me
Me
Me
O
Ph
CH2
(CH2)2COOH
racemic


V-46
Me
Me
Me
O
Ph
CH2
(CH2)2COOH
(S)-


V-47
Me
Et
Me
O
Ph
CH2
(CH2)2COOH
racemic


V-48
Me
Et
Me
O
Ph
CH2
(CH2)2COOH
(S)-


V-49
Me
Me
Me
O
Ph
C(Me)2
Me
racemic


V-50
Me
Me
Me
O
Ph
C(Me)2
Me
(S)-

















TABLE 100








(Va)




embedded image





















Com-










pound







Config-


No.
R1
R2
R3
L2
R4
L3
R5
uration





V-51
Me
Et
Me
O
Ph
C(Me)2
Me
racemic


V-52
Me
Et
Me
O
Ph
C(Me)2
Me
(S)-


V-53
Me
Me
Me
O
Ph
C(Me)2
Et
racemic


V-54
Me
Me
Me
O
Ph
C(Me)2
Et
(S)-


V-55
Me
Et
Me
O
Ph
C(Me)2
Et
racemic


V-56
Me
Et
Me
O
Ph
C(Me)2
Et
(S)-


V-57
Me
Me
Me
O
Ph
C(Me)2
nPr
racemic


V-58
Me
Me
Me
O
Ph
C(Me)2
nPr
(S)-


V-59
Me
Et
Me
O
Ph
C(Me)2
nPr
racemic


V-60
Me
Et
Me
O
Ph
C(Me)2
nPr
(S)-


V-61
Me
Me
Me
O
Ph
C(Me)2
iPr
racemic


V-62
Me
Me
Me
O
Ph
C(Me)2
iPr
(S)-


V-63
Me
Et
Me
O
Ph
C(Me)2
iPr
racemic


V-64
Me
Et
Me
O
Ph
C(Me)2
iPr
(S)-


V-65
Me
Me
Me
O
Ph
C(Me)2
nBu
racemic


V-66
Me
Me
Me
O
Ph
C(Me)2
nBu
(S)-


V-67
Me
Et
Me
O
Ph
C(Me)2
nBu
racemic


V-68
Me
Et
Me
O
Ph
C(Me)2
nBu
(S)-


V-69
Me
Me
Me
O
Ph
C(Me)2
tBu
racemic


V-70
Me
Me
Me
O
Ph
C(Me)2
tBu
(S)-


V-71
Me
Et
Me
O
Ph
C(Me)2
tBu
racemic


V-72
Me
Et
Me
O
Ph
C(Me)2
tBu
(S)-


V-73
Me
Me
Me
O
Ph
C(Me)2
iBu
racemic


V-74
Me
Me
Me
O
Ph
C(Me)2
iBu
(S)-


V-75
Me
Et
Me
O
Ph
C(Me)2
iBu
racemic


V-76
Me
Et
Me
O
Ph
C(Me)2
iBu
(S)-


V-77
Me
Me
Me
O
Ph
C(Me)2
n-Heptyl
racemic


V-78
Me
Me
Me
O
Ph
C(Me)2
n-Heptyl
(S)-


V-79
Me
Et
Me
O
Ph
C(Me)2
n-Heptyl
racemic


V-80
Me
Et
Me
O
Ph
C(Me)2
n-Heptyl
(S)-


V-81
Me
Me
Me
O
Ph
C(Me)2
n-Undecyl
racemic


V-82
Me
Me
Me
O
Ph
C(Me)2
n-Undecyl
(S)-


V-83
Me
Et
Me
O
Ph
C(Me)2
n-Undecyl
racemic


V-84
Me
Et
Me
O
Ph
C(Me)2
n-Undecyl
(S)-


V-85
Me
Me
Me
O
Ph
C(Me)2
Ph
racemic


V-86
Me
Me
Me
O
Ph
C(Me)2
Ph
(S)-


V-87
Me
Et
Me
O
Ph
C(Me)2
Ph
racemic


V-88
Me
Et
Me
O
Ph
C(Me)2
Ph
(S)-


V-89
Me
Me
Me
O
Ph
C(Me)2
OEt
racemic


V-90
Me
Me
Me
O
Ph
C(Me)2
OEt
(S)-


V-91
Me
Et
Me
O
Ph
C(Me)2
OEt
racemic


V-92
Me
Et
Me
O
Ph
C(Me)2
OEt
(S)-


V-93
Me
Me
Me
O
Ph
C(Me)2
(CH2)2COOH
racemic


V-94
Me
Me
Me
O
Ph
C(Me)2
(CH2)2COOH
(S)-


V-95
Me
Et
Me
O
Ph
C(Me)2
(CH2)2COOH
racemic


V-96
Me
Et
Me
O
Ph
C(Me)2
(CH2)2COOH
(S)-


V-97
Me
Me
Me
O
Ph
(CH2)2
Me
racemic


V-98
Me
Me
Me
O
Ph
(CH2)2
Me
(R)-


V-99
Me
Et
Me
O
Ph
(CH2)2
Me
racemic


V-100
Me
Et
Me
O
Ph
(CH2)2
Me
(R)-

















TABLE 101








(Va)




embedded image





















Com-










pound







Config-


No.
R1
R2
R3
L2
R4
L3
R5
uration





V-101
Me
Me
Me
O
Ph
(CH2)2
Et
racemic


V-102
Me
Me
Me
O
Ph
(CH2)2
Et
(R)-


V-103
Me
Et
Me
O
Ph
(CH2)2
Et
racemic


V-104
Me
Et
Me
O
Ph
(CH2)2
Et
(R)-


V-105
Me
Me
Me
O
Ph
(CH2)2
nPr
racemic


V-106
Me
Me
Me
O
Ph
(CH2)2
nPr
(R)-


V-107
Me
Et
Me
O
Ph
(CH2)2
nPr
racemic


V-108
Me
Et
Me
O
Ph
(CH2)2
nPr
(R)-


V-109
Me
Me
Me
O
Ph
(CH2)2
iPr
racemic


V-110
Me
Me
Me
O
Ph
(CH2)2
iPr
(R)-


V-111
Me
Et
Me
O
Ph
(CH2)2
iPr
racemic


V-112
Me
Et
Me
O
Ph
(CH2)2
iPr
(R)-


V-113
Me
Me
Me
O
Ph
(CH2)2
nBu
racemic


V-114
Me
Me
Me
O
Ph
(CH2)2
nBu
(R)-


V-115
Me
Et
Me
O
Ph
(CH2)2
nBu
racemic


V-116
Me
Et
Me
O
Ph
(CH2)2
nBu
(R)-


V-117
Me
Me
Me
O
Ph
(CH2)2
tBu
racemic


V-118
Me
Me
Me
O
Ph
(CH2)2
tBu
(R)-


V-119
Me
Et
Me
O
Ph
(CH2)2
tBu
racemic


V-120
Me
Et
Me
O
Ph
(CH2)2
tBu
(R)-


V-121
Me
Me
Me
O
Ph
(CH2)2
iBu
racemic


V-122
Me
Me
Me
O
Ph
(CH2)2
iBu
(R)-


V-123
Me
Et
Me
O
Ph
(CH2)2
iBu
racemic


V-124
Me
Et
Me
O
Ph
(CH2)2
iBu
(R)-


V-125
Me
Me
Me
O
Ph
(CH2)2
n-Heptyl
racemic


V-126
Me
Me
Me
O
Ph
(CH2)2
n-Heptyl
(R)-


V-127
Me
Et
Me
O
Ph
(CH2)2
n-Heptyl
racemic


V-128
Me
Et
Me
O
Ph
(CH2)2
n-Heptyl
(R)-


V-129
Me
Me
Me
O
Ph
(CH2)2
n-Undecyl
racemic


V-130
Me
Me
Me
O
Ph
(CH2)2
n-Undecyl
(R)-


V-131
Me
Et
Me
O
Ph
(CH2)2
n-Undecyl
racemic


V-132
Me
Et
Me
O
Ph
(CH2)2
n-Undecyl
(R)-


V-133
Me
Me
Me
O
Ph
(CH2)2
Ph
racemic


V-134
Me
Me
Me
O
Ph
(CH2)2
Ph
(R)-


V-135
Me
Et
Me
O
Ph
(CH2)2
Ph
racemic


V-136
Me
Et
Me
O
Ph
(CH2)2
Ph
(R)-


V-137
Me
Me
Me
O
Ph
(CH2)2
OEt
racemic


V-138
Me
Me
Me
O
Ph
(CH2)2
OEt
(R)-


V-139
Me
Et
Me
O
Ph
(CH2)2
OEt
racemic


V-140
Me
Et
Me
O
Ph
(CH2)2
OEt
(R)-


V-141
Me
Me
Me
O
Ph
(CH2)2
(CH2)2COOH
racemic


V-142
Me
Me
Me
O
Ph
(CH2)2
(CH2)2COOH
(R)-


V-143
Me
Et
Me
O
Ph
(CH2)2
(CH2)2COOH
racemic


V-144
Me
Et
Me
O
Ph
(CH2)2
(CH2)2COOH
(R)-


V-145
Me
Me
Me
O
Ph
CH2C(Me)2
Me
racemic


V-146
Me
Me
Me
O
Ph
CH2C(Me)2
Me
(R)-


V-147
Me
Et
Me
O
Ph
CH2C(Me)2
Me
racemic


V-148
Me
Et
Me
O
Ph
CH2C(Me)2
Me
(R)-


V-149
Me
Me
Me
O
Ph
CH2C(Me)2
Et
racemic


V-150
Me
Me
Me
O
Ph
CH2C(Me)2
Et
(R)-

















TABLE 102








(Va)




embedded image





















Com-










pound







Config-


No.
R1
R2
R3
L2
R4
L3
R5
uration





V-151
Me
Et
Me
O
Ph
CH2C(Me)2
Et
racemic


V-152
Me
Et
Me
O
Ph
CH2C(Me)2
Et
(R)-


V-153
Me
Me
Me
O
Ph
CH2C(Me)2
nPr
racemic


V-154
Me
Me
Me
O
Ph
CH2C(Me)2
nPr
(R)-


V-155
Me
Et
Me
O
Ph
CH2C(Me)2
nPr
racemic


V-156
Me
Et
Me
O
Ph
CH2C(Me)2
nPr
(R)-


V-157
Me
Me
Me
O
Ph
CH2C(Me)2
iPr
racemic


V-158
Me
Me
Me
O
Ph
CH2C(Me)2
iPr
(R)-


V-159
Me
Et
Me
O
Ph
CH2C(Me)2
iPr
racemic


V-160
Me
Et
Me
O
Ph
CH2C(Me)2
iPr
(R)-


V-161
Me
Me
Me
O
Ph
CH2C(Me)2
nBu
racemic


V-162
Me
Me
Me
O
Ph
CH2C(Me)2
nBu
(R)-


V-163
Me
Et
Me
O
Ph
CH2C(Me)2
nBu
racemic


V-164
Me
Et
Me
O
Ph
CH2C(Me)2
nBu
(R)-


V-165
Me
Me
Me
O
Ph
CH2C(Me)2
tBu
racemic


V-166
Me
Me
Me
O
Ph
CH2C(Me)2
tBu
(R)-


V-167
Me
Et
Me
O
Ph
CH2C(Me)2
tBu
racemic


V-168
Me
Et
Me
O
Ph
CH2C(Me)2
tBu
(R)-


V-169
Me
Me
Me
O
Ph
CH2C(Me)2
iBu
racemic


V-170
Me
Me
Me
O
Ph
CH2C(Me)2
iBu
(R)-


V-171
Me
Et
Me
O
Ph
CH2C(Me)2
iBu
racemic


V-172
Me
Et
Me
O
Ph
CH2C(Me)2
iBu
(R)-


V-173
Me
Me
Me
O
Ph
CH2C(Me)2
n-Heptyl
racemic


V-174
Me
Me
Me
O
Ph
CH2C(Me)2
n-Heptyl
(R)-


V-175
Me
Et
Me
O
Ph
CH2C(Me)2
n-Heptyl
racemic


V-176
Me
Et
Me
O
Ph
CH2C(Me)2
n-Heptyl
(R)-


V-177
Me
Me
Me
O
Ph
CH2C(Me)2
n-Undecyl
racemic


V-178
Me
Me
Me
O
Ph
CH2C(Me)2
n-Undecyl
(R)-


V-179
Me
Et
Me
O
Ph
CH2C(Me)2
n-Undecyl
racemic


V-180
Me
Et
Me
O
Ph
CH2C(Me)2
n-Undecyl
(R)-


V-181
Me
Me
Me
O
Ph
CH2C(Me)2
Ph
racemic


V-182
Me
Me
Me
O
Ph
CH2C(Me)2
Ph
(R)-


V-183
Me
Et
Me
O
Ph
CH2C(Me)2
Ph
racemic


V-184
Me
Et
Me
O
Ph
CH2C(Me)2
Ph
(R)-


V-185
Me
Me
Me
O
Ph
CH2C(Me)2
OEt
racemic


V-186
Me
Me
Me
O
Ph
CH2C(Me)2
OEt
(R)-


V-187
Me
Et
Me
O
Ph
CH2C(Me)2
OEt
racemic


V-188
Me
Et
Me
O
Ph
CH2C(Me)2
OEt
(R)-


V-189
Me
Me
Me
O
Ph
CH2C(Me)2
(CH2)2COOH
racemic


V-190
Me
Me
Me
O
Ph
CH2C(Me)2
(CH2)2COOH
(R)-


V-191
Me
Et
Me
O
Ph
CH2C(Me)2
(CH2)2COOH
racemic


V-192
Me
Et
Me
O
Ph
CH2C(Me)2
(CH2)2COOH
(R)-


V-193
Me
Me
Me
NH
Ph
CH2
Me
racemic


V-194
Me
Me
Me
NH
Ph
CH2
Me
(S)-


V-195
Me
Et
Me
NH
Ph
CH2
Me
racemic


V-196
Me
Et
Me
NH
Ph
CH2
Me
(S)-


V-197
Me
Me
Me
NH
Ph
CH2
Et
racemic


V-198
Me
Me
Me
NH
Ph
CH2
Et
(S)-


V-199
Me
Et
Me
NH
Ph
CH2
Et
racemic


V-200
Me
Et
Me
NH
Ph
CH2
Et
(S)-

















TABLE 103








(Va)




embedded image





















Com-










pound







Config-


No.
R1
R2
R3
L2
R4
L3
R5
uration





V-201
Me
Me
Me
NH
Ph
CH2
nPr
racemic


V-202
Me
Me
Me
NH
Ph
CH2
nPr
(S)-


V-203
Me
Et
Me
NH
Ph
CH2
nPr
racemic


V-204
Me
Et
Me
NH
Ph
CH2
nPr
(S)-


V-205
Me
Me
Me
NH
Ph
CH2
iPr
racemic


V-206
Me
Me
Me
NH
Ph
CH2
iPr
(S)-


V-207
Me
Et
Me
NH
Ph
CH2
iPr
racemic


V-208
Me
Et
Me
NH
Ph
CH2
iPr
(S)-


V-209
Me
Me
Me
NH
Ph
CH2
nBu
racemic


V-210
Me
Me
Me
NH
Ph
CH2
nBu
(S)-


V-211
Me
Et
Me
NH
Ph
CH2
nBu
racemic


V-212
Me
Et
Me
NH
Ph
CH2
nBu
(S)-


V-213
Me
Me
Me
NH
Ph
CH2
tBu
racemic


V-214
Me
Me
Me
NH
Ph
CH2
tBu
(S)-


V-215
Me
Et
Me
NH
Ph
CH2
tBu
racemic


V-216
Me
Et
Me
NH
Ph
CH2
tBu
(S)-


V-217
Me
Me
Me
NH
Ph
CH2
iBu
racemic


V-218
Me
Me
Me
NH
Ph
CH2
iBu
(S)-


V-219
Me
Et
Me
NH
Ph
CH2
iBu
racemic


V-220
Me
Et
Me
NH
Ph
CH2
iBu
(S)-


V-221
Me
Me
Me
NH
Ph
CH2
n-Heptyl
racemic


V-222
Me
Me
Me
NH
Ph
CH2
n-Heptyl
(S)-


V-223
Me
Et
Me
NH
Ph
CH2
n-Heptyl
racemic


V-224
Me
Et
Me
NH
Ph
CH2
n-Heptyl
(S)-


V-225
Me
Me
Me
NH
Ph
CH2
n-Undecyl
racemic


V-226
Me
Me
Me
NH
Ph
CH2
n-Undecyl
(S)-


V-227
Me
Et
Me
NH
Ph
CH2
n-Undecyl
racemic


V-228
Me
Et
Me
NH
Ph
CH2
n-Undecyl
(S)-


V-229
Me
Me
Me
NH
Ph
CH2
Ph
racemic


V-230
Me
Me
Me
NH
Ph
CH2
Ph
(S)-


V-231
Me
Et
Me
NH
Ph
CH2
Ph
racemic


V-232
Me
Et
Me
NH
Ph
CH2
Ph
(S)-


V-233
Me
Me
Me
NH
Ph
CH2
OEt
racemic


V-234
Me
Me
Me
NH
Ph
CH2
OEt
(S)-


V-235
Me
Et
Me
NH
Ph
CH2
OEt
racemic


V-236
Me
Et
Me
NH
Ph
CH2
OEt
(S)-


V-237
Me
Me
Me
NH
Ph
CH2
(CH2)2COOH
racemic


V-238
Me
Me
Me
NH
Ph
CH2
(CH2)2COOH
(S)-


V-239
Me
Et
Me
NH
Ph
CH2
(CH2)2COOH
racemic


V-240
Me
Et
Me
NH
Ph
CH2
(CH2)2COOH
(S)-


V-241
Me
Me
Me
NH
Ph
C(Me)2
Me
racemic


V-242
Me
Me
Me
NH
Ph
C(Me)2
Me
(S)-


V-243
Me
Et
Me
NH
Ph
C(Me)2
Me
racemic


V-244
Me
Et
Me
NH
Ph
C(Me)2
Me
(S)-


V-245
Me
Me
Me
NH
Ph
C(Me)2
Et
racemic


V-246
Me
Me
Me
NH
Ph
C(Me)2
Et
(S)-


V-247
Me
Et
Me
NH
Ph
C(Me)2
Et
racemic


V-248
Me
Et
Me
NH
Ph
C(Me)2
Et
(S)-


V-249
Me
Me
Me
NH
Ph
C(Me)2
nPr
racemic


V-250
Me
Me
Me
NH
Ph
C(Me)2
nPr
(S)-

















TABLE 104








(Va)




embedded image





















Com-







Con-


pound







figura-


No.
R1
R2
R3
L2
R4
L3
R6
tion





V-251
Me
Et
Me
NH
Ph
C(Me)2
nPr
racemic


V-252
Me
Et
Me
NH
Ph
C(Me)2
nPr
(S)-


V-253
Me
Me
Me
NH
Ph
C(Me)2
iPr
racemic


V-254
Me
Me
Me
NH
Ph
C(Me)2
iPr
(S)-


V-255
Me
Et
Me
NH
Ph
C(Me)2
iPr
racemic


V-256
Me
Et
Me
NH
Ph
C(Me)2
iPr
(S)-


V-257
Me
Me
Me
NH
Ph
C(Me)2
nBu
racemic


V-258
Me
Me
Me
NH
Ph
C(Me)2
nBu
(S)-


V-259
Me
Et
Me
NH
Ph
C(Me)2
nBu
racemic


V-260
Me
Et
Me
NH
Ph
C(Me)2
nBu
(S)-


V-261
Me
Me
Me
NH
Ph
C(Me)2
tBu
racemic


V-262
Me
Me
Me
NH
Ph
C(Me)2
tBu
(S)-


V-263
Me
Et
Me
NH
Ph
C(Me)2
tBu
racemic


V-264
Me
Et
Me
NH
Ph
C(Me)2
tBu
(S)-


V-265
Me
Me
Me
NH
Ph
C(Me)2
iBu
racemic


V-266
Me
Me
Me
NH
Ph
C(Me)2
iBu
(S)-


V-267
Me
Et
Me
NH
Ph
C(Me)2
iBu
racemic


V-268
Me
Et
Me
NH
Ph
C(Me)2
iBu
(S)-


V-269
Me
Me
Me
NH
Ph
C(Me)2
n-Heptyl
racemic


V-270
Me
Me
Me
NH
Ph
C(Me)2
n-Heptyl
(S)-


V-271
Me
Et
Me
NH
Ph
C(Me)2
n-Heptyl
racemic


V-272
Me
Et
Me
NH
Ph
C(Me)2
n-Heptyl
(S)-


V-273
Me
Me
Me
NH
Ph
C(Me)2
n-Undecyl
racemic


V-274
Me
Me
Me
NH
Ph
C(Me)2
n-Undecyl
(S)-


V-275
Me
Et
Me
NH
Ph
C(Me)2
n-Undecyl
racemic


V-276
Me
Et
Me
NH
Ph
C(Me)2
n-Undecyl
(S)-


V-277
Me
Me
Me
NH
Ph
C(Me)2
Ph
racemic


V-278
Me
Me
Me
NH
Ph
C(Me)2
Ph
(S)-


V-279
Me
Et
Me
NH
Ph
C(Me)2
Ph
racemic


V-280
Me
Et
Me
NH
Ph
C(Me)2
Ph
(S)-


V-281
Me
Me
Me
NH
Ph
C(Me)2
OEt
racemic


V-282
Me
Me
Me
NH
Ph
C(Me)2
OEt
(S)-


V-283
Me
Et
Me
NH
Ph
C(Me)2
OEt
racemic


V-284
Me
Et
Me
NH
Ph
C(Me)2
OEt
(S)-


V-285
Me
Me
Me
NH
Ph
C(Me)2
(CH2)2COOH
racemic


V-286
Me
Me
Me
NH
Ph
C(Me)2
(CH2)2COOH
(S)-


V-287
Me
Et
Me
NH
Ph
C(Me)2
(CH2)2COOH
racemic


V-288
Me
Et
Me
NH
Ph
C(Me)2
(CH2)2COOH
(S)-


V-289
Me
Me
Me
NH
Ph
(CH2)2
Me
racemic


V-290
Me
Me
Me
NH
Ph
(CH2)2
Me
(R)-


V-291
Me
Et
Me
NH
Ph
(CH2)2
Me
racemic


V-292
Me
Et
Me
NH
Ph
(CH2)2
Me
(R)-


V-293
Me
Me
Me
NH
Ph
(CH2)2
Et
racemic


V-294
Me
Me
Me
NH
Ph
(CH2)2
Et
(R)-


V-295
Me
Et
Me
NH
Ph
(CH2)2
Et
racemic


V-296
Me
Et
Me
NH
Ph
(CH2)2
Et
(R)-


V-297
Me
Me
Me
NH
Ph
(CH2)2
nPr
racemic


V-298
Me
Me
Me
NH
Ph
(CH2)2
nPr
(R)-


V-299
Me
Et
Me
NH
Ph
(CH2)2
nPr
racemic


V-300
Me
Et
Me
NH
Ph
(CH2)2
nPr
(R)-

















TABLE 105








(Va)




embedded image





















Com-







Con-


pound







figura-


No.
R1
R2
R3
L2
R4
L3
R6
tion





V-301
Me
Me
Me
NH
Ph
(CH2)2
iPr
racemic


V-302
Me
Me
Me
NH
Ph
(CH2)2
iPr
(R)-


V-303
Me
Et
Me
NH
Ph
(CH2)2
iPr
racemic


V-304
Me
Et
Me
NH
Ph
(CH2)2
iPr
(R)-


V-305
Me
Me
Me
NH
Ph
(CH2)2
nBu
racemic


V-306
Me
Me
Me
NH
Ph
(CH2)2
nBu
(R)-


V-307
Me
Et
Me
NH
Ph
(CH2)2
nBu
racemic


V-308
Me
Et
Me
NH
Ph
(CH2)2
nBu
(R)-


V-309
Me
Me
Me
NH
Ph
(CH2)2
tBu
racemic


V-310
Me
Me
Me
NH
Ph
(CH2)2
tBu
(R)-


V-311
Me
Et
Me
NH
Ph
(CH2)2
tBu
racemic


V-312
Me
Et
Me
NH
Ph
(CH2)2
tBu
(R)-


V-313
Me
Me
Me
NH
Ph
(CH2)2
iBu
racemic


V-314
Me
Me
Me
NH
Ph
(CH2)2
iBu
(R)-


V-315
Me
Et
Me
NH
Ph
(CH2)2
iBu
racemic


V-316
Me
Et
Me
NH
Ph
(CH2)2
iBu
(R)-


V-317
Me
Me
Me
NH
Ph
(CH2)2
n-Heptyl
racemic


V-318
Me
Me
Me
NH
Ph
(CH2)2
n-Heptyl
(R)-


V-319
Me
Et
Me
NH
Ph
(CH2)2
n-Heptyl
racemic


V-320
Me
Et
Me
NH
Ph
(CH2)2
n-Heptyl
(R)-


V-321
Me
Me
Me
NH
Ph
(CH2)2
n-Undecyl
racemic


V-322
Me
Me
Me
NH
Ph
(CH2)2
n-Undecyl
(R)-


V-323
Me
Et
Me
NH
Ph
(CH2)2
n-Undecyl
racemic


V-324
Me
Et
Me
NH
Ph
(CH2)2
n-Undecyl
(R)-


V-325
Me
Me
Me
NH
Ph
(CH2)2
Ph
racemic


V-326
Me
Me
Me
NH
Ph
(CH2)2
Ph
(R)-


V-327
Me
Et
Me
NH
Ph
(CH2)2
Ph
racemic


V-328
Me
Et
Me
NH
Ph
(CH2)2
Ph
(R)-


V-329
Me
Me
Me
NH
Ph
(CH2)2
OEt
racemic


V-330
Me
Me
Me
NH
Ph
(CH2)2
OEt
(R)-


V-331
Me
Et
Me
NH
Ph
(CH2)2
OEt
racemic


V-332
Me
Et
Me
NH
Ph
(CH2)2
OEt
(R)-


V-333
Me
Me
Me
NH
Ph
(CH2)2
(CH2)2COOH
racemic


V-334
Me
Me
Me
NH
Ph
(CH2)2
(CH2)2COOH
(R)-


V-335
Me
Et
Me
NH
Ph
(CH2)2
(CH2)2COOH
racemic


V-336
Me
Et
Me
NH
Ph
(CH2)2
(CH2)2COOH
(R)-


V-337
Me
Me
Me
NH
Ph
CH2C(Me)2
Me
racemic


V-338
Me
Me
Me
NH
Ph
CH2C(Me)2
Me
(R)-


V-339
Me
Et
Me
NH
Ph
CH2C(Me)2
Me
racemic


V-340
Me
Et
Me
NH
Ph
CH2C(Me)2
Me
(R)-


V-341
Me
Me
Me
NH
Ph
CH2C(Me)2
Et
racemic


V-342
Me
Me
Me
NH
Ph
CH2C(Me)2
Et
(R)-


V-343
Me
Et
Me
NH
Ph
CH2C(Me)2
Et
racemic


V-344
Me
Et
Me
NH
Ph
CH2C(Me)2
Et
(R)-


V-345
Me
Me
Me
NH
Ph
CH2C(Me)2
nPr
racemic


V-346
Me
Me
Me
NH
Ph
CH2C(Me)2
nPr
(R)-


V-347
Me
Et
Me
NH
Ph
CH2C(Me)2
nPr
racemic


V-348
Me
Et
Me
NH
Ph
CH2C(Me)2
nPr
(R)-


V-349
Me
Me
Me
NH
Ph
CH2C(Me)2
iPr
racemic


V-350
Me
Me
Me
NH
Ph
CH2C(Me)2
iPr
(R)-

















TABLE 106








(Va)




embedded image





















Com-







Con-


pound







figura-


No.
R1
R2
R3
L2
R4
L3
R6
tion





V-351
Me
Et
Me
NH
Ph
CH2C(Me)2
iPr
racemic


V-352
Me
Et
Me
NH
Ph
CH2C(Me)2
iPr
(R)-


V-353
Me
Me
Me
NH
Ph
CH2C(Me)2
nBu
racemic


V-354
Me
Me
Me
NH
Ph
CH2C(Me)2
nBu
(R)-


V-355
Me
Et
Me
NH
Ph
CH2C(Me)2
nBu
racemic


V-356
Me
Et
Me
NH
Ph
CH2C(Me)2
nBu
(R)-


V-357
Me
Me
Me
NH
Ph
CH2C(Me)2
tBu
racemic


V-358
Me
Me
Me
NH
Ph
CH2C(Me)2
tBu
(R)-


V-359
Me
Et
Me
NH
Ph
CH2C(Me)2
tBu
racemic


V-360
Me
Et
Me
NH
Ph
CH2C(Me)2
tBu
(R)-


V-361
Me
Me
Me
NH
Ph
CH2C(Me)2
iBu
racemic


V-362
Me
Me
Me
NH
Ph
CH2C(Me)2
iBu
(R)-


V-363
Me
Et
Me
NH
Ph
CH2C(Me)2
iBu
racemic


V-364
Me
Et
Me
NH
Ph
CH2C(Me)2
iBu
(R)-


V-365
Me
Me
Me
NH
Ph
CH2C(Me)2
n-Heptyl
racemic


V-366
Me
Me
Me
NH
Ph
CH2C(Me)2
n-Heptyl
(R)-


V-367
Me
Et
Me
NH
Ph
CH2C(Me)2
n-Heptyl
racemic


V-368
Me
Et
Me
NH
Ph
CH2C(Me)2
n-Heptyl
(R)-


V-369
Me
Me
Me
NH
Ph
CH2C(Me)2
n-Undecyl
racemic


V-370
Me
Me
Me
NH
Ph
CH2C(Me)2
n-Undecyl
(R)-


V-371
Me
Et
Me
NH
Ph
CH2C(Me)2
n-Undecyl
racemic


V-372
Me
Et
Me
NH
Ph
CH2C(Me)2
n-Undecyl
(R)-


V-373
Me
Me
Me
NH
Ph
CH2C(Me)2
Ph
racemic


V-374
Me
Me
Me
NH
Ph
CH2C(Me)2
Ph
(R)-


V-375
Me
Et
Me
NH
Ph
CH2C(Me)2
Ph
racemic


V-376
Me
Et
Me
NH
Ph
CH2C(Me)2
Ph
(R)-


V-377
Me
Me
Me
NH
Ph
CH2C(Me)2
OEt
racemic


V-378
Me
Me
Me
NH
Ph
CH2C(Me)2
OEt
(R)-


V-379
Me
Et
Me
NH
Ph
CH2C(Me)2
OEt
racemic


V-380
Me
Et
Me
NH
Ph
CH2C(Me)2
OEt
(R)-


V-381
Me
Me
Me
NH
Ph
CH2C(Me)2
(CH2)2COOH
racemic


V-382
Me
Me
Me
NH
Ph
CH2C(Me)2
(CH2)2COOH
(R)-


V-383
Me
Et
Me
NH
Ph
CH2C(Me)2
(CH2)2COOH
racemic


V-384
Me
Et
Me
NH
Ph
CH2C(Me)2
(CH2)2COOH
(R)-


V-385
Me
Me
Me
CH2
Ph
CH2
Me
racemic


V-386
Me
Me
Me
CH2
Ph
CH2
Me
(S)-


V-387
Me
Et
Me
CH2
Ph
CH2
Me
racemic


V-388
Me
Et
Me
CH2
Ph
CH2
Me
(S)-


V-389
Me
Me
Me
CH2
Ph
CH2
Et
racemic


V-390
Me
Me
Me
CH2
Ph
CH2
Et
(S)-


V-391
Me
Et
Me
CH2
Ph
CH2
Et
racemic


V-392
Me
Et
Me
CH2
Ph
CH2
Et
(S)-


V-393
Me
Me
Me
CH2
Ph
CH2
nPr
racemic


V-394
Me
Me
Me
CH2
Ph
CH2
nPr
(S)-


V-395
Me
Et
Me
CH2
Ph
CH2
nPr
racemic


V-396
Me
Et
Me
CH2
Ph
CH2
nPr
(S)-


V-397
Me
Me
Me
CH2
Ph
CH2
iPr
racemic


V-398
Me
Me
Me
CH2
Ph
CH2
iPr
(S)-


V-399
Me
Et
Me
CH2
Ph
CH2
iPr
racemic


V-400
Me
Et
Me
CH2
Ph
CH2
iPr
(S)-

















TABLE 107








(Va)




embedded image





















Com-







Con-


pound







figura-


No.
R1
R2
R3
L2
R4
L3
R6
tion





V-401
Me
Me
Me
CH2
Ph
CH2
nBu
racemic


V-402
Me
Me
Me
CH2
Ph
CH2
nBu
(S)-


V-403
Me
Et
Me
CH2
Ph
CH2
nBu
racemic


V-404
Me
Et
Me
CH2
Ph
CH2
nBu
(S)-


V-405
Me
Me
Me
CH2
Ph
CH2
tBu
racemic


V-406
Me
Me
Me
CH2
Ph
CH2
tBu
(S)-


V-407
Me
Et
Me
CH2
Ph
CH2
tBu
racemic


V-408
Me
Et
Me
CH2
Ph
CH2
tBu
(S)-


V-409
Me
Me
Me
CH2
Ph
CH2
iBu
racemic


V-410
Me
Me
Me
CH2
Ph
CH2
iBu
(S)-


V-411
Me
Et
Me
CH2
Ph
CH2
iBu
racemic


V-412
Me
Et
Me
CH2
Ph
CH2
iBu
(S)-


V-413
Me
Me
Me
CH2
Ph
CH2
n-Heptyl
racemic


V-414
Me
Me
Me
CH2
Ph
CH2
n-Heptyl
(S)-


V-415
Me
Et
Me
CH2
Ph
CH2
n-Heptyl
racemic


V-416
Me
Et
Me
CH2
Ph
CH2
n-Heptyl
(S)-


V-417
Me
Me
Me
CH2
Ph
CH2
n-Undecyl
racemic


V-418
Me
Me
Me
CH2
Ph
CH2
n-Undecyl
(S)-


V-419
Me
Et
Me
CH2
Ph
CH2
n-Undecyl
racemic


V-420
Me
Et
Me
CH2
Ph
CH2
n-Undecyl
(S)-


V-421
Me
Me
Me
CH2
Ph
CH2
Ph
racemic


V-422
Me
Me
Me
CH2
Ph
CH2
Ph
(S)-


V-423
Me
Et
Me
CH2
Ph
CH2
Ph
racemic


V-424
Me
Et
Me
CH2
Ph
CH2
Ph
(S)-


V-425
Me
Me
Me
CH2
Ph
CH2
OEt
racemic


V-426
Me
Me
Me
CH2
Ph
CH2
OEt
(S)-


V-427
Me
Et
Me
CH2
Ph
CH2
OEt
racemic


V-428
Me
Et
Me
CH2
Ph
CH2
OEt
(S)-


V-429
Me
Me
Me
CH2
Ph
CH2
(CH2)2COOH
racemic


V-430
Me
Me
Me
CH2
Ph
CH2
(CH2)2COOH
(S)-


V-431
Me
Et
Me
CH2
Ph
CH2
(CH2)2COOH
racemic


V-432
Me
Et
Me
CH2
Ph
CH2
(CH2)2COOH
(S)-


V-433
Me
Me
Me
CH2
Ph
—
Me
racemic


V-434
Me
Me
Me
CH2
Ph
—
Me
(S)-


V-435
Me
Et
Me
CH2
Ph
—
Me
racemic


V-436
Me
Et
Me
CH2
Ph
—
Me
(S)-


V-437
Me
Me
Me
CH2
Ph
—
Et
racemic


V-438
Me
Me
Me
CH2
Ph
—
Et
(S)-


V-439
Me
Et
Me
CH2
Ph
—
Et
racemic


V-440
Me
Et
Me
CH2
Ph
—
Et
(S)-


V-441
Me
Me
Me
CH2
Ph
—
nPr
racemic


V-442
Me
Me
Me
CH2
Ph
—
nPr
(S)-


V-443
Me
Et
Me
CH2
Ph
—
nPr
racemic


V-444
Me
Et
Me
CH2
Ph
—
nPr
(S)-


V-445
Me
Me
Me
CH2
Ph
—
iPr
racemic


V-446
Me
Me
Me
CH2
Ph
—
iPr
(S)-


V-447
Me
Et
Me
CH2
Ph
—
iPr
racemic


V-448
Me
Et
Me
CH2
Ph
—
iPr
(S)-


V-449
Me
Me
Me
CH2
Ph
—
nBu
racemic


V-450
Me
Me
Me
CH2
Ph
—
nBu
(S)-

















TABLE 108








(Va)




embedded image





















Com-







Con-


pound







figura-


No.
R1
R2
R3
L2
R4
L3
R6
tion





V-451
Me
Et
Me
CH2
Ph
—
nBu
racemic


V-452
Me
Et
Me
CH2
Ph
—
nBu
(S)-


V-453
Me
Me
Me
CH2
Ph
—
tBu
racemic


V-454
Me
Me
Me
CH2
Ph
—
tBu
(S)-


V-455
Me
Et
Me
CH2
Ph
—
tBu
racemic


V-456
Me
Et
Me
CH2
Ph
—
tBu
(S)-


V-457
Me
Me
Me
CH2
Ph
—
iBu
racemic


V-458
Me
Me
Me
CH2
Ph
—
iBu
(S)-


V-459
Me
Et
Me
CH2
Ph
—
iBu
racemic


V-460
Me
Et
Me
CH2
Ph
—
iBu
(S)-


V-461
Me
Me
Me
CH2
Ph
—
n-Heptyl
racemic


V-462
Me
Me
Me
CH2
Ph
—
n-Heptyl
(S)-


V-463
Me
Et
Me
CH2
Ph
—
n-Heptyl
racemic


V-464
Me
Et
Me
CH2
Ph
—
n-Heptyl
(S)-


V-465
Me
Me
Me
CH2
Ph
—
n-Undecyl
racemic


V-466
Me
Me
Me
CH2
Ph
—
n-Undecyl
(S)-


V-467
Me
Et
Me
CH2
Ph
—
n-Undecyl
racemic


V-468
Me
Et
Me
CH2
Ph
—
n-Undecyl
(S)-


V-469
Me
Me
Me
CH2
Ph
—
Ph
racemic


V-470
Me
Me
Me
CH2
Ph
—
Ph
(S)-


V-471
Me
Et
Me
CH2
Ph
—
Ph
racemic


V-472
Me
Et
Me
CH2
Ph
—
Ph
(S)-


V-473
Me
Me
Me
CH2
Ph
—
OEt
racemic


V-474
Me
Me
Me
CH2
Ph
—
OEt
(S)-


V-475
Me
Et
Me
CH2
Ph
—
OEt
racemic


V-476
Me
Et
Me
CH2
Ph
—
OEt
(S)-


V-477
Me
Me
Me
CH2
Ph
—
(CH2)2COOH
racemic


V-478
Me
Me
Me
CH2
Ph
—
(CH2)2COOH
(S)-


V-479
Me
Et
Me
CH2
Ph
—
(CH2)2COOH
racemic


V-480
Me
Et
Me
CH2
Ph
—
(CH2)2COOH
(S)-


V-481
Me
Me
Me
CH2
Ph
C(Me)2
Me
racemic


V-482
Me
Me
Me
CH2
Ph
C(Me)2
Me
(S)-


V-483
Me
Et
Me
CH2
Ph
C(Me)2
Me
racemic


V-484
Me
Et
Me
CH2
Ph
C(Me)2
Me
(S)-


V-485
Me
Me
Me
CH2
Ph
C(Me)2
Et
racemic


V-486
Me
Me
Me
CH2
Ph
C(Me)2
Et
(S)-


V-487
Me
Et
Me
CH2
Ph
C(Me)2
Et
racemic


V-488
Me
Et
Me
CH2
Ph
C(Me)2
Et
(S)-


V-489
Me
Me
Me
CH2
Ph
C(Me)2
nPr
racemic


V-490
Me
Me
Me
CH2
Ph
C(Me)2
nPr
(S)-


V-491
Me
Et
Me
CH2
Ph
C(Me)2
nPr
racemic


V-492
Me
Et
Me
CH2
Ph
C(Me)2
nPr
(S)-


V-493
Me
Me
Me
CH2
Ph
C(Me)2
iPr
racemic


V-494
Me
Me
Me
CH2
Ph
C(Me)2
iPr
(S)-


V-495
Me
Et
Me
CH2
Ph
C(Me)2
iPr
racemic


V-496
Me
Et
Me
CH2
Ph
C(Me)2
iPr
(S)-


V-497
Me
Me
Me
CH2
Ph
C(Me)2
nBu
racemic


V-498
Me
Me
Me
CH2
Ph
C(Me)2
nBu
(S)-


V-499
Me
Et
Me
CH2
Ph
C(Me)2
nBu
racemic


V-500
Me
Et
Me
CH2
Ph
C(Me)2
nBu
(S)-

















TABLE 109








(Va)




embedded image





















Com-







Con-


pound







figura-


No.
R1
R2
R3
L2
R4
L3
R6
tion





V-501
Me
Me
Me
CH2
Ph
C(Me)2
tBu
racemic


V-502
Me
Me
Me
CH2
Ph
C(Me)2
tBu
(S)-


V-503
Me
Et
Me
CH2
Ph
C(Me)2
tBu
racemic


V-504
Me
Et
Me
CH2
Ph
C(Me)2
tBu
(S)-


V-505
Me
Me
Me
CH2
Ph
C(Me)2
iBu
racemic


V-506
Me
Me
Me
CH2
Ph
C(Me)2
iBu
(S)-


V-507
Me
Et
Me
CH2
Ph
C(Me)2
iBu
racemic


V-508
Me
Et
Me
CH2
Ph
C(Me)2
iBu
(S)-


V-509
Me
Me
Me
CH2
Ph
C(Me)2
n-Heptyl
racemic


V-510
Me
Me
Me
CH2
Ph
C(Me)2
n-Heptyl
(S)-


V-511
Me
Et
Me
CH2
Ph
C(Me)2
n-Heptyl
racemic


V-512
Me
Et
Me
CH2
Ph
C(Me)2
n-Heptyl
(S)-


V-513
Me
Me
Me
CH2
Ph
C(Me)2
n-Undecyl
racemic


V-514
Me
Me
Me
CH2
Ph
C(Me)2
n-Undecyl
(S)-


V-515
Me
Et
Me
CH2
Ph
C(Me)2
n-Undecyl
racemic


V-516
Me
Et
Me
CH2
Ph
C(Me)2
n-Undecyl
(S)-


V-517
Me
Me
Me
CH2
Ph
C(Me)2
Ph
racemic


V-518
Me
Me
Me
CH2
Ph
C(Me)2
Ph
(S)-


V-519
Me
Et
Me
CH2
Ph
C(Me)2
Ph
racemic


V-520
Me
Et
Me
CH2
Ph
C(Me)2
Ph
(S)-


V-521
Me
Me
Me
CH2
Ph
C(Me)2
OEt
racemic


V-522
Me
Me
Me
CH2
Ph
C(Me)2
OEt
(S)-


V-523
Me
Et
Me
CH2
Ph
C(Me)2
OEt
racemic


V-524
Me
Et
Me
CH2
Ph
C(Me)2
OEt
(S)-


V-525
Me
Me
Me
CH2
Ph
C(Me)2
(CH2)2COOH
racemic


V-526
Me
Me
Me
CH2
Ph
C(Me)2
(CH2)2COOH
(S)-


V-527
Me
Et
Me
CH2
Ph
C(Me)2
(CH2)2COOH
racemic


V-528
Me
Et
Me
CH2
Ph
C(Me)2
(CH2)2COOH
(S)-


V-529
Me
Me
Me
CH2
Ph
(CH2)2
Me
racemic


V-530
Me
Me
Me
CH2
Ph
(CH2)2
Me
(S)-


V-531
Me
Et
Me
CH2
Ph
(CH2)2
Me
racemic


V-532
Me
Et
Me
CH2
Ph
(CH2)2
Me
(S)-


V-533
Me
Me
Me
CH2
Ph
(CH2)2
Et
racemic


V-534
Me
Me
Me
CH2
Ph
(CH2)2
Et
(S)-


V-535
Me
Et
Me
CH2
Ph
(CH2)2
Et
racemic


V-536
Me
Et
Me
CH2
Ph
(CH2)2
Et
(S)-


V-537
Me
Me
Me
CH2
Ph
(CH2)2
nPr
racemic


V-538
Me
Me
Me
CH2
Ph
(CH2)2
nPr
(S)-


V-539
Me
Et
Me
CH2
Ph
(CH2)2
nPr
racemic


V-540
Me
Et
Me
CH2
Ph
(CH2)2
nPr
(S)-


V-541
Me
Me
Me
CH2
Ph
(CH2)2
iPr
racemic


V-542
Me
Me
Me
CH2
Ph
(CH2)2
iPr
(S)-


V-543
Me
Et
Me
CH2
Ph
(CH2)2
iPr
racemic


V-544
Me
Et
Me
CH2
Ph
(CH2)2
iPr
(S)-


V-545
Me
Me
Me
CH2
Ph
(CH2)2
nBu
racemic


V-546
Me
Me
Me
CH2
Ph
(CH2)2
nBu
(S)-


V-547
Me
Et
Me
CH2
Ph
(CH2)2
nBu
racemic


V-548
Me
Et
Me
CH2
Ph
(CH2)2
nBu
(S)-


V-549
Me
Me
Me
CH2
Ph
(CH2)2
tBu
racemic


V-550
Me
Me
Me
CH2
Ph
(CH2)2
tBu
(S)-

















TABLE 110








(Va)




embedded image





















Com-







Con-


pound







figura-


No.
R1
R2
R3
L2
R4
L3
R6
tion





V-551
Me
Et
Me
CH2
Ph
(CH2)2
tBu
racemic


V-552
Me
Et
Me
CH2
Ph
(CH2)2
tBu
(S)-


V-553
Me
Me
Me
CH2
Ph
(CH2)2
iBu
racemic


V-554
Me
Me
Me
CH2
Ph
(CH2)2
iBu
(S)-


V-555
Me
Et
Me
CH2
Ph
(CH2)2
iBu
racemic


V-556
Me
Et
Me
CH2
Ph
(CH2)2
iBu
(S)-


V-557
Me
Me
Me
CH2
Ph
(CH2)2
n-Heptyl
racemic


V-558
Me
Me
Me
CH2
Ph
(CH2)2
n-Heptyl
(S)-


V-559
Me
Et
Me
CH2
Ph
(CH2)2
n-Heptyl
racemic


V-560
Me
Et
Me
CH2
Ph
(CH2)2
n-Heptyl
(S)-


V-561
Me
Me
Me
CH2
Ph
(CH2)2
n-Undecyl
racemic


V-562
Me
Me
Me
CH2
Ph
(CH2)2
n-Undecyl
(S)-


V-563
Me
Et
Me
CH2
Ph
(CH2)2
n-Undecyl
racemic


V-564
Me
Et
Me
CH2
Ph
(CH2)2
n-Undecyl
(S)-


V-565
Me
Me
Me
CH2
Ph
(CH2)2
Ph
racemic


V-566
Me
Me
Me
CH2
Ph
(CH2)2
Ph
(S)-


V-567
Me
Et
Me
CH2
Ph
(CH2)2
Ph
racemic


V-568
Me
Et
Me
CH2
Ph
(CH2)2
Ph
(S)-


V-569
Me
Me
Me
CH2
Ph
(CH2)2
OEt
racemic


V-570
Me
Me
Me
CH2
Ph
(CH2)2
OEt
(S)-


V-571
Me
Et
Me
CH2
Ph
(CH2)2
OEt
racemic


V-572
Me
Et
Me
CH2
Ph
(CH2)2
OEt
(S)-


V-573
Me
Me
Me
CH2
Ph
(CH2)2
(CH2)2COOH
racemic


V-574
Me
Me
Me
CH2
Ph
(CH2)2
(CH2)2COOH
(S)-


V-575
Me
Et
Me
CH2
Ph
(CH2)2
(CH2)2COOH
racemic


V-576
Me
Et
Me
CH2
Ph
(CH2)2
(CH2)2COOH
(S)-


V-577
Me
Me
Me
CH2
Ph
CH2C(Me)2
Me
racemic


V-578
Me
Me
Me
CH2
Ph
CH2C(Me)2
Me
(S)-


V-579
Me
Et
Me
CH2
Ph
CH2C(Me)2
Me
racemic


V-580
Me
Et
Me
CH2
Ph
CH2C(Me)2
Me
(S)-


V-581
Me
Me
Me
CH2
Ph
CH2C(Me)2
Et
racemic


V-582
Me
Me
Me
CH2
Ph
CH2C(Me)2
Et
(S)-


V-583
Me
Et
Me
CH2
Ph
CH2C(Me)2
Et
racemic


V-584
Me
Et
Me
CH2
Ph
CH2C(Me)2
Et
(S)-


V-585
Me
Me
Me
CH2
Ph
CH2C(Me)2
nPr
racemic


V-586
Me
Me
Me
CH2
Ph
CH2C(Me)2
nPr
(S)-


V-587
Me
Et
Me
CH2
Ph
CH2C(Me)2
nPr
racemic


V-588
Me
Et
Me
CH2
Ph
CH2C(Me)2
nPr
(S)-


V-589
Me
Me
Me
CH2
Ph
CH2C(Me)2
iPr
racemic


V-590
Me
Me
Me
CH2
Ph
CH2C(Me)2
iPr
(S)-


V-591
Me
Et
Me
CH2
Ph
CH2C(Me)2
iPr
racemic


V-592
Me
Et
Me
CH2
Ph
CH2C(Me)2
iPr
(S)-


V-593
Me
Me
Me
CH2
Ph
CH2C(Me)2
nBu
racemic


V-594
Me
Me
Me
CH2
Ph
CH2C(Me)2
nBu
(S)-


V-595
Me
Et
Me
CH2
Ph
CH2C(Me)2
nBu
racemic


V-596
Me
Et
Me
CH2
Ph
CH2C(Me)2
nBu
(S)-


V-597
Me
Me
Me
CH2
Ph
CH2C(Me)2
tBu
racemic


V-598
Me
Me
Me
CH2
Ph
CH2C(Me)2
tBu
(S)-


V-599
Me
Et
Me
CH2
Ph
CH2C(Me)2
tBu
racemic


V-600
Me
Et
Me
CH2
Ph
CH2C(Me)2
tBu
(S)-

















TABLE 111








(Va)




embedded image





















Com-







Con-


pound







figura-


No.
R1
R2
R3
L2
R4
L3
R6
tion





V-601
Me
Me
Me
CH2
Ph
CH2C(Me)2
iBu
racemic


V-602
Me
Me
Me
CH2
Ph
CH2C(Me)2
iBu
(S)-


V-603
Me
Et
Me
CH2
Ph
CH2C(Me)2
iBu
racemic


V-604
Me
Et
Me
CH2
Ph
CH2C(Me)2
iBu
(S)-


V-605
Me
Me
Me
CH2
Ph
CH2C(Me)2
n-Heptyl
racemic


V-606
Me
Me
Me
CH2
Ph
CH2C(Me)2
n-Heptyl
(S)-


V-607
Me
Et
Me
CH2
Ph
CH2C(Me)2
n-Heptyl
racemic


V-608
Me
Et
Me
CH2
Ph
CH2C(Me)2
n-Heptyl
(S)-


V-609
Me
Me
Me
CH2
Ph
CH2C(Me)2
n-Undecyl
racemic


V-610
Me
Me
Me
CH2
Ph
CH2C(Me)2
n-Undecyl
(S)-


V-611
Me
Et
Me
CH2
Ph
CH2C(Me)2
n-Undecyl
racemic


V-612
Me
Et
Me
CH2
Ph
CH2C(Me)2
n-Undecyl
(S)-


V-613
Me
Me
Me
CH2
Ph
CH2C(Me)2
Ph
racemic


V-614
Me
Me
Me
CH2
Ph
CH2C(Me)2
Ph
(S)-


V-615
Me
Et
Me
CH2
Ph
CH2C(Me)2
Ph
racemic


V-616
Me
Et
Me
CH2
Ph
CH2C(Me)2
Ph
(S)-


V-617
Me
Me
Me
CH2
Ph
CH2C(Me)2
OEt
racemic


V-618
Me
Me
Me
CH2
Ph
CH2C(Me)2
OEt
(S)-


V-619
Me
Et
Me
CH2
Ph
CH2C(Me)2
OEt
racemic


V-620
Me
Et
Me
CH2
Ph
CH2C(Me)2
OEt
(S)-


V-621
Me
Me
Me
CH2
Ph
CH2C(Me)2
(CH2)2COOH
racemic


V-622
Me
Me
Me
CH2
Ph
CH2C(Me)2
(CH2)2COOH
(S)-


V-623
Me
Et
Me
CH2
Ph
CH2C(Me)2
(CH2)2COOH
racemic


V-624
Me
Et
Me
CH2
Ph
CH2C(Me)2
(CH2)2COOH
(S)-

















TABLE 112








(Va)




embedded image





















Com-







Con-


pound







figura-


No.
R1
R2
R3
L2
R4
L3
R6
tion





V-1884
Me
Me
Me
—
Ph
—
Me
racemic


V-1885
Me
Me
Me
—
Ph
—
Me
(R)-


V-1886
Me
Et
Me
—
Ph
—
Me
racemic


V-1887
Me
Et
Me
—
Ph
—
Me
(R)-


V-1888
Me
Me
Me
—
Ph
—
Et
racemic


V-1889
Me
Me
Me
—
Ph
—
Et
(R)-


V-1890
Me
Et
Me
—
Ph
—
Et
racemic


V-1891
Me
Et
Me
—
Ph
—
Et
(R)-


V-1892
Me
Me
Me
—
Ph
—
nPr
racemic


V-1893
Me
Me
Me
—
Ph
—
nPr
(R)-


V-1894
Me
Et
Me
—
Ph
—
nPr
racemic


V-1895
Me
Et
Me
—
Ph
—
nPr
(R)-


V-1896
Me
Me
Me
—
Ph
—
iPr
racemic


V-1897
Me
Me
Me
—
Ph
—
iPr
(R)-


V-1898
Me
Et
Me
—
Ph
—
iPr
racemic


V-1899
Me
Et
Me
—
Ph
—
iPr
(R)-


V-1900
Me
Me
Me
—
Ph
—
nBu
racemic


V-1901
Me
Me
Me
—
Ph
—
nBu
(R)-


V-1902
Me
Et
Me
—
Ph
—
nBu
racemic


V-1903
Me
Et
Me
—
Ph
—
nBu
(R)-


V-1904
Me
Me
Me
—
Ph
—
tBu
racemic


V-1905
Me
Me
Me
—
Ph
—
tBu
(R)-


V-1906
Me
Et
Me
—
Ph
—
tBu
racemic


V-1907
Me
Et
Me
—
Ph
—
tBu
(R)-


V-1908
Me
Me
Me
—
Ph
—
iBu
racemic


V-1909
Me
Me
Me
—
Ph
—
iBu
(R)-


V-1910
Me
Et
Me
—
Ph
—
iBu
racemic


V-1911
Me
Et
Me
—
Ph
—
iBu
(R)-


V-1912
Me
Me
Me
—
Ph
—
n-Heptyl
racemic


V-1913
Me
Me
Me
—
Ph
—
n-Heptyl
(R)-


V-1914
Me
Et
Me
—
Ph
—
n-Heptyl
racemic


V-1915
Me
Et
Me
—
Ph
—
n-Heptyl
(R)-


V-1916
Me
Me
Me
—
Ph
—
n-Undecyl
racemic


V-1917
Me
Me
Me
—
Ph
—
n-Undecyl
(R)-


V-1918
Me
Et
Me
—
Ph
—
n-Undecyl
racemic


V-1919
Me
Et
Me
—
Ph
—
n-Undecyl
(R)-


V-1920
Me
Me
Me
—
Ph
—
OEt
racemic


V-1921
Me
Me
Me
—
Ph
—
OEt
(R)-


V-1922
Me
Et
Me
—
Ph
—
OEt
racemic


V-1923
Me
Et
Me
—
Ph
—
OEt
(R)-


V-1924
Me
Me
Me
—
Ph
—
(CH2)2COONa
racemic


V-1925
Me
Me
Me
—
Ph
—
(CH2)2COONa
(R)-


V-1926
Me
Et
Me
—
Ph
—
(CH2)2COONa
racemic


V-1927
Me
Et
Me
—
Ph
—
(CH2)2COONa
(R)-


V-1928
Me
Me
Me
—
Ph
CH2
Me
racemic


V-1929
Me
Me
Me
—
Ph
CH2
Me
(S)-


V-1930
Me
Et
Me
—
Ph
CH2
Me
racemic


V-1931
Me
Et
Me
—
Ph
CH2
Me
(S)-


V-1932
Me
Me
Me
—
Ph
CH2
Et
racemic


V-1933
Me
Me
Me
—
Ph
CH2
Et
(S)-

















TABLE 113








(Va)




embedded image





















Com-







Con-


pound







figura-


No.
R1
R2
R3
L2
R4
L3
R6
tion





V-1934
Me
Et
Me
—
Ph
CH2
Et
racemic


V-1935
Me
Et
Me
—
Ph
CH2
Et
(S)-


V-1936
Me
Me
Me
—
Ph
CH2
nPr
racemic


V-1937
Me
Me
Me
—
Ph
CH2
nPr
(S)-


V-1938
Me
Et
Me
—
Ph
CH2
nPr
racemic


V-1939
Me
Et
Me
—
Ph
CH2
nPr
(S)-


V-1940
Me
Me
Me
—
Ph
CH2
iPr
racemic


V-1941
Me
Me
Me
—
Ph
CH2
iPr
(S)-


V-1942
Me
Et
Me
—
Ph
CH2
iPr
racemic


V-1943
Me
Et
Me
—
Ph
CH2
iPr
(S)-


V-1944
Me
Me
Me
—
Ph
CH2
nBu
racemic


V-1945
Me
Me
Me
—
Ph
CH2
nBu
(S)-


V-1946
Me
Et
Me
—
Ph
CH2
nBu
racemic


V-1947
Me
Et
Me
—
Ph
CH2
nBu
(S)-


V-1948
Me
Me
Me
—
Ph
CH2
tBu
racemic


V-1949
Me
Me
Me
—
Ph
CH2
tBu
(S)-


V-1950
Me
Et
Me
—
Ph
CH2
tBu
racemic


V-1951
Me
Et
Me
—
Ph
CH2
tBu
(S)-


V-1952
Me
Me
Me
—
Ph
CH2
iBu
racemic


V-1953
Me
Me
Me
—
Ph
CH2
iBu
(S)-


V-1954
Me
Et
Me
—
Ph
CH2
iBu
racemic


V-1955
Me
Et
Me
—
Ph
CH2
iBu
(S)-


V-1956
Me
Me
Me
—
Ph
CH2
n-Heptyl
racemic


V-1957
Me
Me
Me
—
Ph
CH2
n-Heptyl
(S)-


V-1958
Me
Et
Me
—
Ph
CH2
n-Heptyl
racemic


V-1959
Me
Et
Me
—
Ph
CH2
n-Heptyl
(S)-


V-1960
Me
Me
Me
—
Ph
CH2
n-Undecyl
racemic


V-1961
Me
Me
Me
—
Ph
CH2
n-Undecyl
(S)-


V-1962
Me
Et
Me
—
Ph
CH2
n-Undecyl
racemic


V-1963
Me
Et
Me
—
Ph
CH2
n-Undecyl
(S)-


V-1964
Me
Me
Me
—
Ph
CH2
OEt
racemic


V-1965
Me
Me
Me
—
Ph
CH2
OEt
(S)-


V-1966
Me
Et
Me
—
Ph
CH2
OEt
racemic


V-1967
Me
Et
Me
—
Ph
CH2
OEt
(S)-


V-1968
Me
Me
Me
—
Ph
CH2
(CH2)2COONa
racemic


V-1969
Me
Me
Me
—
Ph
CH2
(CH2)2COONa
(S)-


V-1970
Me
Et
Me
—
Ph
CH2
(CH2)2COONa
racemic


V-1971
Me
Et
Me
—
Ph
CH2
(CH2)2COONa
(S)-
















TABLE 114







(Vb)




embedded image




















Com-










pound







Configura-


No.
R1
R2
R3
L2
R4
L3
R6
tion





V-625
Me
Me
Me
O
Ph
CH2
Me
racemic


V-626
Me
Me
Me
O
Ph
CH2
Me
(S)-


V-627
Me
Et
Me
O
Ph
CH2
Me
racemic


V-628
Me
Et
Me
O
Ph
CH2
Me
(S)-


V-629
Me
Me
Me
O
Ph
CH2
Et
racemic


V-630
Me
Me
Me
O
Ph
CH2
Et
(S)-


V-631
Me
Et
Me
O
Ph
CH2
Et
racemic


V-632
Me
Et
Me
O
Ph
CH2
Et
(S)-


V-633
Me
Me
Me
O
Ph
CH2
nPr
racemic


V-634
Me
Me
Me
O
Ph
CH2
nPr
(S)-


V-635
Me
Et
Me
O
Ph
CH2
nPr
racemic


V-636
Me
Et
Me
O
Ph
CH2
nPr
(S)-


V-637
Me
Me
Me
O
Ph
CH2
iPr
racemic


V-638
Me
Me
Me
O
Ph
CH2
iPr
(S)-


V-639
Me
Et
Me
O
Ph
CH2
iPr
racemic


V-640
Me
Et
Me
O
Ph
CH2
iPr
(S)-


V-641
Me
Me
Me
O
Ph
CH2
nBu
racemic


V-642
Me
Me
Me
O
Ph
CH2
nBu
(S)-


V-643
Me
Et
Me
O
Ph
CH2
nBu
racemic


V-644
Me
Et
Me
O
Ph
CH2
nBu
(S)-


V-645
Me
Me
Me
O
Ph
CH2
tBu
racemic


V-646
Me
Me
Me
O
Ph
CH2
tBu
(S)-


V-647
Me
Et
Me
O
Ph
CH2
tBu
racemic


V-648
Me
Et
Me
O
Ph
CH2
tBu
(S)-


V-649
Me
Me
Me
O
Ph
CH2
iBu
racemic


V-650
Me
Me
Me
O
Ph
CH2
iBu
(S)-


V-651
Me
Et
Me
O
Ph
CH2
iBu
racemic


V-652
Me
Et
Me
O
Ph
CH2
iBu
(S)-


V-653
Me
Me
Me
O
Ph
CH2
n-Heptyl
racemic


V-654
Me
Me
Me
O
Ph
CH2
n-Heptyl
(S)-


V-655
Me
Et
Me
O
Ph
CH2
n-Heptyl
racemic


V-656
Me
Et
Me
O
Ph
CH2
n-Heptyl
(S)-


V-657
Me
Me
Me
O
Ph
CH2
n-Undecyl
racemic


V-658
Me
Me
Me
O
Ph
CH2
n-Undecyl
(S)-


V-659
Me
Et
Me
O
Ph
CH2
n-Undecyl
racemic


V-660
Me
Et
Me
O
Ph
CH2
n-Undecyl
(S)-


V-661
Me
Me
Me
O
Ph
CH2
Ph
racemic


V-662
Me
Me
Me
O
Ph
CH2
Ph
(S)-


V-663
Me
Et
Me
O
Ph
CH2
Ph
racemic


V-664
Me
Et
Me
O
Ph
CH2
Ph
(S)-


V-665
Me
Me
Me
O
Ph
CH2
OEt
racemic


V-666
Me
Me
Me
O
Ph
CH2
OEt
(S)-


V-667
Me
Et
Me
O
Ph
CH2
OEt
racemic


V-668
Me
Et
Me
O
Ph
CH2
OEt
(S)-


V-669
Me
Me
Me
O
Ph
CH2
(CH2)2COOH
racemic


V-670
Me
Me
Me
O
Ph
CH2
(CH2)2COOH
(S)-


V-671
Me
Et
Me
O
Ph
CH2
(CH2)2COOH
racemic


V-672
Me
Et
Me
O
Ph
CH2
(CH2)2COOH
(S)-


V-673
Me
Me
Me
O
Ph
C(Me)2
Me
racemic


V-674
Me
Me
Me
O
Ph
C(Me)2
Me
(S)-


V-675
Me
Et
Me
O
Ph
C(Me)2
Me
racemic
















TABLE 115







(Vb)




embedded image




















Com-










pound







Configura-


No.
R1
R2
R3
L2
R4
L3
R6
tion





V-676
Me
Et
Me
O
Ph
C(Me)2
Me
(S)-


V-677
Me
Me
Me
O
Ph
C(Me)2
Et
racemic


V-678
Me
Me
Me
O
Ph
C(Me)2
Et
(S)-


V-679
Me
Et
Me
O
Ph
C(Me)2
Et
racemic


V-680
Me
Et
Me
O
Ph
C(Me)2
Et
(S)-


V-681
Me
Me
Me
O
Ph
C(Me)2
nPr
racemic


V-682
Me
Me
Me
O
Ph
C(Me)2
nPr
(S)-


V-683
Me
Et
Me
O
Ph
C(Me)2
nPr
racemic


V-684
Me
Et
Me
O
Ph
C(Me)2
nPr
(S)-


V-685
Me
Me
Me
O
Ph
C(Me)2
iPr
racemic


V-686
Me
Me
Me
O
Ph
C(Me)2
iPr
(S)-


V-687
Me
Et
Me
O
Ph
C(Me)2
iPr
racemic


V-688
Me
Et
Me
O
Ph
C(Me)2
iPr
(S)-


V-689
Me
Me
Me
O
Ph
C(Me)2
nBu
racemic


V-690
Me
Me
Me
O
Ph
C(Me)2
nBu
(S)-


V-691
Me
Et
Me
O
Ph
C(Me)2
nBu
racemic


V-692
Me
Et
Me
O
Ph
C(Me)2
nBu
(S)-


V-693
Me
Me
Me
O
Ph
C(Me)2
tBu
racemic


V-694
Me
Me
Me
O
Ph
C(Me)2
tBu
(S)-


V-695
Me
Et
Me
O
Ph
C(Me)2
tBu
racemic


V-696
Me
Et
Me
O
Ph
C(Me)2
tBu
(S)-


V-697
Me
Me
Me
O
Ph
C(Me)2
iBu
racemic


V-698
Me
Me
Me
O
Ph
C(Me)2
iBu
(S)-


V-699
Me
Et
Me
O
Ph
C(Me)2
iBu
racemic


V-700
Me
Et
Me
O
Ph
C(Me)2
iBu
(S)-


V-701
Me
Me
Me
O
Ph
C(Me)2
n-Heptyl
racemic


V-702
Me
Me
Me
O
Ph
C(Me)2
n-Heptyl
(S)-


V-703
Me
Et
Me
O
Ph
C(Me)2
n-Heptyl
racemic


V-704
Me
Et
Me
O
Ph
C(Me)2
n-Heptyl
(S)-


V-705
Me
Me
Me
O
Ph
C(Me)2
n-Undecyl
racemic


V-706
Me
Me
Me
O
Ph
C(Me)2
n-Undecyl
(S)-


V-707
Me
Et
Me
O
Ph
C(Me)2
n-Undecyl
racemic


V-708
Me
Et
Me
O
Ph
C(Me)2
n-Undecyl
(S)-


V-709
Me
Me
Me
O
Ph
C(Me)2
Ph
racemic


V-710
Me
Me
Me
O
Ph
C(Me)2
Ph
(S)-


V-711
Me
Et
Me
O
Ph
C(Me)2
Ph
racemic


V-712
Me
Et
Me
O
Ph
C(Me)2
Ph
(S)-


V-713
Me
Me
Me
O
Ph
C(Me)2
OEt
racemic


V-714
Me
Me
Me
O
Ph
C(Me)2
OEt
(S)-


V-715
Me
Et
Me
O
Ph
C(Me)2
OEt
racemic


V-716
Me
Et
Me
O
Ph
C(Me)2
OEt
(S)-


V-717
Me
Me
Me
O
Ph
C(Me)2
(CH2)2COOH
racemic


V-718
Me
Me
Me
O
Ph
C(Me)2
(CH2)2COOH
(S)-


V-719
Me
Et
Me
O
Ph
C(Me)2
(CH2)2COOH
racemic


V-720
Me
Et
Me
O
Ph
C(Me)2
(CH2)2COOH
(S)-


V-721
Me
Me
Me
O
Ph
(CH2)2
Me
racemic


V-722
Me
Me
Me
O
Ph
(CH2)2
Me
(R)-


V-723
Me
Et
Me
O
Ph
(CH2)2
Me
racemic


V-724
Me
Et
Me
O
Ph
(CH2)2
Me
(R)-


V-725
Me
Me
Me
O
Ph
(CH2)2
Et
racemic
















TABLE 116







(Vb)




embedded image




















Com-







Con-


pound







figura-


No.
R1
R2
R3
L2
R4
L3
R6
tion





V-726
Me
Me
Me
O
Ph
(CH2)2
Et
(R)-


V-727
Me
Et
Me
O
Ph
(CH2)2
Et
racemic


V-728
Me
Et
Me
O
Ph
(CH2)2
Et
(R)-


V-729
Me
Me
Me
O
Ph
(CH2)2
nPr
racemic


V-730
Me
Me
Me
O
Ph
(CH2)2
nPr
(R)-


V-731
Me
Et
Me
O
Ph
(CH2)2
nPr
racemic


V-732
Me
Et
Me
O
Ph
(CH2)2
nPr
(R)-


V-733
Me
Me
Me
O
Ph
(CH2)2
iPr
racemic


V-734
Me
Me
Me
O
Ph
(CH2)2
iPr
(R)-


V-735
Me
Et
Me
O
Ph
(CH2)2
iPr
racemic


V-736
Me
Et
Me
O
Ph
(CH2)2
iPr
(R)-


V-737
Me
Me
Me
O
Ph
(CH2)2
nBu
racemic


V-738
Me
Me
Me
O
Ph
(CH2)2
nBu
(R)-


V-739
Me
Et
Me
O
Ph
(CH2)2
nBu
racemic


V-740
Me
Et
Me
O
Ph
(CH2)2
nBu
(R)-


V-741
Me
Me
Me
O
Ph
(CH2)2
tBu
racemic


V-742
Me
Me
Me
O
Ph
(CH2)2
tBu
(R)-


V-743
Me
Et
Me
O
Ph
(CH2)2
tBu
racemic


V-744
Me
Et
Me
O
Ph
(CH2)2
tBu
(R)-


V-745
Me
Me
Me
O
Ph
(CH2)2
iBu
racemic


V-746
Me
Me
Me
O
Ph
(CH2)2
iBu
(R)-


V-747
Me
Et
Me
O
Ph
(CH2)2
iBu
racemic


V-748
Me
Et
Me
O
Ph
(CH2)2
iBu
(R)-


V-749
Me
Me
Me
O
Ph
(CH2)2
n-Heptyl
racemic


V-750
Me
Me
Me
O
Ph
(CH2)2
n-Heptyl
(R)-


V-751
Me
Et
Me
O
Ph
(CH2)2
n-Heptyl
racemic


V-752
Me
Et
Me
O
Ph
(CH2)2
n-Heptyl
(R)-


V-753
Me
Me
Me
O
Ph
(CH2)2
n-Undecyl
racemic


V-754
Me
Me
Me
O
Ph
(CH2)2
n-Undecyl
(R)-


V-755
Me
Et
Me
O
Ph
(CH2)2
n-Undecyl
racemic


V-756
Me
Et
Me
O
Ph
(CH2)2
n-Undecyl
(R)-


V-757
Me
Me
Me
O
Ph
(CH2)2
Ph
racemic


V-758
Me
Me
Me
O
Ph
(CH2)2
Ph
(R)-


V-759
Me
Et
Me
O
Ph
(CH2)2
Ph
racemic


V-760
Me
Et
Me
O
Ph
(CH2)2
Ph
(R)-


V-761
Me
Me
Me
O
Ph
(CH2)2
OEt
racemic


V-762
Me
Me
Me
O
Ph
(CH2)2
OEt
(R)-


V-763
Me
Et
Me
O
Ph
(CH2)2
OEt
racemic


V-764
Me
Et
Me
O
Ph
(CH2)2
OEt
(R)-


V-765
Me
Me
Me
O
Ph
(CH2)2
(CH2)2COOH
racemic


V-766
Me
Me
Me
O
Ph
(CH2)2
(CH2)2COOH
(R)-


V-767
Me
Et
Me
O
Ph
(CH2)2
(CH2)2COOH
racemic


V-768
Me
Et
Me
O
Ph
(CH2)2
(CH2)2COOH
(R)-


V-769
Me
Me
Me
O
Ph
CH2C(Me)2
Me
racemic


V-770
Me
Me
Me
O
Ph
CH2C(Me)2
Me
(R)-


V-771
Me
Et
Me
O
Ph
CH2C(Me)2
Me
racemic


V-772
Me
Et
Me
O
Ph
CH2C(Me)2
Me
(R)-


V-773
Me
Me
Me
O
Ph
CH2C(Me)2
Et
racemic


V-774
Me
Me
Me
O
Ph
CH2C(Me)2
Et
(R)-


V-775
Me
Et
Me
O
Ph
CH2C(Me)2
Et
racemic
















TABLE 117







(Vb)




embedded image




















Com-







Con-


pound







figura-


No.
R1
R2
R3
L2
R4
L3
R6
tion





V-776
Me
Et
Me
O
Ph
CH2C(Me)2
Et
(R)-


V-777
Me
Me
Me
O
Ph
CH2C(Me)2
nPr
racemic


V-778
Me
Me
Me
O
Ph
CH2C(Me)2
nPr
(R)-


V-779
Me
Et
Me
O
Ph
CH2C(Me)2
nPr
racemic


V-780
Me
Et
Me
O
Ph
CH2C(Me)2
nPr
(R)-


V-781
Me
Me
Me
O
Ph
CH2C(Me)2
iPr
racemic


V-782
Me
Me
Me
O
Ph
CH2C(Me)2
iPr
(R)-


V-783
Me
Et
Me
O
Ph
CH2C(Me)2
iPr
racemic


V-784
Me
Et
Me
O
Ph
CH2C(Me)2
iPr
(R)-


V-785
Me
Me
Me
O
Ph
CH2C(Me)2
nBu
racemic


V-786
Me
Me
Me
O
Ph
CH2C(Me)2
nBu
(R)-


V-787
Me
Et
Me
O
Ph
CH2C(Me)2
nBu
racemic


V-788
Me
Et
Me
O
Ph
CH2C(Me)2
nBu
(R)-


V-789
Me
Me
Me
O
Ph
CH2C(Me)2
tBu
racemic


V-790
Me
Me
Me
O
Ph
CH2C(Me)2
tBu
(R)-


V-791
Me
Et
Me
O
Ph
CH2C(Me)2
tBu
racemic


V-792
Me
Et
Me
O
Ph
CH2C(Me)2
tBu
(R)-


V-793
Me
Me
Me
O
Ph
CH2C(Me)2
iBu
racemic


V-794
Me
Me
Me
O
Ph
CH2C(Me)2
iBu
(R)-


V-795
Me
Et
Me
O
Ph
CH2C(Me)2
iBu
racemic


V-796
Me
Et
Me
O
Ph
CH2C(Me)2
iBu
(R)-


V-797
Me
Me
Me
O
Ph
CH2C(Me)2
n-Heptyl
racemic


V-798
Me
Me
Me
O
Ph
CH2C(Me)2
n-Heptyl
(R)-


V-799
Me
Et
Me
O
Ph
CH2C(Me)2
n-Heptyl
racemic


V-800
Me
Et
Me
O
Ph
CH2C(Me)2
n-Heptyl
(R)-


V-801
Me
Me
Me
O
Ph
CH2C(Me)2
n-Undecyl
racemic


V-802
Me
Me
Me
O
Ph
CH2C(Me)2
n-Undecyl
(R)-


V-803
Me
Et
Me
O
Ph
CH2C(Me)2
n-Undecyl
racemic


V-804
Me
Et
Me
O
Ph
CH2C(Me)2
n-Undecyl
(R)-


V-805
Me
Me
Me
O
Ph
CH2C(Me)2
Ph
racemic


V-806
Me
Me
Me
O
Ph
CH2C(Me)2
Ph
(R)-


V-807
Me
Et
Me
O
Ph
CH2C(Me)2
Ph
racemic


V-808
Me
Et
Me
O
Ph
CH2C(Me)2
Ph
(R)-


V-809
Me
Me
Me
O
Ph
CH2C(Me)2
OEt
racemic


V-810
Me
Me
Me
O
Ph
CH2C(Me)2
OEt
(R)-


V-811
Me
Et
Me
O
Ph
CH2C(Me)2
OEt
racemic


V-812
Me
Et
Me
O
Ph
CH2C(Me)2
OEt
(R)-


V-813
Me
Me
Me
O
Ph
CH2C(Me)2
(CH2)2COOH
racemic


V-814
Me
Me
Me
O
Ph
CH2C(Me)2
(CH2)2COOH
(R)-


V-815
Me
Et
Me
O
Ph
CH2C(Me)2
(CH2)2COOH
racemic


V-816
Me
Et
Me
O
Ph
CH2C(Me)2
(CH2)2COOH
(R)-


V-817
Me
Me
Me
NH
Ph
CH2
Me
racemic


V-818
Me
Me
Me
NH
Ph
CH2
Me
(S)-


V-819
Me
Et
Me
NH
Ph
CH2
Me
racemic


V-820
Me
Et
Me
NH
Ph
CH2
Me
(S)-


V-821
Me
Me
Me
NH
Ph
CH2
Et
racemic


V-822
Me
Me
Me
NH
Ph
CH2
Et
(S)-


V-823
Me
Et
Me
NH
Ph
CH2
Et
racemic


V-824
Me
Et
Me
NH
Ph
CH2
Et
(S)-


V-825
Me
Me
Me
NH
Ph
CH2
nPr
racemic
















TABLE 118







(Vb)




embedded image




















Com-







Con-


pound







figura-


No.
R1
R2
R3
L2
R4
L3
R6
tion





V-826
Me
Me
Me
NH
Ph
CH2
nPr
(S)-


V-827
Me
Et
Me
NH
Ph
CH2
nPr
racemic


V-828
Me
Et
Me
NH
Ph
CH2
nPr
(S)-


V-829
Me
Me
Me
NH
Ph
CH2
iPr
racemic


V-830
Me
Me
Me
NH
Ph
CH2
iPr
(S)-


V-831
Me
Et
Me
NH
Ph
CH2
iPr
racemic


V-832
Me
Et
Me
NH
Ph
CH2
iPr
(S)-


V-833
Me
Me
Me
NH
Ph
CH2
nBu
racemic


V-834
Me
Me
Me
NH
Ph
CH2
nBu
(S)-


V-835
Me
Et
Me
NH
Ph
CH2
nBu
racemic


V-836
Me
Et
Me
NH
Ph
CH2
nBu
(S)-


V-837
Me
Me
Me
NH
Ph
CH2
tBu
racemic


V-838
Me
Me
Me
NH
Ph
CH2
tBu
(S)-


V-839
Me
Et
Me
NH
Ph
CH2
tBu
racemic


V-840
Me
Et
Me
NH
Ph
CH2
tBu
(S)-


V-841
Me
Me
Me
NH
Ph
CH2
iBu
racemic


V-842
Me
Me
Me
NH
Ph
CH2
iBu
(S)-


V-843
Me
Et
Me
NH
Ph
CH2
iBu
racemic


V-844
Me
Et
Me
NH
Ph
CH2
iBu
(S)-


V-845
Me
Me
Me
NH
Ph
CH2
n-Heptyl
racemic


V-846
Me
Me
Me
NH
Ph
CH2
n-Heptyl
(S)-


V-847
Me
Et
Me
NH
Ph
CH2
n-Heptyl
racemic


V-848
Me
Et
Me
NH
Ph
CH2
n-Heptyl
(S)-


V-849
Me
Me
Me
NH
Ph
CH2
n-Undecyl
racemic


V-850
Me
Me
Me
NH
Ph
CH2
n-Undecyl
(S)-


V-851
Me
Et
Me
NH
Ph
CH2
n-Undecyl
racemic


V-852
Me
Et
Me
NH
Ph
CH2
n-Undecyl
(S)-


V-853
Me
Me
Me
NH
Ph
CH2
Ph
racemic


V-854
Me
Me
Me
NH
Ph
CH2
Ph
(S)-


V-855
Me
Et
Me
NH
Ph
CH2
Ph
racemic


V-856
Me
Et
Me
NH
Ph
CH2
Ph
(S)-


V-857
Me
Me
Me
NH
Ph
CH2
OEt
racemic


V-858
Me
Me
Me
NH
Ph
CH2
OEt
(S)-


V-859
Me
Et
Me
NH
Ph
CH2
OEt
racemic


V-860
Me
Et
Me
NH
Ph
CH2
OEt
(S)-


V-861
Me
Me
Me
NH
Ph
CH2
(CH2)2COOH 
racemic


V-862
Me
Me
Me
NH
Ph
CH2
(CH2)2COOH
(S)-


V-863
Me
Et
Me
NH
Ph
CH2
(CH2)2COOH
racemic


V-864
Me
Et
Me
NH
Ph
CH2
(CH2)2COOH
(S)-


V-865
Me
Me
Me
NH
Ph
C(Me)2
Me
racemic


V-866
Me
Me
Me
NH
Ph
C(Me)2
Me
(S)-


V-867
Me
Et
Me
NH
Ph
C(Me)2
Me
racemic


V-868
Me
Et
Me
NH
Ph
C(Me)2
Me
(S)-


V-869
Me
Me
Me
NH
Ph
C(Me)2
Et
racemic


V-870
Me
Me
Me
NH
Ph
C(Me)2
Et
(S)-


V-871
Me
Et
Me
NH
Ph
C(Me)2
Et
racemic


V-872
Me
Et
Me
NH
Ph
C(Me)2
Et
(S)-


V-873
Me
Me
Me
NH
Ph
C(Me)2
nPr
racemic


V-874
Me
Me
Me
NH
Ph
C(Me)2
nPr
(S)-


V-875
Me
Et
Me
NH
Ph
C(Me)2
nPr
racemic
















TABLE 119







(Vb)




embedded image




















Com-







Con-


pound







figura-


No.
R1
R2
R3
L2
R4
L3
R6
tion





V-876
Me
Et
Me
NH
Ph
C(Me)2
nPr
(S)-


V-877
Me
Me
Me
NH
Ph
C(Me)2
iPr
racemic


V-878
Me
Me
Me
NH
Ph
C(Me)2
iPr
(S)-


V-879
Me
Et
Me
NH
Ph
C(Me)2
iPr
racemic


V-880
Me
Et
Me
NH
Ph
C(Me)2
iPr
(S)-


V-881
Me
Me
Me
NH
Ph
C(Me)2
nBu
racemic


V-882
Me
Me
Me
NH
Ph
C(Me)2
nBu
(S)-


V-883
Me
Et
Me
NH
Ph
C(Me)2
nBu
racemic


V-884
Me
Et
Me
NH
Ph
C(Me)2
nBu
(S)-


V-885
Me
Me
Me
NH
Ph
C(Me)2
tBu
racemic


V-886
Me
Me
Me
NH
Ph
C(Me)2
tBu
(S)-


V-887
Me
Et
Me
NH
Ph
C(Me)2
tBu
racemic


V-888
Me
Et
Me
NH
Ph
C(Me)2
tBu
(S)-


V-889
Me
Me
Me
NH
Ph
C(Me)2
iBu
racemic


V-890
Me
Me
Me
NH
Ph
C(Me)2
iBu
(S)-


V-891
Me
Et
Me
NH
Ph
C(Me)2
iBu
racemic


V-892
Me
Et
Me
NH
Ph
C(Me)2
iBu
(S)-


V-893
Me
Me
Me
NH
Ph
C(Me)2
n-Heptyl
racemic


V-894
Me
Me
Me
NH
Ph
C(Me)2
n-Heptyl
(S)-


V-895
Me
Et
Me
NH
Ph
C(Me)2
n-Heptyl
racemic


V-896
Me
Et
Me
NH
Ph
C(Me)2
n-Heptyl
(S)-


V-897
Me
Me
Me
NH
Ph
C(Me)2
n-Undecyl
racemic


V-898
Me
Me
Me
NH
Ph
C(Me)2
n-Undecyl
(S)-


V-899
Me
Et
Me
NH
Ph
C(Me)2
n-Undecyl
racemic


V-900
Me
Et
Me
NH
Ph
C(Me)2
n-Undecyl
(S)-


V-901
Me
Me
Me
NH
Ph
C(Me)2
Ph
racemic


V-902
Me
Me
Me
NH
Ph
C(Me)2
Ph
(S)-


V-903
Me
Et
Me
NH
Ph
C(Me)2
Ph
racemic


V-904
Me
Et
Me
NH
Ph
C(Me)2
Ph
(S)-


V-905
Me
Me
Me
NH
Ph
C(Me)2
OEt
racemic


V-906
Me
Me
Me
NH
Ph
C(Me)2
OEt
(S)-


V-907
Me
Et
Me
NH
Ph
C(Me)2
OEt
racemic


V-908
Me
Et
Me
NH
Ph
C(Me)2
OEt
(S)-


V-909
Me
Me
Me
NH
Ph
C(Me)2
(CH2)2COOH 
racemic


V-910
Me
Me
Me
NH
Ph
C(Me)2
(CH2)2COOH
(S)-


V-911
Me
Et
Me
NH
Ph
C(Me)2
(CH2)2COOH
racemic


V-912
Me
Et
Me
NH
Ph
C(Me)2
(CH2)2COOH
(S)-


V-913
Me
Me
Me
NH
Ph
(CH2)2
Me
racemic


V-914
Me
Me
Me
NH
Ph
(CH2)2
Me
(R)-


V-915
Me
Et
Me
NH
Ph
(CH2)2
Me
racemic


V-916
Me
Et
Me
NH
Ph
(CH2)2
Me
(R)-


V-917
Me
Me
Me
NH
Ph
(CH2)2
Et
racemic


V-918
Me
Me
Me
NH
Ph
(CH2)2
Et
(R)-


V-919
Me
Et
Me
NH
Ph
(CH2)2
Et
racemic


V-920
Me
Et
Me
NH
Ph
(CH2)2
Et
(R)-


V-921
Me
Me
Me
NH
Ph
(CH2)2
nPr
racemic


V-922
Me
Me
Me
NH
Ph
(CH2)2
nPr
(R)-


V-923
Me
Et
Me
NH
Ph
(CH2)2
nPr
racemic


V-924
Me
Et
Me
NH
Ph
(CH2)2
nPr
(R)-


V-925
Me
Me
Me
NH
Ph
(CH2)2
iPr
racemic
















TABLE 120







(Vb)




embedded image




















Com-







Con-


pound







figura-


No.
R1
R2
R3
L2
R4
L3
R6
tion





V-926
Me
Me
Me
NH
Ph
(CH2)2
iPr
(R)-


V-927
Me
Et
Me
NH
Ph
(CH2)2
iPr
racemic


V-928
Me
Et
Me
NH
Ph
(CH2)2
iPr
(R)-


V-929
Me
Me
Me
NH
Ph
(CH2)2
nBu
racemic


V-930
Me
Me
Me
NH
Ph
(CH2)2
nBu
(R)-


V-931
Me
Et
Me
NH
Ph
(CH2)2
nBu
racemic


V-932
Me
Et
Me
NH
Ph
(CH2)2
nBu
(R)-


V-933
Me
Me
Me
NH
Ph
(CH2)2
tBu
racemic


V-934
Me
Me
Me
NH
Ph
(CH2)2
tBu
(R)-


V-935
Me
Et
Me
NH
Ph
(CH2)2
tBu
racemic


V-936
Me
Et
Me
NH
Ph
(CH2)2
tBu
(R)-


V-937
Me
Me
Me
NH
Ph
(CH2)2
iBu
racemic


V-938
Me
Me
Me
NH
Ph
(CH2)2
iBu
(R)-


V-939
Me
Et
Me
NH
Ph
(CH2)2
iBu
racemic


V-940
Me
Et
Me
NH
Ph
(CH2)2
iBu
(R)-


V-941
Me
Me
Me
NH
Ph
(CH2)2
n-Heptyl
racemic


V-942
Me
Me
Me
NH
Ph
(CH2)2
n-Heptyl
(R)-


V-943
Me
Et
Me
NH
Ph
(CH2)2
n-Heptyl
racemic


V-944
Me
Et
Me
NH
Ph
(CH2)2
n-Heptyl
(R)-


V-945
Me
Me
Me
NH
Ph
(CH2)2
n-Undecyl
racemic


V-946
Me
Me
Me
NH
Ph
(CH2)2
n-Undecyl
(R)-


V-947
Me
Et
Me
NH
Ph
(CH2)2
n-Undecyl
racemic


V-948
Me
Et
Me
NH
Ph
(CH2)2
n-Undecyl
(R)-


V-949
Me
Me
Me
NH
Ph
(CH2)2
Ph
racemic


V-950
Me
Me
Me
NH
Ph
(CH2)2
Ph
(R)-


V-951
Me
Et
Me
NH
Ph
(CH2)2
Ph
racemic


V-952
Me
Et
Me
NH
Ph
(CH2)2
Ph
(R)-


V-953
Me
Me
Me
NH
Ph
(CH2)2
OEt
racemic


V-954
Me
Me
Me
NH
Ph
(CH2)2
OEt
(R)-


V-955
Me
Et
Me
NH
Ph
(CH2)2
OEt
racemic


V-956
Me
Et
Me
NH
Ph
(CH2)2
OEt
(R)-


V-957
Me
Me
Me
NH
Ph
(CH2)2
(CH2)2COOH
racemic


V-958
Me
Me
Me
NH
Ph
(CH2)2
(CH2)2COOH
(R)-


V-959
Me
Et
Me
NH
Ph
(CH2)2
(CH2)2COOH
racemic


V-960
Me
Et
Me
NH
Ph
(CH2)2
(CH2)2COOH
(R)-


V-961
Me
Me
Me
NH
Ph
CH2C(Me)2
Me
racemic


V-962
Me
Me
Me
NH
Ph
CH2C(Me)2
Me
(R)-


V-963
Me
Et
Me
NH
Ph
CH2C(Me)2
Me
racemic


V-964
Me
Et
Me
NH
Ph
CH2C(Me)2
Me
(R)-


V-965
Me
Me
Me
NH
Ph
CH2C(Me)2
Et
racemic


V-966
Me
Me
Me
NH
Ph
CH2C(Me)2
Et
(R)-


V-967
Me
Et
Me
NH
Ph
CH2C(Me)2
Et
racemic


V-968
Me
Et
Me
NH
Ph
CH2C(Me)2
Et
(R)-


V-969
Me
Me
Me
NH
Ph
CH2C(Me)2
nPr
racemic


V-970
Me
Me
Me
NH
Ph
CH2C(Me)2
nPr
(R)-


V-971
Me
Et
Me
NH
Ph
CH2C(Me)2
nPr
racemic


V-972
Me
Et
Me
NH
Ph
CH2C(Me)2
nPr
(R)-


V-973
Me
Me
Me
NH
Ph
CH2C(Me)2
iPr
racemic


V-974
Me
Me
Me
NH
Ph
CH2C(Me)2
iPr
(R)-


V-975
Me
Et
Me
NH
Ph
CH2C(Me)2
iPr
racemic
















TABLE 121







(Vb)




embedded image




















Com-







Con-


pound







figura-


No.
R1
R2
R3
L2
R4
L3
R6
tion





V-976
Me
Et
Me
NH
Ph
CH2C(Me)2
iPr
(R)-


V-977
Me
Me
Me
NH
Ph
CH2C(Me)2
nBu
racemic


V-978
Me
Me
Me
NH
Ph
CH2C(Me)2
nBu
(R)-


V-979
Me
Et
Me
NH
Ph
CH2C(Me)2
nBu
racemic


V-980
Me
Et
Me
NH
Ph
CH2C(Me)2
nBu
(R)-


V-981
Me
Me
Me
NH
Ph
CH2C(Me)2
tBu
racemic


V-982
Me
Me
Me
NH
Ph
CH2C(Me)2
tBu
(R)-


V-983
Me
Et
Me
NH
Ph
CH2C(Me)2
tBu
racemic


V-984
Me
Et
Me
NH
Ph
CH2C(Me)2
tBu
(R)-


V-985
Me
Me
Me
NH
Ph
CH2C(Me)2
iBu
racemic


V-986
Me
Me
Me
NH
Ph
CH2C(Me)2
iBu
(R)-


V-987
Me
Et
Me
NH
Ph
CH2C(Me)2
iBu
racemic


V-988
Me
Et
Me
NH
Ph
CH2C(Me)2
iBu
(R)-


V-989
Me
Me
Me
NH
Ph
CH2C(Me)2
n-Heptyl
racemic


V-990
Me
Me
Me
NH
Ph
CH2C(Me)2
n-Heptyl
(R)-


V-991
Me
Et
Me
NH
Ph
CH2C(Me)2
n-Heptyl
racemic


V-992
Me
Et
Me
NH
Ph
CH2C(Me)2
n-Heptyl
(R)-


V-993
Me
Me
Me
NH
Ph
CH2C(Me)2
n-Undecyl
racemic


V-994
Me
Me
Me
NH
Ph
CH2C(Me)2
n-Undecyl
(R)-


V-995
Me
Et
Me
NH
Ph
CH2C(Me)2
n-Undecyl
racemic


V-996
Me
Et
Me
NH
Ph
CH2C(Me)2
n-Undecyl
(R)-


V-997
Me
Me
Me
NH
Ph
CH2C(Me)2
Ph
racemic


V-998
Me
Me
Me
NH
Ph
CH2C(Me)2
Ph
(R)-


V-999
Me
Et
Me
NH
Ph
CH2C(Me)2
Ph
racemic


V-1000
Me
Et
Me
NH
Ph
CH2C(Me)2
Ph
(R)-


V-1001
Me
Me
Me
NH
Ph
CH2C(Me)2
OEt
racemic


V-1002
Me
Me
Me
NH
Ph
CH2C(Me)2
OEt
(R)-


V-1003
Me
Et
Me
NH
Ph
CH2C(Me)2
OEt
racemic


V-1004
Me
Et
Me
NH
Ph
CH2C(Me)2
OEt
(R)-


V-1005
Me
Me
Me
NH
Ph
CH2C(Me)2
(CH2)2COOH
racemic


V-1006
Me
Me
Me
NH
Ph
CH2C(Me)2
(CH2)2COOH
(R)-


V-1007
Me
Et
Me
NH
Ph
CH2C(Me)2
(CH2)2COOH
racemic


V-1008
Me
Et
Me
NH
Ph
CH2C(Me)2
(CH2)2COOH
(R)-


V-1009
Me
Me
Me
CH2
Ph
CH2
Me
racemic


V-1010
Me
Me
Me
CH2
Ph
CH2
Me
(S)-


V-1011
Me
Et
Me
CH2
Ph
CH2
Me
racemic


V-1012
Me
Et
Me
CH2
Ph
CH2
Me
(S)-


V-1013
Me
Me
Me
CH2
Ph
CH2
Et
racemic


V-1014
Me
Me
Me
CH2
Ph
CH2
Et
(S)-


V-1015
Me
Et
Me
CH2
Ph
CH2
Et
racemic


V-1016
Me
Et
Me
CH2
Ph
CH2
Et
(S)-


V-1017
Me
Me
Me
CH2
Ph
CH2
nPr
racemic


V-1018
Me
Me
Me
CH2
Ph
CH2
nPr
(S)-


V-1019
Me
Et
Me
CH2
Ph
CH2
nPr
racemic


V-1020
Me
Et
Me
CH2
Ph
CH2
nPr
(S)-


V-1021
Me
Me
Me
CH2
Ph
CH2
iPr
racemic


V-1022
Me
Me
Me
CH2
Ph
CH2
iPr
(S)-


V-1023
Me
Et
Me
CH2
Ph
CH2
iPr
racemic


V-1024
Me
Et
Me
CH2
Ph
CH2
iPr
(S)-


V-1025
Me
Me
Me
CH2
Ph
CH2
nBu
racemic
















TABLE 122







(Vb)




embedded image




















Com-







Con-


pound







figura-


No.
R1
R2
R3
L2
R4
L3
R6
tion





V-1026
Me
Me
Me
CH2
Ph
CH2
nBu
(S)-


V-1027
Me
Et
Me
CH2
Ph
CH2
nBu
racemic


V-1028
Me
Et
Me
CH2
Ph
CH2
nBu
(S)-


V-1029
Me
Me
Me
CH2
Ph
CH2
tBu
racemic


V-1030
Me
Me
Me
CH2
Ph
CH2
tBu
(S)-


V-1031
Me
Et
Me
CH2
Ph
CH2
tBu
racemic


V-1032
Me
Et
Me
CH2
Ph
CH2
tBu
(S)-


V-1033
Me
Me
Me
CH2
Ph
CH2
iBu
racemic


V-1034
Me
Me
Me
CH2
Ph
CH2
iBu
(S)-


V-1035
Me
Et
Me
CH2
Ph
CH2
iBu
racemic


V-1036
Me
Et
Me
CH2
Ph
CH2
iBu
(S)-


V-1037
Me
Me
Me
CH2
Ph
CH2
n-Heptyl
racemic


V-1038
Me
Me
Me
CH2
Ph
CH2
n-Heptyl
(S)-


V-1039
Me
Et
Me
CH2
Ph
CH2
n-Heptyl
racemic


V-1040
Me
Et
Me
CH2
Ph
CH2
n-Heptyl
(S)-


V-1041
Me
Me
Me
CH2
Ph
CH2
n-Undecyl
racemic


V-1042
Me
Me
Me
CH2
Ph
CH2
n-Undecyl
(S)-


V-1043
Me
Et
Me
CH2
Ph
CH2
n-Undecyl
racemic


V-1044
Me
Et
Me
CH2
Ph
CH2
n-Undecyl
(S)-


V-1045
Me
Me
Me
CH2
Ph
CH2
Ph
racemic


V-1046
Me
Me
Me
CH2
Ph
CH2
Ph
(S)-


V-1047
Me
Et
Me
CH2
Ph
CH2
Ph
racemic


V-1048
Me
Et
Me
CH2
Ph
CH2
Ph
(S)-


V-1049
Me
Me
Me
CH2
Ph
CH2
OEt
racemic


V-1050
Me
Me
Me
CH2
Ph
CH2
OEt
(S)-


V-1051
Me
Et
Me
CH2
Ph
CH2
OEt
racemic


V-1052
Me
Et
Me
CH2
Ph
CH2
OEt
(S)-


V-1053
Me
Me
Me
CH2
Ph
CH2
(CH2)2COOH
racemic


V-1054
Me
Me
Me
CH2
Ph
CH2
(CH2)2COOH
(S)-


V-1055
Me
Et
Me
CH2
Ph
CH2
(CH2)2COOH
racemic


V-1056
Me
Et
Me
CH2
Ph
CH2
(CH2)2COOH
(S)-


V-1057
Me
Me
Me
CH2
Ph
—
Me
racemic


V-1058
Me
Me
Me
CH2
Ph
—
Me
(S)-


V-1059
Me
Et
Me
CH2
Ph
—
Me
racemic


V-1060
Me
Et
Me
CH2
Ph
—
Me
(S)-


V-1061
Me
Me
Me
CH2
Ph
—
Et
racemic


V-1062
Me
Me
Me
CH2
Ph
—
Et
(S)-


V-1063
Me
Et
Me
CH2
Ph
—
Et
racemic


V-1064
Me
Et
Me
CH2
Ph
—
Et
(S)-


V-1065
Me
Me
Me
CH2
Ph
—
nPr
racemic


V-1066
Me
Me
Me
CH2
Ph
—
nPr
(S)-


V-1067
Me
Et
Me
CH2
Ph
—
nPr
racemic


V-1068
Me
Et
Me
CH2
Ph
—
nPr
(S)-


V-1069
Me
Me
Me
CH2
Ph
—
iPr
racemic


V-1070
Me
Me
Me
CH2
Ph
—
iPr
(S)-


V-1071
Me
Et
Me
CH2
Ph
—
iPr
racemic


V-1072
Me
Et
Me
CH2
Ph
—
iPr
(S)-


V-1073
Me
Me
Me
CH2
Ph
—
nBu
racemic


V-1074
Me
Me
Me
CH2
Ph
—
nBu
(S)-


V-1075
Me
Et
Me
CH2
Ph
—
nBu
racemic
















TABLE 123







(Vb)




embedded image




















Com-







Con-


pound







figura-


No.
R1
R2
R3
L2
R4
L3
R6
tion





V-1076
Me
Et
Me
CH2
Ph
—
nBu
(S)-


V-1077
Me
Me
Me
CH2
Ph
—
tBu
racemic


V-1078
Me
Me
Me
CH2
Ph
—
tBu
(S)-


V-1079
Me
Et
Me
CH2
Ph
—
tBu
racemic


V-1080
Me
Et
Me
CH2
Ph
—
tBu
(S)-


V-1081
Me
Me
Me
CH2
Ph
—
iBu
racemic


V-1082
Me
Me
Me
CH2
Ph
—
iBu
(S)-


V-1083
Me
Et
Me
CH2
Ph
—
iBu
racemic


V-1084
Me
Et
Me
CH2
Ph
—
iBu
(S)-


V-1085
Me
Me
Me
CH2
Ph
—
n-Heptyl
racemic


V-1086
Me
Me
Me
CH2
Ph
—
n-Heptyl
(S)-


V-1087
Me
Et
Me
CH2
Ph
—
n-Heptyl
racemic


V-1088
Me
Et
Me
CH2
Ph
—
n-Heptyl
(S)-


V-1089
Me
Me
Me
CH2
Ph
—
n-Undecyl
racemic


V-1090
Me
Me
Me
CH2
Ph
—
n-Undecyl
(S)-


V-1091
Me
Et
Me
CH2
Ph
—
n-Undecyl
racemic


V-1092
Me
Et
Me
CH2
Ph
—
n-Undecyl
(S)-


V-1093
Me
Me
Me
CH2
Ph
—
Ph
racemic


V-1094
Me
Me
Me
CH2
Ph
—
Ph
(S)-


V-1095
Me
Et
Me
CH2
Ph
—
Ph
racemic


V-1096
Me
Et
Me
CH2
Ph
—
Ph
(S)-


V-1097
Me
Me
Me
CH2
Ph
—
OEt
racemic


V-1098
Me
Me
Me
CH2
Ph
—
OEt
(S)-


V-1099
Me
Et
Me
CH2
Ph
—
OEt
racemic


V-1100
Me
Et
Me
CH2
Ph
—
OEt
(S)-


V-1101
Me
Me
Me
CH2
Ph
—
(CH2)2COOH
racemic


V-1102
Me
Me
Me
CH2
Ph
—
(CH2)2COOH
(S)-


V-1103
Me
Et
Me
CH2
Ph
—
(CH2)2COOH
racemic


V-1104
Me
Et
Me
CH2
Ph
—
(CH2)2COOH
(S)-


V-1105
Me
Me
Me
CH2
Ph
C(Me)2
Me
racemic


V-1106
Me
Me
Me
CH2
Ph
C(Me)2
Me
(S)-


V-1107
Me
Et
Me
CH2
Ph
C(Me)2
Me
racemic


V-1108
Me
Et
Me
CH2
Ph
C(Me)2
Me
(S)-


V-1109
Me
Me
Me
CH2
Ph
C(Me)2
Et
racemic


V-1110
Me
Me
Me
CH2
Ph
C(Me)2
Et
(S)-


V-1111
Me
Et
Me
CH2
Ph
C(Me)2
Et
racemic


V-1112
Me
Et
Me
CH2
Ph
C(Me)2
Et
(S)-


V-1113
Me
Me
Me
CH2
Ph
C(Me)2
nPr
racemic


V-1114
Me
Me
Me
CH2
Ph
C(Me)2
nPr
(S)-


V-1115
Me
Et
Me
CH2
Ph
C(Me)2
nPr
racemic


V-1116
Me
Et
Me
CH2
Ph
C(Me)2
nPr
(S)-


V-1117
Me
Me
Me
CH2
Ph
C(Me)2
iPr
racemic


V-1118
Me
Me
Me
CH2
Ph
C(Me)2
iPr
(S)-


V-1119
Me
Et
Me
CH2
Ph
C(Me)2
iPr
racemic


V-1120
Me
Et
Me
CH2
Ph
C(Me)2
iPr
(S)-


V-1121
Me
Me
Me
CH2
Ph
C(Me)2
nBu
racemic


V-1122
Me
Me
Me
CH2
Ph
C(Me)2
nBu
(S)-


V-1123
Me
Et
Me
CH2
Ph
C(Me)2
nBu
racemic


V-1124
Me
Et
Me
CH2
Ph
C(Me)2
nBu
(S)-


V-1125
Me
Me
Me
CH2
Ph
C(Me)2
tBu
racemic
















TABLE 124







(Vb)




embedded image




















Compound







Con-


No.
R1
R2
R3
L2
R4
L3
R6
figuration





V-1126
Me
Me
Me
CH2
Ph
C(Me)2
tBu
(S)-


V-1127
Me
Et
Me
CH2
Ph
C(Me)2
tBu
racemic


V-1128
Me
Et
Me
CH2
Ph
C(Me)2
tBu
(S)-


V-1129
Me
Me
Me
CH2
Ph
C(Me)2
iBu
racemic


V-1130
Me
Me
Me
CH2
Ph
C(Me)2
iBu
(S)-


V-1131
Me
Et
Me
CH2
Ph
C(Me)2
iBu
racemic


V-1132
Me
Et
Me
CH2
Ph
C(Me)2
iBu
(S)-


V-1133
Me
Me
Me
CH2
Ph
C(Me)2
n-Heptyl
racemic


V-1134
Me
Me
Me
CH2
Ph
C(Me)2
n-Heptyl
(S)-


V-1135
Me
Et
Me
CH2
Ph
C(Me)2
n-Heptyl
racemic


V-1136
Me
Et
Me
CH2
Ph
C(Me)2
n-Heptyl
(S)-


V-1137
Me
Me
Me
CH2
Ph
C(Me)2
n-Undecyl
racemic


V-1138
Me
Me
Me
CH2
Ph
C(Me)2
n-Undecyl
(S)-


V-1139
Me
Et
Me
CH2
Ph
C(Me)2
n-Undecyl
racemic


V-1140
Me
Et
Me
CH2
Ph
C(Me)2
n-Undecyl
(S)-


V-1141
Me
Me
Me
CH2
Ph
C(Me)2
Ph
racemic


V-1142
Me
Me
Me
CH2
Ph
C(Me)2
Ph
(S)-


V-1143
Me
Et
Me
CH2
Ph
C(Me)2
Ph
racemic


V-1144
Me
Et
Me
CH2
Ph
C(Me)2
Ph
(S)-


V-1145
Me
Me
Me
CH2
Ph
C(Me)2
OEt
racemic


V-1146
Me
Me
Me
CH2
Ph
C(Me)2
OEt
(S)-


V-1147
Me
Et
Me
CH2
Ph
C(Me)2
OEt
racemic


V-1148
Me
Et
Me
CH2
Ph
C(Me)2
OEt
(S)-


V-1149
Me
Me
Me
CH2
Ph
C(Me)2
(CH2)2COOH
racemic


V-1150
Me
Me
Me
CH2
Ph
C(Me)2
(CH2)2COOH
(S)-


V-1151
Me
Et
Me
CH2
Ph
C(Me)2
(CH2)2COOH
racemic


V-1152
Me
Et
Me
CH2
Ph
C(Me)2
(CH2)2COOH
(S)-


V-1153
Me
Me
Me
CH2
Ph
(CH2)2
Me
racemic


V-1154
Me
Me
Me
CH2
Ph
(CH2)2
Me
(S)-


V-1155
Me
Et
Me
CH2
Ph
(CH2)2
Me
racemic


V-1156
Me
Et
Me
CH2
Ph
(CH2)2
Me
(S)-


V-1157
Me
Me
Me
CH2
Ph
(CH2)2
Et
racemic


V-1158
Me
Me
Me
CH2
Ph
(CH2)2
Et
(S)-


V-1159
Me
Et
Me
CH2
Ph
(CH2)2
Et
racemic


V-1160
Me
Et
Me
CH2
Ph
(CH2)2
Et
(S)-


V-1161
Me
Me
Me
CH2
Ph
(CH2)2
nPr
racemic


V-1162
Me
Me
Me
CH2
Ph
(CH2)2
nPr
(S)-


V-1163
Me
Et
Me
CH2
Ph
(CH2)2
nPr
racemic


V-1164
Me
Et
Me
CH2
Ph
(CH2)2
nPr
(S)-


V-1165
Me
Me
Me
CH2
Ph
(CH2)2
iPr
racemic


V-1166
Me
Me
Me
CH2
Ph
(CH2)2
iPr
(S)-


V-1167
Me
Et
Me
CH2
Ph
(CH2)2
iPr
racemic


V-1168
Me
Et
Me
CH2
Ph
(CH2)2
iPr
(S)-


V-1169
Me
Me
Me
CH2
Ph
(CH2)2
nBu
racemic


V-1170
Me
Me
Me
CH2
Ph
(CH2)2
nBu
(S)-


V-1171
Me
Et
Me
CH2
Ph
(CH2)2
nBu
racemic


V-1172
Me
Et
Me
CH2
Ph
(CH2)2
nBu
(S)-


V-1173
Me
Me
Me
CH2
Ph
(CH2)2
tBu
racemic


V-1174
Me
Me
Me
CH2
Ph
(CH2)2
tBu
(S)-


V-1175
Me
Et
Me
CH2
Ph
(CH2)2
tBu
racemic
















TABLE 125







(Vb)




embedded image




















Com-







Con-


pound







figura-


No.
R1
R2
R3
L2
R4
L3
R6
tion





V-1176
Me
Et
Me
CH2
Ph
(CH2)2
tBu
(S)-


V-1177
Me
Me
Me
CH2
Ph
(CH2)2
iBu
racemic


V-1178
Me
Me
Me
CH2
Ph
(CH2)2
iBu
(S)-


V-1179
Me
Et
Me
CH2
Ph
(CH2)2
iBu
racemic


V-1180
Me
Et
Me
CH2
Ph
(CH2)2
iBu
(S)-


V-1181
Me
Me
Me
CH2
Ph
(CH2)2
n-Heptyl
racemic


V-1182
Me
Me
Me
CH2
Ph
(CH2)2
n-Heptyl
(S)-


V-1183
Me
Et
Me
CH2
Ph
(CH2)2
n-Heptyl
racemic


V-1184
Me
Et
Me
CH2
Ph
(CH2)2
n-Heptyl
(S)-


V-1185
Me
Me
Me
CH2
Ph
(CH2)2
n-Undecyl
racemic


V-1186
Me
Me
Me
CH2
Ph
(CH2)2
n-Undecyl
(S)-


V-1187
Me
Et
Me
CH2
Ph
(CH2)2
n-Undecyl
racemic


V-1188
Me
Et
Me
CH2
Ph
(CH2)2
n-Undecyl
(S)-


V-1189
Me
Me
Me
CH2
Ph
(CH2)2
Ph
racemic


V-1190
Me
Me
Me
CH2
Ph
(CH2)2
Ph
(S)-


V-1191
Me
Et
Me
CH2
Ph
(CH2)2
Ph
racemic


V-1192
Me
Et
Me
CH2
Ph
(CH2)2
Ph
(S)-


V-1193
Me
Me
Me
CH2
Ph
(CH2)2
OEt
racemic


V-1194
Me
Me
Me
CH2
Ph
(CH2)2
OEt
(S)-


V-1195
Me
Et
Me
CH2
Ph
(CH2)2
OEt
racemic


V-1196
Me
Et
Me
CH2
Ph
(CH2)2
OEt
(S)-


V-1197
Me
Me
Me
CH2
Ph
(CH2)2
(CH2)2COOH
racemic


V-1198
Me
Me
Me
CH2
Ph
(CH2)2
(CH2)2COOH
(S)-


V-1199
Me
Et
Me
CH2
Ph
(CH2)2
(CH2)2COOH
racemic


V-1200
Me
Et
Me
CH2
Ph
(CH2)2
(CH2)2COOH
(S)-


V-1201
Me
Me
Me
CH2
Ph
CH2C(Me)2
Me
racemic


V-1202
Me
Me
Me
CH2
Ph
CH2C(Me)2
Me
(S)-


V-1203
Me
Et
Me
CH2
Ph
CH2C(Me)2
Me
racemic


V-1204
Me
Et
Me
CH2
Ph
CH2C(Me)2
Me
(S)-


V-1205
Me
Me
Me
CH2
Ph
CH2C(Me)2
Et
racemic


V-1206
Me
Me
Me
CH2
Ph
CH2C(Me)2
Et
(S)-


V-1207
Me
Et
Me
CH2
Ph
CH2C(Me)2
Et
racemic


V-1208
Me
Et
Me
CH2
Ph
CH2C(Me)2
Et
(S)-


V-1209
Me
Me
Me
CH2
Ph
CH2C(Me)2
nPr
racemic


V-1210
Me
Me
Me
CH2
Ph
CH2C(Me)2
nPr
(S)-


V-1211
Me
Et
Me
CH2
Ph
CH2C(Me)2
nPr
racemic


V-1212
Me
Et
Me
CH2
Ph
CH2C(Me)2
nPr
(S)-


V-1213
Me
Me
Me
CH2
Ph
CH2C(Me)2
iPr
racemic


V-1214
Me
Me
Me
CH2
Ph
CH2C(Me)2
iPr
(S)-


V-1215
Me
Et
Me
CH2
Ph
CH2C(Me)2
iPr
racemic


V-1216
Me
Et
Me
CH2
Ph
CH2C(Me)2
iPr
(S)-


V-1217
Me
Me
Me
CH2
Ph
CH2C(Me)2
nBu
racemic


V-1218
Me
Me
Me
CH2
Ph
CH2C(Me)2
nBu
(S)-


V-1219
Me
Et
Me
CH2
Ph
CH2C(Me)2
nBu
racemic


V-1220
Me
Et
Me
CH2
Ph
CH2C(Me)2
nBu
(S)-


V-1221
Me
Me
Me
CH2
Ph
CH2C(Me)2
tBu
racemic


V-1222
Me
Me
Me
CH2
Ph
CH2C(Me)2
tBu
(S)-


V-1223
Me
Et
Me
CH2
Ph
CH2C(Me)2
tBu
racemic


V-1224
Me
Et
Me
CH2
Ph
CH2C(Me)2
tBu
(S)-


V-1225
Me
Me
Me
CH2
Ph
CH2C(Me)2
iBu
racemic
















TABLE 126







(Vb)




embedded image




















Com-







Con-


pound







figura-


No.
R1
R2
R3
L2
R4
L3
R6
tion





V-1226
Me
Me
Me
CH2
Ph
CH2C(Me)2
iBu
(S)-


V-1227
Me
Et
Me
CH2
Ph
CH2C(Me)2
iBu
racemic


V-1228
Me
Et
Me
CH2
Ph
CH2C(Me)2
iBu
(S)-


V-1229
Me
Me
Me
CH2
Ph
CH2C(Me)2
n-Heptyl
racemic


V-1230
Me
Me
Me
CH2
Ph
CH2C(Me)2
n-Heptyl
(S)-


V-1231
Me
Et
Me
CH2
Ph
CH2C(Me)2
n-Heptyl
racemic


V-1232
Me
Et
Me
CH2
Ph
CH2C(Me)2
n-Heptyl
(S)-


V-1233
Me
Me
Me
CH2
Ph
CH2C(Me)2
n-Undecyl
racemic


V-1234
Me
Me
Me
CH2
Ph
CH2C(Me)2
n-Undecyl
(S)-


V-1235
Me
Et
Me
CH2
Ph
CH2C(Me)2
n-Undecyl
racemic


V-1236
Me
Et
Me
CH2
Ph
CH2C(Me)2
n-Undecyl
(S)-


V-1237
Me
Me
Me
CH2
Ph
CH2C(Me)2
Ph
racemic


V-1238
Me
Me
Me
CH2
Ph
CH2C(Me)2
Ph
(S)-


V-1239
Me
Et
Me
CH2
Ph
CH2C(Me)2
Ph
racemic


V-1240
Me
Et
Me
CH2
Ph
CH2C(Me)2
Ph
(S)-


V-1241
Me
Me
Me
CH2
Ph
CH2C(Me)2
OEt
racemic


V-1242
Me
Me
Me
CH2
Ph
CH2C(Me)2
OEt
(S)-


V-1243
Me
Et
Me
CH2
Ph
CH2C(Me)2
OEt
racemic


V-1244
Me
Et
Me
CH2
Ph
CH2C(Me)2
OEt
(S)-


V-1245
Me
Me
Me
CH2
Ph
CH2C(Me)2
(CH2)2COOH
racemic


V-1246
Me
Me
Me
CH2
Ph
CH2C(Me)2
(CH2)2COOH
(S)-


V-1247
Me
Et
Me
CH2
Ph
CH2C(Me)2
(CH2)2COOH
racemic


V-1248
Me
Et
Me
CH2
Ph
CH2C(Me)2
(CH2)2COOH
(S)-
















TABLE 127







(Vb)




embedded image




















Compound







Con-


No.
R1
R2
R3
L2
R4
L3
R6
figuration





V-1972
Me
Me
Me
—
Ph
—
Me
racemic


V-1973
Me
Me
Me
—
Ph
—
Me
(R)-


V-1974
Me
Et
Me
—
Ph
—
Me
racemic


V-1975
Me
Et
Me
—
Ph
—
Me
(R)-


V-1976
Me
Me
Me
—
Ph
—
Et
racemic


V-1977
Me
Me
Me
—
Ph
—
Et
(R)-


V-1978
Me
Et
Me
—
Ph
—
Et
racemic


V-1979
Me
Et
Me
—
Ph
—
Et
(R)-


V-1980
Me
Me
Me
—
Ph
—
nPr
racemic


V-1981
Me
Me
Me
—
Ph
—
nPr
(R)-


V-1982
Me
Et
Me
—
Ph
—
nPr
racemic


V-1983
Me
Et
Me
—
Ph
—
nPr
(R)-


V-1984
Me
Me
Me
—
Ph
—
iPr
racemic


V-1985
Me
Me
Me
—
Ph
—
iPr
(R)-


V-1986
Me
Et
Me
—
Ph
—
iPr
racemic


V-1987
Me
Et
Me
—
Ph
—
iPr
(R)-


V-1988
Me
Me
Me
—
Ph
—
nBu
racemic


V-1989
Me
Me
Me
—
Ph
—
nBu
(R)-


V-1990
Me
Et
Me
—
Ph
—
nBu
racemic


V-1991
Me
Et
Me
—
Ph
—
nBu
(R)-


V-1992
Me
Me
Me
—
Ph
—
tBu
racemic


V-1993
Me
Me
Me
—
Ph
—
tBu
(R)-


V-1994
Me
Et
Me
—
Ph
—
tBu
racemic


V-1995
Me
Et
Me
—
Ph
—
tBu
(R)-


V-1996
Me
Me
Me
—
Ph
—
iBu
racemic


V-1997
Me
Me
Me
—
Ph
—
iBu
(R)-


V-1998
Me
Et
Me
—
Ph
—
iBu
racemic


V-1999
Me
Et
Me
—
Ph
—
iBu
(R)-


V-2000
Me
Me
Me
—
Ph
—
n-Heptyl
racemic


V-2001
Me
Me
Me
—
Ph
—
n-Heptyl
(R)-


V-2002
Me
Et
Me
—
Ph
—
n-Heptyl
racemic


V-2003
Me
Et
Me
—
Ph
—
n-Heptyl
(R)-


V-2004
Me
Me
Me
—
Ph
—
n-Undecyl
racemic


V-2005
Me
Me
Me
—
Ph
—
n-Undecyl
(R)-


V-2006
Me
Et
Me
—
Ph
—
n-Undecyl
racemic


V-2007
Me
Et
Me
—
Ph
—
n-Undecyl
(R)-


V-2008
Me
Me
Me
—
Ph
—
OEt
racemic


V-2009
Me
Me
Me
—
Ph
—
OEt
(R)-


V-2010
Me
Et
Me
—
Ph
—
OEt
racemic


V-2011
Me
Et
Me
—
Ph
—
OEt
(R)-


V-2012
Me
Me
Me
—
Ph
—
(CH2)2COONa
racemic


V-2013
Me
Me
Me
—
Ph
—
(CH2)2COONa
(R)-


V-2014
Me
Et
Me
—
Ph
—
(CH2)2COONa
racemic


V-2015
Me
Et
Me
—
Ph
—
(CH2)2COONa
(R)-


V-2016
Me
Me
Me
—
Ph
CH2
Me
racemic


V-2017
Me
Me
Me
—
Ph
CH2
Me
(S)-


V-2018
Me
Et
Me
—
Ph
CH2
Me
racemic


V-2019
Me
Et
Me
—
Ph
CH2
Me
(S)-


V-2020
Me
Me
Me
—
Ph
CH2
Et
racemic


V-2021
Me
Me
Me
—
Ph
CH2
Et
(S)-
















TABLE 128







(Vb)




embedded image




















Compound







Con-


No.
R1
R2
R3
L2
R4
L3
R6
figuration





V-2022
Me
Et
Me
—
Ph
CH2
Et
racemic


V-2023
Me
Et
Me
—
Ph
CH2
Et
(S)-


V-2024
Me
Me
Me
—
Ph
CH2
nPr
racemic


V-2025
Me
Me
Me
—
Ph
CH2
nPr
(S)-


V-2026
Me
Et
Me
—
Ph
CH2
nPr
racemic


V-2027
Me
Et
Me
—
Ph
CH2
nPr
(S)-


V-2028
Me
Me
Me
—
Ph
CH2
iPr
racemic


V-2029
Me
Me
Me
—
Ph
CH2
iPr
(S)-


V-2030
Me
Et
Me
—
Ph
CH2
iPr
racemic


V-2031
Me
Et
Me
—
Ph
CH2
iPr
(S)-


V-2032
Me
Me
Me
—
Ph
CH2
nBu
racemic


V-2033
Me
Me
Me
—
Ph
CH2
nBu
(S)-


V-2034
Me
Et
Me
—
Ph
CH2
nBu
racemic


V-2035
Me
Et
Me
—
Ph
CH2
nBu
(S)-


V-2036
Me
Me
Me
—
Ph
CH2
tBu
racemic


V-2037
Me
Me
Me
—
Ph
CH2
tBu
(S)-


V-2038
Me
Et
Me
—
Ph
CH2
tBu
racemic


V-2039
Me
Et
Me
—
Ph
CH2
tBu
(S)-


V-2040
Me
Me
Me
—
Ph
CH2
iBu
racemic


V-2041
Me
Me
Me
—
Ph
CH2
iBu
(S)-


V-2042
Me
Et
Me
—
Ph
CH2
iBu
racemic


V-2043
Me
Et
Me
—
Ph
CH2
iBu
(S)-


V-2044
Me
Me
Me
—
Ph
CH2
n-Heptyl
racemic


V-2045
Me
Me
Me
—
Ph
CH2
n-Heptyl
(S)-


V-2046
Me
Et
Me
—
Ph
CH2
n-Heptyl
racemic


V-2047
Me
Et
Me
—
Ph
CH2
n-Heptyl
(S)-


V-2048
Me
Me
Me
—
Ph
CH2
n-Undecyl
racemic


V-2049
Me
Me
Me
—
Ph
CH2
n-Undecyl
(S)-


V-2050
Me
Et
Me
—
Ph
CH2
n-Undecyl
racemic


V-2051
Me
Et
Me
—
Ph
CH2
n-Undecyl
(S)-


V-2052
Me
Me
Me
—
Ph
CH2
OEt
racemic


V-2053
Me
Me
Me
—
Ph
CH2
OEt
(S)-


V-2054
Me
Et
Me
—
Ph
CH2
OEt
racemic


V-2055
Me
Et
Me
—
Ph
CH2
OEt
(S)-


V-2056
Me
Me
Me
—
Ph
CH2
(CH2)2COONa
racemic


V-2057
Me
Me
Me
—
Ph
CH2
(CH2)2COONa
(S)-


V-2058
Me
Et
Me
—
Ph
CH2
(CH2)2COONa
racemic


V-2059
Me
Et
Me
—
Ph
CH2
(CH2)2COONa
(S)-
















TABLE 129







(Vc)




embedded image




















Compound







Con-


No.
R1
R2
R3
L2
R4
L3
R6
figuration





V-1249
Me
Me
Me
O
Ph
CH2
Me
racemic


V-1250
Me
Me
Me
O
Ph
CH2
Me
(S)-


V-1251
Me
Et
Me
O
Ph
CH2
Me
racemic


V-1252
Me
Et
Me
O
Ph
CH2
Me
(S)-


V-1253
Me
Me
Me
O
Ph
CH2
Et
racemic


V-1254
Me
Me
Me
O
Ph
CH2
Et
(S)-


V-1255
Me
Et
Me
O
Ph
CH2
Et
racemic


V-1256
Me
Et
Me
O
Ph
CH2
Et
(S)-


V-1257
Me
Me
Me
O
Ph
CH2
nPr
racemic


V-1258
Me
Me
Me
O
Ph
CH2
nPr
(S)-


V-1259
Me
Et
Me
O
Ph
CH2
nPr
racemic


V-1260
Me
Et
Me
O
Ph
CH2
nPr
(S)-


V-1261
Me
Me
Me
O
Ph
CH2
iPr
racemic


V-1262
Me
Me
Me
O
Ph
CH2
iPr
(S)-


V-1263
Me
Et
Me
O
Ph
CH2
iPr
racemic


V-1264
Me
Et
Me
O
Ph
CH2
iPr
(S)-


V-1265
Me
Me
Me
O
Ph
CH2
nBu
racemic


V-1266
Me
Me
Me
O
Ph
CH2
nBu
(S)-


V-1267
Me
Et
Me
O
Ph
CH2
nBu
racemic


V-1268
Me
Et
Me
O
Ph
CH2
nBu
(S)-


V-1269
Me
Me
Me
O
Ph
CH2
tBu
racemic


V-1270
Me
Me
Me
O
Ph
CH2
tBu
(S)-


V-1271
Me
Et
Me
O
Ph
CH2
tBu
racemic


V-1272
Me
Et
Me
O
Ph
CH2
tBu
(S)-


V-1273
Me
Me
Me
O
Ph
CH2
iBu
racemic


V-1274
Me
Me
Me
O
Ph
CH2
iBu
(S)-


V-1275
Me
Et
Me
O
Ph
CH2
iBu
racemic


V-1276
Me
Et
Me
O
Ph
CH2
iBu
(S)-


V-1277
Me
Me
Me
O
Ph
CH2
n-Heptyl
racemic


V-1278
Me
Me
Me
O
Ph
CH2
n-Heptyl
(S)-


V-1279
Me
Et
Me
O
Ph
CH2
n-Heptyl
racemic


V-1280
Me
Et
Me
O
Ph
CH2
n-Heptyl
(S)-


V-1281
Me
Me
Me
O
Ph
CH2
n-Undecyl
racemic


V-1282
Me
Me
Me
O
Ph
CH2
n-Undecyl
(S)-


V-1283
Me
Et
Me
O
Ph
CH2
n-Undecyl
racemic


V-1284
Me
Et
Me
O
Ph
CH2
n-Undecyl
(S)-


V-1285
Me
Me
Me
O
Ph
CH2
Ph
racemic


V-1286
Me
Me
Me
O
Ph
CH2
Ph
(S)-


V-1287
Me
Et
Me
O
Ph
CH2
Ph
racemic


V-1288
Me
Et
Me
O
Ph
CH2
Ph
(S)-


V-1289
Me
Me
Me
O
Ph
CH2
OEt
racemic


V-1290
Me
Me
Me
O
Ph
CH2
OEt
(S)-


V-1291
Me
Et
Me
O
Ph
CH2
OEt
racemic


V-1292
Me
Et
Me
O
Ph
CH2
OEt
(S)-


V-1293
Me
Me
Me
O
Ph
CH2
(CH2)2COOH
racemic


V-1294
Me
Me
Me
O
Ph
CH2
(CH2)2COOH
(S)-


V-1295
Me
Et
Me
O
Ph
CH2
(CH2)2COOH
racemic


V-1296
Me
Et
Me
O
Ph
CH2
(CH2)2COOH
(S)-


V-1297
Me
Me
Me
O
Ph
C(Me)2
Me
racemic


V-1298
Me
Me
Me
O
Ph
C(Me)2
Me
(S)-
















TABLE 130







(Vc)




embedded image




















Compound







Con-


No.
R1
R2
R3
L2
R4
L3
R6
figuration





V-1299
Me
Et
Me
O
Ph
C(Me)2
Me
racemic


V-1300
Me
Et
Me
O
Ph
C(Me)2
Me
(S)-


V-1301
Me
Me
Me
O
Ph
C(Me)2
Et
racemic


V-1302
Me
Me
Me
O
Ph
C(Me)2
Et
(S)-


V-1303
Me
Et
Me
O
Ph
C(Me)2
Et
racemic


V-1304
Me
Et
Me
O
Ph
C(Me)2
Et
(S)-


V-1305
Me
Me
Me
O
Ph
C(Me)2
nPr
racemic


V-1306
Me
Me
Me
O
Ph
C(Me)2
nPr
(S)-


V-1307
Me
Et
Me
O
Ph
C(Me)2
nPr
racemic


V-1308
Me
Et
Me
O
Ph
C(Me)2
nPr
(S)-


V-1309
Me
Me
Me
O
Ph
C(Me)2
iPr
racemic


V-1310
Me
Me
Me
O
Ph
C(Me)2
iPr
(S)-


V-1311
Me
Et
Me
O
Ph
C(Me)2
iPr
racemic


V-1312
Me
Et
Me
O
Ph
C(Me)2
iPr
(S)-


V-1313
Me
Me
Me
O
Ph
C(Me)2
nBu
racemic


V-1314
Me
Me
Me
O
Ph
C(Me)2
nBu
(S)-


V-1315
Me
Et
Me
O
Ph
C(Me)2
nBu
racemic


V-1316
Me
Et
Me
O
Ph
C(Me)2
nBu
(S)-


V-1317
Me
Me
Me
O
Ph
C(Me)2
tBu
racemic


V-1318
Me
Me
Me
O
Ph
C(Me)2
tBu
(S)-


V-1319
Me
Et
Me
O
Ph
C(Me)2
tBu
racemic


V-1320
Me
Et
Me
O
Ph
C(Me)2
tBu
(S)-


V-1321
Me
Me
Me
O
Ph
C(Me)2
iBu
racemic


V-1322
Me
Me
Me
O
Ph
C(Me)2
iBu
(S)-


V-1323
Me
Et
Me
O
Ph
C(Me)2
iBu
racemic


V-1324
Me
Et
Me
O
Ph
C(Me)2
iBu
(S)-


V-1325
Me
Me
Me
O
Ph
C(Me)2
n-Heptyl
racemic


V-1326
Me
Me
Me
O
Ph
C(Me)2
n-Heptyl
(S)-


V-1327
Me
Et
Me
O
Ph
C(Me)2
n-Heptyl
racemic


V-1328
Me
Et
Me
O
Ph
C(Me)2
n-Heptyl
(S)-


V-1329
Me
Me
Me
O
Ph
C(Me)2
n-Undecyl
racemic


V-1330
Me
Me
Me
O
Ph
C(Me)2
n-Undecyl
(S)-


V-1331
Me
Et
Me
O
Ph
C(Me)2
n-Undecyl
racemic


V-1332
Me
Et
Me
O
Ph
C(Me)2
n-Undecyl
(S)-


V-1333
Me
Me
Me
O
Ph
C(Me)2
Ph
racemic


V-1334
Me
Me
Me
O
Ph
C(Me)2
Ph
(S)-


V-1335
Me
Et
Me
O
Ph
C(Me)2
Ph
racemic


V-1336
Me
Et
Me
O
Ph
C(Me)2
Ph
(S)-


V-1337
Me
Me
Me
O
Ph
C(Me)2
OEt
racemic


V-1338
Me
Me
Me
O
Ph
C(Me)2
OEt
(S)-


V-1339
Me
Et
Me
O
Ph
C(Me)2
OEt
racemic


V-1340
Me
Et
Me
O
Ph
C(Me)2
OEt
(S)-


V-1341
Me
Me
Me
O
Ph
C(Me)2
(CH2)2COOH
racemic


V-1342
Me
Me
Me
O
Ph
C(Me)2
(CH2)2COOH
(S)-


V-1343
Me
Et
Me
O
Ph
C(Me)2
(CH2)2COOH
racemic


V-1344
Me
Et
Me
O
Ph
C(Me)2
(CH2)2COOH
(S)-


V-1345
Me
Me
Me
O
Ph
(CH2)2
Me
racemic


V-1346
Me
Me
Me
O
Ph
(CH2)2
Me
(R)-


V-1347
Me
Et
Me
O
Ph
(CH2)2
Me
racemic


V-1348
Me
Et
Me
O
Ph
(CH2)2
Me
(R)-
















TABLE 131







(Vc)




embedded image




















Com-










pound







Con-


No.
R1
R2
R3
L2
R4
L3
R6
figuration





V-1349
Me
Me
Me
O
Ph
(CH2)2
Et
racemic


V-1350
Me
Me
Me
O
Ph
(CH2)2
Et
(R)-


V-1351
Me
Et
Me
O
Ph
(CH2)2
Et
racemic


V-1352
Me
Et
Me
O
Ph
(CH2)2
Et
(R)-


V-1353
Me
Me
Me
O
Ph
(CH2)2
nPr
racemic


V-1354
Me
Me
Me
O
Ph
(CH2)2
nPr
(R)-


V-1355
Me
Et
Me
O
Ph
(CH2)2
nPr
racemic


V-1356
Me
Et
Me
O
Ph
(CH2)2
nPr
(R)-


V-1357
Me
Me
Me
O
Ph
(CH2)2
iPr
racemic


V-1358
Me
Me
Me
O
Ph
(CH2)2
iPr
(R)-


V-1359
Me
Et
Me
O
Ph
(CH2)2
iPr
racemic


V-1360
Me
Et
Me
O
Ph
(CH2)2
iPr
(R)-


V-1361
Me
Me
Me
O
Ph
(CH2)2
nBu
racemic


V-1362
Me
Me
Me
O
Ph
(CH2)2
nBu
(R)-


V-1363
Me
Et
Me
O
Ph
(CH2)2
nBu
racemic


V-1364
Me
Et
Me
O
Ph
(CH2)2
nBu
(R)-


V-1365
Me
Me
Me
O
Ph
(CH2)2
tBu
racemic


V-1366
Me
Me
Me
O
Ph
(CH2)2
tBu
(R)-


V-1367
Me
Et
Me
O
Ph
(CH2)2
tBu
racemic


V-1368
Me
Et
Me
O
Ph
(CH2)2
tBu
(R)-


V-1369
Me
Me
Me
O
Ph
(CH2)2
iBu
racemic


V-1370
Me
Me
Me
O
Ph
(CH2)2
iBu
(R)-


V-1371
Me
Et
Me
O
Ph
(CH2)2
iBu
racemic


V-1372
Me
Et
Me
O
Ph
(CH2)2
iBu
(R)-


V-1373
Me
Me
Me
O
Ph
(CH2)2
n-Heptyl
racemic


V-1374
Me
Me
Me
O
Ph
(CH2)2
n-Heptyl
(R)-


V-1375
Me
Et
Me
O
Ph
(CH2)2
n-Heptyl
racemic


V-1376
Me
Et
Me
O
Ph
(CH2)2
n-Heptyl
(R)-


V-1377
Me
Me
Me
O
Ph
(CH2)2
n-Undecyl
racemic


V-1378
Me
Me
Me
O
Ph
(CH2)2
n-Undecyl
(R)-


V-1379
Me
Et
Me
O
Ph
(CH2)2
n-Undecyl
racemic


V-1380
Me
Et
Me
O
Ph
(CH2)2
n-Undecyl
(R)-


V-1381
Me
Me
Me
O
Ph
(CH2)2
Ph
racemic


V-1382
Me
Me
Me
O
Ph
(CH2)2
Ph
(R)-


V-1383
Me
Et
Me
O
Ph
(CH2)2
Ph
racemic


V-1384
Me
Et
Me
O
Ph
(CH2)2
Ph
(R)-


V-1385
Me
Me
Me
O
Ph
(CH2)2
OEt
racemic


V-1386
Me
Me
Me
O
Ph
(CH2)2
OEt
(R)-


V-1387
Me
Et
Me
O
Ph
(CH2)2
OEt
racemic


V-1388
Me
Et
Me
O
Ph
(CH2)2
OEt
(R)-


V-1389
Me
Me
Me
O
Ph
(CH2)2
(CH2)2COOH
racemic


V-1390
Me
Me
Me
O
Ph
(CH2)2
(CH2)2COOH
(R)-


V-1391
Me
Et
Me
O
Ph
(CH2)2
(CH2)2COOH
racemic


V-1392
Me
Et
Me
O
Ph
(CH2)2
(CH2)2COOH
(R)-


V-1393
Me
Me
Me
O
Ph
CH2C(Me)2
Me
racemic


V-1394
Me
Me
Me
O
Ph
CH2C(Me)2
Me
(R)-


V-1395
Me
Et
Me
O
Ph
CH2C(Me)2
Me
racemic


V-1396
Me
Et
Me
O
Ph
CH2C(Me)2
Me
(R)-


V-1397
Me
Me
Me
O
Ph
CH2C(Me)2
Et
racemic


V-1398
Me
Me
Me
O
Ph
CH2C(Me)2
Et
(R)-
















TABLE 132







(Vc)




embedded image




















Com-










pound







Con-


No.
R1
R2
R3
L2
R4
L3
R6
figuration





V-1399
Me
Et
Me
O
Ph
CH2C(Me)2
Et
racemic


V-1400
Me
Et
Me
O
Ph
CH2C(Me)2
Et
(R)-


V-1401
Me
Me
Me
O
Ph
CH2C(Me)2
nPr
racemic


V-1402
Me
Me
Me
O
Ph
CH2C(Me)2
nPr
(R)-


V-1403
Me
Et
Me
O
Ph
CH2C(Me)2
nPr
racemic


V-1404
Me
Et
Me
O
Ph
CH2C(Me)2
nPr
(R)-


V-1405
Me
Me
Me
O
Ph
CH2C(Me)2
iPr
racemic


V-1406
Me
Me
Me
O
Ph
CH2C(Me)2
iPr
(R)-


V-1407
Me
Et
Me
O
Ph
CH2C(Me)2
iPr
racemic


V-1408
Me
Et
Me
O
Ph
CH2C(Me)2
iPr
(R)-


V-1409
Me
Me
Me
O
Ph
CH2C(Me)2
nBu
racemic


V-1410
Me
Me
Me
O
Ph
CH2C(Me)2
nBu
(R)-


V-1411
Me
Et
Me
O
Ph
CH2C(Me)2
nBu
racemic


V-1412
Me
Et
Me
O
Ph
CH2C(Me)2
nBu
(R)-


V-1413
Me
Me
Me
O
Ph
CH2C(Me)2
tBu
racemic


V-1414
Me
Me
Me
O
Ph
CH2C(Me)2
tBu
(R)-


V-1415
Me
Et
Me
O
Ph
CH2C(Me)2
tBu
racemic


V-1416
Me
Et
Me
O
Ph
CH2C(Me)2
tBu
(R)-


V-1417
Me
Me
Me
O
Ph
CH2C(Me)2
iBu
racemic


V-1418
Me
Me
Me
O
Ph
CH2C(Me)2
iBu
(R)-


V-1419
Me
Et
Me
O
Ph
CH2C(Me)2
iBu
racemic


V-1420
Me
Et
Me
O
Ph
CH2C(Me)2
iBu
(R)-


V-1421
Me
Me
Me
O
Ph
CH2C(Me)2
n-Heptyl
racemic


V-1422
Me
Me
Me
O
Ph
CH2C(Me)2
n-Heptyl
(R)-


V-1423
Me
Et
Me
O
Ph
CH2C(Me)2
n-Heptyl
racemic


V-1424
Me
Et
Me
O
Ph
CH2C(Me)2
n-Heptyl
(R)-


V-1425
Me
Me
Me
O
Ph
CH2C(Me)2
n-Undecyl
racemic


V-1426
Me
Me
Me
O
Ph
CH2C(Me)2
n-Undecyl
(R)-


V-1427
Me
Et
Me
O
Ph
CH2C(Me)2
n-Undecyl
racemic


V-1428
Me
Et
Me
O
Ph
CH2C(Me)2
n-Undecyl
(R)-


V-1429
Me
Me
Me
O
Ph
CH2C(Me)2
Ph
racemic


V-1430
Me
Me
Me
O
Ph
CH2C(Me)2
Ph
(R)-


V-1431
Me
Et
Me
O
Ph
CH2C(Me)2
Ph
racemic


V-1432
Me
Et
Me
O
Ph
CH2C(Me)2
Ph
(R)-


V-1433
Me
Me
Me
O
Ph
CH2C(Me)2
OEt
racemic


V-1434
Me
Me
Me
O
Ph
CH2C(Me)2
OEt
(R)-


V-1435
Me
Et
Me
O
Ph
CH2C(Me)2
OEt
racemic


V-1436
Me
Et
Me
O
Ph
CH2C(Me)2
OEt
(R)-


V-1437
Me
Me
Me
O
Ph
CH2C(Me)2
(CH2)2COOH
racemic


V-1438
Me
Me
Me
O
Ph
CH2C(Me)2
(CH2)2COOH
(R)-


V-1439
Me
Et
Me
O
Ph
CH2C(Me)2
(CH2)2COOH
racemic


V-1440
Me
Et
Me
O
Ph
CH2C(Me)2
(CH2)2COOH
(R)-


V-1441
Me
Me
Me
NH
Ph
CH2
Me
racemic


V-1442
Me
Me
Me
NH
Ph
CH2
Me
(S)-


V-1443
Me
Et
Me
NH
Ph
CH2
Me
racemic


V-1444
Me
Et
Me
NH
Ph
CH2
Me
(S)-


V-1445
Me
Me
Me
NH
Ph
CH2
Et
racemic


V-1446
Me
Me
Me
NH
Ph
CH2
Et
(S)-


V-1447
Me
Et
Me
NH
Ph
CH2
Et
racemic


V-1448
Me
Et
Me
NH
Ph
CH2
Et
(S)-
















TABLE 133







(Vc)




embedded image




















Compound







Con-


No.
R1
R2
R3
L2
R4
L3
R6
figuration





V-1449
Me
Me
Me
NH
Ph
CH2
nPr
racemic


V-1450
Me
Me
Me
NH
Ph
CH2
nPr
(S)-


V-1451
Me
Et
Me
NH
Ph
CH2
nPr
racemic


V-1452
Me
Et
Me
NH
Ph
CH2
nPr
(S)-


V-1453
Me
Me
Me
NH
Ph
CH2
iPr
racemic


V-1454
Me
Me
Me
NH
Ph
CH2
iPr
(S)-


V-1455
Me
Et
Me
NH
Ph
CH2
iPr
racemic


V-1456
Me
Et
Me
NH
Ph
CH2
iPr
(S)-


V-1457
Me
Me
Me
NH
Ph
CH2
nBu
racemic


V-1458
Me
Me
Me
NH
Ph
CH2
nBu
(S)-


V-1459
Me
Et
Me
NH
Ph
CH2
nBu
racemic


V-1460
Me
Et
Me
NH
Ph
CH2
nBu
(S)-


V-1461
Me
Me
Me
NH
Ph
CH2
tBu
racemic


V-1462
Me
Me
Me
NH
Ph
CH2
tBu
(S)-


V-1463
Me
Et
Me
NH
Ph
CH2
tBu
racemic


V-1464
Me
Et
Me
NH
Ph
CH2
tBu
(S)-


V-1465
Me
Me
Me
NH
Ph
CH2
iBu
racemic


V-1466
Me
Me
Me
NH
Ph
CH2
iBu
(S)-


V-1467
Me
Et
Me
NH
Ph
CH2
iBu
racemic


V-1468
Me
Et
Me
NH
Ph
CH2
iBu
(S)-


V-1469
Me
Me
Me
NH
Ph
CH2
n-Heptyl
racemic


V-1470
Me
Me
Me
NH
Ph
CH2
n-Heptyl
(S)-


V-1471
Me
Et
Me
NH
Ph
CH2
n-Heptyl
racemic


V-1472
Me
Et
Me
NH
Ph
CH2
n-Heptyl
(S)-


V-1473
Me
Me
Me
NH
Ph
CH2
n-Undecyl
racemic


V-1474
Me
Me
Me
NH
Ph
CH2
n-Undecyl
(S)-


V-1475
Me
Et
Me
NH
Ph
CH2
n-Undecyl
racemic


V-1476
Me
Et
Me
NH
Ph
CH2
n-Undecyl
(S)-


V-1477
Me
Me
Me
NH
Ph
CH2
n-Pentadecyl
racemic


V-1478
Me
Me
Me
NH
Ph
CH2
n-Pentadecyl
(S)-


V-1479
Me
Et
Me
NH
Ph
CH2
n-Pentadecyl
racemic


V-1480
Me
Et
Me
NH
Ph
CH2
n-Pentadecyl
(S)-


V-1481
Me
Me
Me
NH
Ph
CH2
Ph
racemic


V-1482
Me
Me
Me
NH
Ph
CH2
Ph
(S)-


V-1483
Me
Et
Me
NH
Ph
CH2
Ph
racemic


V-1484
Me
Et
Me
NH
Ph
CH2
Ph
(S)-


V-1485
Me
Me
Me
NH
Ph
CH2
OEt
racemic


V-1486
Me
Me
Me
NH
Ph
CH2
OEt
(S)-


V-1487
Me
Et
Me
NH
Ph
CH2
OEt
racemic


V-1488
Me
Et
Me
NH
Ph
CH2
OEt
(S)-


V-1489
Me
Me
Me
NH
Ph
CH2
(CH2)2COOH
racemic


V-1490
Me
Me
Me
NH
Ph
CH2
(CH2)2COOH
(S)-


V-1491
Me
Et
Me
NH
Ph
CH2
(CH2)2COOH
racemic


V-1492
Me
Et
Me
NH
Ph
CH2
(CH2)2COOH
(S)-


V-1493
Me
Me
Me
NH
Ph
CH2
H
racemic


V-1494
Me
Me
Me
NH
Ph
CH2
H
(S)-


V-1495
Me
Et
Me
NH
Ph
CH2
H
racemic


V-1496
Me
Et
Me
NH
Ph
CH2
H
(S)-


V-1497
Me
Me
Me
NH
Ph
CH2
(5-Methyl-2-oxo-
racemic









1,3-dioxol-4-










yl)methoxy



V-1498
Me
Me
Me
NH
Ph
CH2
(5-Methyl-2-oxo-
(S)-









1,3-dioxol-4-










yl)methoxy
















TABLE 134







(Vc)




embedded image




















Com-










pound







Con-


No.
R1
R2
R3
L2
R4
L3
R6
figuration





V-1499
Me
Et
Me
NH
Ph
CH2
(5-Methyl-2-oxo-
racemic









1,3-dioxol-4-yl)










methoxy



V-1500
Me
Et
Me
NH
Ph
CH2
(5-Methyl-2-oxo-
(S)-









1,3-dioxol-4-yl)










methoxy



V-1501
Me
Me
Me
NH
Ph
C(Me)2
Me
(S)-


V-1502
Me
Et
Me
NH
Ph
C(Me)2
Me
racemic


V-1503
Me
Et
Me
NH
Ph
C(Me)2
Me
(S)-


V-1504
Me
Me
Me
NH
Ph
C(Me)2
Et
racemic


V-1505
Me
Me
Me
NH
Ph
C(Me)2
Et
(S)-


V-1506
Me
Et
Me
NH
Ph
C(Me)2
Et
racemic


V-1507
Me
Et
Me
NH
Ph
C(Me)2
Et
(S)-


V-1508
Me
Me
Me
NH
Ph
C(Me)2
nPr
racemic


V-1509
Me
Me
Me
NH
Ph
C(Me)2
nPr
(S)-


V-1510
Me
Et
Me
NH
Ph
C(Me)2
nPr
racemic


V-1511
Me
Et
Me
NH
Ph
C(Me)2
nPr
(S)-


V-1512
Me
Me
Me
NH
Ph
C(Me)2
iPr
racemic


V-1513
Me
Me
Me
NH
Ph
C(Me)2
iPr
(S)-


V-1514
Me
Et
Me
NH
Ph
C(Me)2
iPr
racemic


V-1515
Me
Et
Me
NH
Ph
C(Me)2
iPr
(S)-


V-1516
Me
Me
Me
NH
Ph
C(Me)2
nBu
racemic


V-1517
Me
Me
Me
NH
Ph
C(Me)2
nBu
(S)-


V-1518
Me
Et
Me
NH
Ph
C(Me)2
nBu
racemic


V-1519
Me
Et
Me
NH
Ph
C(Me)2
nBu
(S)-


V-1520
Me
Me
Me
NH
Ph
C(Me)2
tBu
racemic


V-1521
Me
Me
Me
NH
Ph
C(Me)2
tBu
(S)-


V-1522
Me
Et
Me
NH
Ph
C(Me)2
tBu
racemic


V-1523
Me
Et
Me
NH
Ph
C(Me)2
tBu
(S)-


V-1524
Me
Me
Me
NH
Ph
C(Me)2
iBu
racemic


V-1525
Me
Me
Me
NH
Ph
C(Me)2
iBu
(S)-


V-1526
Me
Et
Me
NH
Ph
C(Me)2
iBu
racemic


V-1527
Me
Et
Me
NH
Ph
C(Me)2
iBu
(S)-


V-1528
Me
Me
Me
NH
Ph
C(Me)2
n-Heptyl
racemic


V-1529
Me
Me
Me
NH
Ph
C(Me)2
n-Heptyl
(S)-


V-1530
Me
Et
Me
NH
Ph
C(Me)2
n-Heptyl
racemic


V-1531
Me
Et
Me
NH
Ph
C(Me)2
n-Heptyl
(S)-


V-1532
Me
Me
Me
NH
Ph
C(Me)2
n-Undecyl
racemic


V-1533
Me
Me
Me
NH
Ph
C(Me)2
n-Undecyl
(S)-


V-1534
Me
Et
Me
NH
Ph
C(Me)2
n-Undecyl
racemic


V-1535
Me
Et
Me
NH
Ph
C(Me)2
n-Undecyl
(S)-


V-1536
Me
Me
Me
NH
Ph
C(Me)2
Ph
racemic


V-1537
Me
Me
Me
NH
Ph
C(Me)2
Ph
(S)-


V-1538
Me
Et
Me
NH
Ph
C(Me)2
Ph
racemic


V-1539
Me
Et
Me
NH
Ph
C(Me)2
Ph
(S)-


V-1540
Me
Me
Me
NH
Ph
C(Me)2
OEt
racemic


V-1541
Me
Me
Me
NH
Ph
C(Me)2
OEt
(S)-


V-1542
Me
Et
Me
NH
Ph
C(Me)2
OEt
racemic


V-1543
Me
Et
Me
NH
Ph
C(Me)2
OEt
(S)-


V-1544
Me
Me
Me
NH
Ph
C(Me)2
(CH2)2COOH
racemic


V-1545
Me
Me
Me
NH
Ph
C(Me)2
(CH2)2COOH
(S)-


V-1546
Me
Et
Me
NH
Ph
C(Me)2
(CH2)2COOH
racemic


V-1547
Me
Et
Me
NH
Ph
C(Me)2
(CH2)2COOH
(S)-


V-1548
Me
Me
Me
NH
Ph
(CH2)2
Me
racemic
















TABLE 135







(Vc)




embedded image




















Com-










pound







Con-


No.
R1
R2
R3
L2
R4
L3
R6
figuration





V-1549
Me
Me
Me
NH
Ph
(CH2)2
Me
(R)-


V-1550
Me
Et
Me
NH
Ph
(CH2)2
Me
racemic


V-1551
Me
Et
Me
NH
Ph
(CH2)2
Me
(R)-


V-1552
Me
Me
Me
NH
Ph
(CH2)2
Et
racemic


V-1553
Me
Me
Me
NH
Ph
(CH2)2
Et
(R)-


V-1554
Me
Et
Me
NH
Ph
(CH2)2
Et
racemic


V-1555
Me
Et
Me
NH
Ph
(CH2)2
Et
(R)-


V-1556
Me
Me
Me
NH
Ph
(CH2)2
nPr
racemic


V-1557
Me
Me
Me
NH
Ph
(CH2)2
nPr
(R)-


V-1558
Me
Et
Me
NH
Ph
(CH2)2
nPr
racemic


V-1559
Me
Et
Me
NH
Ph
(CH2)2
nPr
(R)-


V-1560
Me
Me
Me
NH
Ph
(CH2)2
iPr
racemic


V-1561
Me
Me
Me
NH
Ph
(CH2)2
iPr
(R)-


V-1562
Me
Et
Me
NH
Ph
(CH2)2
iPr
racemic


V-1563
Me
Et
Me
NH
Ph
(CH2)2
iPr
(R)-


V-1564
Me
Me
Me
NH
Ph
(CH2)2
nBu
racemic


V-1565
Me
Me
Me
NH
Ph
(CH2)2
nBu
(R)-


V-1566
Me
Et
Me
NH
Ph
(CH2)2
nBu
racemic


V-1567
Me
Et
Me
NH
Ph
(CH2)2
nBu
(R)-


V-1568
Me
Me
Me
NH
Ph
(CH2)2
tBu
racemic


V-1569
Me
Me
Me
NH
Ph
(CH2)2
tBu
(R)-


V-1570
Me
Et
Me
NH
Ph
(CH2)2
tBu
racemic


V-1571
Me
Et
Me
NH
Ph
(CH2)2
tBu
(R)-


V-1572
Me
Me
Me
NH
Ph
(CH2)2
iBu
racemic


V-1573
Me
Me
Me
NH
Ph
(CH2)2
iBu
(R)-


V-1574
Me
Et
Me
NH
Ph
(CH2)2
iBu
racemic


V-1575
Me
Et
Me
NH
Ph
(CH2)2
iBu
(R)-


V-1576
Me
Me
Me
NH
Ph
(CH2)2
n-Heptyl
racemic


V-1577
Me
Me
Me
NH
Ph
(CH2)2
n-Heptyl
(R)-


V-1578
Me
Et
Me
NH
Ph
(CH2)2
n-Heptyl
racemic


V-1579
Me
Et
Me
NH
Ph
(CH2)2
n-Heptyl
(R)-


V-1580
Me
Me
Me
NH
Ph
(CH2)2
n-Undecyl
racemic


V-1581
Me
Me
Me
NH
Ph
(CH2)2
n-Undecyl
(R)-


V-1582
Me
Et
Me
NH
Ph
(CH2)2
n-Undecyl
racemic


V-1583
Me
Et
Me
NH
Ph
(CH2)2
n-Undecyl
(R)-


V-1584
Me
Me
Me
NH
Ph
(CH2)2
Ph
racemic


V-1585
Me
Me
Me
NH
Ph
(CH2)2
Ph
(R)-


V-1586
Me
Et
Me
NH
Ph
(CH2)2
Ph
racemic


V-1587
Me
Et
Me
NH
Ph
(CH2)2
Ph
(R)-


V-1588
Me
Me
Me
NH
Ph
(CH2)2
OEt
racemic


V-1589
Me
Me
Me
NH
Ph
(CH2)2
OEt
(R)-


V-1590
Me
Et
Me
NH
Ph
(CH2)2
OEt
racemic


V-1591
Me
Et
Me
NH
Ph
(CH2)2
OEt
(R)-


V-1592
Me
Me
Me
NH
Ph
(CH2)2
(CH2)2COOH
racemic


V-1593
Me
Me
Me
NH
Ph
(CH2)2
(CH2)2COOH
(R)-


V-1594
Me
Et
Me
NH
Ph
(CH2)2
(CH2)2COOH
racemic


V-1595
Me
Et
Me
NH
Ph
(CH2)2
(CH2)2COOH
(R)-


V-1596
Me
Me
Me
NH
Ph
CH2C(Me)2
Me
racemic


V-1597
Me
Me
Me
NH
Ph
CH2C(Me)2
Me
(R)-


V-1598
Me
Et
Me
NH
Ph
CH2C(Me)2
Me
racemic
















TABLE 136







(Vc)




embedded image




















Com-







Con-


pound







figu-


No.
R1
R2
R3
L2
R4
L3
R6
ration





V-1599
Me
Et
Me
NH
Ph
CH2C(Me)2
Me
(R)-


V-1600
Me
Me
Me
NH
Ph
CH2C(Me)2
Et
racemic


V-1601
Me
Me
Me
NH
Ph
CH2C(Me)2
Et
(R)-


V-1602
Me
Et
Me
NH
Ph
CH2C(Me)2
Et
racemic


V-1603
Me
Et
Me
NH
Ph
CH2C(Me)2
Et
(R)-


V-1604
Me
Me
Me
NH
Ph
CH2C(Me)2
nPr
racemic


V-1605
Me
Me
Me
NH
Ph
CH2C(Me)2
nPr
(R)-


V-1606
Me
Et
Me
NH
Ph
CH2C(Me)2
nPr
racemic


V-1607
Me
Et
Me
NH
Ph
CH2C(Me)2
nPr
(R)-


V-1608
Me
Me
Me
NH
Ph
CH2C(Me)2
iPr
racemic


V-1609
Me
Me
Me
NH
Ph
CH2C(Me)2
iPr
(R)-


V-1610
Me
Et
Me
NH
Ph
CH2C(Me)2
iPr
racemic


V-1611
Me
Et
Me
NH
Ph
CH2C(Me)2
iPr
(R)-


V-1612
Me
Me
Me
NH
Ph
CH2C(Me)2
nBu
racemic


V-1613
Me
Me
Me
NH
Ph
CH2C(Me)2
nBu
(R)-


V-1614
Me
Et
Me
NH
Ph
CH2C(Me)2
nBu
racemic


V-1615
Me
Et
Me
NH
Ph
CH2C(Me)2
nBu
(R)-


V-1616
Me
Me
Me
NH
Ph
CH2C(Me)2
tBu
racemic


V-1617
Me
Me
Me
NH
Ph
CH2C(Me)2
tBu
(R)-


V-1618
Me
Et
Me
NH
Ph
CH2C(Me)2
tBu
racemic


V-1619
Me
Et
Me
NH
Ph
CH2C(Me)2
tBu
(R)-


V-1620
Me
Me
Me
NH
Ph
CH2C(Me)2
iBu
racemic


V-1621
Me
Me
Me
NH
Ph
CH2C(Me)2
iBu
(R)-


V-1622
Me
Et
Me
NH
Ph
CH2C(Me)2
iBu
racemic


V-1623
Me
Et
Me
NH
Ph
CH2C(Me)2
iBu
(R)-


V-1624
Me
Me
Me
NH
Ph
CH2C(Me)2
n-Heptyl
racemic


V-1625
Me
Me
Me
NH
Ph
CH2C(Me)2
n-Heptyl
(R)-


V-1626
Me
Et
Me
NH
Ph
CH2C(Me)2
n-Heptyl
racemic


V-1627
Me
Et
Me
NH
Ph
CH2C(Me)2
n-Heptyl
(R)-


V-1628
Me
Me
Me
NH
Ph
CH2C(Me)2
n-Undecyl
racemic


V-1629
Me
Me
Me
NH
Ph
CH2C(Me)2
n-Undecyl
(R)-


V-1630
Me
Et
Me
NH
Ph
CH2C(Me)2
n-Undecyl
racemic


V-1631
Me
Et
Me
NH
Ph
CH2C(Me)2
n-Undecyl
(R)-


V-1632
Me
Me
Me
NH
Ph
CH2C(Me)2
Ph
racemic


V-1633
Me
Me
Me
NH
Ph
CH2C(Me)2
Ph
(R)-


V-1634
Me
Et
Me
NH
Ph
CH2C(Me)2
Ph
racemic


V-1635
Me
Et
Me
NH
Ph
CH2C(Me)2
Ph
(R)-


V-1636
Me
Me
Me
NH
Ph
CH2C(Me)2
OEt
racemic


V-1637
Me
Me
Me
NH
Ph
CH2C(Me)2
OEt
(R)-


V-1638
Me
Et
Me
NH
Ph
CH2C(Me)2
OEt
racemic


V-1639
Me
Et
Me
NH
Ph
CH2C(Me)2
OEt
(R)-


V-1640
Me
Me
Me
NH
Ph
CH2C(Me)2
(CH2)2COOH
racemic


V-1641
Me
Me
Me
NH
Ph
CH2C(Me)2
(CH2)2COOH
(R)-


V-1642
Me
Et
Me
NH
Ph
CH2C(Me)2
(CH2)2COOH
racemic


V-1643
Me
Et
Me
NH
Ph
CH2C(Me)2
(CH2)2COOH
(R)-


V-1644
Me
Me
Me
CH2
Ph
CH2
Me
racemic


V-1645
Me
Me
Me
CH2
Ph
CH2
Me
(S)-


V-1646
Me
Et
Me
CH2
Ph
CH2
Me
racemic


V-1647
Me
Et
Me
CH2
Ph
CH2
Me
(S)-


V-1648
Me
Me
Me
CH2
Ph
CH2
Et
racemic
















TABLE 137







(Vc)




embedded image




















Compound










No.
R1
R2
R3
L2
R4
L3
R6
Configuration





V-1649
Me
Me
Me
CH2
Ph
CH2
Et
(S)-


V-1650
Me
Et
Me
CH2
Ph
CH2
Et
racemic


V-1651
Me
Et
Me
CH2
Ph
CH2
Et
(S)-


V-1652
Me
Me
Me
CH2
Ph
CH2
nPr
racemic


V-1653
Me
Me
Me
CH2
Ph
CH2
nPr
(S)-


V-1654
Me
Et
Me
CH2
Ph
CH2
nPr
racemic


V-1655
Me
Et
Me
CH2
Ph
CH2
nPr
(S)-


V-1656
Me
Me
Me
CH2
Ph
CH2
iPr
racemic


V-1657
Me
Me
Me
CH2
Ph
CH2
iPr
(S)-


V-1658
Me
Et
Me
CH2
Ph
CH2
iPr
racemic


V-1659
Me
Et
Me
CH2
Ph
CH2
iPr
(S)-


V-1660
Me
Me
Me
CH2
Ph
CH2
nBu
racemic


V-1661
Me
Me
Me
CH2
Ph
CH2
nBu
(S)-


V-1662
Me
Et
Me
CH2
Ph
CH2
nBu
racemic


V-1663
Me
Et
Me
CH2
Ph
CH2
nBu
(S)-


V-1664
Me
Me
Me
CH2
Ph
CH2
tBu
racemic


V-1665
Me
Me
Me
CH2
Ph
CH2
tBu
(S)-


V-1666
Me
Et
Me
CH2
Ph
CH2
tBu
racemic


V-1667
Me
Et
Me
CH2
Ph
CH2
tBu
(S)-


V-1668
Me
Me
Me
CH2
Ph
CH2
iBu
racemic


V-1669
Me
Me
Me
CH2
Ph
CH2
iBu
(S)-


V-1670
Me
Et
Me
CH2
Ph
CH2
iBu
racemic


V-1671
Me
Et
Me
CH2
Ph
CH2
iBu
(S)-


V-1672
Me
Me
Me
CH2
Ph
CH2
n-Heptyl
racemic


V-1673
Me
Me
Me
CH2
Ph
CH2
n-Heptyl
(S)-


V-1674
Me
Et
Me
CH2
Ph
CH2
n-Heptyl
racemic


V-1675
Me
Et
Me
CH2
Ph
CH2
n-Heptyl
(S)-


V-1676
Me
Me
Me
CH2
Ph
CH2
n-Undecyl
racemic


V-1677
Me
Me
Me
CH2
Ph
CH2
n-Undecyl
(S)-


V-1678
Me
Et
Me
CH2
Ph
CH2
n-Undecyl
racemic


V-1679
Me
Et
Me
CH2
Ph
CH2
n-Undecyl
(S)-


V-1680
Me
Me
Me
CH2
Ph
CH2
Ph
racemic


V-1681
Me
Me
Me
CH2
Ph
CH2
Ph
(S)-


V-1682
Me
Et
Me
CH2
Ph
CH2
Ph
racemic


V-1683
Me
Et
Me
CH2
Ph
CH2
Ph
(S)-


V-1684
Me
Me
Me
CH2
Ph
CH2
OEt
racemic


V-1685
Me
Me
Me
CH2
Ph
CH2
OEt
(S)-


V-1686
Me
Et
Me
CH2
Ph
CH2
OEt
racemic


V-1687
Me
Et
Me
CH2
Ph
CH2
OEt
(S)-


V-1688
Me
Me
Me
CH2
Ph
CH2
(CH2)2COOH
racemic


V-1689
Me
Me
Me
CH2
Ph
CH2
(CH2)2COOH
(S)-


V-1690
Me
Et
Me
CH2
Ph
CH2
(CH2)2COOH
racemic


V-1691
Me
Et
Me
CH2
Ph
CH2
(CH2)2COOH
(S)-


V-1692
Me
Me
Me
CH2
Ph
—
Me
racemic


V-1693
Me
Me
Me
CH2
Ph
—
Me
(S)-


V-1694
Me
Et
Me
CH2
Ph
—
Me
racemic


V-1695
Me
Et
Me
CH2
Ph
—
Me
(S)-


V-1696
Me
Me
Me
CH2
Ph
—
Et
racemic


V-1697
Me
Me
Me
CH2
Ph
—
Et
(S)-


V-1698
Me
Et
Me
CH2
Ph
—
Et
racemic
















TABLE 138







(Vc)




embedded image




















Com-










pound










No.
R1
R2
R3
L2
R4
L3
R6
Configuration





V-1699
Me
Et
Me
CH2
Ph
—
Et
(S)-


V-1700
Me
Me
Me
CH2
Ph
—
nPr
racemic


V-1701
Me
Me
Me
CH2
Ph
—
nPr
(S)-


V-1702
Me
Et
Me
CH2
Ph
—
nPr
racemic


V-1703
Me
Et
Me
CH2
Ph
—
nPr
(S)-


V-1704
Me
Me
Me
CH2
Ph
—
iPr
racemic


V-1705
Me
Me
Me
CH2
Ph
—
iPr
(S)-


V-1706
Me
Et
Me
CH2
Ph
—
iPr
racemic


V-1707
Me
Et
Me
CH2
Ph
—
iPr
(S)-


V-1708
Me
Me
Me
CH2
Ph
—
nBu
racemic


V-1709
Me
Me
Me
CH2
Ph
—
nBu
(S)-


V-1710
Me
Et
Me
CH2
Ph
—
nBu
racemic


V-1711
Me
Et
Me
CH2
Ph
—
nBu
(S)-


V-1712
Me
Me
Me
CH2
Ph
—
tBu
racemic


V-1713
Me
Me
Me
CH2
Ph
—
tBu
(S)-


V-1714
Me
Et
Me
CH2
Ph
—
tBu
racemic


V-1715
Me
Et
Me
CH2
Ph
—
tBu
(S)-


V-1716
Me
Me
Me
CH2
Ph
—
iBu
racemic


V-1717
Me
Me
Me
CH2
Ph
—
iBu
(S)-


V-1718
Me
Et
Me
CH2
Ph
—
iBu
racemic


V-1719
Me
Et
Me
CH2
Ph
—
iBu
(S)-


V-1720
Me
Me
Me
CH2
Ph
—
n-Heptyl
racemic


V-1721
Me
Me
Me
CH2
Ph
—
n-Heptyl
(S)-


V-1722
Me
Et
Me
CH2
Ph
—
n-Heptyl
racemic


V-1723
Me
Et
Me
CH2
Ph
—
n-Heptyl
(S)-


V-1724
Me
Me
Me
CH2
Ph
—
n-Undecyl
racemic


V-1725
Me
Me
Me
CH2
Ph
—
n-Undecyl
(S)-


V-1726
Me
Et
Me
CH2
Ph
—
n-Undecyl
racemic


V-1727
Me
Et
Me
CH2
Ph
—
n-Undecyl
(S)-


V-1728
Me
Me
Me
CH2
Ph
—
Ph
racemic


V-1729
Me
Me
Me
CH2
Ph
—
Ph
(S)-


V-1730
Me
Et
Me
CH2
Ph
—
Ph
racemic


V-1731
Me
Et
Me
CH2
Ph
—
Ph
(S)-


V-1732
Me
Me
Me
CH2
Ph
—
OEt
racemic


V-1733
Me
Me
Me
CH2
Ph
—
OEt
(S)-


V-1734
Me
Et
Me
CH2
Ph
—
OEt
racemic


V-1735
Me
Et
Me
CH2
Ph
—
OEt
(S)-


V-1736
Me
Me
Me
CH2
Ph
—
(CH2)2COOH
racemic


V-1737
Me
Me
Me
CH2
Ph
—
(CH2)2COOH
(S)-


V-1738
Me
Et
Me
CH2
Ph
—
(CH2)2COOH
racemic


V-1739
Me
Et
Me
CH2
Ph
—
(CH2)2COOH
(S)-


V-1740
Me
Me
Me
CH2
Ph
C(Me)2
Me
racemic


V-1741
Me
Me
Me
CH2
Ph
C(Me)2
Me
(S)-


V-1742
Me
Et
Me
CH2
Ph
C(Me)2
Me
racemic


V-1743
Me
Et
Me
CH2
Ph
C(Me)2
Me
(S)-


V-1744
Me
Me
Me
CH2
Ph
C(Me)2
Et
racemic


V-1745
Me
Me
Me
CH2
Ph
C(Me)2
Et
(S)-


V-1746
Me
Et
Me
CH2
Ph
C(Me)2
Et
racemic


V-1747
Me
Et
Me
CH2
Ph
C(Me)2
Et
(S)-


V-1748
Me
Me
Me
CH2
Ph
C(Me)2
nPr
racemic
















TABLE 139







(Vc)




embedded image




















Com-










pound










No.
R1
R2
R3
L2
R4
L3
R6
Configuration





V-1749
Me
Me
Me
CH2
Ph
C(Me)2
nPr
(S)-


V-1750
Me
Et
Me
CH2
Ph
C(Me)2
nPr
racemic


V-1751
Me
Et
Me
CH2
Ph
C(Me)2
nPr
(S)-


V-1752
Me
Me
Me
CH2
Ph
C(Me)2
iPr
racemic


V-1753
Me
Me
Me
CH2
Ph
C(Me)2
iPr
(S)-


V-1754
Me
Et
Me
CH2
Ph
C(Me)2
iPr
racemic


V-1755
Me
Et
Me
CH2
Ph
C(Me)2
iPr
(S)-


V-1756
Me
Me
Me
CH2
Ph
C(Me)2
nBu
racemic


V-1757
Me
Me
Me
CH2
Ph
C(Me)2
nBu
(S)-


V-1758
Me
Et
Me
CH2
Ph
C(Me)2
nBu
racemic


V-1759
Me
Et
Me
CH2
Ph
C(Me)2
nBu
(S)-


V-1760
Me
Me
Me
CH2
Ph
C(Me)2
tBu
racemic


V-1761
Me
Me
Me
CH2
Ph
C(Me)2
tBu
(S)-


V-1762
Me
Et
Me
CH2
Ph
C(Me)2
tBu
racemic


V-1763
Me
Et
Me
CH2
Ph
C(Me)2
tBu
(S)-


V-1764
Me
Me
Me
CH2
Ph
C(Me)2
iBu
racemic


V-1765
Me
Me
Me
CH2
Ph
C(Me)2
iBu
(S)-


V-1766
Me
Et
Me
CH2
Ph
C(Me)2
iBu
racemic


V-1767
Me
Et
Me
CH2
Ph
C(Me)2
iBu
(S)-


V-1768
Me
Me
Me
CH2
Ph
C(Me)2
n-Heptyl
racemic


V-1769
Me
Me
Me
CH2
Ph
C(Me)2
n-Heptyl
(S)-


V-1770
Me
Et
Me
CH2
Ph
C(Me)2
n-Heptyl
racemic


V-1771
Me
Et
Me
CH2
Ph
C(Me)2
n-Heptyl
(S)-


V-1772
Me
Me
Me
CH2
Ph
C(Me)2
n-Undecyl
racemic


V-1773
Me
Me
Me
CH2
Ph
C(Me)2
n-Undecyl
(S)-


V-1774
Me
Et
Me
CH2
Ph
C(Me)2
n-Undecyl
racemic


V-1775
Me
Et
Me
CH2
Ph
C(Me)2
n-Undecyl
(S)-


V-1776
Me
Me
Me
CH2
Ph
C(Me)2
Ph
racemic


V-1777
Me
Me
Me
CH2
Ph
C(Me)2
Ph
(S)-


V-1778
Me
Et
Me
CH2
Ph
C(Me)2
Ph
racemic


V-1779
Me
Et
Me
CH2
Ph
C(Me)2
Ph
(S)-


V-1780
Me
Me
Me
CH2
Ph
C(Me)2
OEt
racemic


V-1781
Me
Me
Me
CH2
Ph
C(Me)2
OEt
(S)-


V-1782
Me
Et
Me
CH2
Ph
C(Me)2
OEt
racemic


V-1783
Me
Et
Me
CH2
Ph
C(Me)2
OEt
(S)-


V-1784
Me
Me
Me
CH2
Ph
C(Me)2
(CH2)2COOH
racemic


V-1785
Me
Me
Me
CH2
Ph
C(Me)2
(CH2)2COOH
(S)-


V-1786
Me
Et
Me
CH2
Ph
C(Me)2
(CH2)2COOH
racemic


V-1787
Me
Et
Me
CH2
Ph
C(Me)2
(CH2)2COOH
(S)-


V-1788
Me
Me
Me
CH2
Ph
(CH2)2
Me
racemic


V-1789
Me
Me
Me
CH2
Ph
(CH2)2
Me
(S)-


V-1790
Me
Et
Me
CH2
Ph
(CH2)2
Me
racemic


V-1791
Me
Et
Me
CH2
Ph
(CH2)2
Me
(S)-


V-1792
Me
Me
Me
CH2
Ph
(CH2)2
Et
racemic


V-1793
Me
Me
Me
CH2
Ph
(CH2)2
Et
(S)-


V-1794
Me
Et
Me
CH2
Ph
(CH2)2
Et
racemic


V-1795
Me
Et
Me
CH2
Ph
(CH2)2
Et
(S)-


V-1796
Me
Me
Me
CH2
Ph
(CH2)2
nPr
racemic


V-1797
Me
Me
Me
CH2
Ph
(CH2)2
nPr
(S)-


V-1798
Me
Et
Me
CH2
Ph
(CH2)2
nPr
racemic
















TABLE 140







(Vc)




embedded image




















Com-







Con-


pound







figu-


No.
R1
R2
R3
L2
R4
L3
R6
ration





V-1799
Me
Et
Me
CH2
Ph
(CH2)2
nPr
(S)-


V-1800
Me
Me
Me
CH2
Ph
(CH2)2
iPr
racemic


V-1801
Me
Me
Me
CH2
Ph
(CH2)2
iPr
(S)-


V-1802
Me
Et
Me
CH2
Ph
(CH2)2
iPr
racemic


V-1803
Me
Et
Me
CH2
Ph
(CH2)2
iPr
(S)-


V-1804
Me
Me
Me
CH2
Ph
(CH2)2
nBu
racemic


V-1805
Me
Me
Me
CH2
Ph
(CH2)2
nBu
(S)-


V-1806
Me
Et
Me
CH2
Ph
(CH2)2
nBu
racemic


V-1807
Me
Et
Me
CH2
Ph
(CH2)2
nBu
(S)-


V-1808
Me
Me
Me
CH2
Ph
(CH2)2
tBu
racemic


V-1809
Me
Me
Me
CH2
Ph
(CH2)2
tBu
(S)-


V-1810
Me
Et
Me
CH2
Ph
(CH2)2
tBu
racemic


V-1811
Me
Et
Me
CH2
Ph
(CH2)2
tBu
(S)-


V-1812
Me
Me
Me
CH2
Ph
(CH2)2
iBu
racemic


V-1813
Me
Me
Me
CH2
Ph
(CH2)2
iBu
(S)-


V-1814
Me
Et
Me
CH2
Ph
(CH2)2
iBu
racemic


V-1815
Me
Et
Me
CH2
Ph
(CH2)2
iBu
(S)-


V-1816
Me
Me
Me
CH2
Ph
(CH2)2
n-Heptyl
racemic


V-1817
Me
Me
Me
CH2
Ph
(CH2)2
n-Heptyl
(S)-


V-1818
Me
Et
Me
CH2
Ph
(CH2)2
n-Heptyl
racemic


V-1819
Me
Et
Me
CH2
Ph
(CH2)2
n-Heptyl
(S)-


V-1820
Me
Me
Me
CH2
Ph
(CH2)2
n-Undecyl
racemic


V-1821
Me
Me
Me
CH2
Ph
(CH2)2
n-Undecyl
(S)-


V-1822
Me
Et
Me
CH2
Ph
(CH2)2
n-Undecyl
racemic


V-1823
Me
Et
Me
CH2
Ph
(CH2)2
n-Undecyl
(S)-


V-1824
Me
Me
Me
CH2
Ph
(CH2)2
Ph
racemic


V-1825
Me
Me
Me
CH2
Ph
(CH2)2
Ph
(S)-


V-1826
Me
Et
Me
CH2
Ph
(CH2)2
Ph
racemic


V-1827
Me
Et
Me
CH2
Ph
(CH2)2
Ph
(S)-


V-1828
Me
Me
Me
CH2
Ph
(CH2)2
OEt
racemic


V-1829
Me
Me
Me
CH2
Ph
(CH2)2
OEt
(S)-


V-1830
Me
Et
Me
CH2
Ph
(CH2)2
OEt
racemic


V-1831
Me
Et
Me
CH2
Ph
(CH2)2
OEt
(S)-


V-1832
Me
Me
Me
CH2
Ph
(CH2)2
(CH2)2COOH
racemic


V-1833
Me
Me
Me
CH2
Ph
(CH2)2
(CH2)2COOH
(S)-


V-1834
Me
Et
Me
CH2
Ph
(CH2)2
(CH2)2COOH
racemic


V-1835
Me
Et
Me
CH2
Ph
(CH2)2
(CH2)2COOH
(S)-


V-1836
Me
Me
Me
CH2
Ph
CH2C(Me)2
Me
racemic


V-1837
Me
Me
Me
CH2
Ph
CH2C(Me)2
Me
(S)-


V-1838
Me
Et
Me
CH2
Ph
CH2C(Me)2
Me
racemic


V-1839
Me
Et
Me
CH2
Ph
CH2C(Me)2
Me
(S)-


V-1840
Me
Me
Me
CH2
Ph
CH2C(Me)2
Et
racemic


V-1841
Me
Me
Me
CH2
Ph
CH2C(Me)2
Et
(S)-


V-1842
Me
Et
Me
CH2
Ph
CH2C(Me)2
Et
racemic


V-1843
Me
Et
Me
CH2
Ph
CH2C(Me)2
Et
(S)-


V-1844
Me
Me
Me
CH2
Ph
CH2C(Me)2
nPr
racemic


V-1845
Me
Me
Me
CH2
Ph
CH2C(Me)2
nPr
(S)-


V-1846
Me
Et
Me
CH2
Ph
CH2C(Me)2
nPr
racemic


V-1847
Me
Et
Me
CH2
Ph
CH2C(Me)2
nPr
(S)-


V-1848
Me
Me
Me
CH2
Ph
CH2C(Me)2
iPr
racemic
















TABLE 141







(Vc)




embedded image




















Com-







Con-


pound







figu-


No.
R1
R2
R3
L2
R4
L3
R6
ration





V-1849
Me
Me
Me
CH2
Ph
CH2C(Me)2
iPr
(S)-


V-1850
Me
Et
Me
CH2
Ph
CH2C(Me)2
iPr
racemic


V-1851
Me
Et
Me
CH2
Ph
CH2C(Me)2
iPr
(S)-


V-1852
Me
Me
Me
CH2
Ph
CH2C(Me)2
nBu
racemic


V-1853
Me
Me
Me
CH2
Ph
CH2C(Me)2
nBu
(S)-


V-1854
Me
Et
Me
CH2
Ph
CH2C(Me)2
nBu
racemic


V-1855
Me
Et
Me
CH2
Ph
CH2C(Me)2
nBu
(S)-


V-1856
Me
Me
Me
CH2
Ph
CH2C(Me)2
tBu
racemic


V-1857
Me
Me
Me
CH2
Ph
CH2C(Me)2
tBu
(S)-


V-1858
Me
Et
Me
CH2
Ph
CH2C(Me)2
tBu
racemic


V-1859
Me
Et
Me
CH2
Ph
CH2C(Me)2
tBu
(S)-


V-1860
Me
Me
Me
CH2
Ph
CH2C(Me)2
iBu
racemic


V-1861
Me
Me
Me
CH2
Ph
CH2C(Me)2
iBu
(S)-


V-1862
Me
Et
Me
CH2
Ph
CH2C(Me)2
iBu
racemic


V-1863
Me
Et
Me
CH2
Ph
CH2C(Me)2
iBu
(S)-


V-1864
Me
Me
Me
CH2
Ph
CH2C(Me)2
n-Heptyl
racemic


V-1865
Me
Me
Me
CH2
Ph
CH2C(Me)2
n-Heptyl
(S)-


V-1866
Me
Et
Me
CH2
Ph
CH2C(Me)2
n-Heptyl
racemic


V-1867
Me
Et
Me
CH2
Ph
CH2C(Me)2
n-Heptyl
(S)-


V-1868
Me
Me
Me
CH2
Ph
CH2C(Me)2
n-Undecyl
racemic


V-1869
Me
Me
Me
CH2
Ph
CH2C(Me)2
n-Undecyl
(S)-


V-1870
Me
Et
Me
CH2
Ph
CH2C(Me)2
n-Undecyl
racemic


V-1871
Me
Et
Me
CH2
Ph
CH2C(Me)2
n-Undecyl
(S)-


V-1872
Me
Me
Me
CH2
Ph
CH2C(Me)2
Ph
racemic


V-1873
Me
Me
Me
CH2
Ph
CH2C(Me)2
Ph
(S)-


V-1874
Me
Et
Me
CH2
Ph
CH2C(Me)2
Ph
racemic


V-1875
Me
Et
Me
CH2
Ph
CH2C(Me)2
Ph
(S)-


V-1876
Me
Me
Me
CH2
Ph
CH2C(Me)2
OEt
racemic


V-1877
Me
Me
Me
CH2
Ph
CH2C(Me)2
OEt
(S)-


V-1878
Me
Et
Me
CH2
Ph
CH2C(Me)2
OEt
racemic


V-1879
Me
Et
Me
CH2
Ph
CH2C(Me)2
OEt
(S)-


V-1880
Me
Me
Me
CH2
Ph
CH2C(Me)2
(CH2)2COOH
racemic


V-1881
Me
Me
Me
CH2
Ph
CH2C(Me)2
(CH2)2COOH
(S)-


V-1882
Me
Et
Me
CH2
Ph
CH2C(Me)2
(CH2)2COOH
racemic


V-1883
Me
Et
Me
CH2
Ph
CH2C(Me)2
(CH2)2COOH
(S)-
















TABLE 142







(Vc)




embedded image




















Com-










pound










No.
R1
R2
R3
L2
R4
L3
R6
Configuration





V-2060
Me
Me
Me
—
Ph
—
Me
racemic


V-2061
Me
Me
Me
—
Ph
—
Me
(R)-


V-2062
Me
Et
Me
—
Ph
—
Me
racemic


V-2063
Me
Et
Me
—
Ph
—
Me
(R)-


V-2064
Me
Me
Me
—
Ph
—
Et
racemic


V-2065
Me
Me
Me
—
Ph
—
Et
(R)-


V-2066
Me
Et
Me
—
Ph
—
Et
racemic


V-2067
Me
Et
Me
—
Ph
—
Et
(R)-


V-2068
Me
Me
Me
—
Ph
—
nPr
racemic


V-2069
Me
Me
Me
—
Ph
—
nPr
(R)-


V-2070
Me
Et
Me
—
Ph
—
nPr
racemic


V-2071
Me
Et
Me
—
Ph
—
nPr
(R)-


V-2072
Me
Me
Me
—
Ph
—
iPr
racemic


V-2073
Me
Me
Me
—
Ph
—
iPr
(R)-


V-2074
Me
Et
Me
—
Ph
—
iPr
racemic


V-2075
Me
Et
Me
—
Ph
—
iPr
(R)-


V-2076
Me
Me
Me
—
Ph
—
nBu
racemic


V-2077
Me
Me
Me
—
Ph
—
nBu
(R)-


V-2078
Me
Et
Me
—
Ph
—
nBu
racemic


V-2079
Me
Et
Me
—
Ph
—
nBu
(R)-


V-2080
Me
Me
Me
—
Ph
—
tBu
racemic


V-2081
Me
Me
Me
—
Ph
—
tBu
(R)-


V-2082
Me
Et
Me
—
Ph
—
tBu
racemic


V-2083
Me
Et
Me
—
Ph
—
tBu
(R)-


V-2084
Me
Me
Me
—
Ph
—
iBu
racemic


V-2085
Me
Me
Me
—
Ph
—
iBu
(R)-


V-2086
Me
Et
Me
—
Ph
—
iBu
racemic


V-2087
Me
Et
Me
—
Ph
—
iBu
(R)-


V-2088
Me
Me
Me
—
Ph
—
n-Heptyl
racemic


V-2089
Me
Me
Me
—
Ph
—
n-Heptyl
(R)-


V-2090
Me
Et
Me
—
Ph
—
n-Heptyl
racemic


V-2091
Me
Et
Me
—
Ph
—
n-Heptyl
(R)-


V-2092
Me
Me
Me
—
Ph
—
n-Undecyl
racemic


V-2093
Me
Me
Me
—
Ph
—
n-Undecyl
(R)-


V-2094
Me
Et
Me
—
Ph
—
n-Undecyl
racemic


V-2095
Me
Et
Me
—
Ph
—
n-Undecyl
(R)-


V-2096
Me
Me
Me
—
Ph
—
OEt
racemic


V-2097
Me
Me
Me
—
Ph
—
OEt
(R)-


V-2098
Me
Et
Me
—
Ph
—
OEt
racemic


V-2099
Me
Et
Me
—
Ph
—
OEt
(R)-


V-2100
Me
Me
Me
—
Ph
—
(CH2)2COONa
racemic


V-2101
Me
Me
Me
—
Ph
—
(CH2)2COONa
(R)-


V-2102
Me
Et
Me
—
Ph
—
(CH2)2COONa
racemic


V-2103
Me
Et
Me
—
Ph
—
(CH2)2COONa
(R)-


V-2104
Me
Me
Me
—
Ph
CH2
Me
racemic


V-2105
Me
Me
Me
—
Ph
CH2
Me
(S)-


V-2106
Me
Et
Me
—
Ph
CH2
Me
racemic


V-2107
Me
Et
Me
—
Ph
CH2
Me
(S)-


V-2108
Me
Me
Me
—
Ph
CH2
Et
racemic


V-2109
Me
Me
Me
—
Ph
CH2
Et
(S)-
















TABLE 143







(Vc)




embedded image




















Com-










pound










No.
R1
R2
R3
L2
R4
L3
R6
Configuration





V-2110
Me
Et
Me
—
Ph
CH2
Et
racemic


V-2111
Me
Et
Me
—
Ph
CH2
Et
(S)-


V-2112
Me
Me
Me
—
Ph
CH2
nPr
racemic


V-2113
Me
Me
Me
—
Ph
CH2
nPr
(S)-


V-2114
Me
Et
Me
—
Ph
CH2
nPr
racemic


V-2115
Me
Et
Me
—
Ph
CH2
nPr
(S)-


V-2116
Me
Me
Me
—
Ph
CH2
iPr
racemic


V-2117
Me
Me
Me
—
Ph
CH2
iPr
(S)-


V-2118
Me
Et
Me
—
Ph
CH2
iPr
racemic


V-2119
Me
Et
Me
—
Ph
CH2
iPr
(S)-


V-2120
Me
Me
Me
—
Ph
CH2
nBu
racemic


V-2121
Me
Me
Me
—
Ph
CH2
nBu
(S)-


V-2122
Me
Et
Me
—
Ph
CH2
nBu
racemic


V-2123
Me
Et
Me
—
Ph
CH2
nBu
(S)-


V-2124
Me
Me
Me
—
Ph
CH2
tBu
racemic


V-2125
Me
Me
Me
—
Ph
CH2
tBu
(S)-


V-2126
Me
Et
Me
—
Ph
CH2
tBu
racemic


V-2127
Me
Et
Me
—
Ph
CH2
tBu
(S)-


V-2128
Me
Me
Me
—
Ph
CH2
iBu
racemic


V-2129
Me
Me
Me
—
Ph
CH2
iBu
(S)-


V-2130
Me
Et
Me
—
Ph
CH2
iBu
racemic


V-2131
Me
Et
Me
—
Ph
CH2
iBu
(S)-


V-2132
Me
Me
Me
—
Ph
CH2
n-Heptyl
racemic


V-2133
Me
Me
Me
—
Ph
CH2
n-Heptyl
(S)-


V-2134
Me
Et
Me
—
Ph
CH2
n-Heptyl
racemic


V-2135
Me
Et
Me
—
Ph
CH2
n-Heptyl
(S)-


V-2136
Me
Me
Me
—
Ph
CH2
n-Undecyl
racemic


V-2137
Me
Me
Me
—
Ph
CH2
n-Undecyl
(S)-


V-2138
Me
Et
Me
—
Ph
CH2
n-Undecyl
racemic


V-2139
Me
Et
Me
—
Ph
CH2
n-Undecyl
(S)-


V-2140
Me
Me
Me
—
Ph
CH2
OEt
racemic


V-2141
Me
Me
Me
—
Ph
CH2
OEt
(S)-


V-2142
Me
Et
Me
—
Ph
CH2
OEt
racemic


V-2143
Me
Et
Me
—
Ph
CH2
OEt
(S)-


V-2144
Me
Me
Me
—
Ph
CH2
(CH2)2COONa
racemic


V-2145
Me
Me
Me
—
Ph
CH2
(CH2)2COONa
(S)-


V-2146
Me
Et
Me
—
Ph
CH2
(CH2)2COONa
racemic


V-2147
Me
Et
Me
—
Ph
CH2
(CH2)2COONa
(S)-
















TABLE 144







(VIa)




embedded image






















Compound












No.
R1
R2
R3
L2
R4
L3
R8
R9
R7
Configuration





VI-1 
Me
Me
Me
O
Ph
CH2
H
H
Me
racemic


VI-2 
Me
Me
Me
O
Ph
CH2
H
H
Me
(S)-


VI-3 
Me
Me
Me
O
Ph
CH2
Me
H
Me
racemic


VI-4 
Me
Me
Me
O
Ph
CH2
Me
H
Me
(S)-


VI-5 
Me
Me
Me
O
Ph
CH2
H
Me
Me
racemic


VI-6 
Me
Me
Me
O
Ph
CH2
H
Me
Me
(S)-


VI-7 
Me
Me
Me
O
Ph
CH2
Me
Me
Me
racemic


VI-8 
Me
Me
Me
O
Ph
CH2
Me
Me
Me
(S)-


VI-9 
Me
Et
Me
O
Ph
CH2
H
H
Me
racemic


VI-10
Me
Et
Me
O
Ph
CH2
H
H
Me
(S)-


VI-11
Me
Et
Me
O
Ph
CH2
Me
H
Me
racemic


VI-12
Me
Et
Me
O
Ph
CH2
Me
H
Me
(S)-


VT-13
Me
Et
Me
O
Ph
CH2
H
Me
Me
racemic


VI-14
Me
Et
Me
O
Ph
CH2
H
Me
Me
(S)-


VI-15
Me
Et
Me
O
Ph
CH2
Me
Me
Me
racemic


VI-16
Me
Et
Me
O
Ph
CH2
Me
Me
Me
(S)-


VI-17
Me
Me
Me
O
Ph
CH2
H
H
Et
racemic


VI-18
Me
Me
Me
O
Ph
CH2
H
H
Et
(S)-


VI-19
Me
Me
Me
O
Ph
CH2
Me
H
Et
racemic


VI-20
Me
Me
Me
O
Ph
CH2
Me
H
Et
(S)-


VI-21
Me
Me
Me
O
Ph
CH2
H
Me
Et
racemic


VI-22
Me
Me
Me
O
Ph
CH2
H
Me
Et
(S)-


VI-23
Me
Me
Me
O
Ph
CH2
Me
Me
Et
racemic


VI-24
Me
Me
Me
O
Ph
CH2
Me
Me
Et
(S)-


VI-25
Me
Et
Me
O
Ph
CH2
H
H
Et
racemic


VI-26
Me
Et
Me
O
Ph
CH2
H
H
Et
(S)-


VI-27
Me
Et
Me
O
Ph
CH2
Me
H
Et
racemic


VI-28
Me
Et
Me
O
Ph
CH2
Me
H
Et
(S)-


VI-29
Me
Et
Me
O
Ph
CH2
H
Me
Et
racemic


VI-30
Me
Et
Me
O
Ph
CH2
H
Me
Et
(S)-


VI-31
Me
Et
Me
O
Ph
CH2
Me
Me
Et
racemic


VI-32
Me
Et
Me
O
Ph
CH2
Me
Me
Et
(S)-


VI-33
Me
Me
Me
NH
Ph
CH2
H
H
Me
racemic


VI-34
Me
Me
Me
NH
Ph
CH2
H
H
Me
(S)-


VI-35
Me
Me
Me
NH
Ph
CH2
Me
H
Me
racemic


VI-36
Me
Me
Me
NH
Ph
CH2
Me
H
Me
(S)-


VI-37
Me
Me
Me
NH
Ph
CH2
H
Me
Me
racemic


VI-38
Me
Me
Me
NH
Ph
CH2
H
Me
Me
(S)-


VI-39
Me
Me
Me
NH
Ph
CH2
Me
Me
Me
racemic


VI-40
Me
Me
Me
NH
Ph
CH2
Me
Me
Me
(S)-


VI-41
Me
Et
Me
NH
Ph
CH2
H
H
Me
racemic


VI-42
Me
Et
Me
NH
Ph
CH2
H
H
Me
(S)-


VI-43
Me
Et
Me
NH
Ph
CH2
Me
H
Me
racemic


VI-44
Me
Et
Me
NH
Ph
CH2
Me
H
Me
(S)-


VI-45
Me
Et
Me
NH
Ph
CH2
H
Me
Me
racemic


VI-46
Me
Et
Me
NH
Ph
CH2
H
Me
Me
(S)-


VI-47
Me
Et
Me
NH
Ph
CH2
Me
Me
Me
racemic


VI-48
Me
Et
Me
NH
Ph
CH2
Me
Me
Me
(S)-


VI-49
Me
Me
Me
NH
Ph
CH2
H
H
Et
racemic


VI-50
Me
Me
Me
NH
Ph
CH2
H
H
Et
(S)-
















TABLE 145







(VIa)




embedded image






















Com-












pound









Config-


No.
R1
R2
R3
L2
R4
L3
R8
R9
R7
uration





VI-51
Me
Me
Me
NH
Ph
CH2
Me
H
Et
racemic


VI-52
Me
Me
Me
NH
Ph
CH2
Me
H
Et
(S)-


VI-53
Me
Me
Me
NH
Ph
CH2
H
Me
Et
racemic


VI-54
Me
Me
Me
NH
Ph
CH2
H
Me
Et
(S)-


VI-55
Me
Me
Me
NH
Ph
CH2
Me
Me
Et
racemic


VI-56
Me
Me
Me
NH
Ph
CH2
Me
Me
Et
(S)-


VI-57
Me
Et
Me
NH
Ph
CH2
H
H
Et
racemic


VI-58
Me
Et
Me
NH
Ph
CH2
H
H
Et
(S)-


VI-59
Me
Et
Me
NH
Ph
CH2
Me
H
Et
racemic


VI-60
Me
Et
Me
NH
Ph
CH2
Me
H
Et
(S)-


VI-61
Me
Et
Me
NH
Ph
CH2
H
Me
Et
racemic


VI-62
Me
Et
Me
NH
Ph
CH2
H
Me
Et
(S)-


VI-63
Me
Et
Me
NH
Ph
CH2
Me
Me
Et
racemic


VI-64
Me
Et
Me
NH
Ph
CH2
Me
Me
Et
(S)-


VI-65
Me
Me
Me
NH
Ph
CH2
H
H
C(═O)Me
racemic


VI-66
Me
Me
Me
NH
Ph
CH2
H
H
C(═O)Me
(S)-


VI-67
Me
Me
Me
NH
Ph
CH2
Me
H
C(═O)Me
racemic


VI-68
Me
Me
Me
NH
Ph
CH2
Me
H
C(═O)Me
(S)-


VI-69
Me
Me
Me
NH
Ph
CH2
H
Me
C(═O)Me
racemic


VI-70
Me
Me
Me
NH
Ph
CH2
H
Me
C(═O)Me
(S)-


VI-71
Me
Me
Me
NH
Ph
CH2
Me
Me
C(═O)Me
racemic


VI-72
Me
Me
Me
NH
Ph
CH2
Me
Me
C(═O)Me
(S)-


VI-73
Me
Et
Me
NH
Ph
CH2
H
H
C(═O)Me
racemic


VI-74
Me
Et
Me
NH
Ph
CH2
H
H
C(═O)Me
(S)-


VI-75
Me
Et
Me
NH
Ph
CH2
Me
H
C(═O)Me
racemic


VI-76
Me
Et
Me
NH
Ph
CH2
Me
H
C(═O)Me
(S)-


VI-77
Me
Et
Me
NH
Ph
CH2
H
Me
C(═O)Me
racemic


VI-78
Me
Et
Me
NH
Ph
CH2
H
Me
C(═O)Me
(S)-


VI-79
Me
Et
Me
NH
Ph
CH2
Me
Me
C(═O)Me
racemic


VI-80
Me
Et
Me
NH
Ph
CH2
Me
Me
C(═O)Me
(S)-


VI-81
Me
Me
Me
NH
Ph
CH2
H
H
C(═O)Et
racemic


VI-82
Me
Me
Me
NH
Ph
CH2
H
H
C(═O)Et
(S)-


VI-83
Me
Me
Me
NH
Ph
CH2
Me
H
C(═O)Et
racemic


VI-84
Me
Me
Me
NH
Ph
CH2
Me
H
C(═O)Et
(S)-


VI-85
Me
Me
Me
NH
Ph
CH2
H
Me
C(═O)Et
racemic


VI-86
Me
Me
Me
NH
Ph
CH2
H
Me
C(═O)Et
(S)-


VI-87
Me
Me
Me
NH
Ph
CH2
Me
Me
C(═O)Et
racemic


VI-88
Me
Me
Me
NH
Ph
CH2
Me
Me
C(═O)Et
(S)-


VI-89
Me
Et
Me
NH
Ph
CH2
H
H
C(═O)Et
racemic


VI-90
Me
Et
Me
NH
Ph
CH2
H
H
C(═O)Et
(S)-


VI-91
Me
Et
Me
NH
Ph
CH2
Me
H
C(═O)Et
racemic


VI-92
Me
Et
Me
NH
Ph
CH2
Me
H
C(═O)Et
(S)-


VI-93
Me
Et
Me
NH
Ph
CH2
H
Me
C(═O)Et
racemic


VI-94
Me
Et
Me
NH
Ph
CH2
H
Me
C(═O)Et
(S)-


VI-95
Me
Et
Me
NH
Ph
CH2
Me
Me
C(═O)Et
racemic


VI-96
Me
Et
Me
NH
Ph
CH2
Me
Me
C(═O)Et
(S)-


VI-97
Me
Me
Me
NH
Ph
CH2
H
H
C(═O)tBu
racemic


VI-98
Me
Me
Me
NH
Ph
CH2
H
H
C(═O)tBu
(S)-


VI-99
Me
Me
Me
NH
Ph
CH2
Me
H
C(═O)tBu
racemic


VI-100
Me
Me
Me
NH
Ph
CH2
Me
H
C(═O)tBu
(S)-
















TABLE 146







(VIa)




embedded image






















Com-












pound









Config-


No.
R1
R2
R3
L2
R4
L3
R8
R9
R7
uration





VI-101
Me
Me
Me
NH
Ph
CH2
H
Me
C(═O)tBu
racemic


VI-102
Me
Me
Me
NH
Ph
CH2
H
Me
C(═O)tBu
(S)-


VI-103
Me
Me
Me
NH
Ph
CH2
Me
Me
C(═O)tBu
racemic


VI-104
Me
Me
Me
NH
Ph
CH2
Me
Me
C(═O)tBu
(S)-


VI-105
Me
Et
Me
NH
Ph
CH2
H
H
C(═O)tBu
racemic


VI-106
Me
Et
Me
NH
Ph
CH2
H
H
C(═O)tBu
(S)-


VI-107
Me
Et
Me
NH
Ph
CH2
Me
H
C(═O)tBu
racemic


VI-108
Me
Et
Me
NH
Ph
CH2
Me
H
C(═O)tBu
(S)-


VI-109
Me
Et
Me
NH
Ph
CH2
H
Me
C(═O)tBu
racemic


VI-110
Me
Et
Me
NH
Ph
CH2
H
Me
C(═O)tBu
(S)-


VI-111
Me
Et
Me
NH
Ph
CH2
Me
Me
C(═O)tBu
racemic


VI-112
Me
Et
Me
NH
Ph
CH2
Me
Me
C(═O)tBu
(S)-


VI-113
Me
Me
Me
NH
Ph
CH2
H
H
C(═O)OEt
racemic


VI-114
Me
Me
Me
NH
Ph
CH2
H
H
C(═O)OEt
(S)-


VI-115
Me
Me
Me
NH
Ph
CH2
Me
H
C(═O)OEt
racemic


VI-116
Me
Me
Me
NH
Ph
CH2
Me
H
C(═O)OEt
(S)-


VI-117
Me
Me
Me
NH
Ph
CH2
H
Me
C(═O)OEt
racemic


VI-118
Me
Me
Me
NH
Ph
CH2
H
Me
C(═O)OEt
(S)-


VI-119
Me
Me
Me
NH
Ph
CH2
Me
Me
C(═O)OEt
racemic


VI-120
Me
Me
Me
NH
Ph
CH2
Me
Me
C(═O)OEt
(S)-


VI-121
Me
Et
Me
NH
Ph
CH2
H
H
C(═O)OEt
racemic


VI-122
Me
Et
Me
NH
Ph
CH2
H
H
C(═O)OEt
(S)-


VI-123
Me
Et
Me
NH
Ph
CH2
Me
H
C(═O)OEt
racemic


VI-124
Me
Et
Me
NH
Ph
CH2
Me
H
C(═O)OEt
(S)-


VI-125
Me
Et
Me
NH
Ph
CH2
H
Me
C(═O)OEt
racemic


VI-126
Me
Et
Me
NH
Ph
CH2
H
Me
C(═O)OEt
(S)-


VI-127
Me
Et
Me
NH
Ph
CH2
Me
Me
C(═O)OEt
racemic


VI-128
Me
Et
Me
NH
Ph
CH2
Me
Me
C(═O)OEt
(S)-


VI-129
Me
Me
Me
NH
Ph
CH2
H
H
C(═O)Oc
racemic











Hex



VI-130
Me
Me
Me
NH
Ph
CH2
H
H
C(═O)Oc
(S)-











Hex



VI-131
Me
Me
Me
NH
Ph
CH2
Me
H
C(═O)Oc
racemic











Hex



VI-132
Me
Me
Me
NH
Ph
CH2
Me
H
C(═O)Oc
(S)-











Hex



VI-133
Me
Me
Me
NH
Ph
CH2
H
Me
C(═O)Oc
racemic











Hex



VI-134
Me
Me
Me
NH
Ph
CH2
H
Me
C(═O)Oc
(S)-











Hex



VI-135
Me
Me
Me
NH
Ph
CH2
Me
Me
C(═O)Oc
racemic











Hex



VI-136
Me
Me
Me
NH
Ph
CH2
Me
Me
C(═O)Oc
(S)-











Hex



VI-137
Me
Et
Me
NH
Ph
CH2
H
H
C(═O)Oc
racemic











Hex



VI-138
Me
Et
Me
NH
Ph
CH2
H
H
C(═O)Oc
(S)-











Hex



VI-139
Me
Et
Me
NH
Ph
CH2
Me
H
C(═O)Oc
racemic











Hex



VI-140
Me
Et
Me
NH
Ph
CH2
Me
H
C(═O)Oc
(S)-











Hex



VI-141
Me
Et
Me
NH
Ph
CH2
H
Me
C(═O)Oc
racemic











Hex



VI-142
Me
Et
Me
NH
Ph
CH2
H
Me
C(═O)Oc
(S)-











Hex



VI-143
Me
Et
Me
NH
Ph
CH2
Me
Me
C(═O)Oc
racemic











Hex



VI-144
Me
Et
Me
NH
Ph
CH2
Me
Me
C(═O)Oc
(S)-











Hex



VI-145
Me
Me
Me
CH2
Ph
CH2
H
H
Me
racemic


VI-146
Me
Me
Me
CH2
Ph
CH2
H
H
Me
(S)-


VI-147
Me
Me
Me
CH2
Ph
CH2
Me
H
Me
racemic


VI-148
Me
Me
Me
CH2
Ph
CH2
Me
H
Me
(S)-


VI-149
Me
Me
Me
CH2
Ph
CH2
H
Me
Me
racemic


VI-150
Me
Me
Me
CH2
Ph
CH2
H
Me
Me
(S)-
















TABLE 147







(VIa)




embedded image






















Com-












pound









Config-


No.
R1
R2
R3
L2
R4
L3
R8
R9
R7
uraton





VI-151
Me
Me
Me
CH2
Ph
CH2
Me
Me
Me
racemic


VI-152
Me
Me
Me
CH2
Ph
CH2
Me
Me
Me
(S)-


VI-153
Me
Et
Me
CH2
Ph
CH2
H
H
Me
racemic


VI-154
Me
Et
Me
CH2
Ph
CH2
H
H
Me
(S)-


VI-155
Me
Et
Me
CH2
Ph
CH2
Me
H
Me
racemic


VI-156
Me
Et
Me
CH2
Ph
CH2
Me
H
Me
(S)-


VI-157
Me
Et
Me
CH2
Ph
CH2
H
Me
Me
racemic


VI-158
Me
Et
Me
CH2
Ph
CH2
H
Me
Me
(S)-


VI-159
Me
Et
Me
CH2
Ph
CH2
Me
Me
Me
racemic


VI-160
Me
Et
Me
CH2
Ph
CH2
Me
Me
Me
(S)-


VI-161
Me
Me
Me
CH2
Ph
CH2
H
H
Et
racemic


VI-162
Me
Me
Me
CH2
Ph
CH2
H
H
Et
(S)-


VI-163
Me
Me
Me
CH2
Ph
CH2
Me
H
Et
racemic


VI-164
Me
Me
Me
CH2
Ph
CH2
Me
H
Et
(S)-


VI-165
Me
Me
Me
CH2
Ph
CH2
H
Me
Et
racemic


VI-166
Me
Me
Me
CH2
Ph
CH2
H
Me
Et
(S)-


VI-167
Me
Me
Me
CH2
Ph
CH2
Me
Me
Et
racemic


VI-168
Me
Me
Me
CH2
Ph
CH2
Me
Me
Et
(S)-


VI-169
Me
Et
Me
CH2
Ph
CH2
H
H
Et
racemic


VI-170
Me
Et
Me
CH2
Ph
CH2
H
H
Et
(S)-


VI-171
Me
Et
Me
CH2
Ph
CH2
Me
H
Et
racemic


VI-172
Me
Et
Me
CH2
Ph
CH2
Me
H
Et
(S)-


VI-173
Me
Et
Me
CH2
Ph
CH2
H
Me
Et
racemic


VI-174
Me
Et
Me
CH2
Ph
CH2
H
Me
Et
(S)-


VI-175
Me
Et
Me
CH2
Ph
CH2
Me
Me
Et
racemic


VI-176
Me
Et
Me
CH2
Ph
CH2
Me
Me
Et
(S)-
















TABLE 148







(VIa)




embedded image






















Com-












pound









Config-


No.
R1
R2
R3
L2
R4
L3
R8
R9
R7
uration





VI-553
Me
Me
Me
NH
Ph
(CH2)2
H
H
Me
racemic


VI-554
Me
Me
Me
NH
Ph
(CH2)2
H
H
Me
(R)-


VI-555
Me
Me
Me
NH
Ph
(CH2)2
Me
H
Me
racemic


VI-556
Me
Me
Me
NH
Ph
(CH2)2
Me
H
Me
(R)-


VI-557
Me
Me
Me
NH
Ph
(CH2)2
H
Me
Me
racemic


VI-558
Me
Me
Me
NH
Ph
(CH2)2
H
Me
Me
(R)-


VI-559
Me
Me
Me
NH
Ph
(CH2)2
Me
Me
Me
racemic


VI-560
Me
Me
Me
NH
Ph
(CH2)2
Me
Me
Me
(R)-


VI-561
Me
Et
Me
NH
Ph
(CH2)2
H
H
Me
racemic


VI-562
Me
Et
Me
NH
Ph
(CH2)2
H
H
Me
(R)-


VI-563
Me
Et
Me
NH
Ph
(CH2)2
Me
H
Me
racemic


VI-564
Me
Et
Me
NH
Ph
(CH2)2
Me
H
Me
(R)-


VI-565
Me
Et
Me
NH
Ph
(CH2)2
H
Me
Me
racemic


VI-566
Me
Et
Me
NH
Ph
(CH2)2
H
Me
Me
(R)-


VI-567
Me
Et
Me
NH
Ph
(CH2)2
Me
Me
Me
racemic


VI-568
Me
Et
Me
NH
Ph
(CH2)2
Me
Me
Me
(R)-


VI-569
Me
Me
Me
NH
Ph
(CH2)2
H
H
C(═O)Me
racemic


VI-570
Me
Me
Me
NH
Ph
(CH2)2
H
H
C(═O)Me
(R)-


VI-571
Me
Me
Me
NH
Ph
(CH2)2
Me
H
C(═O)Me
racemic


VI-572
Me
Me
Me
NH
Ph
(CH2)2
Me
H
C(═O)Me
(R)-


VI-573
Me
Me
Me
NH
Ph
(CH2)2
H
Me
C(═O)Me
racemic


VI-574
Me
Me
Me
NH
Ph
(CH2)2
H
Me
C(═O)Me
(R)-


VI-575
Me
Me
Me
NH
Ph
(CH2)2
Me
Me
C(═O)Me
racemic


VI-576
Me
Me
Me
NH
Ph
(CH2)2
Me
Me
C(═O)Me
(R)-


VI-577
Me
Et
Me
NH
Ph
(CH2)2
H
H
C(═O)Me
racemic


VI-578
Me
Et
Me
NH
Ph
(CH2)2
H
H
C(═O)Me
(R)-


VI-579
Me
Et
Me
NH
Ph
(CH2)2
Me
H
C(═O)Me
racemic


VI-580
Me
Et
Me
NH
Ph
(CH2)2
Me
H
C(═O)Me
(R)-


VI-581
Me
Et
Me
NH
Ph
(CH2)2
H
Me
C(═O)Me
racemic


VI-582
Me
Et
Me
NH
Ph
(CH2)2
H
Me
C(═O)Me
(R)-


VI-583
Me
Et
Me
NH
Ph
(CH2)2
Me
Me
C(═O)Me
racemic


VI-584
Me
Et
Me
NH
Ph
(CH2)2
Me
Me
C(═O)Me
(R)-


VI-585
Me
Me
Me
NH
Ph
(CH2)2
H
H
C(═O)Et
racemic


VI-586
Me
Me
Me
NH
Ph
(CH2)2
H
H
C(═O)Et
(R)-


VI-587
Me
Me
Me
NH
Ph
(CH2)2
Me
H
C(═O)Et
racemic


VI-588
Me
Me
Me
NH
Ph
(CH2)2
Me
H
C(═O)Et
(R)-


VI-589
Me
Me
Me
NH
Ph
(CH2)2
H
Me
C(═O)Et
racemic


VI-590
Me
Me
Me
NH
Ph
(CH2)2
H
Me
C(═O)Et
(R)-


VI-591
Me
Me
Me
NH
Ph
(CH2)2
Me
Me
C(═O)Et
racemic


VI-592
Me
Me
Me
NH
Ph
(CH2)2
Me
Me
C(═O)Et
(R)-


VI-593
Me
Et
Me
NH
Ph
(CH2)2
H
H
C(═O)Et
racemic


VI-594
Me
Et
Me
NH
Ph
(CH2)2
H
H
C(═O)Et
(R)-


VI-595
Me
Et
Me
NH
Ph
(CH2)2
Me
H
C(═O)Et
racemic


VI-596
Me
Et
Me
NH
Ph
(CH2)2
Me
H
C(═O)Et
(R)-


VI-597
Me
Et
Me
NH
Ph
(CH2)2
H
Me
C(═O)Et
racemic


VI-598
Me
Et
Me
NH
Ph
(CH2)2
H
Me
C(═O)Et
(R)-


VI-599
Me
Et
Me
NH
Ph
(CH2)2
Me
Me
C(═O)Et
racemic


VI-600
Me
Et
Me
NH
Ph
(CH2)2
Me
Me
C(═O)Et
(R)-


VI-601
Me
Me
Me
—
Ph
—
H
H
Me
racemic


VI-602
Me
Me
Me
—
Ph
—
H
H
Me
(R)-


VI-603
Me
Me
Me
—
Ph
—
Me
H
Me
racemic
















TABLE 149







(VIa)




embedded image






















Com-












pound









Config-


No.
R1
R2
R3
L2
R4
L3
R8
R9
R7
uration





VI-604
Me
Me
Me
—
Ph
—
Me
H
Me
(R)-


VI-605
Me
Me
Me
—
Ph
—
H
Me
Me
racemic


VI-606
Me
Me
Me
—
Ph
—
H
Me
Me
(R)-


VI-607
Me
Me
Me
—
Ph
—
Me
Me
Me
racemic


VI-608
Me
Me
Me
—
Ph
—
Me
Me
Me
(R)-


VI-609
Me
Et
Me
—
Ph
—
H
H
Me
racemic


VI-610
Me
Et
Me
—
Ph
—
H
H
Me
(R)-


VI-611
Me
Et
Me
—
Ph
—
Me
H
Me
racemic


VI-612
Me
Et
Me
—
Ph
—
Me
H
Me
(R)-


VI-613
Me
Et
Me
—
Ph
—
H
Me
Me
racemic


VI-614
Me
Et
Me
—
Ph
—
H
Me
Me
(R)-


VI-615
Me
Et
Me
—
Ph
—
Me
Me
Me
racemic


VI-616
Me
Et
Me
—
Ph
—
Me
Me
Me
(R)-


VI-617
Me
Me
Me
—
Ph
—
H
H
C(═O)Me
racemic


VI-618
Me
Me
Me
—
Ph
—
H
H
C(═O)Me
(R)-


VI-619
Me
Me
Me
—
Ph
—
Me
H
C(═O)Me
racemic


VI-620
Me
Me
Me
—
Ph
—
Me
H
C(═O)Me
(R)-


VI-621
Me
Me
Me
—
Ph
—
H
Me
C(═O)Me
racemic


VI-622
Me
Me
Me
—
Ph
—
H
Me
C(═O)Me
(R)-


VI-623
Me
Me
Me
—
Ph
—
Me
Me
C(═O)Me
racemic


VI-624
Me
Me
Me
—
Ph
—
Me
Me
C(═O)Me
(R)-


VI-625
Me
Et
Me
—
Ph
—
H
H
C(═O)Me
racemic


VI-626
Me
Et
Me
—
Ph
—
H
H
C(═O)Me
(R)-


VI-627
Me
Et
Me
—
Ph
—
Me
H
C(═O)Me
racemic


VI-628
Me
Et
Me
—
Ph
—
Me
H
C(═O)Me
(R)-


VI-629
Me
Et
Me
—
Ph
—
H
Me
C(═O)Me
racemic


VI-630
Me
Et
Me
—
Ph
—
H
Me
C(═O)Me
(R)-


VI-631
Me
Et
Me
—
Ph
—
Me
Me
C(═O)Me
racemic


VI-632
Me
Et
Me
—
Ph
—
Me
Me
C(═O)Me
(R)-


VI-633
Me
Me
Me
—
Ph
—
H
H
C(═O)Et
racemic


VI-634
Me
Me
Me
—
Ph
—
H
H
C(═O)Et
(R)-


VI-635
Me
Me
Me
—
Ph
—
Me
H
C(═O)Et
racemic


VI-636
Me
Me
Me
—
Ph
—
Me
H
C(═O)Et
(R)-


VI-637
Me
Me
Me
—
Ph
—
H
Me
C(═O)Et
racemic


VI-638
Me
Me
Me
—
Ph
—
H
Me
C(═O)Et
(R)-


VI-639
Me
Me
Me
—
Ph
—
Me
Me
C(═O)Et
racemic


VI-640
Me
Me
Me
—
Ph
—
Me
Me
C(═O)Et
(R)-


VI-641
Me
Et
Me
—
Ph
—
H
H
C(═O)Et
racemic


VI-642
Me
Et
Me
—
Ph
—
H
H
C(═O)Et
(R)-


VI-643
Me
Et
Me
—
Ph
—
Me
H
C(═O)Et
racemic


VI-644
Me
Et
Me
—
Ph
—
Me
H
C(═O)Et
(R)-


VI-645
Me
Et
Me
—
Ph
—
H
Me
C(═O)Et
racemic


VI-646
Me
Et
Me
—
Ph
—
H
Me
C(═O)Et
(R)-


VI-647
Me
Et
Me
—
Ph
—
Me
Me
C(═O)Et
racemic


VI-648
Me
Et
Me
—
Ph
—
Me
Me
C(═O)Et
(R)-


VI-649
Me
Me
Me
—
Ph
CH2
H
H
Me
racemic


VI-650
Me
Me
Me
—
Ph
CH2
H
H
Me
(S)-


VI-651
Me
Me
Me
—
Ph
CH2
Me
H
Me
racemic


VI-652
Me
Me
Me
—
Ph
CH2
Me
H
Me
(S)-


VI-653
Me
Me
Me
—
Ph
CH2
H
Me
Me
racemic
















TABLE 150







(VIa)




embedded image






















Com-












pound









Config-


No.
R1
R2
R3
L2
R4
L3
R8
R9
R7
uration





VI-654
Me
Me
Me
—
Ph
CH2
H
Me
Me
(S)-


VI-655
Me
Me
Me
—
Ph
CH2
Me
Me
Me
racemic


VI-656
Me
Me
Me
—
Ph
CH2
Me
Me
Me
(S)-


VI-657
Me
Et
Me
—
Ph
CH2
H
H
Me
racemic


VI-658
Me
Et
Me
—
Ph
CH2
H
H
Me
(S)-


VI-659
Me
Et
Me
—
Ph
CH2
Me
H
Me
racemic


VI-660
Me
Et
Me
—
Ph
CH2
Me
H
Me
(S)-


VI-661
Me
Et
Me
—
Ph
CH2
H
Me
Me
racemic


VI-662
Me
Et
Me
—
Ph
CH2
H
Me
Me
(S)-


VI-663
Me
Et
Me
—
Ph
CH2
Me
Me
Me
racemic


VI-664
Me
Et
Me
—
Ph
CH2
Me
Me
Me
(S)-


VI-665
Me
Me
Me
—
Ph
CH2
H
H
C(═O)Me
racemic


VI-666
Me
Me
Me
—
Ph
CH2
H
H
C(═O)Me
(S)-


VI-667
Me
Me
Me
—
Ph
CH2
Me
H
C(═O)Me
racemic


VI-668
Me
Me
Me
—
Ph
CH2
Me
H
C(═O)Me
(S)-


VI-669
Me
Me
Me
—
Ph
CH2
H
Me
C(═O)Me
racemic


VI-670
Me
Me
Me
—
Ph
CH2
H
Me
C(═O)Me
(S)-


VI-671
Me
Me
Me
—
Ph
CH2
Me
Me
C(═O)Me
racemic


VI-672
Me
Me
Me
—
Ph
CH2
Me
Me
C(═O)Me
(S)-


VI-673
Me
Et
Me
—
Ph
CH2
H
H
C(═O)Me
racemic


VI-674
Me
Et
Me
—
Ph
CH2
H
H
C(═O)Me
(S)-


VI-675
Me
Et
Me
—
Ph
CH2
Me
H
C(═O)Me
racemic


VI-676
Me
Et
Me
—
Ph
CH2
Me
H
C(═O)Me
(S)-


VI-677
Me
Et
Me
—
Ph
CH2
H
Me
C(═O)Me
racemic


VI-678
Me
Et
Me
—
Ph
CH2
H
Me
C(═O)Me
(S)-


VI-679
Me
Et
Me
—
Ph
CH2
Me
Me
C(═O)Me
racemic


VI-680
Me
Et
Me
—
Ph
CH2
Me
Me
C(═O)Me
(S)-


VI-681
Me
Me
Me
—
Ph
CH2
H
H
C(═O)Et
racemic


VI-682
Me
Me
Me
—
Ph
CH2
H
H
C(═O)Et
(S)-


VI-683
Me
Me
Me
—
Ph
CH2
Me
H
C(═O)Et
racemic


VI-684
Me
Me
Me
—
Ph
CH2
Me
H
C(═O)Et
(S)-


VI-685
Me
Me
Me
—
Ph
CH2
H
Me
C(═O)Et
racemic


VI-686
Me
Me
Me
—
Ph
CH2
H
Me
C(═O)Et
(S)-


VI-687
Me
Me
Me
—
Ph
CH2
Me
Me
C(═O)Et
racemic


VI-688
Me
Me
Me
—
Ph
CH2
Me
Me
C(═O)Et
(S)-


VI-689
Me
Et
Me
—
Ph
CH2
H
H
C(═O)Et
racemic


VI-690
Me
Et
Me
—
Ph
CH2
H
H
C(═O)Et
(S)-


VI-691
Me
Et
Me
—
Ph
CH2
Me
H
C(═O)Et
racemic


VI-692
Me
Et
Me
—
Ph
CH2
Me
H
C(═O)Et
(S)-


VI-693
Me
Et
Me
—
Ph
CH2
H
Me
C(═O)Et
racemic


VI-694
Me
Et
Me
—
Ph
CH2
H
Me
C(═O)Et
(S)-


VI-695
Me
Et
Me
—
Ph
CH2
Me
Me
C(═O)Et
racemic


VI-696
Me
Et
Me
—
Ph
CH2
Me
Me
C(═O)Et
(S)-
















TABLE 151







(VIb)




embedded image






















Com-












pound









Config-


No.
R1
R2
R3
L2
R4
L3
R8
R9
R7
uration





VI-177
Me
Me
Me
O
Ph
CH2
H
H
Me
racemic


VI-178
Me
Me
Me
O
Ph
CH2
H
H
Me
(S)-


VI-179
Me
Me
Me
O
Ph
CH2
Me
H
Me
racemic


VI-180
Me
Me
Me
O
Ph
CH2
Me
H
Me
(S)-


VI-181
Me
Me
Me
O
Ph
CH2
H
Me
Me
racemic


VI-182
Me
Me
Me
O
Ph
CH2
H
Me
Me
(S)-


VI-183
Me
Me
Me
O
Ph
CH2
Me
Me
Me
racemic


VI-184
Me
Me
Me
O
Ph
CH2
Me
Me
Me
(S)-


VI-185
Me
Et
Me
O
Ph
CH2
H
H
Me
racemic


VI-186
Me
Et
Me
O
Ph
CH2
H
H
Me
(S)-


VI-187
Me
Et
Me
O
Ph
CH2
Me
H
Me
racemic


VI-188
Me
Et
Me
O
Ph
CH2
Me
H
Me
(S)-


VI-189
Me
Et
Me
O
Ph
CH2
H
Me
Me
racemic


VI-190
Me
Et
Me
O
Ph
CH2
H
Me
Me
(S)-


VI-191
Me
Et
Me
O
Ph
CH2
Me
Me
Me
racemic


VI-192
Me
Et
Me
O
Ph
CH2
Me
Me
Me
(S)-


VI-193
Me
Me
Me
O
Ph
CH2
H
H
Et
racemic


VI-194
Me
Me
Me
O
Ph
CH2
H
H
Et
(S)-


VI-195
Me
Me
Me
O
Ph
CH2
Me
H
Et
racemic


VI-196
Me
Me
Me
O
Ph
CH2
Me
H
Et
(S)-


VI-197
Me
Me
Me
O
Ph
CH2
H
Me
Et
racemic


VI-198
Me
Me
Me
O
Ph
CH2
H
Me
Et
(S)-


VI-199
Me
Me
Me
O
Ph
CH2
Me
Me
Et
racemic


VI-200
Me
Me
Me
O
Ph
CH2
Me
Me
Et
(S)-


VI-201
Me
Et
Me
O
Ph
CH2
H
H
Et
racemic


VI-202
Me
Et
Me
O
Ph
CH2
H
H
Et
(S)-


VI-203
Me
Et
Me
O
Ph
CH2
Me
H
Et
racemic


VI-204
Me
Et
Me
O
Ph
CH2
Me
H
Et
(S)-


VI-205
Me
Et
Me
O
Ph
CH2
H
Me
Et
racemic


VI-206
Me
Et
Me
O
Ph
CH2
H
Me
Et
(S)-


VI-207
Me
Et
Me
O
Ph
CH2
Me
Me
Et
racemic


VI-208
Me
Et
Me
O
Ph
CH2
Me
Me
Et
(S)-


VI-209
Me
Me
Me
NH
Ph
CH2
H
H
Me
racemic


VI-210
Me
Me
Me
NH
Ph
CH2
H
H
Me
(S)-


VI-211
Me
Me
Me
NH
Ph
CH2
Me
H
Me
racemic


VI-212
Me
Me
Me
NH
Ph
CH2
Me
H
Me
(S)-


VI-213
Me
Me
Me
NH
Ph
CH2
H
Me
Me
racemic


VI-214
Me
Me
Me
NH
Ph
CH2
H
Me
Me
(S)-


VI-215
Me
Me
Me
NH
Ph
CH2
Me
Me
Me
racemic


VI-216
Me
Me
Me
NH
Ph
CH2
Me
Me
Me
(S)-


VI-217
Me
Et
Me
NH
Ph
CH2
H
H
Me
racemic


VI-218
Me
Et
Me
NH
Ph
CH2
H
H
Me
(S)-


VI-219
Me
Et
Me
NH
Ph
CH2
Me
H
Me
racemic


VI-220
Me
Et
Me
NH
Ph
CH2
Me
H
Me
(S)-


VI-221
Me
Et
Me
NH
Ph
CH2
H
Me
Me
racemic


VI-222
Me
Et
Me
NH
Ph
CH2
H
Me
Me
(S)-


VI-223
Me
Et
Me
NH
Ph
CH2
Me
Me
Me
racemic


VI-224
Me
Et
Me
NH
Ph
CH2
Me
Me
Me
(S)-


VI-225
Me
Me
Me
NH
Ph
CH2
H
H
Et
racemic


VI-226
Me
Me
Me
NH
Ph
CH2
H
H
Et
(S)-
















TABLE 152







(VIb)




embedded image






















Com-












pound









Config-


No.
R1
R2
R3
L2
R4
L3
R10
R11
R9
uration





VI-227
Me
Me
Me
NH
Ph
CH2
Me
H
Et
racemic


VI-228
Me
Me
Me
NH
Ph
CH2
Me
H
Et
(S)-


VI-229
Me
Me
Me
NH
Ph
CH2
H
Me
Et
racemic


VI-230
Me
Me
Me
NH
Ph
CH2
H
Me
Et
(S)-


VI-231
Me
Me
Me
NH
Ph
CH2
Me
Me
Et
racemic


VI-232
Me
Me
Me
NH
Ph
CH2
Me
Me
Et
(S)-


VI-233
Me
Et
Me
NH
Ph
CH2
H
H
Et
racemic


VI-234
Me
Et
Me
NH
Ph
CH2
H
H
Et
(S)-


VI-235
Me
Et
Me
NH
Ph
CH2
Me
H
Et
racemic


VI-236
Me
Et
Me
NH
Ph
CH2
Me
H
Et
(S)-


VI-237
Me
Et
Me
NH
Ph
CH2
H
Me
Et
racemic


VI-238
Me
Et
Me
NH
Ph
CH2
H
Me
Et
(S)-


VI-239
Me
Et
Me
NH
Ph
CH2
Me
Me
Et
racemic


VI-240
Me
Et
Me
NH
Ph
CH2
Me
Me
Et
(S)-


VI-241
Me
Me
Me
NH
Ph
CH2
H
H
C(═O)Me
racemic


VI-242
Me
Me
Me
NH
Ph
CH2
H
H
C(═O)Me
(S)-


VI-243
Me
Me
Me
NH
Ph
CH2
Me
H
C(═O)Me
racemic


VI-244
Me
Me
Me
NH
Ph
CH2
Me
H
C(═O)Me
(S)-


VI-245
Me
Me
Me
NH
Ph
CH2
H
Me
C(═O)Me
racemic


VI-246
Me
Me
Me
NH
Ph
CH2
H
Me
C(═O)Me
(S)-


VI-247
Me
Me
Me
NH
Ph
CH2
Me
Me
C(═O)Me
racemic


VI-248
Me
Me
Me
NH
Ph
CH2
Me
Me
C(═O)Me
(S)-


VI-249
Me
Et
Me
NH
Ph
CH2
H
H
C(═O)Me
racemic


VI-250
Me
Et
Me
NH
Ph
CH2
H
H
C(═O)Me
(S)-


VI-251
Me
Et
Me
NH
Ph
CH2
Me
H
C(═O)Me
racemic


VI-252
Me
Et
Me
NH
Ph
CH2
Me
H
C(═O)Me
(S)-


VI-253
Me
Et
Me
NH
Ph
CH2
H
Me
C(═O)Me
racemic


VI-254
Me
Et
Me
NH
Ph
CH2
H
Me
C(═O)Me
(S)-


VI-255
Me
Et
Me
NH
Ph
CH2
Me
Me
C(═O)Me
racemic


VI-256
Me
Et
Me
NH
Ph
CH2
Me
Me
C(═O)Me
(S)-


VI-257
Me
Me
Me
NH
Ph
CH2
H
H
C(═O)Et
racemic


VI-258
Me
Me
Me
NH
Ph
CH2
H
H
C(═O)Et
(S)-


VI-259
Me
Me
Me
NH
Ph
CH2
Me
H
C(═O)Et
racemic


VI-260
Me
Me
Me
NH
Ph
CH2
Me
H
C(═O)Et
(S)-


VI-261
Me
Me
Me
NH
Ph
CH2
H
Me
C(═O)Et
racemic


VI-262
Me
Me
Me
NH
Ph
CH2
H
Me
C(═O)Et
(S)-


VI-263
Me
Me
Me
NH
Ph
CH2
Me
Me
C(═O)Et
racemic


VI-264
Me
Me
Me
NH
Ph
CH2
Me
Me
C(═O)Et
(S)-


VI-265
Me
Et
Me
NH
Ph
CH2
H
H
C(═O)Et
racemic


VI-266
Me
Et
Me
NH
Ph
CH2
H
H
C(═O)Et
(S)-


VI-267
Me
Et
Me
NH
Ph
CH2
Me
H
C(═O)Et
racemic


VI-268
Me
Et
Me
NH
Ph
CH2
Me
H
C(═O)Et
(S)-


VI-269
Me
Et
Me
NH
Ph
CH2
H
Me
C(═O)Et
racemic


VI-270
Me
Et
Me
NH
Ph
CH2
H
Me
C(═O)Et
(S)-


VI-271
Me
Et
Me
NH
Ph
CH2
Me
Me
C(═O)Et
racemic


VI-272
Me
Et
Me
NH
Ph
CH2
Me
Me
C(═O)Et
(S)-


VI-273
Me
Me
Me
NH
Ph
CH2
H
H
C(═O)tBu
racemic


VI-274
Me
Me
Me
NH
Ph
CH2
H
H
C(═O)tBu
(S)-


VI-275
Me
Me
Me
NH
Ph
CH2
Me
H
C(═O)tBu
racemic


VI-276
Me
Me
Me
NH
Ph
CH2
Me
H
C(═O)tBu
(S)-
















TABLE 153







(VIb)




embedded image






















Com-












pound









Config-


No.
R1
R2
R3
L2
R4
L3
R10
R11
R9
uration





VI-277
Me
Me
Me
NH
Ph
CH2
H
Me
C(═O)tBu
racemic


VI-278
Me
Me
Me
NH
Ph
CH2
H
Me
C(═O)tBu
(S)-


VI-279
Me
Me
Me
NH
Ph
CH2
Me
Me
C(═O)tBu
racemic


VI-280
Me
Me
Me
NH
Ph
CH2
Me
Me
C(═O)tBu
(S)-


VI-281
Me
Et
Me
NH
Ph
CH2
H
H
C(═O)tBu
racemic


VI-282
Me
Et
Me
NH
Ph
CH2
H
H
C(═O)tBu
(S)-


VI-283
Me
Et
Me
NH
Ph
CH2
Me
H
C(═O)tBu
racemic


VI-284
Me
Et
Me
NH
Ph
CH2
Me
H
C(═O)tBu
(S)-


VI-285
Me
Et
Me
NH
Ph
CH2
H
Me
C(═O)tBu
racemic


VI-286
Me
Et
Me
NH
Ph
CH2
H
Me
C(═O)tBu
(S)-


VI-287
Me
Et
Me
NH
Ph
CH2
Me
Me
C(═O)tBu
racemic


VI-288
Me
Et
Me
NH
Ph
CH2
Me
Me
C(═O)tBu
(S)-


VI-289
Me
Me
Me
NH
Ph
CH2
H
H
C(═O)OEt
racemic


VI-290
Me
Me
Me
NH
Ph
CH2
H
H
C(═O)OEt
(S)-


VI-291
Me
Me
Me
NH
Ph
CH2
Me
H
C(═O)OEt
racemic


VI-292
Me
Me
Me
NH
Ph
CH2
Me
H
C(═O)OEt
(S)-


VI-293
Me
Me
Me
NH
Ph
CH2
H
Me
C(═O)OEt
racemic


VI-294
Me
Me
Me
NH
Ph
CH2
H
Me
C(═O)OEt
(S)-


VI-295
Me
Me
Me
NH
Ph
CH2
Me
Me
C(═O)OEt
racemic


VI-296
Me
Me
Me
NH
Ph
CH2
Me
Me
C(═O)OEt
(S)-


VI-297
Me
Et
Me
NH
Ph
CH2
H
H
C(═O)OEt
racemic


VI-298
Me
Et
Me
NH
Ph
CH2
H
H
C(═O)OEt
(S)-


VI-299
Me
Et
Me
NH
Ph
CH2
Me
H
C(═O)OEt
racemic


VI-300
Me
Et
Me
NH
Ph
CH2
Me
H
C(═O)OEt
(S)-


VI-301
Me
Et
Me
NH
Ph
CH2
H
Me
C(═O)OEt
racemic


VI-302
Me
Et
Me
NH
Ph
CH2
H
Me
C(═O)OEt
(S)-


VI-303
Me
Et
Me
NH
Ph
CH2
Me
Me
C(═O)OEt
racemic


VI-304
Me
Et
Me
NH
Ph
CH2
Me
Me
C(═O)OEt
(S)-


VI-305
Me
Me
Me
NH
Ph
CH2
H
H
C(═O)Oc
racemic











Hex



VI-306
Me
Me
Me
NH
Ph
CH2
H
H
C(═O)Oc
(S)-











Hex



VI-307
Me
Me
Me
NH
Ph
CH2
Me
H
C(═O)Oc
racemic











Hex



VI-308
Me
Me
Me
NH
Ph
CH2
Me
H
C(═O)Oc
(S)-











Hex



VI-309
Me
Me
Me
NH
Ph
CH2
H
Me
C(═O)Oc
racemic











Hex



VI-310
Me
Me
Me
NH
Ph
CH2
H
Me
C(═O)Oc
(S)-











Hex



VI-311
Me
Me
Me
NH
Ph
CH2
Me
Me
C(═O)Oc
racemic











Hex



VI-312
Me
Me
Me
NH
Ph
CH2
Me
Me
C(═O)Oc
(S)-











Hex



VI-313
Me
Et
Me
NH
Ph
CH2
H
H
C(═O)Oc
racemic











Hex



VI-314
Me
Et
Me
NH
Ph
CH2
H
H
C(═O)Oc
(S)-











Hex



VI-315
Me
Et
Me
NH
Ph
CH2
Me
H
C(═O)Oc
racemic











Hex



VI-316
Me
Et
Me
NH
Ph
CH2
Me
H
C(═O)Oc
(S)-











Hex



VI-317
Me
Et
Me
NH
Ph
CH2
H
Me
C(═O)Oc
racemic











Hex



VI-318
Me
Et
Me
NH
Ph
CH2
H
Me
C(═O)Oc
(S)-











Hex



VI-319
Me
Et
Me
NH
Ph
CH2
Me
Me
C(═O)Oc
racemic











Hex



VI-320
Me
Et
Me
NH
Ph
CH2
Me
Me
C(═O)Oc
(S)-











Hex



VI-321
Me
Me
Me
CH2
Ph
CH2
H
H
Me
racemic


VI-322
Me
Me
Me
CH2
Ph
CH2
H
H
Me
(S)-


VI-323
Me
Me
Me
CH2
Ph
CH2
Me
H
Me
racemic


VI-324
Me
Me
Me
CH2
Ph
CH2
Me
H
Me
(S)-


VI-325
Me
Me
Me
CH2
Ph
CH2
H
Me
Me
racemic


VI-326
Me
Me
Me
CH2
Ph
CH2
H
Me
Me
(S)-
















TABLE 154







(VIb)




embedded image






















Com-












pound









Config-


No.
R1
R2
R3
L2
R4
L3
R10
R11
R9
uration





VI-327
Me
Me
Me
CH2
Ph
CH2
Me
Me
Me
racemic


VI-328
Me
Me
Me
CH2
Ph
CH2
Me
Me
Me
(S)-


VI-329
Me
Et
Me
CH2
Ph
CH2
H
H
Me
racemic


VI-330
Me
Et
Me
CH2
Ph
CH2
H
H
Me
(S)-


VI-331
Me
Et
Me
CH2
Ph
CH2
Me
H
Me
racemic


VI-332
Me
Et
Me
CH2
Ph
CH2
Me
H
Me
(S)-


VI-333
Me
Et
Me
CH2
Ph
CH2
H
Me
Me
racemic


VI-334
Me
Et
Me
CH2
Ph
CH2
H
Me
Me
(S)-


VI-335
Me
Et
Me
CH2
Ph
CH2
Me
Me
Me
racemic


VI-336
Me
Et
Me
CH2
Ph
CH2
Me
Me
Me
(S)-


VI-337
Me
Me
Me
CH2
Ph
CH2
H
H
Et
racemic


VI-338
Me
Me
Me
CH2
Ph
CH2
H
H
Et
(S)-


VI-339
Me
Me
Me
CH2
Ph
CH2
Me
H
Et
racemic


VI-340
Me
Me
Me
CH2
Ph
CH2
Me
H
Et
(S)-


VI-341
Me
Me
Me
CH2
Ph
CH2
H
Me
Et
racemic


VI-342
Me
Me
Me
CH2
Ph
CH2
H
Me
Et
(S)-


VI-343
Me
Me
Me
CH2
Ph
CH2
Me
Me
Et
racemic


VI-344
Me
Me
Me
CH2
Ph
CH2
Me
Me
Et
(S)-


VI-345
Me
Et
Me
CH2
Ph
CH2
H
H
Et
racemic


VI-346
Me
Et
Me
CH2
Ph
CH2
H
H
Et
(S)-


VI-347
Me
Et
Me
CH2
Ph
CH2
Me
H
Et
racemic


VI-348
Me
Et
Me
CH2
Ph
CH2
Me
H
Et
(S)-


VI-349
Me
Et
Me
CH2
Ph
CH2
H
Me
Et
racemic


VI-350
Me
Et
Me
CH2
Ph
CH2
H
Me
Et
(S)-


VI-351
Me
Et
Me
CH2
Ph
CH2
Me
Me
Et
racemic


VI-352
Me
Et
Me
CH2
Ph
CH2
Me
Me
Et
(S)-
















TABLE 155







(VIb)




embedded image






















Com-












pound









Config-


No.
R1
R2
R3
L2
R4
L3
R8
R9
R7
uration





VI-697
Me
Me
Me
NH
Ph
(CH2)2
H
H
Me
racemic


VI-698
Me
Me
Me
NH
Ph
(CH2)2
H
H
Me
(R)-


VI-699
Me
Me
Me
NH
Ph
(CH2)2
Me
H
Me
racemic


VI-700
Me
Me
Me
NH
Ph
(CH2)2
Me
H
Me
(R)-


VI-701
Me
Me
Me
NH
Ph
(CH2)2
H
Me
Me
racemic


VI-702
Me
Me
Me
NH
Ph
(CH2)2
H
Me
Me
(R)-


VI-703
Me
Me
Me
NH
Ph
(CH2)2
Me
Me
Me
racemic


VI-704
Me
Me
Me
NH
Ph
(CH2)2
Me
Me
Me
(R)-


VI-705
Me
Et
Me
NH
Ph
(CH2)2
H
H
Me
racemic


VI-706
Me
Et
Me
NH
Ph
(CH2)2
H
H
Me
(R)-


VI-707
Me
Et
Me
NH
Ph
(CH2)2
Me
H
Me
racemic


VI-708
Me
Et
Me
NH
Ph
(CH2)2
Me
H
Me
(R)-


VI-709
Me
Et
Me
NH
Ph
(CH2)2
H
Me
Me
racemic


VI-710
Me
Et
Me
NH
Ph
(CH2)2
H
Me
Me
(R)-


VI-711
Me
Et
Me
NH
Ph
(CH2)2
Me
Me
Me
racemic


VI-712
Me
Et
Me
NH
Ph
(CH2)2
Me
Me
Me
(R)-


VI-713
Me
Me
Me
NH
Ph
(CH2)2
H
H
C(═O)Me
racemic


VI-714
Me
Me
Me
NH
Ph
(CH2)2
H
H
C(═O)Me
(R)-


VI-715
Me
Me
Me
NH
Ph
(CH2)2
Me
H
C(═O)Me
racemic


VI-716
Me
Me
Me
NH
Ph
(CH2)2
Me
H
C(═O)Me
(R)-


VI-717
Me
Me
Me
NH
Ph
(CH2)2
H
Me
C(═O)Me
racemic


VI-718
Me
Me
Me
NH
Ph
(CH2)2
H
Me
C(═O)Me
(R)-


VI-719
Me
Me
Me
NH
Ph
(CH2)2
Me
Me
C(═O)Me
racemic


VI-720
Me
Me
Me
NH
Ph
(CH2)2
Me
Me
C(═O)Me
(R)-


VI-721
Me
Et
Me
NH
Ph
(CH2)2
H
H
C(═O)Me
racemic


VI-722
Me
Et
Me
NH
Ph
(CH2)2
H
H
C(═O)Me
(R)-


VI-723
Me
Et
Me
NH
Ph
(CH2)2
Me
H
C(═O)Me
racemic


VI-724
Me
Et
Me
NH
Ph
(CH2)2
Me
H
C(═O)Me
(R)-


VI-725
Me
Et
Me
NH
Ph
(CH2)2
H
Me
C(═O)Me
racemic


VI-726
Me
Et
Me
NH
Ph
(CH2)2
H
Me
C(═O)Me
(R)-


VI-727
Me
Et
Me
NH
Ph
(CH2)2
Me
Me
C(═O)Me
racemic


VI-728
Me
Et
Me
NH
Ph
(CH2)2
Me
Me
C(═O)Me
(R)-


VI-729
Me
Me
Me
NH
Ph
(CH2)2
H
H
C(═O)Et
racemic


VI-730
Me
Me
Me
NH
Ph
(CH2)2
H
H
C(═O)Et
(R)-


VI-731
Me
Me
Me
NH
Ph
(CH2)2
Me
H
C(═O)Et
racemic


VI-732
Me
Me
Me
NH
Ph
(CH2)2
Me
H
C(═O)Et
(R)-


VI-733
Me
Me
Me
NH
Ph
(CH2)2
H
Me
C(═O)Et
racemic


VI-734
Me
Me
Me
NH
Ph
(CH2)2
H
Me
C(═O)Et
(R)-


VI-735
Me
Me
Me
NH
Ph
(CH2)2
Me
Me
C(═O)Et
racemic


VI-736
Me
Me
Me
NH
Ph
(CH2)2
Me
Me
C(═O)Et
(R)-


VI-737
Me
Et
Me
NH
Ph
(CH2)2
H
H
C(═O)Et
racemic


VI-738
Me
Et
Me
NH
Ph
(CH2)2
H
H
C(═O)Et
(R)-


VI-739
Me
Et
Me
NH
Ph
(CH2)2
Me
H
C(═O)Et
racemic


VI-740
Me
Et
Me
NH
Ph
(CH2)2
Me
H
C(═O)Et
(R)-


VI-741
Me
Et
Me
NH
Ph
(CH2)2
H
Me
C(═O)Et
racemic


VI-742
Me
Et
Me
NH
Ph
(CH2)2
H
Me
C(═O)Et
(R)-


VI-743
Me
Et
Me
NH
Ph
(CH2)2
Me
Me
C(═O)Et
racemic


VI-744
Me
Et
Me
NH
Ph
(CH2)2
Me
Me
C(═O)Et
(R)-


VI-745
Me
Me
Me
—
Ph
—
H
H
Me
racemic


VI-746
Me
Me
Me
—
Ph
—
H
H
Me
(R)-
















TABLE 156







(VIb)




embedded image






















Com-












pound









Con-


No.
R1
R2
R3
L2
R4
L3
R8
R9
R7
figuration





VI-747
Me
Me
Me
—
Ph
—
Me
H
Me
racemic


VI-748
Me
Me
Me
—
Ph
—
Me
H
Me
(R)-


VI-749
Me
Me
Me
—
Ph
—
H
Me
Me
racemic


VI-750
Me
Me
Me
—
Ph
—
H
Me
Me
(R)-


VI-751
Me
Me
Me
—
Ph
—
Me
Me
Me
racemic


VI-752
Me
Me
Me
—
Ph
—
Me
Me
Me
(R)-


VI-753
Me
Et
Me
—
Ph
—
H
H
Me
racemic


VI-754
Me
Et
Me
—
Ph
—
H
H
Me
(R)-


VI-755
Me
Et
Me
—
Ph
—
Me
H
Me
racemic


VI-756
Me
Et
Me
—
Ph
—
Me
H
Me
(R)-


VI-757
Me
Et
Me
—
Ph
—
H
Me
Me
racemic


VI-758
Me
Et
Me
—
Ph
—
H
Me
Me
(R)-


VI-759
Me
Et
Me
—
Ph
—
Me
Me
Me
racemic


VI-760
Me
Et
Me
—
Ph
—
Me
Me
Me
(R)-


VI-761
Me
Me
Me
—
Ph
—
H
H
C(═O)Me
racemic


VI-762
Me
Me
Me
—
Ph
—
H
H
C(═O)Me
(R)-


VI-763
Me
Me
Me
—
Ph
—
Me
H
C(═O)Me
racemic


VI-764
Me
Me
Me
—
Ph
—
Me
H
C(═O)Me
(R)-


VI-765
Me
Me
Me
—
Ph
—
H
Me
C(═O)Me
racemic


VI-766
Me
Me
Me
—
Ph
—
H
Me
C(═O)Me
(R)-


VI-767
Me
Me
Me
—
Ph
—
Me
Me
C(═O)Me
racemic


VI-768
Me
Me
Me
—
Ph
—
Me
Me
C(═O)Me
(R)-


VI-769
Me
Et
Me
—
Ph
—
H
H
C(═O)Me
racemic


VI-770
Me
Et
Me
—
Ph
—
H
H
C(═O)Me
(R)-


VI-771
Me
Et
Me
—
Ph
—
Me
H
C(═O)Me
racemic


VI-772
Me
Et
Me
—
Ph
—
Me
H
C(═O)Me
(R)-


VI-773
Me
Et
Me
—
Ph
—
H
Me
C(═O)Me
racemic


VI-774
Me
Et
Me
—
Ph
—
H
Me
C(═O)Me
(R)-


VI-775
Me
Et
Me
—
Ph
—
Me
Me
C(═O)Me
racemic


VI-776
Me
Et
Me
—
Ph
—
Me
Me
C(═O)Me
(R)-


VI-777
Me
Me
Me
—
Ph
—
H
H
C(═O)Et
racemic


VI-778
Me
Me
Me
—
Ph
—
H
H
C(═O)Et
(R)-


VI-779
Me
Me
Me
—
Ph
—
Me
H
C(═O)Et
racemic


VI-780
Me
Me
Me
—
Ph
—
Me
H
C(═O)Et
(R)-


VI-781
Me
Me
Me
—
Ph
—
H
Me
C(═O)Et
racemic


VI-782
Me
Me
Me
—
Ph
—
H
Me
C(═O)Et
(R)-


VI-783
Me
Me
Me
—
Ph
—
Me
Me
C(═O)Et
racemic


VI-784
Me
Me
Me
—
Ph
—
Me
Me
C(═O)Et
(R)-


VI-785
Me
Et
Me
—
Ph
—
H
H
C(═O)Et
racemic


VI-786
Me
Et
Me
—
Ph
—
H
H
C(═O)Et
(R)-


VI-787
Me
Et
Me
—
Ph
—
Me
H
C(═O)Et
racemic


VI-788
Me
Et
Me
—
Ph
—
Me
H
C(═O)Et
(R)-


VI-789
Me
Et
Me
—
Ph
—
H
Me
C(═O)Et
racemic


VI-790
Me
Et
Me
—
Ph
—
H
Me
C(═O)Et
(R)-


VI-791
Me
Et
Me
—
Ph
—
Me
Me
C(═O)Et
racemic


VI-792
Me
Et
Me
—
Ph
—
Me
Me
C(═O)Et
(R)-


VI-793
Me
Me
Me
—
Ph
CH2
H
H
Me
racemic


VI-794
Me
Me
Me
—
Ph
CH2
H
H
Me
(S)-


VI-795
Me
Me
Me
—
Ph
CH2
Me
H
Me
racemic


VI-796
Me
Me
Me
—
Ph
CH2
Me
H
Me
(S)-
















TABLE 157







(VIb)




embedded image






















Com-












pound









Con-


No.
R1
R2
R3
L2
R4
L3
R8
R9
R7
figuration





VI-797
Me
Me
Me
—
Ph
CH2
H
Me
Me
racemic


VI-798
Me
Me
Me
—
Ph
CH2
H
Me
Me
(S)-


VI-799
Me
Me
Me
—
Ph
CH2
Me
Me
Me
racemic


VI-800
Me
Me
Me
—
Ph
CH2
Me
Me
Me
(S)-


VI-801
Me
Et
Me
—
Ph
CH2
H
H
Me
racemic


VI-802
Me
Et
Me
—
Ph
CH2
H
H
Me
(S)-


VI-803
Me
Et
Me
—
Ph
CH2
Me
H
Me
racemic


VI-804
Me
Et
Me
—
Ph
CH2
Me
H
Me
(S)-


VI-805
Me
Et
Me
—
Ph
CH2
H
Me
Me
racemic


VI-806
Me
Et
Me
—
Ph
CH2
H
Me
Me
(S)-


VI-807
Me
Et
Me
—
Ph
CH2
Me
Me
Me
racemic


VI-808
Me
Et
Me
—
Ph
CH2
Me
Me
Me
(S)-


VI-809
Me
Me
Me
—
Ph
CH2
H
H
C(═O)Me
racemic


VI-810
Me
Me
Me
—
Ph
CH2
H
H
C(═O)Me
(S)-


VI-811
Me
Me
Me
—
Ph
CH2
Me
H
C(═O)Me
racemic


VI-812
Me
Me
Me
—
Ph
CH2
Me
H
C(═O)Me
(S)-


VI-813
Me
Me
Me
—
Ph
CH2
H
Me
C(═O)Me
racemic


VI-814
Me
Me
Me
—
Ph
CH2
H
Me
C(═O)Me
(S)-


VI-815
Me
Me
Me
—
Ph
CH2
Me
Me
C(═O)Me
racemic


VI-816
Me
Me
Me
—
Ph
CH2
Me
Me
C(═O)Me
(S)-


VI-817
Me
Et
Me
—
Ph
CH2
H
H
C(═O)Me
racemic


VI-818
Me
Et
Me
—
Ph
CH2
H
H
C(═O)Me
(S)-


VI-819
Me
Et
Me
—
Ph
CH2
Me
H
C(═O)Me
racemic


VI-820
Me
Et
Me
—
Ph
CH2
Me
H
C(═O)Me
(S)-


VI-821
Me
Et
Me
—
Ph
CH2
H
Me
C(═O)Me
racemic


VI-822
Me
Et
Me
—
Ph
CH2
H
Me
C(═O)Me
(S)-


VI-823
Me
Et
Me
—
Ph
CH2
Me
Me
C(═O)Me
racemic


VI-824
Me
Et
Me
—
Ph
CH2
Me
Me
C(═O)Me
(S)-


VI-825
Me
Me
Me
—
Ph
CH2
H
H
C(═O)Et
racemic


VI-826
Me
Me
Me
—
Ph
CH2
H
H
C(═O)Et
(S)-


VI-827
Me
Me
Me
—
Ph
CH2
Me
H
C(═O)Et
racemic


VI-828
Me
Me
Me
—
Ph
CH2
Me
H
C(═O)Et
(S)-


VI-829
Me
Me
Me
—
Ph
CH2
H
Me
C(═O)Et
racemic


VI-830
Me
Me
Me
—
Ph
CH2
H
Me
C(═O)Et
(S)-


VI-831
Me
Me
Me
—
Ph
CH2
Me
Me
C(═O)Et
racemic


VI-832
Me
Me
Me
—
Ph
CH2
Me
Me
C(═O)Et
(S)-


VI-833
Me
Et
Me
—
Ph
CH2
H
H
C(═O)Et
racemic


VI-834
Me
Et
Me
—
Ph
CH2
H
H
C(═O)Et
(S)-


VI-835
Me
Et
Me
—
Ph
CH2
Me
H
C(═O)Et
racemic


VI-836
Me
Et
Me
—
Ph
CH2
Me
H
C(═O)Et
(S)-


VI-837
Me
Et
Me
—
Ph
CH2
H
Me
C(═O)Et
racemic


VI-838
Me
Et
Me
—
Ph
CH2
H
Me
C(═O)Et
(S)-


VI-839
Me
Et
Me
—
Ph
CH2
Me
Me
C(═O)Et
racemic


VI-840
Me
Et
Me
—
Ph
CH2
Me
Me
C(═O)Et
(S)-
















TABLE 158







(VIc)




embedded image






















Compound












No.
R1
R2
R3
L2
R4
L3
R8
R9
R7
Configuration





VI-353
Me
Me
Me
O
Ph
CH2
H
H
Me
racemic


VI-354
Me
Me
Me
O
Ph
CH2
H
H
Me
(S)-


VI-355
Me
Me
Me
O
Ph
CH2
Me
H
Me
racemic


VI-356
Me
Me
Me
O
Ph
CH2
Me
H
Me
(S)-


VI-357
Me
Me
Me
O
Ph
CH2
H
Me
Me
racemic


VI-358
Me
Me
Me
O
Ph
CH2
H
Me
Me
(S)-


VI-359
Me
Me
Me
O
Ph
CH2
Me
Me
Me
racemic


VI-360
Me
Me
Me
O
Ph
CH2
Me
Me
Me
(S)-


VI-361
Me
Et
Me
O
Ph
CH2
H
H
Me
racemic


VI-362
Me
Et
Me
O
Ph
CH2
H
H
Me
(S)-


VI-363
Me
Et
Me
O
Ph
CH2
Me
H
Me
racemic


VI-364
Me
Et
Me
O
Ph
CH2
Me
H
Me
(S)-


VI-365
Me
Et
Me
O
Ph
CH2
H
Me
Me
racemic


VI-366
Me
Et
Me
O
Ph
CH2
H
Me
Me
(S)-


VI-367
Me
Et
Me
O
Ph
CH2
Me
Me
Me
racemic


VI-368
Me
Et
Me
O
Ph
CH2
Me
Me
Me
(S)-


VI-369
Me
Me
Me
O
Ph
CH2
H
H
Et
racemic


VI-370
Me
Me
Me
O
Ph
CH2
H
H
Et
(S)-


VI-371
Me
Me
Me
O
Ph
CH2
Me
H
Et
racemic


VI-372
Me
Me
Me
O
Ph
CH2
Me
H
Et
(S)-


VI-373
Me
Me
Me
O
Ph
CH2
H
Me
Et
racemic


VI-374
Me
Me
Me
O
Ph
CH2
H
Me
Et
(S)-


VI-375
Me
Me
Me
O
Ph
CH2
Me
Me
Et
racemic


VI-376
Me
Me
Me
O
Ph
CH2
Me
Me
Et
(S)-


VI-377
Me
Et
Me
O
Ph
CH2
H
H
Et
racemic


VI-378
Me
Et
Me
O
Ph
CH2
H
H
Et
(S)-


VI-379
Me
Et
Me
O
Ph
CH2
Me
H
Et
racemic


VI-380
Me
Et
Me
O
Ph
CH2
Me
H
Et
(S)-


VI-381
Me
Et
Me
O
Ph
CH2
H
Me
Et
racemic


VI-382
Me
Et
Me
O
Ph
CH2
H
Me
Et
(S)-


VI-383
Me
Et
Me
O
Ph
CH2
Me
Me
Et
racemic


VI-384
Me
Et
Me
O
Ph
CH2
Me
Me
Et
(S)-


VI-385
Me
Me
Me
NH
Ph
CH2
H
H
Me
racemic


VI-386
Me
Me
Me
NH
Ph
CH2
H
H
Me
(S)-


VI-387
Me
Me
Me
NH
Ph
CH2
Me
H
Me
racemic


VI-388
Me
Me
Me
NH
Ph
CH2
Me
H
Me
(S)-


VI-389
Me
Me
Me
NH
Ph
CH2
H
Me
Me
racemic


VI-390
Me
Me
Me
NH
Ph
CH2
H
Me
Me
(S)-


VI-391
Me
Me
Me
NH
Ph
CH2
Me
Me
Me
racemic


VI-392
Me
Me
Me
NH
Ph
CH2
Me
Me
Me
(S)-


VI-393
Me
Et
Me
NH
Ph
CH2
H
H
Me
racemic


VI-394
Me
Et
Me
NH
Ph
CH2
H
H
Me
(S)-


VI-395
Me
Et
Me
NH
Ph
CH2
Me
H
Me
racemic


VI-396
Me
Et
Me
NH
Ph
CH2
Me
H
Me
(S)-


VI-397
Me
Et
Me
NH
Ph
CH2
H
Me
Me
racemic


VI-398
Me
Et
Me
NH
Ph
CH2
H
Me
Me
(S)-


VI-399
Me
Et
Me
NH
Ph
CH2
Me
Me
Me
racemic


VI-400
Me
Et
Me
NH
Ph
CH2
Me
Me
Me
(S)-


VI-401
Me
Me
Me
NH
Ph
CH2
H
H
Et
racemic


VI-402
Me
Me
Me
NH
Ph
CH2
H
H
Et
(S)-
















TABLE 159







(VIc)




embedded image






















Com-









Con-


pound









figu-


No.
R1
R2
R3
L2
R4
L3
R8
R9
R7
ration





VI-403
Me
Me
Me
NH
Ph
CH2
Me
H
Et
racemic


VI-404
Me
Me
Me
NH
Ph
CH2
Me
H
Et
(S)-


VI-405
Me
Me
Me
NH
Ph
CH2
H
Me
Et
racemic


VI-406
Me
Me
Me
NH
Ph
CH2
H
Me
Et
(S)-


VI-407
Me
Me
Me
NH
Ph
CH2
Me
Me
Et
racemic


VI-408
Me
Me
Me
NH
Ph
CH2
Me
Me
Et
(S)-


VI-409
Me
Et
Me
NH
Ph
CH2
H
H
Et
racemic


VI-410
Me
Et
Me
NH
Ph
CH2
H
H
Et
(S)-


VI-411
Me
Et
Me
NH
Ph
CH2
Me
H
Et
racemic


VI-412
Me
Et
Me
NH
Ph
CH2
Me
H
Et
(S)-


VI-413
Me
Et
Me
NH
Ph
CH2
H
Me
Et
racemic


VI-414
Me
Et
Me
NH
Ph
CH2
H
Me
Et
(S)-


VI-415
Me
Et
Me
NH
Ph
CH2
Me
Me
Et
racemic


VI-416
Me
Et
Me
NH
Ph
CH2
Me
Me
Et
(S)-


VI-417
Me
Me
Me
NH
Ph
CH2
H
H
(5-Methyl-2-
racemic











oxo-1,3-












dioxol-4-yl)












methyl



VI-418
Me
Me
Me
NH
Ph
CH2
H
H
(5-Methyl-2-
(S)-











oxo-1,3-












dioxol-4-yl)












methyl



VI-419
Me
Me
Me
NH
Ph
CH2
Me
H
(5-Methyl-2-
racemic











oxo-1,3-












dioxol-4-yl)












methyl



VI-420
Me
Me
Me
NH
Ph
CH2
Me
H
(5-Methyl-2-
(S)-











oxo-1,3-












dioxol-4-yl)












methyl



VI-421
Me
Me
Me
NH
Ph
CH2
H
Me
(5-Methyl-2-
racemic











oxo-1,3-












dioxol-4-yl)












methyl



VI-422
Me
Me
Me
NH
Ph
CH2
H
Me
(5-Methyl-2-
(S)-











oxo-1,3-












dioxol-4-yl)












methyl



VI-423
Me
Me
Me
NH
Ph
CH2
Me
Me
(5-Methyl-2-
racemic











oxo-1,3-












dioxol-4-yl)












methyl



VI-424
Me
Me
Me
NH
Ph
CH2
Me
Me
(5-Methyl-2-
(S)-











oxo-1,3-












dioxol-4-yl)












methyl



VI-425
Me
Me
Me
NH
Ph
CH2
H
H
C(═O)H
racemic


VI-426
Me
Me
Me
NH
Ph
CH2
H
H
C(═O)H
(S)-


VI-427
Me
Me
Me
NH
Ph
CH2
Me
H
C(═O)H
racemic


VI-428
Me
Me
Me
NH
Ph
CH2
Me
H
C(═O)H
(S)-


VI-429
Me
Me
Me
NH
Ph
CH2
H
Me
C(═O)H
racemic


VI-430
Me
Me
Me
NH
Ph
CH2
H
Me
C(═O)H
(S)-


VI-431
Me
Me
Me
NH
Ph
CH2
Me
Me
C(═O)H
racemic


VI-432
Me
Me
Me
NH
Ph
CH2
Me
Me
C(═O)H
(S)-


VI-433
Me
Et
Me
NH
Ph
CH2
H
H
C(═O)H
racemic


VI-434
Me
Et
Me
NH
Ph
CH2
H
H
C(═O)H
(S)-


VI-435
Me
Et
Me
NH
Ph
CH2
Me
H
C(═O)H
racemic


VI-436
Me
Et
Me
NH
Ph
CH2
Me
H
C(═O)H
(S)-


VI-437
Me
Et
Me
NH
Ph
CH2
H
Me
C(═O)H
racemic


VI-438
Me
Et
Me
NH
Ph
CH2
H
Me
C(═O)H
(S)-


VI-439
Me
Et
Me
NH
Ph
CH2
Me
Me
C(═O)H
racemic


VI-440
Me
Et
Me
NH
Ph
CH2
Me
Me
C(═O)H
(S)-


VI-441
Me
Me
Me
NH
Ph
CH2
H
H
C(═O)Me
racemic


VI-442
Me
Me
Me
NH
Ph
CH2
H
H
C(═O)Me
(S)-


VI-443
Me
Me
Me
NH
Ph
CH2
Me
H
C(═O)Me
racemic


VI-444
Me
Me
Me
NH
Ph
CH2
Me
H
C(═O)Me
(S)-


VI-445
Me
Me
Me
NH
Ph
CH2
H
Me
C(═O)Me
racemic


VI-446
Me
Me
Me
NH
Ph
CH2
H
Me
C(═O)Me
(S)-


VI-447
Me
Me
Me
NH
Ph
CH2
Me
Me
C(═O)Me
racemic


VI-448
Me
Me
Me
NH
Ph
CH2
Me
Me
C(═O)Me
(S)-


VI-449
Me
Et
Me
NH
Ph
CH2
H
H
C(═O)Me
racemic


VI-450
Me
Et
Me
NH
Ph
CH2
H
H
C(═O)Me
(S)-


VI-451
Me
Et
Me
NH
Ph
CH2
Me
H
C(═O)Me
racemic


VI-452
Me
Et
Me
NH
Ph
CH2
Me
H
C(═O)Me
(S)-
















TABLE 160







(VIc)




embedded image






















Com-












pound









Con-


No.
R1
R2
R3
L2
R4
L3
R8
R9
R7
figuration





VI-453
Me
Et
Me
NH
Ph
CH2
H
Me
C(═O)Me
racemic


VI-454
Me
Et
Me
NH
Ph
CH2
H
Me
C(═O)Me
(S)-


VI-455
Me
Et
Me
NH
Ph
CH2
Me
Me
C(═O)Me
racemic


VI-456
Me
Et
Me
NH
Ph
CH2
Me
Me
C(═O)Me
(S)-


VI-457
Me
Me
Me
NH
Ph
CH2
H
H
C(═O)Et
racemic


VI-458
Me
Me
Me
NH
Ph
CH2
H
H
C(═O)Et
(S)-


VI-459
Me
Me
Me
NH
Ph
CH2
Me
H
C(═O)Et
racemic


VI-460
Me
Me
Me
NH
Ph
CH2
Me
H
C(═O)Et
(S)-


VI-461
Me
Me
Me
NH
Ph
CH2
H
Me
C(═O)Et
racemic


VI-462
Me
Me
Me
NH
Ph
CH2
H
Me
C(═O)Et
(S)-


VI-463
Me
Me
Me
NH
Ph
CH2
Me
Me
C(═O)Et
racemic


VI-464
Me
Me
Me
NH
Ph
CH2
Me
Me
C(═O)Et
(S)-


VI-465
Me
Et
Me
NH
Ph
CH2
H
H
C(═O)Et
racemic


VI-466
Me
Et
Me
NH
Ph
CH2
H
H
C(═O)Et
(S)-


VI-467
Me
Et
Me
NH
Ph
CH2
Me
H
C(═O)Et
racemic


VI-468
Me
Et
Me
NH
Ph
CH2
Me
H
C(═O)Et
(S)-


VI-469
Me
Et
Me
NH
Ph
CH2
H
Me
C(═O)Et
racemic


VI-470
Me
Et
Me
NH
Ph
CH2
H
Me
C(═O)Et
(S)-


VI-471
Me
Et
Me
NH
Ph
CH2
Me
Me
C(═O)Et
racemic


VI-472
Me
Et
Me
NH
Ph
CH2
Me
Me
C(═O)Et
(S)-


VI-473
Me
Me
Me
NH
Ph
CH2
H
H
C(═O)tBu
racemic


VI-474
Me
Me
Me
NH
Ph
CH2
H
H
C(═O)tBu
(S)-


VI-475
Me
Me
Me
NH
Ph
CH2
Me
H
C(═O)tBu
racemic


VI-476
Me
Me
Me
NH
Ph
CH2
Me
H
C(═O)tBu
(S)-


VI-477
Me
Me
Me
NH
Ph
CH2
H
Me
C(═O)tBu
racemic


VI-478
Me
Me
Me
NH
Ph
CH2
H
Me
C(═O)tBu
(S)-


VI-479
Me
Me
Me
NH
Ph
CH2
Me
Me
C(═O)tBu
racemic


VI-480
Me
Me
Me
NH
Ph
CH2
Me
Me
C(═O)tBu
(S)-


VI-481
Me
Et
Me
NH
Ph
CH2
H
H
C(═O)tBu
racemic


VI-482
Me
Et
Me
NH
Ph
CH2
H
H
C(═O)tBu
(S)-


VI-483
Me
Et
Me
NH
Ph
CH2
Me
H
C(═O)tBu
racemic


VI-484
Me
Et
Me
NH
Ph
CH2
Me
H
C(═O)tBu
(S)-


VI-485
Me
Et
Me
NH
Ph
CH2
H
Me
C(═O)tBu
racemic


VI-486
Me
Et
Me
NH
Ph
CH2
H
Me
C(═O)tBu
(S)-


VI-487
Me
Et
Me
NH
Ph
CH2
Me
Me
C(═O)tBu
racemic


VI-488
Me
Et
Me
NH
Ph
CH2
Me
Me
C(═O)tBu
(S)-


VI-489
Me
Me
Me
NH
Ph
CH2
H
H
C(═O)OEt
racemic


VI-490
Me
Me
Me
NH
Ph
CH2
H
H
C(═O)OEt
(S)-


VI-491
Me
Me
Me
NH
Ph
CH2
Me
H
C(═O)OEt
racemic


VI-492
Me
Me
Me
NH
Ph
CH2
Me
H
C(═O)OEt
(S)-


VI-493
Me
Me
Me
NH
Ph
CH2
H
Me
C(═O)OEt
racemic


VI-494
Me
Me
Me
NH
Ph
CH2
H
Me
C(═O)OEt
(S)-


VI-495
Me
Me
Me
NH
Ph
CH2
Me
Me
C(═O)OEt
racemic


VI-496
Me
Me
Me
NH
Ph
CH2
Me
Me
C(═O)OEt
(S)-


VI-497
Me
Et
Me
NH
Ph
CH2
H
H
C(═O)OEt
racemic


VI-498
Me
Et
Me
NH
Ph
CH2
H
H
C(═O)OEt
(S)-


VI-499
Me
Et
Me
NH
Ph
CH2
Me
H
C(═O)OEt
racemic


VI-500
Me
Et
Me
NH
Ph
CH2
Me
H
C(═O)OEt
(S)-


VI-501
Me
Et
Me
NH
Ph
CH2
H
Me
C(═O)OEt
racemic


VI-502
Me
Et
Me
NH
Ph
CH2
H
Me
C(═O)OEt
(S)-
















TABLE 161







(VIc)




embedded image






















Com-









Con-


pound









figu-


No.
R1
R2
R3
L2
R4
L3
R8
R9
R7
ration





VI-503
Me
Et
Me
NH
Ph
CH2
Me
Me
C(═O)OEt
racemic


VI-504
Me
Et
Me
NH
Ph
CH2
Me
Me
C(═O)OEt
(S)-


VI-505
Me
Me
Me
NH
Ph
CH2
H
H
C(═O)Oc
racemic











Hex



VI-506
Me
Me
Me
NH
Ph
CH2
H
H
C(═O)Oc
(S)-











Hex



VI-507
Me
Me
Me
NH
Ph
CH2
Me
H
C(═O)Oc
racemic











Hex



VI-508
Me
Me
Me
NH
Ph
CH2
Me
H
C(═O)Oc
S)-











Hex



VI-509
Me
Me
Me
NH
Ph
CH2
H
Me
C(═O)Oc
racemic











Hex



VI-510
Me
Me
Me
NH
Ph
CH2
H
Me
C(═O)Oc
(S)-











Hex



VI-511
Me
Me
Me
NH
Ph
CH2
Me
Me
C(═O)Oc
racemic











Hex



VI-512
Me
Me
Me
NH
Ph
CH2
Me
Me
C(═O)Oc
(S)-











Hex



VI-513
Me
Et
Me
NH
Ph
CH2
H
H
C(═O)Oc
racemic











Hex



VI-514
Me
Et
Me
NH
Ph
CH2
H
H
C(═O)Oc
(S)-











Hex



VI-515
Me
Et
Me
NH
Ph
CH2
Me
H
C(═O)Oc
racemic











Hex



VI-516
Me
Et
Me
NH
Ph
CH2
Me
H
C(═O)Oc
(S)-











Hex



VI-517
Me
Et
Me
NH
Ph
CH2
H
Me
C(═O)Oc
racemic











Hex



VI-518
Me
Et
Me
NH
Ph
CH2
H
Me
C(═O)Oc
(S)-











Hex



VI-519
Me
Et
Me
NH
Ph
CH2
Me
Me
C(═O)Oc
racemic











Hex



VI-520
Me
Et
Me
NH
Ph
CH2
Me
Me
C(═O)Oc
(S)-











Hex



VI-521
Me
Me
Me
CH2
Ph
CH2
H
H
Me
racemic


VI-522
Me
Me
Me
CH2
Ph
CH2
H
H
Me
(S)-


VI-523
Me
Me
Me
CH2
Ph
CH2
Me
H
Me
racemic


VI-524
Me
Me
Me
CH2
Ph
CH2
Me
H
Me
(S)-


VI-525
Me
Me
Me
CH2
Ph
CH2
H
Me
Me
racemic


VI-526
Me
Me
Me
CH2
Ph
CH2
H
Me
Me
(S)-


VI-527
Me
Me
Me
CH2
Ph
CH2
Me
Me
Me
racemic


VI-528
Me
Me
Me
CH2
Ph
CH2
Me
Me
Me
(S)-


VI-529
Me
Et
Me
CH2
Ph
CH2
H
H
Me
racemic


VI-530
Me
Et
Me
CH2
Ph
CH2
H
H
Me
(S)-


VI-531
Me
Et
Me
CH2
Ph
CH2
Me
H
Me
racemic


VI-532
Me
Et
Me
CH2
Ph
CH2
Me
H
Me
(S)-


VI-533
Me
Et
Me
CH2
Ph
CH2
H
Me
Me
racemic


VI-534
Me
Et
Me
CH2
Ph
CH2
H
Me
Me
(S)-


VI-535
Me
Et
Me
CH2
Ph
CH2
Me
Me
Me
racemic


VI-536
Me
Et
Me
CH2
Ph
CH2
Me
Me
Me
(S)-


VI-537
Me
Me
Me
CH2
Ph
CH2
H
H
Et
racemic


VI-538
Me
Me
Me
CH2
Ph
CH2
H
H
Et
(S)-


VI-539
Me
Me
Me
CH2
Ph
CH2
Me
H
Et
racemic


VI-540
Me
Me
Me
CH2
Ph
CH2
Me
H
Et
(S)-


VI-541
Me
Me
Me
CH2
Ph
CH2
H
Me
Et
racemic


VI-542
Me
Me
Me
CH2
Ph
CH2
H
Me
Et
(S)-


VI-543
Me
Me
Me
CH2
Ph
CH2
Me
Me
Et
racemic


VI-544
Me
Me
Me
CH2
Ph
CH2
Me
Me
Et
(S)-


VI-545
Me
Et
Me
CH2
Ph
CH2
H
H
Et
racemic


VI-546
Me
Et
Me
CH2
Ph
CH2
H
H
Et
(S)-


VI-547
Me
Et
Me
CH2
Ph
CH2
Me
H
Et
racemic


VI-548
Me
Et
Me
CH2
Ph
CH2
Me
H
Et
(S)-


VI-549
Me
Et
Me
CH2
Ph
CH2
H
Me
Et
racemic


VI-550
Me
Et
Me
CH2
Ph
CH2
H
Me
Et
(S)-


VI-551
Me
Et
Me
CH2
Ph
CH2
Me
Me
Et
racemic


VI-552
Me
Et
Me
CH2
Ph
CH2
Me
Me
Et
(S)-
















TABLE 162







(VIc)




embedded image






















Com-









Con-


pound









figu-


No.
R1
R2
R3
L2
R4
L3
R8
R9
R7
ration





VI-841
Me
Me
Me
NH
Ph
(CH2)2
H
H
Me
racemic


VI-842
Me
Me
Me
NH
Ph
(CH2)2
H
H
Me
(R)-


VI-843
Me
Me
Me
NH
Ph
(CH2)2
Me
H
Me
racemic


VI-844
Me
Me
Me
NH
Ph
(CH2)2
Me
H
Me
(R)-


VI-845
Me
Me
Me
NH
Ph
(CH2)2
H
Me
Me
racemic


VI-846
Me
Me
Me
NH
Ph
(CH2)2
H
Me
Me
(R)-


VI-847
Me
Me
Me
NH
Ph
(CH2)2
Me
Me
Me
racemic


VI-848
Me
Me
Me
NH
Ph
(CH2)2
Me
Me
Me
(R)-


VI-849
Me
Et
Me
NH
Ph
(CH2)2
H
H
Me
racemic


VI-850
Me
Et
Me
NH
Ph
(CH2)2
H
H
Me
(R)-


VI-851
Me
Et
Me
NH
Ph
(CH2)2
Me
H
Me
racemic


VI-852
Me
Et
Me
NH
Ph
(CH2)2
Me
H
Me
(R)-


VI-853
Me
Et
Me
NH
Ph
(CH2)2
H
Me
Me
racemic


VI-854
Me
Et
Me
NH
Ph
(CH2)2
H
Me
Me
(R)-


VI-855
Me
Et
Me
NH
Ph
(CH2)2
Me
Me
Me
racemic


VI-856
Me
Et
Me
NH
Ph
(CH2)2
Me
Me
Me
(R)-


VI-857
Me
Me
Me
NH
Ph
(CH2)2
H
H
C(═O)Me
racemic


VI-858
Me
Me
Me
NH
Ph
(CH2)2
H
H
C(═O)Me
(R)-


VI-859
Me
Me
Me
NH
Ph
(CH2)2
Me
H
C(═O)Me
racemic


VI-860
Me
Me
Me
NH
Ph
(CH2)2
Me
H
C(═O)Me
(R)-


VI-861
Me
Me
Me
NH
Ph
(CH2)2
H
Me
C(═O)Me
racemic


VI-862
Me
Me
Me
NH
Ph
(CH2)2
H
Me
C(═O)Me
(R)-


VI-863
Me
Me
Me
NH
Ph
(CH2)2
Me
Me
C(═O)Me
racemic


VI-864
Me
Me
Me
NH
Ph
(CH2)2
Me
Me
C(═O)Me
(R)-


VI-865
Me
Et
Me
NH
Ph
(CH2)2
H
H
C(═O)Me
racemic


VI-866
Me
Et
Me
NH
Ph
(CH2)2
H
H
C(═O)Me
(R)-


VI-867
Me
Et
Me
NH
Ph
(CH2)2
Me
H
C(═O)Me
racemic


VI-868
Me
Et
Me
NH
Ph
(CH2)2
Me
H
C(═O)Me
(R)-


VI-869
Me
Et
Me
NH
Ph
(CH2)2
H
Me
C(═O)Me
racemic


VI-870
Me
Et
Me
NH
Ph
(CH2)2
H
Me
C(═O)Me
(R)-


VI-871
Me
Et
Me
NH
Ph
(CH2)2
Me
Me
C(═O)Me
racemic


VI-872
Me
Et
Me
NH
Ph
(CH2)2
Me
Me
C(═O)Me
(R)-


VI-873
Me
Me
Me
NH
Ph
(CH2)2
H
H
C(═O)Et
racemic


VI-874
Me
Me
Me
NH
Ph
(CH2)2
H
H
C(═O)Et
(R)-


VI-875
Me
Me
Me
NH
Ph
(CH2)2
Me
H
C(═O)Et
racemic


VI-876
Me
Me
Me
NH
Ph
(CH2)2
Me
H
C(═O)Et
(R)-


VI-877
Me
Me
Me
NH
Ph
(CH2)2
H
Me
C(═O)Et
racemic


VI-878
Me
Me
Me
NH
Ph
(CH2)2
H
Me
C(═O)Et
(R)-


VI-879
Me
Me
Me
NH
Ph
(CH2)2
Me
Me
C(═O)Et
racemic


VI-880
Me
Me
Me
NH
Ph
(CH2)2
Me
Me
C(═O)Et
(R)-


VI-881
Me
Et
Me
NH
Ph
(CH2)2
H
H
C(═O)Et
racemic


VI-882
Me
Et
Me
NH
Ph
(CH2)2
H
H
C(═O)Et
(R)-


VI-883
Me
Et
Me
NH
Ph
(CH2)2
Me
H
C(═O)Et
racemic


VI-884
Me
Et
Me
NH
Ph
(CH2)2
Me
H
C(═O)Et
(R)-


VI-885
Me
Et
Me
NH
Ph
(CH2)2
H
Me
C(═O)Et
racemic


VI-886
Me
Et
Me
NH
Ph
(CH2)2
H
Me
C(═O)Et
(R)-


VI-887
Me
Et
Me
NH
Ph
(CH2)2
Me
Me
C(═O)Et
racemic


VI-888
Me
Et
Me
NH
Ph
(CH2)2
Me
Me
C(═O)Et
(R)-


VI-889
Me
Me
Me
—
Ph
—
H
H
Me
racemic


VI-890
Me
Me
Me
—
Ph
—
H
H
Me
(R)-
















TABLE 163







(VIc)




embedded image






















Com-












pound









Con-


No.
R1
R2
R3
L2
R4
L3
R8
R9
R7
figuration





VI-891
Me
Me
Me
—
Ph
—
Me
H
Me
racemic


VI-892
Me
Me
Me
—
Ph
—
Me
H
Me
(R)-


VI-893
Me
Me
Me
—
Ph
—
H
Me
Me
racemic


VI-894
Me
Me
Me
—
Ph
—
H
Me
Me
(R)-


VI-895
Me
Me
Me
—
Ph
—
Me
Me
Me
racemic


VI-896
Me
Me
Me
—
Ph
—
Me
Me
Me
(R)-


VI-897
Me
Et
Me
—
Ph
—
H
H
Me
racemic


VI-898
Me
Et
Me
—
Ph
—
H
H
Me
(R)-


VI-899
Me
Et
Me
—
Ph
—
Me
H
Me
racemic


VI-900
Me
Et
Me
—
Ph
—
Me
H
Me
(R)-


VI-901
Me
Et
Me
—
Ph
—
H
Me
Me
racemic


VI-902
Me
Et
Me
—
Ph
—
H
Me
Me
(R)-


VI-903
Me
Et
Me
—
Ph
—
Me
Me
Me
racemic


VI-904
Me
Et
Me
—
Ph
—
Me
Me
Me
(R)-


VI-905
Me
Me
Me
—
Ph
—
H
H
C(═O)Me
racemic


VI-906
Me
Me
Me
—
Ph
—
H
H
C(═O)Me
(R)-


VI-907
Me
Me
Me
—
Ph
—
Me
H
C(═O)Me
racemic


VI-908
Me
Me
Me
—
Ph
—
Me
H
C(═O)Me
(R)-


VI-909
Me
Me
Me
—
Ph
—
H
Me
C(═O)Me
racemic


VI-910
Me
Me
Me
—
Ph
—
H
Me
C(═O)Me
(R)-


VI-911
Me
Me
Me
—
Ph
—
Me
Me
C(═O)Me
racemic


VI-912
Me
Me
Me
—
Ph
—
Me
Me
C(═O)Me
(R)-


VI-913
Me
Et
Me
—
Ph
—
H
H
C(═O)Me
racemic


VI-914
Me
Et
Me
—
Ph
—
H
H
C(═O)Me
(R)-


VI-915
Me
Et
Me
—
Ph
—
Me
H
C(═O)Me
racemic


VI-916
Me
Et
Me
—
Ph
—
Me
H
C(═O)Me
(R)-


VI-917
Me
Et
Me
—
Ph
—
H
Me
C(═O)Me
racemic


VI-918
Me
Et
Me
—
Ph
—
H
Me
C(═O)Me
(R)-


VI-919
Me
Et
Me
—
Ph
—
Me
Me
C(═O)Me
racemic


VI-920
Me
Et
Me
—
Ph
—
Me
Me
C(═O)Me
(R)-


VI-921
Me
Me
Me
—
Ph
—
H
H
C(═O)Et
racemic


VI-922
Me
Me
Me
—
Ph
—
H
H
C(═O)Et
(R)-


VI-923
Me
Me
Me
—
Ph
—
Me
H
C(═O)Et
racemic


VI-924
Me
Me
Me
—
Ph
—
Me
H
C(═O)Et
(R)-


VI-925
Me
Me
Me
—
Ph
—
H
Me
C(═O)Et
racemic


VI-926
Me
Me
Me
—
Ph
—
H
Me
C(═O)Et
(R)-


VI-927
Me
Me
Me
—
Ph
—
Me
Me
C(═O)Et
racemic


VI-928
Me
Me
Me
—
Ph
—
Me
Me
C(═O)Et
(R)-


VI-929
Me
Et
Me
—
Ph
—
H
H
C(═O)Et
racemic


VI-930
Me
Et
Me
—
Ph
—
H
H
C(═O)Et
(R)-


VI-931
Me
Et
Me
—
Ph
—
Me
H
C(═O)Et
racemic


VI-932
Me
Et
Me
—
Ph
—
Me
H
C(═O)Et
(R)-


VI-933
Me
Et
Me
—
Ph
—
H
Me
C(═O)Et
racemic


VI-934
Me
Et
Me
—
Ph
—
H
Me
C(═O)Et
(R)-


VI-935
Me
Et
Me
—
Ph
—
Me
Me
C(═O)Et
racemic


VI-936
Me
Et
Me
—
Ph
—
Me
Me
C(═O)Et
(R)-


VI-937
Me
Me
Me
—
Ph
CH2
H
H
Me
racemic


VI-938
Me
Me
Me
—
Ph
CH2
H
H
Me
(S)-


VI-939
Me
Me
Me
—
Ph
CH2
Me
H
Me
racemic


VI-940
Me
Me
Me
—
Ph
CH2
Me
H
Me
(S)-
















TABLE 164







(VIc)




embedded image






















Com-












pound









Con-


No.
R1
R2
R3
L2
R4
L3
R8
R9
R7
figuration





VI-941
Me
Me
Me
—
Ph
CH2
H
Me
Me
racemic


VI-942
Me
Me
Me
—
Ph
CH2
H
Me
Me
(S)-


VI-943
Me
Me
Me
—
Ph
CH2
Me
Me
Me
racemic


VI-944
Me
Me
Me
—
Ph
CH2
Me
Me
Me
(S)-


VI-945
Me
Et
Me
—
Ph
CH2
H
H
Me
racemic


VI-946
Me
Et
Me
—
Ph
CH2
H
H
Me
(S)-


VI-947
Me
Et
Me
—
Ph
CH2
Me
H
Me
racemic


VI-948
Me
Et
Me
—
Ph
CH2
Me
H
Me
(S)-


VI-949
Me
Et
Me
—
Ph
CH2
H
Me
Me
racemic


VI-950
Me
Et
Me
—
Ph
CH2
H
Me
Me
(S)-


VI-951
Me
Et
Me
—
Ph
CH2
Me
Me
Me
racemic


VI-952
Me
Et
Me
—
Ph
CH2
Me
Me
Me
(S)-


VI-953
Me
Me
Me
—
Ph
CH2
H
H
C(═O)Me
racemic


VI-954
Me
Me
Me
—
Ph
CH2
H
H
C(═O)Me
(S)-


VI-955
Me
Me
Me
—
Ph
CH2
Me
H
C(═O)Me
racemic


VI-956
Me
Me
Me
—
Ph
CH2
Me
H
C(═O)Me
(S)-


VI-957
Me
Me
Me
—
Ph
CH2
H
Me
C(═O)Me
racemic


VI-958
Me
Me
Me
—
Ph
CH2
H
Me
C(═O)Me
(S)-


VI-959
Me
Me
Me
—
Ph
CH2
Me
Me
C(═O)Me
racemic


VI-960
Me
Me
Me
—
Ph
CH2
Me
Me
C(═O)Me
(S)-


VI-961
Me
Et
Me
—
Ph
CH2
H
H
C(═O)Me
racemic


VI-962
Me
Et
Me
—
Ph
CH2
H
H
C(═O)Me
(S)-


VI-963
Me
Et
Me
—
Ph
CH2
Me
H
C(═O)Me
racemic


VI-964
Me
Et
Me
—
Ph
CH2
Me
H
C(═O)Me
(S)-


VI-965
Me
Et
Me
—
Ph
CH2
H
Me
C(═O)Me
racemic


VI-966
Me
Et
Me
—
Ph
CH2
H
Me
C(═O)Me
(S)-


VI-967
Me
Et
Me
—
Ph
CH2
Me
Me
C(═O)Me
racemic


VI-968
Me
Et
Me
—
Ph
CH2
Me
Me
C(═O)Me
(S)-


VI-969
Me
Me
Me
—
Ph
CH2
H
H
C(═O)Et
racemic


VI-970
Me
Me
Me
—
Ph
CH2
H
H
C(═O)Et
(S)-


VI-971
Me
Me
Me
—
Ph
CH2
Me
H
C(═O)Et
racemic


VI-972
Me
Me
Me
—
Ph
CH2
Me
H
C(═O)Et
(S)-


VI-973
Me
Me
Me
—
Ph
CH2
H
Me
C(═O)Et
racemic


VI-974
Me
Me
Me
—
Ph
CH2
H
Me
C(═O)Et
(S)-


VI-975
Me
Me
Me
—
Ph
CH2
Me
Me
C(═O)Et
racemic


VI-976
Me
Me
Me
—
Ph
CH2
Me
Me
C(═O)Et
(S)-


VI-977
Me
Et
Me
—
Ph
CH2
H
H
C(═O)Et
racemic


VI-978
Me
Et
Me
—
Ph
CH2
H
H
C(═O)Et
(S)-


VI-979
Me
Et
Me
—
Ph
CH2
Me
H
C(═O)Et
racemic


VI-980
Me
Et
Me
—
Ph
CH2
Me
H
C(═O)Et
(S)-


VI-981
Me
Et
Me
—
Ph
CH2
H
Me
C(═O)Et
racemic


VI-982
Me
Et
Me
—
Ph
CH2
H
Me
C(═O)Et
(S)-


VI-983
Me
Et
Me
—
Ph
CH2
Me
Me
C(═O)Et
racemic


VI-984
Me
Et
Me
—
Ph
CH2
Me
Me
C(═O)Et
(S)-









Advantageous Effects of Invention

As for a novel substituted dihydropyrrolopyrazole compound having a particular structure represented by formula (I) of the present invention or a pharmacologically acceptable salt thereof, the compound itself or a metabolite thereof has excellent CDK7 inhibitory activity, high selectivity for a kinase inhibitory effect, and excellent safety. Thus, the compound represented by formula (I) or the pharmacologically acceptable salt thereof is pharmaceutically useful as a therapeutic agent and/or a prophylactic agent for cancers or inflammatory diseases.







DESCRIPTION OF EMBODIMENTS

One embodiment of the present invention will be described below. In the present specification, each “compound represented by formula (I)”, etc. is also referred to as “compound (I)”, etc. for the sake of convenience. Various substituents defined or illustrated below can be arbitrarily selected and combined.


In the present specification, the “prodrug” means a compound or a salt thereof which forms a compound having a CDK7 inhibitory effect by undergoing metabolic reaction when administered into an animal body.


One embodiment of the present invention is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.




embedded image


In formula (I),


L1 is an optionally substituted linear or branched C1-6 alkylene group, an optionally substituted linear or branched C2-6 alkenylene group, an optionally substituted linear or branched C2-6 alkynylene group, an optionally substituted C3-6 cycloalkylene group, or an optionally substituted C3-6 cycloalkenylene group,


L2 is a single bond, an oxygen atom, an optionally substituted nitrogen atom, an optionally substituted linear or branched C1-6 alkylene group, an optionally substituted linear or branched C2-6 alkenylene group, an optionally substituted linear or branched C2-6 alkynylene group, an optionally substituted C3-6 cycloalkylene group, or an optionally substituted C3-6 cycloalkenylene group,


L3 is a single bond, an optionally substituted linear or branched C1-6 alkylene group, an optionally substituted linear or branched C2-6 alkenyl group, an optionally substituted linear or branched C2-6 alkynyl group, an optionally substituted C3-6 cycloalkylene group, or an optionally substituted C3-6 cycloalkenylene group,


R1, R2, and R3 each independently are an optionally substituted linear or branched C1-4 alkyl group, an optionally substituted linear or branched C2-4 alkenyl group, an optionally substituted linear or branched C2-4 alkynyl group, an optionally substituted C6-10 aryl group, or an optionally substituted heterocyclic group,


R4 is a hydrogen atom, an optionally substituted linear or branched C1-6 alkyl group, an optionally substituted linear or branched C2-6 alkenyl group, an optionally substituted linear or branched C2-6 alkynyl group, an optionally substituted C3-6 cycloalkyl group, an optionally substituted C3-6 cycloalkenyl group, an optionally substituted C6-10 aryl group, or an optionally substituted heterocyclic group, and


R5 is a hydrogen atom, an optionally substituted linear or branched C1-16 alkyl group, an optionally substituted linear or branched C2-16 alkenyl group, an optionally substituted linear or branched C2-16 alkynyl group, an optionally substituted C3-6 cycloalkyl group, an optionally substituted C3-6 cycloalkenyl group, an optionally substituted C6-10 aryl group, or an optionally substituted heterocyclic group.


In the present specification, the term “optionally substituted” means that the group concerned may be unsubstituted or may be further substituted by a substituent.


The substituent means a monovalent group, and examples thereof include linear or branched C1-6 alkyl groups, C3-6 cycloalkyl groups, linear or branched C2-6 alkenyl groups, C3-6 cycloalkenyl groups, linear or branched C2-6 alkynyl groups, C1-6 alkoxy groups, halogen atoms, a hydroxy group, a cyano group, an oxo group (═O), an amino group, C1-6 alkylamino groups, a nitro group, a carboxy group (—COOH), a carbamoyl group (—CONH2), N-mono-C1-6 alkylcarbamoyl groups, N,N-di-C1-6 alkylcarbamoyl groups, C1-6 alkanoyloxy groups (—OCOR; R is a C1-6 alkyl group), C6-10 aryl groups, heterocyclic groups, C6-10 aryloxy groups, C7-12 aralkyl groups, and C7-12 aralkyloxy groups. The substituent may be further substituted by a halogen atom, a hydroxy group, an amino group, a cyano group, an oxo group (═O), a linear or branched C1-6 alkyl group, or the like. In the case where the substituent is an amino group or a carboxy group, the form may be a salt thereof.


In the case where the group concerned has two or more substituents, two substituents may be bonded to each other to form a cyclic structure. Examples of the case where two substituents are bonded to each other to form a cyclic structure include a cyclopropyl group, a cyclobutyl group, and a methylenedioxy group. Specifically, in the case where a methylenedioxy group is bonded to a benzene ring, the substituent becomes a 1,3-benzodioxole group; in the case where the same carbon atom of a 1,2-ethylene group has two methyl groups which are bonded to each other, the group becomes a group represented by the following formula (M-1) or (M-2); and in the case where the same carbon atom of a 1,2-ethylene group has a methyl group and an ethyl group and 2-position of the ethyl group is bonded to the methyl group, the group becomes a group represented by the following formula (N-1) or (N-2).




embedded image


The linear or branched C1-6 alkyl group described in the present specification means a linear or branched alkyl group having 1 to 6 carbon atoms. Examples of the linear or branched C1-6 alkyl group include C1-6 alkyl groups such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a neopentyl group, a tert-pentyl group, a 1-ethylpropyl group, a 1-methylbutyl group, a 2-methylbutyl group, a 1,2-dimethylpropyl group, a hexyl group, a 1-methylpentyl group, a 2-methylpentyl group, a 3-methylpentyl group, a 4-methylpentyl group, a 1-ethylbutyl group, a 2-ethylbutyl group, a 1,1-dimethylbutyl group, a 2,2-dimethylbutyl group, a 3,3-dimethylbutyl group, a 1,2-dimethylbutyl group, a 1,3-dimethylbutyl group, and a 2,3-dimethylbutyl group. The substituent is preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, or a tert-butyl group.


Examples of a C1-6 alkyl group substituted by a halogen atom include a chloromethyl group, a bromomethyl group, an iodomethyl group, a difluoromethyl group, a dichloromethyl group, a dibromomethyl group, a diiodomethyl group, a trifluoromethyl group, a trichloromethyl group, a 1-fluoroethyl group, a 2-fluoroethyl group, a 2-chloroethyl group, a 2-bromoethyl group, a 2,2-difluoroethyl group, a 2,2,2-trifluoroethyl group, a pentafluoroethyl group, a 2,2-dichloroethyl group, a 2,2,2-trichloroethyl group, a 1-fluoropropyl group, a 2-fluoropropyl group, a 3-fluoropropyl group, a 3,3,3-trifluoropropyl group, a perfluoropropyl group, a 1-fluoromethylethyl group, a 1-difluoromethylethyl group, a 1-trifluoromethylethyl group, a 1-fluoro-1-methylethyl group, a 4-fluorobutyl group, a perfluorobutyl group, a 5-fluoropentyl group, a perfluoropentyl group, a 6-fluorohexyl group, and a perfluorohexyl group.


A C1-6 alkyl group substituted by an aryl group may be, for example, a C7-11 aralkyl group. The C7-11 aralkyl group means an alkyl group having an aryl group and having a total of 7 to 11 carbon atoms, and examples thereof include a benzyl group, a phenylethyl group, and a naphthylmethyl group.


The C3-6 cycloalkyl group described in the present specification means a cyclic alkyl group having 3 to 6 carbon atoms. Examples of the C3-6 cycloalkyl group include: monocyclic rings such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group; condensed rings such as a bicyclo[3.1.0]hexyl group; and spiro rings such as a spiro[2.3]hexyl group. The substituent is preferably a cyclopropyl group or a cyclobutyl group.


The linear or branched C2-6 alkenyl group described in the present specification means a linear or branched alkenyl group having 2 to 6 carbon atoms. Examples of the linear or branched C2-6 alkenyl group include alkenyl groups such as a vinyl group, a propen-1-yl group, a propen-2-yl group, a 1-butenyl group, a 2-butenyl group, a 3-butenyl group, a 1-methyl-1-propenyl group, a 2-methyl-1-propenyl group, a 1-pentenyl group, a 2-pentenyl group, a 3-pentenyl group, a 4-pentenyl group, a 5-pentenyl group, a 1-methyl-1-butenyl group, a 2-methyl-1-butenyl group, a 3-methyl-1-butenyl group, a 4-methyl-1-butenyl group, a 1-methyl-2-butenyl group, a 2-methyl-2-butenyl group, a 3-methyl-2-butenyl group, a 4-methyl-2-butenyl group, a 1-methyl-3-butenyl group, a 2-methyl-3-butenyl group, a 3-methyl-3-butenyl group, a 4-methyl-3-butenyl group, a 1,2-dimethyl-1-propenyl group, a 1-hexenyl group, a 2-hexenyl group, a 3-hexenyl group, a 4-hexenyl group, a 5-hexenyl group, a 6-hexenyl group, and structural isomers thereof.


The C3-6 cycloalkenyl group described in the present specification means a cycloalkenyl group having 3 to 6 carbon atoms. Examples of the C3-6 cycloalkenyl group include a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, and a cyclohexenyl group.


The C2-6 alkynyl group described in the present specification means an alkynyl group having 2 to 6 carbon atoms. Examples of the C2-6 alkynyl group include an ethynyl group, a propargyl group, a butynyl group, a pentynyl group, and a hexynyl group.


The C1-6 alkoxy group described in the present specification means a group consisting of an oxy group (—O—) and a linear or branched C1-6 alkyl group or a C3-6 cycloalkyl group bonded to the oxy group. Examples of the C1-6 alkoxy group include a methoxy group, an ethoxy group, a propyloxy group, an isopropyloxy group, a cyclopropyloxy group, a butoxy group, a cyclobutyloxy group, a pentyloxy group, a cyclopentyloxy group, a hexyloxy group, and a cyclohexyloxy group.


The C1-6 alkylamino group described in the present specification means an amino group substituted by one or two independently selected aforementioned linear or branched C1-6 alkyl groups or C3-6 cycloalkyl groups. Examples of the C1-6 alkylamino group include a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, a cyclopropylamino group, a butoxy group, a cyclobutylamino group, a pentylamino group, a cyclopentylamino group, a hexylamino group, a cyclohexylamino group, a dimethylamino group, a diethylamino group, an ethylmethylamino group, an isopropylmethylamino group, and a cyclopropylmethylamino group.


The halogen atom described in the present specification means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.


The C6-10 aryl group described in the present specification means an aryl group having 6 to 10 carbon atoms. Examples of the C6-10 aryl group include a phenyl group and a naphthyl group.


The heterocyclic group described in the present specification means a cyclic group having at least one nitrogen atom, oxygen atom, or sulfur atom and may be an aromatic heterocyclic group or may be a nonaromatic heterocyclic group. Examples of the aromatic heterocyclic group include a pyridine group, a pyrimidine group, a pyridazine group, a pyrazine group, a triazine group, a pyrrole group, an imidazole group, a pyrazole group, an indole group, an indazole group, a furan group, a benzofuran group, a thiophene group, a benzothiophene group, a thiazole group, an isothiazole group, an oxazole group, an isoxazole group, and an oxadiazole group. Examples of the nonaromatic heterocyclic group include a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, and a thiomorpholinyl group.


The C6-10 aryloxy group described in the present specification means a group consisting of an oxy group (—O—) and the aforementioned C6-10 aryl group bonded to the oxy group. Examples of the C6-10 aryloxy group include a phenyloxy group, a 1-naphthyloxy group, and a 2-naphthyloxy group.


The C7-12 aralkyl group described in the present specification means the aforementioned C1-6 alkyl group substituted by the aforementioned C6-10 aryl group. Examples of the C7-12 aralkyl group include a benzyl group, a phenylethyl group, a naphthylmethyl group, and a naphthylethyl group.


The C7-12 aralkyloxy group described in the present specification means a group consisting of an oxy group (—O—) and the aforementioned C7-12 aralkyl group bonded to the oxy group. Examples of the C7-12 aralkyloxy group include a benzyloxy group, a phenylethyloxy group, a naphthylmethyloxy group, and a naphthylethyloxy group.


The linear or branched C1-6 alkylene group as L1, L2, or L3 means a divalent group prepared by further removing one hydrogen atom from the aforementioned C1-6 alkyl group. Examples of the C1-6 alkylene group include a methylene group, a 1,1-ethylene group, a 1,2-ethylene group, a 1,1-propylene group, a 1,2-propylene group, a 2,2-propylene group, and a 1,3-propylene group.


The linear or branched C2-6 alkenylene group as L1, L2, or L3 means a divalent group prepared by further removing one hydrogen atom from the aforementioned C2-6 alkenyl group. Examples of the C2-6 alkenylene group include a vinylene group and a propenylene group.


The linear or branched C2-6 alkynylene group as L1, L2, or L3 means a divalent group prepared by further removing one hydrogen atom from the aforementioned C2-6 alkynyl group. Examples of the C2-6 alkynylene group include an ethynylene group and a propynylene group.


The C3-6 cycloalkylene group as L1, L2, or L3 means a divalent group prepared by further removing one hydrogen atom from the aforementioned C3-6 cycloalkyl group, and examples thereof include a 1,1-cyclopropylene group, a 1,2-cyclopropylene group, a 1,1-cyclobutylene group, a 1,2-cyclobutylene group, a 1,3-cyclobutylene group, a 1,4-cyclobutylene group, a 1,1-cyclopentylene group, a 1,2-cyclopentylene group, a 1,3-cyclopentylene group, a 1,1-cyclohexylene group, a 1,2-cyclohexylene group, a 1,3-cyclohexylene group, a 1,4-cyclohexylene group, a 5,5-spiro[2.3]hexylene group, and a 6,6-bicyclo[3.1.0]hexylene group.


The C3-6 cycloalkenylene group as L1, L2, or L3 means a divalent group prepared by further removing one hydrogen atom from the aforementioned C3-6 cycloalkenyl group, and examples thereof include a 1,2-cyclopropenylene group, a 1,2-cyclobutenylene group, a 1,3-cyclobutenylene group, a 3,3-cyclobutenylene group, a 1,2-cyclopentenylene group, a 1,2-cyclopentenylene group, a 1,3-cyclopentenylene group, a 3,3-cyclopentenylene group, a 4,4-cyclopentenylene group, a 1,2-cyclohexenylene group, a 1,3-cyclohexenylene group, a 1,3-cyclohexenylene group, a 1,3-cyclohexenylene group, a 3,3-cyclohexenylene group, and a 4,4-cyclohexenylene group.


The optionally substituted nitrogen atom as L2 may be an unsubstituted nitrogen atom (divalent amino group represented by —NH—) or may be a divalent amino group having the aforementioned substituent bonded to the nitrogen atom.


The linear or branched C1-4 alkyl group as R1, R2, or R3 is a linear or branched alkyl group having 1 to 4 carbon atoms and corresponds to one having 1 to 4 carbon atoms among the C1-6 alkyl groups described above.


The linear or branched C2-4 alkenyl group as R1, R2, or R3 is a linear or branched alkenyl group having 2 to 4 carbon atoms and corresponds to one having 2 to 4 carbon atoms among the C2-6 alkenyl groups described above.


The linear or branched C2-4 alkynyl group as R1, R2, or R3 is a linear or branched alkynyl group having 2 to 4 carbon atoms and corresponds to one having 2 to 4 carbon atoms among the C2-6 alkynyl groups described above.


The linear or branched C1-6 alkyl group, the linear or branched C2-6 alkenyl group, the linear or branched C2-6 alkynyl group, the C6-10 aryl group, and the heterocyclic group as R4 are defined as in the substituents described above.


The linear or branched C1-16 alkyl group as R5 means an alkyl group having 1 to 16 carbon atoms. Examples of the linear or branched C1-16 alkyl group include C1-16 alkyl groups such as a methyl group, an ethyl group, a propyl group, a butyl group, an isobutyl group, a pentyl group, an isopentyl group, a neopentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, a decyl group, an undecyl group, a dodecyl group, a tridecyl group, a tetradecyl group, a pentadecyl group, and a hexadecyl group.


The linear or branched C2-16 alkenyl group as R5 means a monovalent linear or branched alkenyl group having 2 to 16 carbon atoms, and the linear or branched C2-16 alkynyl group means a monovalent linear or branched alkynyl group having 2 to 16 carbon atoms. The C3-6 cycloalkyl group, the C3-6 cycloalkenyl group, the C6-10 aryl group, and the heterocyclic group as R5 are defined as in the substituents described above and L1, etc.


The compound according to the present embodiment may be a compound represented by any chemical formula of formula (II), formula (III), or formula (IV).




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In formula (II), formula (III), and formula (IV), L2, L3, R1, R2, R3, R4, and R5 are defined as in formula (I).


In the formulas (I) to (IV), L2 may be an oxygen atom, an unsubstituted nitrogen atom, or a methylene group. L3 may be a single bond, or an optionally substituted linear or branched C1-6 alkylene group or C2-6 alkynylene group, or may be a linear or branched C1-6 alkylene group, C2-6 alkenylene group, or C2-6 alkynylene group substituted by an oxo group which forms an ester group together with the oxygen atom bonded to R5.


In the formulas (I) to (IV), R1, R2, and R3 may each independently be an optionally substituted linear or branched C1-4 alkyl group. R4 may be a hydrogen atom, an optionally substituted linear or branched C1-6 alkyl group, an optionally substituted C3-6 cycloalkyl group, an optionally substituted C6-10 aryl group, or an optionally substituted heterocyclic group. R5 may be a hydrogen atom, an optionally substituted linear or branched C1-16 alkyl group, an optionally substituted C3-6 cycloalkyl group, an optionally substituted C6-10 aryl group, or an optionally substituted heterocyclic group.


In the formulas (I) to (IV), preferably, L2 is a single bond or an unsubstituted nitrogen atom, L3 is a single bond or an optionally substituted linear or branched C1-6 alkylene group, R1, R2, and R3 are each independently an optionally substituted linear or branched C1-4 alkyl group, R4 is an optionally substituted linear or branched C1-6 alkyl group, an optionally substituted C6-10 aryl group, or an optionally substituted heterocyclic group, and R5 is a hydrogen atom, an optionally substituted linear or branched C1-16 alkyl group, or an optionally substituted C3-6 cycloalkyl group.


In the formulas (I) to (IV), more preferably, L2 is a single bond or an unsubstituted nitrogen atom, L3 is a single bond or an optionally substituted linear or branched C1-6 alkylene group, R1, R2, and R3 are each independently a linear or branched C1-4 alkyl group, R4 is an optionally substituted linear or branched C1-6 alkyl group, an optionally substituted C6-10 aryl group, or an optionally substituted heterocyclic group, and R5 is a hydrogen atom, a linear or branched C1-16 alkyl group, a linear or branched C1-16 alkyl group substituted by a halogen atom, an oxo group, or a linear or branched C1-6 alkyl group, or a C3-6 cycloalkyl group optionally substituted by a halogen atom.


In the formulas (I) to (IV), particularly preferably, L2 is a single bond or an unsubstituted nitrogen atom, L3 is a single bond or a group represented by the following formula (O-1), (O-2), (O-3), or (O-4), R1, R2, and R3 are each independently a linear or branched C1-4 alkyl group, R4 is an optionally substituted phenyl group or thienyl group, and R5 is a hydrogen atom, a linear or branched C1-16 alkyl group, a linear or branched C1-16 alkyl group substituted by a halogen atom, or a C3-6 cycloalkyl group. In the present specification, the chemical formula represented by formula (O-1) is also referred to as “C(Me)2CH2”, the chemical formula represented by formula (O-2) is also referred to as “CH2C(Me)2”, the chemical formula represented by formula (M-2) is also referred to as “CH2-1,1-cyclopropylene”, and the chemical formula represented by formula (N-1) is also referred to as “1,1-cyclobutylene-CH2”.




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Among compounds (I) according to the present embodiment or pharmacologically acceptable salts thereof, a compound as represented by formula (V) wherein R5 is substituted by an oxo group, and the oxo group and the oxygen atom bonded to R5 form an ester bond, or a compound as represented by formula (VI) wherein R5 is an alkylene group substituted by a substituent containing an oxygen atom, and an acetal group containing the oxygen atom and the oxygen atom bonded to R5 is formed can be a compound that acts as a prodrug. The compound (V) or the compound (VI) tends to have better oral absorbability and skin penetration and can form compound (I) (wherein R5 is a hydrogen atom) by metabolism.




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In formula (V) and formula (VI), R1, R2, R3, R4, L1, L2, and L3 are defined as in formula (I). R6 is a hydrogen atom, an optionally substituted linear or branched C1-15 alkyl group, an optionally substituted linear or branched C2-15 alkenyl group, an optionally substituted linear or branched C2-15 alkynyl group, an optionally substituted C3-6 cycloalkyl group, an optionally substituted C3-6 cycloalkenyl group, an optionally substituted C6-10 aryl group, or an optionally substituted heterocyclic group, and R8 and R9 are each independently a hydrogen atom or a C1-4 alkyl group. R7 is a linear or branched C1-15 alkyl group optionally having a substituent, an optionally substituted linear or branched C2-15 alkenyl group, an optionally substituted linear or branched C2-15 alkynyl group, an optionally substituted C3-6 cycloalkyl group, or an optionally substituted C3-6 cycloalkenyl group. The linear or branched C1-15 alkyl group, the linear or branched C2-15 alkenyl group, the linear or branched C2-15 alkynyl group, the C3-6 cycloalkyl group, the C3-6 cycloalkenyl group, the C6-10 aryl group, and the heterocyclic group as R6 or R7, and substituents added to these are defined as in the groups in the formulas (I) to (IV).


R6 may be an optionally substituted linear or branched C1-15 alkyl group, an optionally substituted C6-10 aryl group, or an optionally substituted C1-15 alkoxy group. R7 may be an optionally substituted linear or branched C1-16 alkyl group.


In formula (V), preferably, L1 is a cyclopropylene group or a cyclobutylene group, L2 is a single bond or an unsubstituted nitrogen atom, L3 is a single bond or an optionally substituted linear or branched C1-6 alkylene group, R1, R2, and R3 are each independently an optionally substituted linear or branched C1-4 alkyl group, R4 is an optionally substituted linear or branched C1-6 alkyl group, an optionally substituted C6-10 aryl group, or an optionally substituted heterocyclic group, and R6 is an optionally substituted linear or branched C1-15 alkyl group.


In formula (V), more preferably, L1 is a cyclobutylene group, L2 is a single bond or an unsubstituted nitrogen atom, L3 is a single bond or an optionally substituted linear or branched C1-6 alkylene group, R1, R2, and R3 are each independently a linear or branched C1-4 alkyl group, R4 is an optionally substituted linear or branched C1-6 alkyl group, an optionally substituted C6-10 aryl group, or an optionally substituted heterocyclic group, and R6 is an optionally substituted linear or branched C1-15 alkyl group.


The compound according to the present embodiment or a pharmacologically acceptable salt thereof is specifically a compound selected from a compound group shown below or a pharmacologically acceptable salt thereof.

  • (S)—N-(2-hydroxy-1-phenylethyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (S)—N-(2-hydroxy-1-phenylethyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (S)—N-(2-hydroxy-1-phenylethyl)-6,6-dimethyl-3-[2-methyl-2-(trimethylsilyl)propaneamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (S)-3-[1-(ethyldimethylsilyl)cyclobutanecarboxamido]-N-(2-hydroxy-1-phenylethyl)-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (S)-3-[2-(ethyldimethylsilyl)-2-methylpropaneamido]-N-(2-hydroxy-1-phenylethyl)-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (S)—N-(2-hydroxy-1-phenylethyl)-N,6,6-trimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (S)-2-[(2-methoxypropan-2-yl)oxy]-1-phenylethyl6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate,
  • (S)-2-hydroxy-1-phenylethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate,
  • 2-Methoxy-1-phenylethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate,
  • N-[5-(4-hydroxy-3-phenylbutanoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide,
  • N-[5-(3-hydroxy-3-phenylpropanoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide,
  • (R)—N-(3-hydroxy-1-phenylpropyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (R)—N-(3-hydroxy-1-phenylpropyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (R)—N-(4-hydroxy-1-phenylbutyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (R)—N-(5-hydroxy-1-phenylpentyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (S)—N-(2-hydroxy-2-methyl-1-phenylpropyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (S)—N-(2-hydroxy-2-methyl-1-phenylpropyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • N-(3-hydroxy-2,2-dimethyl-1-phenylpropyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (R)—N-(3-hydroxy-3-methyl-1-phenylbutyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (S)—N-(2-methoxy-1-phenylethyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (S)—N-[2-(difluoromethoxy)-1-phenylethyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (S)—N-(2-ethoxy-1-phenylethyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (R)—N-(3-methoxy-1-phenylpropyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • Sodium
  • (S)-2-{6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylacetate,
  • (R)—N-(2-hydroxy-1-phenylethyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • N-[1-(2-fluorophenyl)-2-hydroxyethyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (S)—N-[1-(3-fluorophenyl)-2-hydroxyethyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (S)—N-[1-(4-fluorophenyl)-2-hydroxyethyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • N-[2-hydroxy-1-(pyridin-2-yl)ethyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • N-[2-hydroxy-1-(pyridin-3-yl)ethyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • N-[1-(benzo[d][1,3]dioxol-4-yl)-2-hydroxyethyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (S)—N-(1-cyclohexyl-2-hydroxyethyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (S)—N-(1-hydroxy-3-methylbutan-2-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (S)—N-(1-hydroxypropan-2-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • N-(2-hydroxyethyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • N-(2-hydroxy-2-phenylethyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • N-(2-hydroxypropyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • N-[(2S)-1-hydroxy-3-methyl-1-phenylbutan-2-yl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • N-(4-hydroxy-1-phenyl-2-butyn-1-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (S)-2-{6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylethyl acetate,
  • (S)-2-{6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylethyl propionate,
  • (S)-2-{6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylethyl butanoate,
  • (S)-2-{6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylethyl pentanoate,
  • (S)-2-{6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylethyl octanoate,
  • (S)-2-{6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylethyl dodecanoate,
  • (S)-2-{6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylethyl palmitate,
  • (S)-2-{6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylethyl isobutanoate,
  • (S)-2-{6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylethyl pivalate,
  • (S)-2-{6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylethyl 3-methylbutanoate,
  • (S)-2-{6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylethyl benzoate,
  • (S)-2-{6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylethyl ethylcarbonate,
  • Sodium
  • (S)-4-(2-{6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylethoxy)-4-oxobutanoate,
  • (S)-(2-{6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylethoxy)methyl pivalate,
  • (S)-2-acetoxy-1-phenylethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydro pyrrolo[3,4-c]pyrazole-5(1H)-carboxylate,
  • (S)-benzyl 2-{6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylacetate,
  • (S)-methyl 2-{6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylacetate,
  • N-(2,2-difluoro-3-hydroxy-1-phenylpropyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • N-(2-isopropoxy-1-phenylethyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • 6,6-Dimethyl-N-(2-phenoxy-1-phenylethyl)-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (S)—N-[1-(2-chlorophenyl)-2-hydroxyethyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (S)—N-[2-hydroxy-1-(o-tolyl)ethyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (S)—N-(1-hydroxy-3-phenylpropan-2-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • N-(2-hydroxy-3-methylbutyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (R)—N-(1-hydroxy-3-phenylpropan-2-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (R)—N-(2-hydroxy-2-phenylethyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (S)—N-(2-hydroxy-2-phenylethyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • 2-Hydroxy-2-phenylethyl
  • 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate,
  • (R)—N-[6,6-dimethyl-5-(2-phenoxypropanoyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide,
  • (S)—N-[6,6-dimethyl-5-(2-phenoxypropanoyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide,
  • N-[6,6-dimethyl-5-(2-phenoxyacetyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide,
  • (R)—N-[6,6-dimethyl-5-(2-phenoxypropanoyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclopropanecarboxamide,
  • N-{5-[3-(benzyloxy)-2-phenoxypropanoyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide,
  • N-[5-(3-hydroxy-2-phenoxypropanoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide,
  • N-{5-[2-(4-chlorophenoxy)propanoyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide,
  • N-{5-[2-(2-chlorophenoxy)propanoyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide,
  • N-{5-[2-(cyclohexyloxy)propanoyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide,
  • N-{5-[2-(3-chlorophenoxy)propanoyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide,
  • N-[5-(2-methoxypropanoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide,
  • N-[5-(3-methoxy-2-phenoxypropanoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide,
  • N-{6,6-dimethyl-5-[2-(pyridin-3-yloxy)propanoyl]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide,
  • N-{5-[3-(dimethylamino)-2-phenoxypropanoyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide,
  • N-[6,6-dimethyl-5-(2-phenoxy-2-phenylacetyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide,
  • N-{5-[3-(3,3-difluoropyrrolidin-1-yl)-2-phenoxypropanoyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide,
  • N-[5-(3-hydroxy-2-phenylpropanoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide,
  • (S)—N-[5-(3-hydroxy-2-phenylpropanoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide
  • (R)—N-{5-[3-(benzyloxy)-2-phenylpropanoyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide,
  • (R)—N-[5-(3-hydroxy-2-phenylpropanoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide
  • (R)—N-[5-(2-methoxy-2-phenylacetyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide,
  • (S)—N-[5-(2-methoxy-2-phenylacetyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide,
  • N-[5-(3-methoxy-2-phenylpropanoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide,
  • N-[5-(4-methoxy-2-phenylbutanoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide,
  • (S)—N-[5-(3-hydroxy-2-phenylpropanoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclopropanecarboxamide,
  • (R)—N-[5-(2-methoxy-2-phenylacetyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclopropanecarboxamide,
  • (R)—N-{5-[2-(difluoromethoxy)-2-phenylacetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide,
  • (R)—N-[5-(2-ethoxy-2-phenylacetyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide,
  • (R)-1-(ethyldimethylsilyl)-N-[5-(2-methoxy-2-phenylacetyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]cyclobutanecarboxamide,
  • (R)—N-[5-(2-cyclopropoxy-2-phenylacetyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide,
  • (R)—N-[5-(2-isopropoxy-2-phenylacetyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide,
  • (R)—N-{6,6-dimethyl-5-[2-phenyl-2-(trifluoromethoxy)acetyl]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide,
  • (R)—N-[6,6-dimethyl-5-(2-phenyl-2-propoxyacetyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide,
  • N-{5-[2-(4-fluorophenyl)-2-methoxyacetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide,
  • N-{5-[2-(3-fluorophenyl)-2-methoxyacetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide,
  • (R)—N-{5-[2-(2-fluorophenyl)-2-methoxyacetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide,
  • N-{5-[2-methoxy-2-(thiophen-2-yl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide,
  • (−)-N-{5-[2-methoxy-2-(thiophen-2-yl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide,
  • (+)-N-{5-[2-methoxy-2-(thiophen-2-yl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide,
  • N-{[1-(hydroxymethyl)cyclobutyl](phenyl)methyl}-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (R)—N-[2-(1-hydroxycyclopropyl)-1-phenylethyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (R)—N-(3-ethyl-3-hydroxy-1-phenylpentyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (R)—N-[1-(4-fluorophenyl)-3-hydroxy-3-methylbutyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (R)—N-[1-(3-fluorophenyl)-3-hydroxy-3-methylbutyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (R)—N-[1-(2-fluorophenyl)-3-hydroxy-3-methylbutyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (R)—N-(5-hydroxy-2,5-dimethylhexan-3-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • N-[1-(4-fluorophenyl)-3-hydroxy2,2-dimethylpropyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • N-[1-(3-fluorophenyl)-3-hydroxy-2,2-dimethylpropyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (−)-N-[1-(3-fluorophenyl)-3-hydroxy-2,2-dimethylpropyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (+)-N-[1-(3-fluorophenyl)-3-hydroxy-2,2-dimethylpropyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • N-[1-(2-fluorophenyl)-3-hydroxy-2,2-dimethylpropyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • N-(1-hydroxy-2,2,4-trimethylpentan-3-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (R)—N-(3-hydroxy-3-methyl-1-phenylbutyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • N-(3-hydroxy-2,2-dimethyl-1-phenylpropyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (−)-N-(3-hydroxy-2,2-dimethyl-1-phenylpropyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (+)-N-(3-hydroxy-2,2-dimethyl-1-phenylpropyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,
  • (R)—N-[5-(2-butoxy-2-phenylacetyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide, and
  • N-(3-methoxy-2,2-dimethyl-1-phenylpropyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide.


The compound or the pharmacologically acceptable salt thereof according to the present embodiment may be a single optically active form or may be a mixture of a plurality of optically active forms.


In the case where geometric isomers or rotational isomers are present in the compound according to the present embodiment, these isomers are also included in the scope of the present invention, and in the case where proton tautomers are present, these tautomers are also encompassed in the present invention.


The “pharmacologically acceptable salt” according to the present embodiment is not particularly limited as long as being a salt acceptable as a drug, and examples thereof include: salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, and phosphoric acid; salts with organic carboxylic acids such as acetic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, adipic acid, lactic acid, and trifluoroacetic acid; salts with organic sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and naphthalenesulfonic acid; salts with alkali metals such as lithium, sodium, and potassium; salts with alkaline earth metals such as calcium and magnesium; and quaternary ammonium salts such as ammonia, morpholine, glucosamine, ethylenediamine, guanidine, diethylamine, triethylamine, dicyclohexylamine, diethanolamine, and piperazine.


The compound or the pharmacologically acceptable salt thereof according to the present embodiment can form a hydrate or a solvate, and each one or a mixture thereof is encompassed in the present invention.


The compound according to the present embodiment may contain a non-natural ratio of an atomic isotope for one or more of the constituting atoms. Examples of the atomic isotope include deuterium (2H), tritium (3H), carbon-14 (14C), fluorine-18 (18F), sulfur-35 (35S), and iodine-125 (125I). These compounds are useful as therapeutic or prophylactic agents, research reagents, for example, assay reagents, and diagnostic agents, for example, in vivo diagnostic imaging agents. All isotopic variants of the compound according to the present embodiment are encompassed in the present invention, regardless of whether to be radioactive.


The compound or the pharmacologically acceptable salt thereof according to the present embodiment can be used as a pharmaceutical composition, if necessary, by adding an excipient, a lubricant, a binder, a disintegrant, a coating agent, a stabilizer, a tonicity agent, a buffer, a pH adjuster, a solubilizer, a thickener, a preservative, an antioxidant, a sweetener, a colorant, a flavor, and the like. The pharmaceutical composition can be appropriately prepared according to a purpose by a known method described in, for example, General Rules for Preparations, Japanese Pharmacopoeia 16th edition.


In the pharmaceutical composition, the content of the compound or the pharmacologically acceptable salt thereof according to the present embodiment can be appropriately adjusted.


The pharmaceutical composition can be in a dosage form described in General Rules for Preparations, Japanese Pharmacopoeia 16th edition, for example, a preparation for oral administration such as tablets, capsules, granules, or powders, or a preparation for parenteral administration such as injections (e.g., intravenous administration, subcutaneous administration, intramuscular administration, and intraperitoneal administration), eye drops, nasal drops, suppositories, ointments, lotions, creams, gels, sprays, patches, inhalants, or percutaneous absorption preparations.


Examples of the excipient include lactose, mannitol, starch, crystalline cellulose, light anhydrous silicic acid, calcium carbonate, and calcium hydrogen phosphate, and examples of the lubricant include stearic acid, magnesium stearate, and talc. Examples of the binder include starch, hydroxypropylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone, and examples of the disintegrant include carboxymethylcellulose, low-substituted hydroxypropylmethylcellulose, and calcium citrate. Examples of the coating agent include hydroxypropylmethylcellulose, macrogol, and silicone resins, and examples of the stabilizer include ethyl p-hydroxybenzoate and benzyl alcohol.


Examples of the tonicity agent include glycerin, propylene glycol, sodium chloride, potassium chloride, sorbitol, and mannitol, examples of the buffer include boric acid, boric acid salts, phosphoric acid, phosphoric acid salts, citric acid, citric acid salts, acetic acid, acetic acid salts, ε-aminocaproic acid, and trometamol, and examples of the pH adjuster include hydrochloric acid, citric acid, phosphoric acid, glacial acetic acid, sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium bicarbonate. Examples of the solubilizer include polysorbate 80, polyoxyethylene hydrogenated castor oil 60, macrogol 4000, purified soybean lecithin, and polyoxyethylene (160) polyoxypropylene (30) glycol, and examples of the thickener include cellulose polymers such as hydroxypropylmethylcellulose and hydroxypropylcellulose, polyvinyl alcohol, and polyvinylpyrrolidone. Examples of the stabilizer include edetic acid and sodium edetate, and examples of the preservative include sorbic acid, potassium sorbate, benzalkonium chloride, benzethonium chloride, methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, and chlorobutanol.


Examples of ingredients that may be contained in pharmaceutical compositions for percutaneous administration such as ointments, lotions, creams, gels, patches, and sprays include: absorption promoters such as lauryl alcohol, myristyl alcohol, salicylic acid ethylene glycol, and pyrrothiodecane; fatty acid esters such as diisopropyl adipate, isopropyl myristate, cetyl lactate, myristyl lactate, isopropyl palmitate, diethyl sebacate, hexyl laurate, and cetyl isooctanoate; aliphatic alcohols such as cetyl alcohol, stearyl alcohol, oleyl alcohol, hexadecyl alcohol, and behenyl alcohol; glycols such as propylene glycol, propylenediol, polyethylene glycol, and dipropylene glycol; and surfactants such as sorbitan fatty acid ester, glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene glycerin fatty acid ester, polyethylene glycol fatty acid ester, polyoxyethylene alkyl ether, polyoxyethylene castor oil, and polyoxyethylene hydrogenated castor oil.


The dose of the compound or the pharmacologically acceptable salt thereof according to the present embodiment can be appropriately varied according to symptoms, age, a dosage form, etc. In the case of, for example, oral administration, it can usually be administered in one portion or several divided portions of 0.01 to 2000 mg, preferably 1 to 500 mg per day.


As for ointments, lotions, creams, or gels, one having a concentration of 0.00001% (w/v) to 10% (w/v), preferably 0.001% (w/v) to 5% (w/v) can usually be administered in one portion or several divided portions.


Next, a method for producing the compound or the pharmacologically acceptable salt thereof according to the present embodiment will be described. The compound or the pharmacologically acceptable salt thereof according to the present invention is not limited to compounds or pharmacologically acceptable salts thereof produced by production methods described below.


In the production methods given below, in the case where partial structures that inhibit the desired reactions or receive side reactions (e.g., a hydroxy group, an amino group, a carbonyl group, a carboxyl group, an amide group, a thiol group and the like) are present in compounds, the compounds of interest can be obtained by introducing protective groups to these partial structures, performing the desired reactions, and then removing the protective groups.


The introduction reaction and removal reaction of a protective group can be carried out according to a method routinely used in organic synthetic chemistry (e.g., a method described in, for example, Protective Groups in Organic Synthesis, 4th ed., T.W. Greene, P.G.M. Wuts, John Wiley & Sons Inc. (2006)).


Specific methods for producing the individual compounds of the present invention will be described in detail in Examples mentioned later.


Compound (I) can be produced, for example, by methods of production methods 1 to 4 given below with compound (A) as a starting material. A method for producing the compound (A) will be mentioned later.


<Production Method 1 for Compound (I)>


Production method 1 is a method for producing compound (I) through steps 1 to 3 with compound (A) as a starting material. Production method 1 is a suitable production method in the case where L2 is an oxygen atom or an optionally substituted nitrogen atom. In production method 1, R1, R2, R3, R4, R5, L1, L2, and L3 are defined as in formula (I). P1 group is a protective group for the amino group, and X is a leaving group. The P1 group can substitute an acidic proton of pyrazole in the 4,6-dihydropyrrolo[3,4-c]pyrazole skeleton. Thus, the P1 group may be added to position 1 of the 4,6-dihydropyrrolo[3,4-c]pyrazole skeleton or may be added to 2-position. Compound (A) will be described by using a chemical formula wherein it is added to 1-position of the 4,6-dihydropyrrolo[3,4-c]pyrazole skeleton, for the sake of convenience.




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The P1 group is not particularly limited as long as being a substituent known as a protective group for the amino group to those skilled in the art. Examples of the P1 group include: optionally substituted C7-11 aralkyl groups such as a benzyl group, a p-methoxyphenylmethyl group, and a o-nitrophenylmethyl group; optionally substituted acyl groups such as an acetyl group, a trifluoroacetyl group, and a benzoyl group; optionally substituted C1-6 alkoxycarbonyl groups such as a methoxycarbonyl group, an ethoxycarbonyl group, a Boc group (tert-butoxycarbonyl group), a Cbz group (benzyloxycarbonyl group), a Fmoc group (fluorenylmethyloxycarbonyl group), and a Teoc group (trimethylsilylethyloxycarbonyl group); alkenyloxycarbonyl groups such as an Alloc group (allyloxycarbonyl group); alkylsulfonyl groups such as a methanesulfonyl group; and C6-10 arylsulfonyl groups such as a p-toluenesulfonyl group.


The X group is not particularly limited as long as being a substituent known as a leaving group to those skilled in the art. Examples of X include: halogen atoms; an imidazolyl group; aminooxy groups such as a succinyl-N-oxy group and a benzotriazolyl-N-oxy group; and acyloxy groups such as a pivaloyloxy group and a benzoyloxy group. Alternatively, X may be a hydroxy group.


(Step 1)


Step 1 is the step of reacting compound (A) with an acylating agent to obtain compound (B).


As the acylating agent, for example, phosgene, diphosgene, triphosgene, carbonyldiimidazole (CDI), N,N′-disuccinimidyl carbonate, or carbonic acid ester can be used.


The amount of the acylating agent used is preferably 0.4 to 3.0 mol, more preferably 0.7 to 1.5 mol, with respect to 1 mol of the compound (A).


The reaction of step 1 may be performed in a solvent or may be performed without a solvent. In the case of using a solvent, there is no limitation as long as the solvent does not have influence on the reaction, and an organic solvent is preferred. Examples of the organic solvent include dichloromethane, 1,2-dichloroethane, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran (THF), N,N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO).


In step 1, a base can be further added in order to accelerate the reaction. Examples of the base include organic amines such as triethylamine, diisopropylethylamine (DIPEA), 1,5-diazabicyclo[4.3.0]nonene (DBN), 1,8-diazabicyclo[5.4.0]undecene (DBU), pyridine, and 4-dimethylaminopyridine (DMAP).


The amount of the base added is preferably 1 to 10 mol, more preferably 3 to 6 mol, with respect to 1 mol of the compound (A).


The reaction temperature of step 1 can be appropriately set by those skilled in the art. The reaction temperature is usually −100 to −20° C., preferably −80 to −60° C.


(Step 2)


Step 2 is the step of reacting compound (B) with compound (C) to obtain compound (D).


In step 2, the L2 group is an oxygen atom or an optionally substituted nitrogen atom. Specifically, the compound (C) is an alcohol or an amine


The amount of the compound (C) used is preferably 1 to 20 mol, more preferably 2 to 5 mol, with respect to 1 mol of the compound (B). The compound (C) and the compound (B) may be dissolved in an organic solvent and added to the reaction solution.


The reaction of step 2 may be performed in a solvent or may be performed without a solvent. In the case of using a solvent, there is no limitation as long as the solvent does not have influence on the reaction, and an organic solvent is preferred. Examples of the organic solvent include dichloromethane, 1,2-dichloroethane, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran (THF), 1,4-dioxane, N,N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO).


In step 2, a base can be further added in order to accelerate the reaction. Examples of the base include: organic amines such as triethylamine, diisopropylethylamine (DIPEA), 1,5-diazabicyclo[4.3.0]nonene (DBN), 1,8-diazabicyclo[5.4.0]undecene (DBU), pyridine, and 4-dimethylaminopyridine (DMAP); and inorganic bases such as potassium carbonate and sodium carbonate.


The amount of the base added is preferably 1 to 20 mol, more preferably 2 to 5 mol, with respect to 1 mol of the compound (A).


The reaction temperature of step 2 can be appropriately set by those skilled in the art. The reaction temperature is usually 0 to 120° C., preferably 25 to 100° C.


(Step 3)


Step 3 is the step of removing the P1 group of compound (D) to produce compound (I).


The reaction conditions of step 3 can be appropriately selected by those skilled in the art according to the type of the P1 group used. In the case where the P1 group is, for example, an aralkyl group, it may be performed by hydrogenolysis or may be performed by using protonic acid or Lewis acid. In the case where the P1 group is a Boc group, it can be performed by treatment with protonic acid or Lewis acid; in the case where the P1 group is a Cbz group, it can be performed by hydrogenolysis or treatment with a base; and in the case where the P1 group is a Teoc group, a reagent that forms a fluoride ion such as tetrabutylammonium fluoride can be used. In the case where the P1 group is an alkoxycarbonyl group such as a methoxycarbonyl group or an ethoxycarbonyl group, it may be performed by heating in the presence of an organic amine such as triethylamine or diisopropylethylamine (DIPEA), or an inorganic base such as potassium carbonate or sodium carbonate.


The compound (I) obtained by step 3 can be converted to a pharmacologically acceptable salt thereof by a method well known to those skilled in the art.


<Production Method 2 for Compound (I)>


Production method 2 is a method for obtaining compound (D) through steps 4 and 5 with compound (C) as a starting material, followed by conversion to compound (1) according to step 3 of production method 1 described above. Production method 2 is a suitable production method in the case where L2 is an oxygen atom or an optionally substituted nitrogen atom. In production method 2, R1, R2, R3, R4, R5, L1, L2, L3, P1, and X are defined as in production method 1 described above.




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(Step 4)


Step 4 is the step of reacting compound (C) with an acylating agent to obtain compound (E).


In step 4, the L2 group is an oxygen atom or an optionally substituted nitrogen atom. Specifically, the compound (C) is an alcohol or an amine


As the acylating agent, for example, phosgene, diphosgene, triphosgene, carbonyldiimidazole (CDI), N,N′-disuccinimidyl carbonate, or carbonic acid ester can be used.


The amount of the acylating agent used is preferably 1 to 5 mol, more preferably 1 to 2 mol, with respect to 1 mol of the compound (C).


The reaction of step 4 may be performed in a solvent or may be performed without a solvent. In the case of using a solvent, there is no limitation as long as the solvent does not have influence on the reaction, and an organic solvent is preferred. Examples of the organic solvent include acetonitrile, dichloromethane, diethyl ether, tetrahydrofuran (THF), N,N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO).


In step 4, a base can be further added in order to accelerate the reaction. Examples of the base include organic amines such as triethylamine, diisopropylethylamine (DIPEA), 1,5-diazabicyclo[4.3.0]nonene (DBN), 1,8-diazabicyclo[5.4.0]undecene (DBU), pyridine, and 4-dimethylaminopyridine (DMAP).


The amount of the base added is preferably 1 to 5 mol, more preferably 1 to 2 mol, with respect to 1 mol of the compound (C).


The reaction temperature of step 4 can be appropriately set by those skilled in the art. The reaction temperature is usually 0 to 100° C., preferably 20 to 40° C.


(Step 5)


Step 5 is the step of reacting compound (E) with compound (A) to obtain compound (D).


The amount of the compound (E) used is preferably 1 to 5 mol, more preferably 1 to 2 mol, with respect to 1 mol of the compound (A). The compound (E) and the compound (A) may be dissolved in an organic solvent and added to the reaction solution.


The reaction of step 5 may be performed in a solvent or may be performed without a solvent. In the case of using a solvent, there is no limitation as long as the solvent does not have influence on the reaction, and an organic solvent is preferred. Examples of the organic solvent include dichloromethane, diethyl ether, tetrahydrofuran (THF), N,N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO).


In step 5, a base can be further added in order to accelerate the reaction. Examples of the base include organic amines such as triethylamine, diisopropylethylamine (DIPEA), 1,5-diazabicyclo[4.3.0]nonene (DBN), 1,8-diazabicyclo[5.4.0]undecene (DBU), pyridine, and 4-dimethylaminopyridine (DMAP).


The amount of the base added is preferably 1 to 10 mol, more preferably 1 to 5 mol, with respect to 1 mol of the compound (A).


The reaction temperature of step 5 can be appropriately set by those skilled in the art. The reaction temperature is usually 0 to 100° C., preferably 20 to 40° C.


<Production Method 3 for Compound (I)>


Production method 3 is a method for reacting compound (A) with compound (F) to obtain compound (D), followed by conversion to compound (I) according to step 3 of production method 1 described above. Production method 3 is a suitable production method in the case where L2 is a single bond, an optionally substituted linear or branched C1-6 alkylene group, an optionally substituted linear or branched C2-6 alkenylene group, an optionally substituted linear or branched C2-6 alkynylene group, an optionally substituted C3-6 cycloalkylene group, or an optionally substituted C3-6 cycloalkenylene group. In production method 3, R1, R2, R3, R4, R5, L1, L3, and P1 are defined as in production method 1 described above.




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(Step 6)


Step 6 is the step of condensing compound (A) with compound (F) to obtain compound (D). The condensation reaction involves converting the compound (F) to an acid halide, a carboxylic anhydride, an acid azide, or an active ester by using a reagent used in amide bond formation reaction, followed by reaction with the compound (A). The reagent used in amide bond formation reaction is not particularly limited as long as being a reagent known as a reagent used in amide bond formation reaction to those skilled in the art.


The amount of the compound (F) used is preferably 1 to 10 mol, more preferably 1 to 5 mol, with respect to 1 mol of the compound (A). The compound (F) may be dissolved in an organic solvent and added to the reaction solution.


The reaction of step 6 may be performed in a solvent or may be performed without a solvent. In the case of using a solvent, there is no limitation as long as the solvent does not have influence on the reaction, and an organic solvent is preferred. Examples of the organic solvent include dichloromethane, 1,2-dichloroethane, diethyl ether, tetrahydrofuran (THF), N,N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO).


In step 6, a base can be further added in order to accelerate the reaction. Examples of the base include organic amines such as triethylamine, diisopropylethylamine (DIPEA), 1,5-diazabicyclo[4.3.0]nonene (DBN), 1,8-diazabicyclo[5.4.0]undecene (DBU), pyridine, and 4-dimethylaminopyridine (DMAP).


The amount of the base added is preferably 1 to 10 mol, more preferably 1 to 5 mol, with respect to 1 mol of the compound (A).


The reaction temperature of step 6 can be appropriately set by those skilled in the art. The reaction temperature is usually 0 to 100° C., preferably 20 to 40° C.


<Production Method 4 for Compound (I)>


Production method 4 is a method for obtaining compound (D) through step 7 and step 8 with compound (H) as a starting material, followed by conversion to compound (I) according to step 3 of production method 1 described above. In production method 4, R1, R2, R3, R4, L1, L2, and L3 are defined as in formula (I). P1 group is a protective group for the amino group, and P2 is a protective group for the hydroxy group. The P1 group is defined as in production method 1 described above.




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The P2 group is not particularly limited as long as being a substituent known as a protective group for the hydroxy group to those skilled in the art. Examples of the P2 group include: optionally substituted C7-11 aralkyl groups such as a benzyl group, a p-methoxyphenylmethyl group, and a o-nitrophenylmethyl group; optionally substituted acyl groups such as an acetyl group, a trifluoroacetyl group, and a benzoyl group; and substituted silyl groups such as a trimethylsilyl group, a tert-butyldimethylsilyl group, a triethylsilyl group, a triisopropylsilyl group, and a tert-butyldiphenylsilyl group.


(Step 7)


Step 7 is the step of performing the deprotection reaction of compound (H) to obtain compound (J). The removal reaction of the P2 group can also be performed by a method well known to those skilled in the art (e.g., a method described in, for example, Protective Groups in Organic Synthesis, 4th ed., T.W. Greene, P.G.M. Wuts, John Wiley & Sons Inc. (2006)).


(Step 8)


Step 8 is the step of reacting compound (J) with an acid halide, an acid anhydride, or an alkyl halide to obtain compound (D).


The amount of the acid halide, the acid anhydride, or the alkyl halide used is preferably 1 to 10 mol, more preferably 1 to 2 mol, with respect to 1 mol of the compound (J).


The reaction of step 7 may be performed in a solvent or may be performed without a solvent. In the case of using a solvent, there is no limitation as long as the solvent does not have influence on the reaction, and an organic solvent is preferred. Examples of the organic solvent include dichloromethane, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, N,N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO).


In step 8, a base can be further added in order to accelerate the reaction. Examples of the base include organic amines such as triethylamine, diisopropylethylamine (DIPEA), 1,5-diazabicyclo[4.3.0]nonene (DBN), 1,8-diazabicyclo[5.4.0]undecene (DBU), pyridine, and 4-dimethylaminopyridine (DMAP).


The amount of the base added is preferably 1 to 20 mol, more preferably 1 to 5 mol, with respect to 1 mol of the compound (J).


The reaction temperature of step 8 can be appropriately set by those skilled in the art. The reaction temperature is usually −20 to 120° C., preferably 15 to 100° C.


<Method for Producing Compound (A)>


The compound (A) can be produced, for example, by the following method with compound (A1) as a starting material. Compound (A1) can be produced, for example, with reference to WO2007/72153 or through the following steps 11 to 15.




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The compound (A1) is 3-amino-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole in which the nitrogen atom on the pyrazole skeleton may be substituted by P1 group, and the nitrogen atom at 5-position may be substituted by P3 group. The P1 group can substitute an acidic proton of pyrazole in the 4,6-dihydropyrrolo[3,4-c]pyrazole skeleton. Thus, the P1 group may be added to position 1 of the 4,6-dihydropyrrolo[3,4-c]pyrazole skeleton or may be added to 2-position. Compound (A1) and compound (A2) will be described by using a chemical formula wherein it is added to 1-position of the 4,6-dihydropyrrolo[3,4-c]pyrazole skeleton, for the sake of convenience.


In the compound (A1), P1 has the same meaning as defined in compound (A). The P3 group is not particularly limited as long as being a substituent known as a protective group for the amino group to those skilled in the art. Examples of the P3 group include: optionally substituted C7-11 aralkyl groups such as a benzyl group, a p-methoxyphenylmethyl group, and a o-nitrophenylmethyl group; optionally substituted C1-6 alkylcarbonyl groups such as an acetyl group and a trifluoroacetyl group; optionally substituted C6-10 arylcarbonyl groups such as a benzoyl group; optionally substituted C1-6 alkoxycarbonyl groups such as a methoxycarbonyl group, an ethoxycarbonyl group, a Boc group (tert-butoxycarbonyl group), a Cbz group (benzyloxycarbonyl group), a Fmoc group (fluorenylmethyloxycarbonyl group), and a Teoc group (trimethylsilylethyloxycarbonyl group); alkenyloxycarbonyl groups such as an Alloc group (allyloxycarbonyl group); alkylsulfonyl groups such as a methanesulfonyl group; and optionally substituted C6-10 arylsulfonyl groups such as a p-toluenesulfonyl group.


In the formulas (A2) and (A3), R1, R2, R3, and L1 have the same meanings as defined in compound (I). The group X is not particularly limited as long as being a substituent known as a leaving group to those skilled in the art. Examples of X include: halogen atoms; an imidazolyl group; aminooxy groups such as a succinyl-N-oxy group and a benzotriazolyl-N-oxy group; and acyloxy groups such as a pivaloyloxy group and a benzoyloxy group. Alternatively, X may be a hydroxy group.


In the case where the compound (A2) is a carboxylic acid (i.e., X is a hydroxy group), it may be converted to an acid anhydride by a method well known to those skilled in the art and then reacted with the compound (A1), or may be reacted with the compound (A1) by using a reagent known as a condensing agent used in amide bond formation reaction to those skilled in the art.


(Step 9)


Step 9 is the step of reacting compound (A1) with compound (A2) to obtain compound (A3).


The amount of the compound (A2) used is preferably 1 to 10 mol, more preferably 1 to 3 mol, with respect to 1 mol of the compound (A1).


The reaction of step 9 may be performed in a solvent or may be performed without a solvent. In the case of using a solvent, there is no limitation as long as the solvent does not have influence on the reaction, and an organic solvent is preferred. Examples of the organic solvent include dichloromethane, diethyl ether, tetrahydrofuran (THF), N,N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO).


In step 9, a base can be further added in order to accelerate the reaction. Examples of the base include organic amines such as triethylamine, diisopropylethylamine (DIPEA), 1,5-diazabicyclo[4.3.0]nonene (DBN), 1,8-diazabicyclo[5.4.0]undecene (DBU), pyridine, and 4-dimethylaminopyridine (DMAP).


The amount of the base added is preferably 1 to 20 mol, more preferably 1 to 5 mol, with respect to 1 mol of the compound (A1).


The reaction temperature of step 9 can be appropriately set by those skilled in the art. The reaction temperature is usually −40 to 100° C., preferably −20 to 20° C.


(Step 10)


Step 10 is the step of performing the deprotection reaction of compound (A3) to obtain compound (A). The removal reaction of the P3 group can also be performed by a method well known to those skilled in the art (e.g., a method described in, for example, Protective Groups in Organic Synthesis, 4th ed., T.W. Greene, P.G.M. Wuts, John Wiley & Sons Inc. (2006)).


<Method for Producing Compound (A1)>




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In the formulas (A6), (A7), and (A8), P3 has the same meaning as defined in compound (A1).


(Step 11)


Step 11 is the step of reacting compound (A4) with acrylonitrile to obtain compound (A5).


The amount of the acrylonitrile used is preferably 1 to 10 mol, more preferably 1 to 3 mol, with respect to 1 mol of the compound (A4).


In step 11, there is no limitation as long as a solvent does not have influence on the reaction, and an aqueous solvent is preferred.


In step 11, a base can be further added in order to accelerate the reaction. Examples of the base include inorganic bases such as potassium hydroxide. The amount of the base added is preferably 0.8 to 2 mol, with respect to 1 mol of the compound (A1).


The reaction temperature of step 11 can be appropriately set by those skilled in the art. The reaction temperature is usually 0 to 100° C., preferably 50 to 90° C.


(Step 12)


Step 12 is the step of protecting the amino group of compound (A5) with P3 group to obtain compound (A6). The protection reaction of the amino group with the P3 group can be performed by a method well known to those skilled in the art (e.g., a method described in, for example, Protective Groups in Organic Synthesis, 4th ed., T.W. Greene, P.G.M. Wuts, John Wiley & Sons Inc. (2006)).


(Step 13)


Step 13 is the step of performing the cyclization reaction of compound (A6) to obtain compound (A7).


The reaction of step 13 may be performed in a solvent or may be performed without a solvent. In the case of using a solvent, there is no limitation as long as the solvent does not have influence on the reaction, and an organic solvent is preferred. Examples of the organic solvent include diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, N,N-dimethylformamide (DMF) toluene.


In step 13, a base can be further added in order to accelerate the reaction. Examples of the base include sodium hydride, potassium hydride, sodium methoxide, sodiumethoxide, n-butyllithium, and tert-butoxy potassium. The amount of the base added is preferably 1 to 3 mol with respect to 1 mol of the compound (A6).


The reaction temperature of step 13 can be appropriately set by those skilled in the art. The reaction temperature is usually 20 to 150° C., preferably 50 to 100° C.


(Step 14)


Step 14 is the step of reacting compound (A7) with hydrazine to obtain compound (A8).


The reaction of step 14 may be performed in a solvent or may be performed without a solvent. In the case of using a solvent, there is no limitation as long as the solvent does not have influence on the reaction, and an organic solvent is preferred. Examples of the organic solvent include ethanol, n-propanol, and n-butanol.


In step 14, an acid can be further added in order to accelerate the reaction. Examples of the acid include acetic acid, hydrochloric acid, and sulfuric acid. The amount of the acid added is preferably 1 to 10 mol with respect to 1 mol of the compound (A7).


The reaction temperature of step 14 can be appropriately set by those skilled in the art. The reaction temperature is usually 20 to 150° C., preferably 50 to 120° C.


(Step 15)


Step 15 is the step of protecting the amino group of compound (A7) with P1 group to obtain compound (A1). The protection reaction of the amino group with the P1 group can be performed by a method well known to those skilled in the art (e.g., a method described in, for example, Protective Groups in Organic Synthesis, 4th ed., T.W. Greene, P.G.M. Wuts, John Wiley & Sons Inc. (2006)).


Example

Hereinafter, the present invention will be described further specifically as to the compound according to the present embodiment or the pharmaceutically acceptable salt thereof by showing Examples (Examples 1 to 125), Reference Examples (Reference Examples 1 to 137), and Test Examples (Test Examples 1 to 12); however, these examples are given for more understanding the present invention and does not limit the scope of the present invention.


DIOL silica gel in silica gel column chromatography represents CHROMATOREX (trade name) DIOL MB 100-40/75 manufactured by Fuji Silysia Chemical Ltd.


DNH silica gel in silica gel column chromatography represents CHROMATOREX (trade name) DNH MB 100-40/75 manufactured by Fuji Silysia Chemical Ltd.


In the case where a plurality of values of mass spectra are observed due to the presence of isotopes, only one having minimum m/z was described. DUIS in an ionization mode of a mass spectrum is a mixed mode of ESI and APCI.



1H-NMR is indicated by chemical shift (6) with tetramethylsilane as an internal standard (0 ppm), and a coupling constant (J value) is indicated by Hz unit, unless otherwise specified. An abbreviation for the split pattern of each peak has the following meaning: s: singlet, d: doublet, t: triplet, q: quartet, and br: broad.


Abbreviations described in Examples and Reference Examples are usually used as meanings generally used in the fields of organic chemistry and pharmacy. Each abbreviation is specifically understood by those skilled in the art as follows.

  • ATP: adenosine triphosphate
  • Boc: tert-butyloxycarbonyl
  • DIPEA: N,N-diisopropylethylamine
  • DMF: N,N-dimethylformamide
  • DMSO: dimethyl sulfoxide
  • DTT: dithiothreitol
  • Et: ethyl
  • FBS: fetal bovine serum
  • HEPES: N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid
  • MBP: myelin basic protein
  • n-: normal
  • NADPH: nicotinamide adenine dinucleotide phosphate
  • PBMC: peripheral blood mononuclear cell
  • PBS: aqueous solution of phosphate-buffered sodium chloride
  • TBME: tert-butyl methyl ether
  • TBS: tert-butyldimethylsilyl
  • tert-: tertiary
  • THF: tetrahydrofuran
  • Tris: trishydroxyaminomethane


Example 1
(S)—N-(2-Hydroxy-1-phenylethyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound No. IV-114)



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To a solution of 308 mg (0.698 mmol) of ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 3 in 6 ml of THF, 0.23 ml (1.4 mmol) of DIPEA and 472 mg (3.44 mmol) of (S)-(+)-2-phenylglycinol were added at room temperature, then applied to a microwave reaction apparatus, and reacted at 80° C. for 1 hour. Subsequently, 2.7 ml (67 mmol) of methanol and 2.7 ml (19 mmol) of triethylamine were added to the reaction solution, then applied to a microwave reaction apparatus, and reacted at 80° C. for 0.5 hours.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: 1,2-dichloroethane:methanol=100:0 to 98:2 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. For the obtained concentration residue, crystallization was performed with ethyl acetate/diethyl ether, and the obtained solid was collected by filtration. 20 ml of water was added to the obtained solid and stirred, and then, insoluble matter was collected by filtration and dried under reduced pressure to obtain 152 mg of the title compound (yield: 46%) as a white solid.


Mass spectrum (DUIS, m/z): 470 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.20 & 11.65 (br s, total 1H), 9.66-9.46 (m, 1H), 7.41-7.25 (m, 4H), 7.22-7.15 (m, 1H), 6.18 & 6.06 (d, J=7.7 Hz, total 1H), 4.88 (t, J=5.9 Hz, 1H), 4.83-4.71 (m, 1H), 4.62-4.41 (m, 2H), 3.69-3.52 (m, 2H), 2.49-2.41 (m, 2H), 2.30-2.12 (m, 2H), 1.93-1.73 (m, 2H), 1.68-1.44 (m, 6H), 0.17-0.04 (m, 9H).


Example 2
(S)—N-(2-Hydroxy-1-phenylethyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound No. III-114)



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To a solution of 433 mg (1.08 mmol) of ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate hydrochloride synthesized in the similar manner as in Reference Example 7 in 7.5 ml of dehydrated dichloromethane, 0.90 ml (5.2 mmol) of DIPEA was added at room temperature in a nitrogen atmosphere, and then, a solution of 275 mg (0.928 mmol) of bis(trichloromethyl)carbonate in 2.5 ml of dehydrated dichloromethane was added dropwise at −78° C. and stirred at the same temperature as above for 2.5 hours.


After the completion of the reaction, 10 ml of a saturated aqueous solution of sodium bicarbonate was added to the reaction solution and stirred while the temperature was raised to room temperature for a while. The organic layer and the aqueous layer were separated, and then, the aqueous layer was subjected to extraction with dichloromethane twice. All of the obtained organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=90:10 to 80:20 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain a concentration residue.


To a solution of 457 mg of the obtained concentration residue in 4 ml of dehydrated THF, 0.40 ml (2.2 mmol) of DIPEA and 528 mg (3.85 mmol) of (S)-(+)-2-phenylglycinol were added at room temperature in a nitrogen atmosphere and then stirred for 3.75 hours while heated to reflux. Subsequently, 0.90 ml (6.5 mmol) of triethylamine and 0.90 ml (22 mmol) of methanol were added to the reaction solution and then stirred for 1 hour while heated to reflux.


After the completion of the reaction, water was added to the reaction solution, followed by extraction with dichloromethane three times. All of the obtained organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DNH silica gel, elution solvent: dichloromethane:methanol=100:0 to 97:3 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. For the obtained concentration residue, crystallization was performed with ethyl acetate/diisopropyl ether/n-hexane, and the deposited solid was collected by filtration, washed by sousing with n-hexane, and then dried under reduced pressure to obtain 388 mg of the title compound (yield: 79% [2 steps]) as a white solid.


Mass spectrum (CI, m/z): 456 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.02 & 11.54 (br s, total 1H), 9.44 & 9.25 (br s, total 1H), 7.40-7.33 (m, 2H), 7.33-7.24 (m, 2H), 7.23-7.16 (m, 1H), 5.88-5.69 (m, 1H), 4.86-4.79 (m, 1H), 4.61 (t, J=5.6 Hz, 1H), 4.55-4.37 (m, 2H), 3.71-3.64 (m, 2H), 1.63 (s, 3H), 1.57 (s, 3H), 1.08-1.01 (m, 2H), 0.83-0.60 (m, 2H), 0.07 (s, 9H).


Example 3
(S)—N-(2-Hydroxy-1-phenylethyl)-6,6-dimethyl-3-[2-methyl-2-(trimethylsilyl)propanamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound No. II-114)



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To a solution of 337 mg (0.714 mmol) of 5-tert-butyl 1-ethyl 6,6-dimethyl-3-[2-methyl-2-(trimethylsilyl)propanamido]pyrrolo[3,4-c]pyrazole-1,5(4H,6H)-dicarboxylate synthesized in the similar manner as in Reference Example 9 in 3 ml of dehydrated dichloromethane, 0.25 ml (2.2 mmol) of 2,6-lutidine and 0.39 ml (2.2 mmol) of trimethylsilyl trifluoromethanesulfonate were added in this order at 0° C. in a nitrogen atmosphere and stirred at the same temperature as above for 1.5 hours.


After the completion of the reaction, the reaction solution was diluted with dichloromethane and subsequently washed with a saturated aqueous solution of sodium bicarbonate. The organic layer and the aqueous layer were separated, and then, the aqueous layer was subjected to extraction with dichloromethane twice. All of the obtained organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The operation of adding 25 ml of toluene to the obtained concentration residue and concentrating it under reduced pressure was repeated three times, followed by drying under reduced pressure to obtain a concentration residue.


To a solution of 292 mg of the obtained concentration residue in 5 ml of dehydrated dichloromethane, 0.38 ml (2.2 mmol) of DIPEA was added at room temperature in a nitrogen atmosphere, and then, 149 mg (0.502 mmol) of bis(trichloromethyl)carbonate was added at −78° C. and stirred at the same temperature as above for 2.5 hours.


After the completion of the reaction, 7 ml of a saturated aqueous solution of sodium bicarbonate was added to the reaction solution and stirred while the temperature was raised to room temperature for a while. The organic layer and the aqueous layer were separated, and then, the aqueous layer was subjected to extraction with dichloromethane once. All of the organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=90:10 to 85:15 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain a concentration residue.


To a solution of 262 mg of the obtained concentration residue in 3 ml of dehydrated THF, 0.27 ml (1.6 mmol) of DIPEA and 255 mg (1.86 mmol) of (S)-(+)-2-phenylglycinol were added at room temperature in a nitrogen atmosphere and then stirred for 2.5 hours while heated to reflux. Subsequently, 1.0 ml (7.2 mmol) of triethylamine and 1.0 ml (25 mmol) of methanol were added to the reaction solution and then stirred for 5.5 hours while heated to reflux.


After the completion of the reaction, water was added to the reaction solution, followed by extraction with dichloromethane three times. All of the obtained organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. 0.10 ml of acetic acid was added to the obtained concentration residue and then subjected to silica gel column chromatography (DIOL silica gel, elution solvent: dichloromethane:methanol=100:0 to 97:3 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. For the obtained concentration residue, crystallization was performed with ethyl acetate/n-hexane, and the obtained solid was collected by filtration, washed by sousing with n-hexane, and then dried under reduced pressure to obtain 206 mg of the title compound (yield: 63% [3 steps]) as a pale yellow solid.


Mass spectrum (CI, m/z): 458 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.25 & 11.64 (br s, total 1H), 9.42-9.11 (m, 1H), 7.38-7.25 (m, 4H), 7.23-7.15 (m, 1H), 6.21-6.05 (m, 1H), 4.87 (t, J=5.9 Hz, 1H), 4.81-4.73 (m, 1H), 4.57-4.41 (m, 2H), 3.70-3.54 (m, 2H), 1.66-1.47 (m, 6H), 1.25 (s, 6H), 0.04 (s, 9H).


Example 4
(S)-3-[1-(Ethyldimethylsilyl)cyclobutanecarboxamido]-N-(2-hydroxy-1-phenylethyl)-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound No. IV-117)



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To a solution of 454 mg (0.997 mmol) of ethyl 5-(chlorocarbonyl)-3-[1-(ethyl dimethylsilyl)cyclobutanecarboxamido]-6,6-dimethyl-5,6-dihydropyrrolo[3,4-c]pyrazole-2 (4H)-carboxylate synthesized in the similar manner as in Reference Example 13 in 10 ml of dehydrated THF, 700 mg (5.10 mmol) of (S)-(+)-2-phenylglycinol and 0.35 ml (2.0 mmol) of DIPEA were added at room temperature in an argon atmosphere and then stirred at 60° C. for 4 hours. Subsequently, 6 ml of methanol and 2 ml of triethylamine were added to the reaction solution and stirred at 60° C. for 2 hours.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure, a saturated aqueous solution of sodium bicarbonate was added to the obtained concentration residue, and the mixed solution was subjected to extraction with dichloromethane three times. All of the obtained organic layers were dried over anhydrous magnesium sulfate and filtered, and then, the filtrate was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: 1,2-dichloroethane:methanol=100:0 to 98:2 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. For the concentration residue, crystallization was performed with dichloromethane/diisopropyl ether, and the deposited solid was collected by filtration and subsequently dried under reduced pressure to obtain 404 mg of the title compound (yield: 84%) as a white solid.


Mass spectrum (DUIS, m/z): 484 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.20 & 11.66 (br s, total 1H), 9.64-9.47 (m, 1H), 7.40-7.14 (m, 5H), 6.26-6.01 (m, 1H), 4.88 (t, J=5.8 Hz, 1H), 4.83-4.71 (m, 1H), 4.60-4.43 (m, 2H), 3.66-3.54 (m, 2H), 2.48-2.42 (m, 2H), 2.33-2.14 (m, 2H), 1.93-1.72 (m, 2H), 1.67-1.45 (m, 6H), 0.92 (t, J=7.9 Hz, 3H), 0.60 (q, J=7.9 Hz, 2H), 0.08 (s, 6H).


Example 5
(S)-3-[2-(Ethyldimethylsilyl)-2-methylpropanamido]-N-(2-hydroxy-1-phenylethyl)-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound No. II-116)



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To a solution of 2.44 g (6.41 mmol) of ethyl 3-[2-(ethyldimethylsilyl)-2-methylpropanamido]-6,6-dimethyl-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-carboxylate synthesized in the similar manner as in Reference Example 16 in 30 ml of dehydrated dichloromethane, 5.6 ml (32 mmol) of DIPEA and a solution of 1.33 g (4.48 mmol) of bis(trichloromethyl)carbonate in 10 ml of dehydrated dichloromethane were added in this order at −78° C. in a nitrogen atmosphere and stirred at the same temperature as above for 1 hour.


After the completion of the reaction, a saturated aqueous solution of sodium bicarbonate was added to the reaction solution, and the temperature was raised to room temperature for a while with stirring. After separation into an aqueous layer and an organic layer, the aqueous layer was subjected to extraction with dichloromethane. All of the obtained organic layers were dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=95:5 to 70:30 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 2.51 g of a concentration residue.


To a solution of 474 mg of the obtained concentration residue in ml of dehydrated THF, 700 mg (5.10 mmol) of (S)-2-amino-2-phenylethanol and 0.35 ml (2.0 mmol) of DIPEA were added at room temperature in an argon atmosphere, then applied to a microwave reaction apparatus, and reacted at 100° C. for 2 hours. After standing to cool, 6 ml of methanol and 2 ml of triethylamine were added, applied to a microwave reaction apparatus, and reacted at 80° C. for 3 hours.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure, a saturated aqueous solution of sodium bicarbonate was added to the obtained concentration residue, and the mixed solution was subjected to extraction with dichloromethane three times. All of the obtained organic layers were dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: 1,2-dichloroethane:methanol=100:0 to 98:2 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. For the concentration residue, crystallization was performed with dichloromethane/diisopropyl ether, and the deposited solid was collected by filtration and subsequently dried under reduced pressure to obtain 321 mg of the title compound (yield: 56% [2 steps]) as a white solid.


Mass spectrum (DUIS, m/z): 472 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.26 & 11.67 (br s, total 1H), 9.42-9.16 (m, 1H), 7.38-7.25 (m, 4H), 7.25-7.14 (m, 1H), 6.20-6.04 (m, 1H), 4.88 (t, J=5.8 Hz, 1H), 4.82-4.72 (m, 1H), 4.55-4.42 (m, 2H), 3.66-3.55 (m, 2H), 1.64-1.48 (m, 6H), 1.26 (s, 6H), 0.90 (t, J=7.9 Hz, 3H), 0.56 (q, J=7.9 Hz, 2H), 0.02 (s, 6H).


Example 6
(S)—N-(2-Hydroxy-1-phenylethyl)-N,6,6-trimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound No. IV-119)



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To a solution of 210 mg (1.39 mmol) of (S)-2-(methylamino)-2-phenylethanol [synthesized according to the method described in J. Org. Chem., 1992, 57, 5383-5394] in 3 ml of dehydrated 1,4-dioxane, 0.24 ml (1.37 mmol) of DIPEA and 200 mg (0.454 mmol) of ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 3 were added in an argon atmosphere and stirred at 100° C. for 3 hours. Subsequently, 1 ml of triethylamine and 1 ml of methanol were added to the reaction solution and stirred at room temperature for 16 hours.


After the completion of the reaction, water was added to the reaction solution, followed by extraction from the mixed solution with ethyl acetate. The obtained organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel chromatography (elution solvent: n-hexane:ethyl acetate=90:10 to 0:100 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was subjected again to silica gel chromatography (elution solvent: n-hexane:ethyl acetate=50:50 to 0:100 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was repulp-washed in hexane, and the solid was collected by filtration and then dried under reduced pressure to obtain 105 mg of the title compound (yield: 48%) as a white solid.


Mass spectrum (CI, m/z): 484 [M+1]+



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.21 & 11.84 (br s, total 1H), 9.75-9.42 (m, 1H), 7.41-7.21 (m, 5H), 4.85 (t, J=5.2 Hz, 1H), 4.82-4.76 (m, 1H), 4.58-4.35 (m, 2H), 3.96-3.78 (m, 2H), 2.52 (s, 3H), 2.47-2.38 (m, 2H), 2.23-2.11 (m, 2H), 1.87-1.72 (m, 2H), 1.71-1.52 (m, 6H), 0.05 (s, 9H).


Example 7
(S)-2-[(2-Methoxypropan-2-yl)oxy]-1-phenylethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate (Compound No. VI-360)



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To 205 mg of crude ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-carboxylate [containing impurities] obtained through the same reaction as in Reference Example 5 from 225 mg (0.470 mmol) of 5-tert-butyl 1-ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]pyrrolo[3,4-c]pyrazole-1,5(4H,6H)-dicarboxylate synthesized in the similar manner as in Reference Example 4, a solution of 187 mg (0.533 mmol) of (S)-2,5-dioxopyrrolidin-1-yl {2-[(2-methoxypropan-2-yl)oxy]-1-phenylethyl}carbonate synthesized in the similar manner as in Reference Example 18 in 3 ml of THF and 0.28 ml (1.6 mmol) of DIPEA were added at room temperature in a nitrogen atmosphere and stirred at the same temperature as above for 15 hours. Subsequently, 1.0 ml (7.2 mmol) of triethylamine and 0.70 ml (17 mmol) of methanol were added to the reaction solution and stirred at room temperature 4.5 hours and for 2 hours while heated to reflux, and then, 247 mg (1.80 mmol) of (S)-2-amino-2-phenylethanol was added to the reaction solution and stirred for 4.5 hours while heated to reflux.


After the completion of the reaction, water was added to the reaction solution, followed by extraction with dichloromethane three times. All of the obtained organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=80:20 to 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. For the obtained concentration residue, crystallization was performed with ethyl acetate/n-hexane, and the deposited solid was collected by filtration, washed by sousing with n-hexane, and then dried under reduced pressure to obtain 22.7 mg of the title compound (yield: 9% [2 steps]) as a white solid. The filtrate was further concentrated under reduced pressure and dried under reduced pressure to obtain 178 mg of the title compound (yield: 70% [2 steps]) as a white foam.


Mass spectrum (ESI, m/z): 565 [M+23(Na)]+, 541 [M−1]−.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.35-12.19 & 11.96-11.80 (m, total 1H), 9.85-9.44 (m, 1H), 7.45-7.26 (m, 5H), 5.81-5.68 (m, 1H), 4.63-4.18 (m, 2H), 3.72-3.50 (m, 2H), 3.08-2.94 (m, 3H), 2.56-2.38 (m, 2H), 2.30-2.10 (m, 2H), 1.94-1.75 (m, 2H), 1.73-1.45 (m, 6H), 1.32-1.18 (m, 6H), 0.13-0.02 (m, 9H).


Example 8
(S)-2-Hydroxy-1-phenylethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate (Compound No. IV-2)



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To a solution of 175 mg (0.322 mmol) of (S)-2-[(2-methoxypropan-2-yl)oxy]-1-phenylethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate synthesized in the similar manner as in Example 7 in 2.5 ml of methanol, 9.6 mg (0.038 mmol) of pyridinium p-toluenesulfonate was added at 0° C. in a nitrogen atmosphere and stirred at the same temperature as above for 70 minutes.


After the completion of the reaction, 0.1 ml of triethylamine was added to the reaction solution and then concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=65:35 to 25:75 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. For the obtained concentration residue, crystallization was performed with ethyl acetate/n-hexane, and the deposited solid was collected by filtration, washed by sousing with n-hexane, and then dried under reduced pressure to obtain 124 mg of the title compound (yield: 82%) as a white solid.


Mass spectrum (CI, m/z): 471 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.35-12.11 & 11.97-11.79 (m, total 1H), 9.84-9.46 (m, 1H), 7.46-7.20 (m, 5H), 5.71-5.58 (m, 1H), 5.12-4.95 (m, 1H), 4.72-4.18 (m, 2H), 3.80-3.54 (m, 2H), 2.60-2.38 (m, 2H), 2.30-2.10 (m, 2H), 1.93-1.74 (m, 2H), 1.74-1.43 (m, 6H), 0.16-0.02 (m, 9H).


Example 9
2-Methoxy-1-phenylethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate (Compound No. III-5)



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To a solution of 2.15 g (5.36 mmol) of ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate hydrochloride synthesized in the similar manner as in Reference Example 7 in 72 ml of dehydrated dichloromethane, 3.6 ml (21 mmol) of DIPEA was added at room temperature and subsequently cooled in a dry ice/acetone coolant, and then, a solution of 1.17 g (3.94 mmol) of bis(trichloromethyl)carbonate in 12 ml of dehydrated dichloromethane was added dropwise over 30 minutes and stirred at the same temperature as above for 6 hours. During this reaction, 3.6 ml (21 mmol) of DIPEA 4 times and DIPEA (1.0 ml, 5.7 mmol) once were added in this order.


After the completion of the reaction, 46 ml of a saturated aqueous solution of sodium bicarbonate was added at −78° C., and then, the temperature was raised to room temperature for a while. The reaction solution was separated into an aqueous layer and an organic layer, then the aqueous layer was subjected to extraction with 50 ml of dichloromethane twice, all of the obtained organic layers were dried over anhydrous magnesium sulfate and filtered, and then, the filtrate was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=78:22 to 57:43 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. 20 ml of n-hexane was added to the concentration residue and cooled in ice, and then, the deposited solid was collected by filtration and dried under reduced pressure to obtain 1.96 g of white solid.


To 40.4 mg (0.0946 mmol) of the obtained white solid, 224 mg (1.48 mmol) of 2-methoxy-1-phenylethanol [synthesized according to the method described in WO 2012/138648], 26.0 mg (0.188 mmol) of potassium carbonate, 0.8 ml of 1,2-dimethoxyethane, and 80 mg of molecular sieve 4A (powder) were added at room temperature and then stirred at 80° C. for 26 hours.


After the completion of the reaction, insoluble matter was filtered, and 10 ml of ethyl acetate, 5 ml of water, and 5 ml of a saturated aqueous solution of sodium chloride were added to the filtrate and then the aqueous layer and the organic layer were separated. The obtained organic layer was dried over anhydrous magnesium sulfate and filtered, and then, the filtrate was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography four times (silica gel (1st run), elution solvent: 1,2-dichloroethane:methanol=100:0 to 93:7 (V/V); silica gel (2nd run), elution solvent: ethyl acetate:methanol=98:2 to 95:5 (V/V); silica gel (3rd run), elution solvent: 1,2-dichloroethane:methanol=98:2 to 95:5 (V/V); and DNH silica gel, elution solvent: 1,2-dichloroethane:methanol=98:2 to 95:5 (V/V)) and preparative HPLC (column: X-Bridge (trade name) ODS, elution solvent: 0.1% aqueous formic acid solution: 0.1% formic acid:acetonitrile=50:50 to 5:95 (V/V))), and a fraction containing the compound of interest was neutralized with dilute aqueous ammonia solution and then concentrated under reduced pressure. The obtained concentration residue was dissolved by adding acetonitrile and water and then freeze-dried to obtain 4.1 mg of the title compound (yield: 8% [2 steps]) as a white foam.


Mass spectrum (DUIS, m/z): 471 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.40-11.86 (m, 1H), 10.11-9.61 (m, 1H), 7.49-7.22 (m, 5H), 5.90-5.71 (m, 1H), 4.63-4.14 (m, 2H), 3.77-3.51 (m, 2H), 3.30-3.29 (m, 3H), 1.78-1.40 (m, 6H), 1.11-0.92 (m, 2H), 0.81-0.59 (m, 2H), 0.11-0.04 (m, 9H).


Example 10
N-[5-(4-Hydroxy-3-phenylbutanoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide (Compound No. IV-558)



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To a solution of 160 mg (0.536 mmol) of ethyl 4-(benzyloxy)-3-phenylbutanoate synthesized in the similar manner as in Reference Example 19 in a mixture of 3 ml of THF/1.5 ml of water, 48 mg (1.1 mmol) of lithium hydroxide monohydrate was added at room temperature in an argon atmosphere, stirred at the same temperature as above for 2 hours, and then stirred at 60° C. for 3 hours. The reaction solution was concentrated under reduced pressure, and 3 ml of ethanol and 1.0 ml (2.0 mmol) of a 2 N aqueous sodium hydroxide solution were added to the obtained concentration residue at room temperature and heated and stirred at 60° C. for 1 hour.


After the completion of the reaction, 1 N hydrochloric acid was added to the reaction solution, followed by extraction from the mixed solution with ethyl acetate. The obtained organic layer was washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel chromatography (elution solvent: n-hexane:ethyl acetate=90:10 to 50:50 (V/V)), and a fraction containing 4-(benzyloxy)-3-phenylbutanoic acid was concentrated under reduced pressure and dried under reduced pressure to obtain a concentration residue.


To a solution of 137 mg of the obtained concentration residue, 165 mg (0.436 mmol) of ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-carboxylate synthesized in the similar manner as in Reference Example 5, and 201 mg (0.529 mmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate in 3 ml of dehydrated dichloromethane, 0.185 ml (1.06 mmol) of DIPEA was added at room temperature in an argon atmosphere and stirred at room temperature for 16 hours.


After the completion of the reaction, water was added to the reaction solution, followed by extraction from the mixed solution with ethyl acetate. The obtained organic layer was washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography (elution solvent: n-hexane:ethyl acetate=70:30 to 0:100 (V/V)), and a fraction containing ethyl 5-[4-(benzyloxy)-3-phenylbutanoyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-carboxylate was concentrated under reduced pressure and dried under reduced pressure to obtain a concentration residue.


To a solution of 256 mg of the obtained concentration residue in a mixture of 2 ml of THF/2 ml of methanol, 2 ml of triethylamine was added at room temperature in an argon atmosphere and stirred at the same temperature as above for 16 hours. Subsequently, 0.20 ml (3.3 mmol) of 2-aminoethanol was added at room temperature and stirred at the same temperature as above for 30 minutes.


After the completion of the reaction, water was added to the reaction solution, followed by extraction from the mixed solution with ethyl acetate. The obtained organic layer was washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a concentration residue.


To a solution of 250 mg of the obtained concentration residue in 3 ml of ethanol, 25 mg of 20% palladium hydroxide/carbon (containing 50% water) was added in an argon atmosphere and after replacement with a hydrogen atmosphere under reduced pressure, stirred at room temperature for 2 hours.


After the completion of the reaction, replacement with an argon atmosphere was performed, and the reaction solution was filtered through celite. The solid on the celite was washed with ethanol, and all of the filtrates were concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=50:50 to 0:100 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 93 mg of the title compound (yield: 45% [3 steps]) as a white solid.


Mass spectrum (CI, m/z): 469 [M+1]+



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.19 & 11.83 (br s, total 1H), 9.84-9.47 (m, 1H), 7.27-7.21 (m, 4H), 7.18-7.12 (m, 1H), 4.72 (t, J=5.3 Hz, 1H), 4.57 (d, J=12.4 Hz, 1H), 4.44 (d, J=12.4 Hz, 1H), 3.60-3.52 (m, 2H), 3.27-3.19 (m, 1H), 2.75 (dd, J=6.0, 15.9 Hz, 1H), 2.58-2.52 (m, 1H), 2.48-2.40 (m, 2H), 2.25-2.12 (m, 2H), 1.89-1.72 (m, 2H), 1.61 (s, 3H), 1.49 (s, 3H), 0.08 (s, 9H).


Example 11
N-[5-(3-Hydroxy-3-phenylpropanoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide (Compound No. IV-562)



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To a solution of 285 mg (0.543 mmol) of a mixture of ethyl 6,6-dimethyl-5-(3-oxo-3-phenylpropanoyl)-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 20 and (Z)-ethyl 5-(3-hydroxy-3-phenylacryloyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate as a tautomer in 5 ml of methanol, 9.2 mg (0.24 mmol) of sodium borohydride was added at 0° C. in a nitrogen atmosphere and stirred for 1.5 hours after the temperature was raised to room temperature.


After the completion of the reaction, 10 ml of a saturated aqueous solution of ammonium chloride and dichloromethane were added to the reaction solution and then the aqueous layer and the organic layer were separated. The aqueous layer was subjected to extraction with dichloromethane, all of the obtained organic layers were dried over anhydrous magnesium sulfate and filtered, and then, the filtrate was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: 1,2-dichloroethane:methanol=100:0 to 98:2 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. For the obtained concentration residue, crystallization was performed with dichloromethane/n-hexane, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 88 mg of the title compound (yield: 35%) as a white solid.


Mass spectrum (DUIS, m/z): 455 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.23 & 11.85 (br s, total 1H), 9.75-9.43 (m, 1H), 7.44-7.13 (m, 5H), 5.35 (d, J=4.1 Hz, 1H), 5.05-4.98 (m, 1H), 4.57 (d, J=11.7 Hz, 1H), 4.35 (d, J=11.7 Hz, 1H), 2.65 (dd, J=8.9, 15.1 Hz, 1H), 2.57-2.35 (m, 3H), 2.25-2.09 (m, 2H), 1.89-1.72 (m, 2H), 1.65 (s, 3H), 1.61 (s, 3H), 0.06 (s, 9H).


Example 12
(R)—N-(3-Hydroxy-1-phenylpropyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound No. IV-227)



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To a solution of 216 mg (0.489 mmol) of ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2 (4H)-carboxylate synthesized in the similar manner as in Reference Example 3 in 4.5 ml of 1,4-dioxane, 379 mg (2.51 mmol) of (R)-3-amino-3-phenylpropan-1-ol [purchased from Ark Pharm, Inc.] and 0.17 ml (0.99 mmol) of DIPEA were added at room temperature in an argon atmosphere, then applied to a microwave reaction apparatus, and reacted at 100° C. for 1 hour. After standing to cool, 1.0 ml of methanol and 0.5 ml of triethylamine were added, applied to a microwave reaction apparatus, and reacted at 80° C. for 1 hour.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure, and ethyl acetate, water, and a saturated aqueous solution of sodium chloride were added thereto and then the aqueous layer and the organic layer were separated. The organic layer was dried over anhydrous magnesium sulfate and filtered, and then, the filtrate was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: 1,2-dichloroethane:methanol=99:1 to 96:4 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. For the obtained concentration residue, crystallization was performed with ethyl acetate/diisopropyl ether, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 173 mg of the title compound (yield: 73%) as a white solid.


Mass spectrum (CI, m/z): 484 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.19 & 11.66 (s, total 1H), 9.61-9.47 (m, 1H), 7.39-7.13 (m, 5H), 6.46 & 6.38 (d, J=8.0 Hz, total 1H), 4.92-4.83 (m, 1H), 4.66-4.33 (m, 3H), 3.46-3.34 (m, 2H), 2.50-2.41 (m, 2H), 2.26-2.13 (m, 2H), 2.01-1.72 (m, 4H), 1.65-1.47 (m, 6H), 0.12-0.06 (m, 9H).


Example 13
(R)—N-(3-Hydroxy-1-phenylpropyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound No. III-226)



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To a solution of 468 mg (1.17 mmol) of ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate hydrochloride synthesized in the similar manner as in Reference Example 7 in 10 ml of dehydrated dichloromethane, 0.72 ml (4.1 mmol) of DIPEA was added at room temperature in a nitrogen atmosphere, and then, 235 mg (0.791 mmol) of bis(trichloromethyl)carbonate was added at −78° C. and stirred at the same temperature as above for 3 hours.


After the completion of the reaction, 20 ml of a saturated aqueous solution of sodium bicarbonate was added to the reaction solution and stirred while the temperature was raised to room temperature for a while. The organic layer and the aqueous layer were separated, and then, the aqueous layer was subjected to extraction with dichloromethane twice. All of the obtained organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=90:10 to 75:25 (V/V)), and a fraction containing ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2 (4H)-carboxylate was concentrated under reduced pressure and dried under reduced pressure to obtain 490 mg of a concentration residue.


To a solution of 113 mg of the obtained concentration residue in 2 ml of dehydrated THF, 0.14 ml (0.80 mmol) of DIPEA and 105 mg (0.692 mmol) of (R)-3-amino-3-phenylpropan-1-ol [purchased from Ark Pharm, Inc.] were added at room temperature in a nitrogen atmosphere and then stirred for 2.5 hours while heated to reflux. Subsequently, 0.10 ml (1.7 mmol) of 2-aminoethanol was added and then stirred for 2 hours while heated to reflux.


After the completion of the reaction, a saturated aqueous solution of sodium bicarbonate was added to the reaction solution, followed by extraction with dichloromethane three times. All of the obtained organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. 0.1 ml of acetic acid was added to the obtained concentration residue and then subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=50:50 to 15:85 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was subjected again to silica gel column chromatography (elution solvent: dichloromethane:methanol=99:1 to 95:5 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. For the obtained concentration residue, crystallization was performed with ethyl acetate/n-hexane, and the deposited solid was collected by filtration, washed by sousing with n-hexane, and then dried under reduced pressure to obtain 49 mg of the title compound (yield: 39% [2 steps]) as a white solid.


Mass spectrum (CI, m/z): 470 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.22 & 11.84 (br s, total 1H), 9.91-9.66 (m, 1H), 7.37-7.26 (m, 4H), 7.21-7.14 (m, 1H), 6.50-6.28 (m, 1H), 4.92-4.80 (m, 1H), 4.65-4.52 (m, 1H), 4.49-4.31 (m, 2H), 3.44-3.36 (m, 2H), 2.00-1.77 (m, 2H), 1.59 (br s, 3H), 1.51 (br s, 3H), 1.06-0.93 (m, 2H), 0.81-0.61 (m, 2H), 0.03 (s, 9H).


Example 14
(R)—N-(4-Hydroxy-1-phenylbutyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound No. IV-283)



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To a solution of 100 mg (0.227 mmol) of ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2 (4H)-carboxylate synthesized in the similar manner as in Reference Example 3 and 138 mg (0.684 mmol) of (R)-4-amino-4-phenylbutan-1-ol hydrochloride [purchased from NetChem, Inc.] in 2 ml of dehydrated 1,4-dioxane, 0.24 ml (1.4 mmol) of DIPEA was added at room temperature in an argon atmosphere and stirred at 100° C. for 3 hours. Subsequently, 1 ml of triethylamine and 1 ml of ethanol were added to the reaction solution and heated and stirred at 80° C. for 5 hours.


After the completion of the reaction, water was added to the reaction solution, followed by extraction from the mixed solution with ethyl acetate. The obtained organic layer was washed with a saturated aqueous solution of sodium chloride, dried by adding anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=50:50 to 0:100 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 91.3 mg of the title compound (yield: 81%) as a white solid.


Mass spectrum (CI, m/z): 498 [M+1]+



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.18 & 11.73 (s, total 1H), 9.66-9.40 (m, 1H), 7.38-7.33 (m, 2H), 7.33-7.26 (m, 2H), 7.21-7.13 (m, 1H), 6.43-6.16 (m, 1H), 4.75-4.66 (m, 1H), 4.47 (br s, 2H), 4.38 (t, J=5.2 Hz, 1H), 3.45-3.35 (m, 2H), 2.49-2.42 (m, 2H), 2.25-2.14 (m, 2H), 1.88-1.64 (m, 4H), 1.60 (br s, 3H), 1.55-1.28 (m, 5H), 0.09 (s, 9H).


Example 15
(R)—N-(5-Hydroxy-1-phenylpentyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound No. IV-291)



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To a solution of 9.50 ml (9.50 mmol) of 1 M lithium aluminum hydride/THF solution in 40 ml of dehydrated THF, a solution of 2.02 g (6.28 mmol) of (R)-ethyl 5-[(tert-butoxycarbonyl)amino]-5-phenylpentanoate [synthesized according to the method described in Tetrahedron Lett., 1998, 39, 5951-5954] in 20 ml of dehydrated THF was added dropwise with stirring at 0° C. in an argon atmosphere and stirred at the same temperature as above for 2 hours.


After the completion of the reaction, 50 ml of THF was added, and then, 0.4 ml of water and 1.6 ml (1.6 mmol) of a 1 N aqueous sodium hydroxide solution were added and stirred at the same temperature as above for 30 minutes. The deposited solid was filtered using a celite filter, and the solid was washed with ethyl acetate. The obtained filtrate was concentrated under reduced pressure and dried under reduced pressure to obtain a concentration residue.


To a solution of 1.68 g of the obtained concentration residue in 20 ml of dichloromethane, 2 ml of trifluoroacetic acid was added at room temperature in an argon atmosphere and stirred at the same temperature as above for 2 hours.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure and dried under reduced pressure to obtain 1.35 g of a concentration residue.


To a solution of 905 mg of the obtained concentration residue in 3 ml of dehydrated THF, 0.60 ml (3.4 mmol) of DIPEA was added with stirring in an argon atmosphere, and then, 205 mg (0.465 mmol) of ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarbox amido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 3 was added at room temperature and stirred at 60° C. for 4 hours. Subsequently, 0.5 ml of triethylamine and 1 ml of methanol were added to the reaction solution, heated and stirred at 60° C. for 3 hours, and subsequently stirred at room temperature for 15 hours.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel chromatography (DIOL silica gel, elution solvent: dichloromethane:methanol=100:0 to 90:10 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure. The obtained concentration residue was further subjected to silica gel chromatography (DNH silica gel, elution solvent: dichloromethane:methanol=100:0 to 93:7 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure. The obtained concentration residue was subjected to silica gel chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=70:30 to 0:100 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 131 mg of the title compound (yield: 55%) as a white solid.


Mass spectrum (CI, m/z): 512 [M+1]+



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.18 & 11.64 (br s, total 1H), 9.58-9.47 (m, 1H), 7.38-7.33 (m, 2H), 7.32-7.25 (m, 2H), 7.21-7.14 (m, 1H), 6.38-6.15 (m, 1H), 4.75-4.65 (m, 1H), 4.52-4.38 (m, 2H), 4.33 (t, J=5.2 Hz, 1H), 3.39-3.33 (m, 2H), 2.49-2.42 (m, 2H), 2.26-2.14 (m, 2H), 1.88-1.72 (m, 3H), 1.72-1.30 (m, 10H), 1.27-1.14 (m, 1H), 0.13-0.06 (m, 9H).


Example 16
(S)—N-(2-Hydroxy-2-methyl-1-phenylpropyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound No. IV-171)



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To a solution of 200 mg (0.454 mmol) of ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 3 in 3 ml of dehydrated THF, 0.16 ml (0.92 mmol) of DIPEA and 385 mg (2.33 mmol) of (S)-1-amino-2-methyl-1-phenylpropan-2-ol [purchased from IS Chemical Technology Ltd.] were added at room temperature in an argon atmosphere and stirred at 60° C. for 4 hours. Subsequently, 1 ml of methanol and 1 ml of triethylamine were added at room temperature and stirred at the same temperature as above for 15 hours.


After the completion of the reaction, water was added to the reaction solution, followed by extraction from the mixed solution with ethyl acetate. The obtained organic layer was washed with a saturated aqueous solution of sodium chloride, dried by adding anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel chromatography (DIOL silica gel, elution solvent: dichloromethane:methanol=100:0 to 90:10 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure. The obtained concentration residue was subjected again to silica gel chromatography (DIOL silica gel, elution solvent: dichloromethane:methanol=100:0 to 90:10 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 182 mg of the title compound (yield: 81%) as a white solid.


Mass spectrum (DUIS, m/z): 498 [M+1]+



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.22 & 11.78 (br s, total 1H), 9.74-9.49 (m, 1H), 7.38-7.16 (m, 5H), 5.90-5.74 (m, 1H), 4.85 (s, 1H), 4.65-4.35 (m, 3H), 2.49-2.41 (m, 2H), 2.28-2.15 (m, 2H), 1.91-1.73 (m, 2H), 1.67-1.44 (m, 6H), 1.22 (s, 3H), 0.91 (s, 3H), 0.09 s, 9H).


Example 17
(S)—N-(2-Hydroxy-2-methyl-1-phenylpropyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound No. III-170)



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To a solution of 468 mg (1.17 mmol) of ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate hydrochloride synthesized in the similar manner as in Reference Example 7 in 10 ml of dehydrated dichloromethane, 0.72 ml (4.1 mmol) of DIPEA was added at room temperature in a nitrogen atmosphere, and then, 235 mg (0.791 mmol) of bis(trichloromethyl)carbonate was added at −78° C. and stirred at the same temperature as above for 3 hours.


After the completion of the reaction, 20 ml of a saturated aqueous solution of sodium bicarbonate was added to the reaction solution and stirred while the temperature was raised to room temperature for a while. The organic layer and the aqueous layer were separated, and then, the aqueous layer was subjected to extraction with dichloromethane twice. All of the obtained organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=90:10 to 75:25 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 490 mg of a concentration residue.


To a solution of 112 mg of the obtained concentration residue in 2 ml of dehydrated THF, 0.14 ml (0.80 mmol) of DIPEA and 109 mg (0.660 mmol) of (S)-1-amino-2-methyl-1-phenylpropan-2-ol [purchased from IS Chemical Technology Ltd.] were added in this order at room temperature in a nitrogen atmosphere and then stirred for 3 hours while heated to reflux. Subsequently, 0.10 ml (1.7 mmol) of 2-aminoethanol was added and then stirred for 2.5 hours while heated to reflux.


After the completion of the reaction, a saturated aqueous solution of sodium bicarbonate was added to the reaction solution, followed by extraction with dichloromethane three times. All of the obtained organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. 0.1 ml of acetic acid was added to the obtained concentration residue and then subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=50:50 to 20:80 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. For the obtained concentration residue, crystallization was performed with ethyl acetate/n-hexane, and the deposited solid was collected by filtration, washed by sousing with n-hexane, and then dried under reduced pressure to obtain 100 mg of the title compound (yield: 77% [2 steps]) as a white solid.


Mass spectrum (CI, m/z): 484 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.24 & 11.90 (br s, total 1H), 10.02-9.68 (m, 1H), 7.38-7.16 (m, 5H), 5.89-5.71 (m, 1H), 4.82 (s, 1H), 4.59 (d, J=8.4 Hz, 1H), 4.56-4.31 (m, 2H), 1.66-1.43 (m, 6H), 1.21 (s, 3H), 1.06-0.97 (m, 2H), 0.91 (s, 3H), 0.81-0.61 (m, 2H), 0.04 (s, 9H).


Example 18
N-(3-Hydroxy-2,2-dimethyl-1-phenylpropyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound No. IV-354)



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To a solution of 152 mg (0.346 mmol) of ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 3 and 201 mg (1.12 mmol) of 3-amino-2,2-dimethyl-3-phenylpropan-1-ol [synthesized according to the method described in Synthetic Communications 1994, 24 (7), 899-906] in 4 ml of 1,4-dioxane, 0.18 ml (1.0 mmol) of DIPEA was added at room temperature in an argon atmosphere, then applied to a microwave reaction apparatus, and reacted at 100° C. for 1 hour. After standing to cool, the reaction solution was concentrated under reduced pressure, and 4 ml of methanol and 1 ml of triethylamine were added to the obtained concentration residue and stirred at room temperature for 15 hours.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure, the obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: ethyl acetate:methanol=99:1 to 97:3 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was subjected again to silica gel column chromatography (DIOL silica gel, elution solvent: 1,2-dichloroethane:methanol=99:1 to 92:8 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. For the obtained concentration residue, crystallization was performed with dichloromethane/n-hexane, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 55 mg of the title compound (yield: 31%) as a white solid.


Mass spectrum (DUIS, m/z): 512 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.21 & 11.95 (br s, total 1H), 9.89-9.36 (m, 1H), 7.36-7.17 (m, 5H), 6.85 (d, J=8.1 Hz, 1H), 5.50-5.39 (m, 1H), 4.64 (d, J=8.1 Hz, 1H), 4.47-4.28 (m, 2H), 3.30-3.22 (m, 1H), 3.03 (dd, J=4.1, 10.4 Hz, 1H), 2.49-2.40 (m, 2H), 2.28-2.13 (m, 2H), 1.92-1.71 (m, 2H), 1.60 (br s, 3H), 1.53 (s, 3H), 1.06 (s, 3H), 0.64 (s, 3H), 0.09 (s, 9H).


Example 19
(R)—N-(3-Hydroxy-3-methyl-1-phenylbutyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound No. IV-299)



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To a solution of 132 mg (0.300 mmol) of ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 3 and 155 mg (0.865 mmol) of (R)-4-amino-2-methyl-4-phenylbutan-2-ol synthesized in the similar manner as in Reference Example 23 in 4 ml of 1,4-dioxane, 0.15 ml (0.86 mmol) of DIPEA was added at room temperature in an argon atmosphere and then stirred at 100° C. for 2 hours. After standing to cool, the reaction solution was concentrated under reduced pressure, and 4 ml of methanol and 1 ml of triethylamine were added to the obtained concentration residue and stirred at room temperature for 18 hours.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure, and ethyl acetate, water, and a saturated aqueous solution of sodium chloride were added to the obtained concentration residue and then the aqueous layer and the organic layer were separated. The obtained organic layer was dried over anhydrous magnesium sulfate and filtered, and then, the filtrate was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: 1,2-dichloroethane:methanol=98:2 to 91:9 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. For the obtained concentration residue, crystallization was performed with dichloromethane/diethyl ether/n-hexane, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 104 mg of the title compound (yield: 68%) as a white solid.


Mass spectrum (DUIS, m/z): 512 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.20 & 11.73 (br s, 1H), 9.66-9.40 (m, 1H), 7.37-7.25 (m, 4H), 7.19-7.13 (m, 1H), 6.54 (d, J=5.3 Hz, 1H), 4.95-4.84 (m, 1H), 4.75-4.57 (m, 1H), 4.45 (br s, 2H), 2.47-2.42 (m, 2H), 2.25-2.14 (m, 2H), 2.02-1.74 (m, 3H), 1.65 (dd, J=3.3, 14.3 Hz, 1H), 1.58 (s, 3H), 1.53 (s, 3H), 1.16 (s, 3H), 1.13 (s, 3H), 0.09 (s, 9H).


Example 20
(S)—N-(2-Methoxy-1-phenylethyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound No. IV-123)



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To a solution of 201 mg (0.456 mmol) of ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2 (4H)-carboxylate synthesized in the similar manner as in Reference Example 3 in 4.5 ml of 1,4-dioxane, 0.16 ml (0.91 mmol) of DIPEA and 213 mg (1.41 mmol) of (S)-2-methoxy-1-phenylamine [synthesized according to the method described in J. Chem. Soc., Perkin Transactions 1, 2002, 20, 2237-2242] were added at room temperature, then applied to a microwave reaction apparatus, and reacted at 100° C. for 1 hour. Subsequently, 1 ml of methanol and 0.5 ml of triethylamine were added and then reacted at 80° C. for 1 hour in a microwave reaction apparatus again.


After the completion of the reaction, 8 ml of ethyl acetate, 0.4 ml of water, and 8 ml of a saturated aqueous solution of sodium chloride were added to the reaction solution and then the aqueous layer and the organic layer were separated. The aqueous layer was subjected to extraction with 10 ml of dichloromethane. All of the obtained organic layers were dried over anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: 1,2-dichloroethane:methanol=100:0 to 95:5 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. Diethyl ether was added to the obtained concentration residue and ultrasonicated, and then, the deposited insoluble matter was collected by filtration and dried under reduced pressure to obtain 180 mg of the title compound (yield: 82%) as a white solid.


Mass spectrum (CI, m/z): 484 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.20 & 11.67 (br s, total 1H), 9.68-9.41 (m, 1H), 7.41-7.35 (m, 2H), 7.34-7.27 (m, 2H), 7.25-7.17 (m, 1H), 6.44-6.13 (m, 1H), 5.02-4.92 (m, 1H), 4.57-4.39 (m, 2H), 3.63 (dd, J=7.9, 9.9 Hz, 1H), 3.50 (dd, J=6.0, 9.9 Hz, 1H), 3.26 (s, 3H), 2.49-2.42 (m, 2H), 2.26-2.15 (m, 2H), 1.92-1.73 (m, 2H), 1.60 (br s, 3H), 1.53 (br s, 3H), 0.09 (s, 9H).


Example 21
(S)—N-[2-(Difluoromethoxy)-1-phenylethyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound No. IV-131)



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To a solution of 210 mg (0.697 mmol) of (S)-2-(difluoromethoxy)-1-phenylethanamine trifluoroacetate synthesized in the similar manner as in Reference Example 25 and 0.425 ml (2.43 mmol) of DIPEA in 3 ml of dehydrated 1,4-dioxane, 107 mg (0.243 mmol) of ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2 (4H)-carboxylate synthesized in the similar manner as in Reference Example 3 was added at room temperature in an argon atmosphere and heated and stirred at 100° C. for 1 hour. Subsequently, 1 ml of triethylamine and 1 ml of methanol were added to the reaction solution and heated and stirred at 80° C. for 1 hour.


After the completion of the reaction, water was added to the reaction solution, followed by extraction from the mixed solution with ethyl acetate. The obtained organic layer was washed with a saturated aqueous solution of sodium chloride, dried by adding anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=50:50 to 0:100 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 40.5 mg of the title compound (yield: 32%) as a white solid.


Mass spectrum (CI, m/z): 520 [M+1]+



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.20 (br s, 1H), 10.12-9.41 (m, 1H), 7.43-7.38 (m, 2H), 7.38-7.32 (m, 2H), 7.28-7.23 (m, 1H), 6.70 (t, J=76.0 Hz, 1H), 6.59-6.46 (m, 1H), 5.10-5.01 (m, 1H), 4.52-4.43 (m, 2H), 4.13 (dd, J=8.3, 10.4 Hz, 1H), 4.05-3.99 (m, 1H), 2.48-2.42 (m, 2H), 2.24-2.15 (m, 2H), 1.88-1.75 (m, 2H), 1.60 (s, 3H), 1.53 (s, 3H), 0.09 (s, 9H).


Example 22
(S)—N-(2-Ethoxy-1-phenylethyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound No. IV-139)



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To a solution of 136 mg (0.308 mmol) of ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2 (4H)-carboxylate synthesized in the similar manner as in Reference Example 3 and 162 mg (0.979 mmol) of (S)-2-ethoxy-1-phenylethanamine synthesized in the similar manner as in Reference Example 26 in 4 ml of 1,4-dioxane, 0.16 ml (0.92 mmol) of DIPEA was added at room temperature in an argon atmosphere and then stirred at 100° C. for 2 hours. After standing to cool, the reaction solution was concentrated under reduced pressure, and 4 ml of methanol and 1 ml of triethylamine were added to the obtained concentration residue, applied to a microwave reaction apparatus, and reacted at 80° C. for 1 hour.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure, ethyl acetate was added to the obtained concentration residue, then the organic layer obtained by washing with a 10% aqueous potassium dihydrogen phosphate solution, a saturated aqueous solution of sodium bicarbonate, and a saturated aqueous solution of sodium chloride in this order was dried over anhydrous magnesium sulfate and filtered, and then, the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: 1,2-dichloroethane:methanol=98:2 to 91:9 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. For the obtained concentration residue, crystallization was performed with dichloromethane/diethyl ether/n-hexane, and the deposited solid was collected by filtration. The obtained solid was subjected again to silica gel column chromatography (DIOL silica gel, elution solvent: 1,2-dichloroethane:methanol=100:0 to 93:7 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was subjected again to silica gel column chromatography (DIOL silica gel, elution solvent: 1,2-dichloroethane:ethyl acetate=100:0 to 67:33 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. Diethyl ether and n-hexane were added to the obtained concentration residue, and after ultrasonication, the deposited solid was collected by filtration and dried under reduced pressure to obtain 81 mg of the title compound (yield: 53%) as a white solid.


Mass spectrum (DUIS, m/z): 498 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.20 & 11.71 (br s, total 1H), 9.67-9.47 (m, 1H), 7.41-7.34 (m, 2H), 7.34-7.27 (m, 2H), 7.25-7.17 (m, 1H), 6.38-6.11 (m, 1H), 4.99-4.91 (m, 1H), 4.56-4.38 (m, 2H), 3.65 (dd, J=8.0, 9.9 Hz, 1H), 3.54 (dd, J=6.0, 9.9 Hz, 1H), 3.51-3.41 (m, 2H), 2.49-2.41 (m, 2H), 2.28-2.14 (m, 2H), 1.91-1.71 (m, 2H), 1.61 (br s, 3H), 1.54 (br s, 3H), 1.08 (t, J=7.0 Hz, 3H), 0.09 (s, 9H).


Example 23
(R)—N-(3-Methoxy-1-phenylpropyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound No. IV-235)



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To a solution of 138 mg (0.314 mmol) of ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2 (4H)-carboxylate synthesized in the similar manner as in Reference Example 3 and 163 mg (0.987 mmol) of (R)-3-methoxy-1-phenylpropan-1-amine synthesized in the similar manner as in Reference Example 27 in 4 ml of 1,4-dioxane, 0.16 ml (0.92 mmol) of DIPEA was added at room temperature in an argon atmosphere and then stirred at 100° C. for 2 hours. After standing to cool, the reaction solution was concentrated under reduced pressure, and 4 ml of methanol and 1 ml of triethylamine were added to the obtained residue and stirred at room temperature for 18 hours.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure, ethyl acetate was added to the obtained concentration residue, then the organic layer obtained by washing with a 10% aqueous potassium dihydrogen phosphate solution, a saturated aqueous solution of sodium bicarbonate, and a saturated aqueous solution of sodium chloride in this order was dried over anhydrous magnesium sulfate and filtered, and then, the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: 1,2-dichloroethane:methanol=95:5 to 88:12 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. Diethyl ether and n-hexane were added to the obtained concentration residue and ultrasonicated, and then, the deposited solid was collected by filtration and dried under reduced pressure to obtain 88 mg of the title compound (yield: 56%) as a white solid.


Mass spectrum (DUIS, m/z): 498 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.18 & 11.73 (br s, total 1H), 9.54 (br s, 1H), 7.35-7.28 (m, 4H), 7.22-7.16 (m, 1H), 6.41 (br s, 1H), 4.91-4.79 (m, 1H), 4.53-4.40 (m, 2H), 3.32-3.27 (m, 2H), 3.23 (s, 3H), 2.50-2.42 (m, 2H), 2.26-2.15 (m, 2H), 2.08-1.70 (m, 4H), 1.60 (s, 3H), 1.52 (s, 3H), 0.09 (s, 9H).


Example 24
Sodium
(S)-2-{6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylacetate (Sodium Salt of Compound No. IV-403)



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To a solution of 98.0 mg (0.171 mmol) of (S)-benzyl 2-{6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylacetate synthesized in the similar manner as in Example 55 in 15 ml of ethanol, 19.9 mg of palladium/carbon [ASCA2 (trade name), manufactured by N.E. Chemcat Corp., containing 52% water] was added in a nitrogen atmosphere and then, after replacement with a hydrogen atmosphere under reduced pressure, stirred at room temperature for 50 minutes.


After the completion of the reaction, replacement with an argon atmosphere was performed, and the reaction solution was filtered through celite. 14.8 mg (0.176 mmol) of sodium bicarbonate was added to the obtained filtrate and concentrated under reduced pressure. Purified water and diethyl ether were added to the obtained concentration residue and then dried under reduced pressure to obtain 82 mg of the title compound (yield: 95%) as a white solid.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.41 (br s, 1H), 9.95 (br. s, 1H), 7.38-7.30 (m, 2H), 7.24-7.17 (m, 2H), 7.14-7.08 (m, 1H), 6.42 (d, J=4.6 Hz, 1H), 4.68 (d, J=4.6 Hz, 1H), 4.48 (d, J=11.3 Hz, 1H), 4.45 (d, J=11.3 Hz, 1H), 2.51-2.41 (m, 2H), 2.28-2.14 (m, 2H), 1.90-1.74 (m, 2H), 1.59 (s, 3H), 1.55 (s, 3H), 0.08 (s, 9H).


Example 25
(R)—N-(2-Hydroxy-1-phenylethyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound No. IV-115)



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To a solution of 127 mg (0.287 mmol) of ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 3 and 203 mg (1.48 mmol) of (R)-2-amino-2-phenylethanol in 3 ml of THF, 0.15 ml (0.86 mmol) of DIPEA was added at room temperature in an argon atmosphere and then stirred at 60° C. for 3 hours.


After the completion of the reaction, ethyl acetate, water, and a saturated aqueous solution of sodium chloride were added to the reaction solution and then the aqueous layer and the organic layer were separated. The obtained organic layer was dried over anhydrous magnesium sulfate and filtered, and then, the filtrate was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: 1,2-dichloroethane:methanol=100:0 to 98:2 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was subjected again to silica gel column chromatography (elution solvent: ethyl acetate:a mixed solution of 28% aqueous ammonia solution/ethanol [1:5 (V/V)]=98:2 to 95:5 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 82 mg of the title compound (yield: 61%) as a white foam.


Mass spectrum (DUIS, m/z): 470 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.20 & 11.79 (br s, total 1H), 9.73-9.49 (m, 1H), 7.44-7.11 (m, 5H), 6.25-6.00 (m, 1H), 4.95-4.70 (m, 2H), 4.62-4.41 (m, 2H), 3.71-3.52 (m, 2H), 2.48-2.41 (m, 2H), 2.27-2.13 (m, 2H), 1.93-1.73 (m, 2H), 1.71-1.43 (m, 6H), 0.09 (br s, 9H).


Example 26
N-[1-(2-Fluorophenyl)-2-hydroxyethyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound No. IV-510)



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To a solution of 201 mg (0.456 mmol) of ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarbox amido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2 (4H)-carboxylate synthesized in the similar manner as in Reference Example 3 in 5 ml of 1,4-dioxane, 0.23 ml (1.4 mmol) of DIPEA and 212 mg (1.37 mmol) of 2-amino-2-(2-fluorophenyl)ethanol [purchased from Amatek Chemical Co., Ltd.] were added at room temperature in an argon atmosphere and then reacted at 100° C. for 1 hour. The reaction solution was concentrated under reduced pressure, and then, 4 ml of methanol and 1 ml of triethylamine were added to the concentration residue and reacted at 65° C. for 4.5 hours and further at 70° C. for 1.5 hours.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained concentration residue was dissolved in 5 ml of ethyl acetate and washed with 10 ml of a 5% aqueous potassium bisulfate solution twice. All of the obtained organic layers were washed with 10 ml of a saturated aqueous solution of sodium bicarbonate, then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: 1,2-dichloroethane:methanol=100:0 to 98:2 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 131 mg of the title compound (yield: 59%) as a white foam.


Mass spectrum (CI, m/z): 488 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.41-11.66 (m, 1H), 9.94-9.30 (m, 1H), 7.51-7.42 (m, 1H), 7.31-7.06 (m, 3H), 6.19 (br s, 1H), 5.15-5.04 (m, 1H), 4.98 (t, J=6.0 Hz, 1H), 4.54 (br s, 2H), 3.64-3.54 (m, 2H), 2.49-2.42 (m, 2H), 2.26-2.15 (m, 2H), 1.87-1.76 (m, 2H), 1.60 (s, 3H), 1.51 (s, 3H), 0.10 (s, 9H).


Example 27
(S)—N-[1-(3-Fluorophenyl)-2-hydroxyethyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound No. IV-519)



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To a solution of 201 mg (0.456 mmol) of ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 3 in 5.0 ml of 1,4-dioxane, 0.23 ml (1.4 mmol) of DIPEA and 212 mg (1.37 mmol) of (S)-2-amino-2-(3-fluorophenyl)ethanol [purchased from Amatek Chemical Co., Ltd.] were added at room temperature in an argon atmosphere and then reacted at 100° C. for 1 hour. The reaction solution was concentrated under reduced pressure, and then, 4 ml of methanol and 1 ml of triethylamine were added to the concentration residue and reacted at room temperature for 17 hours.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained concentration residue was dissolved in 5 ml of ethyl acetate, washed with 10 ml of a 5% aqueous potassium dihydrogen phosphate solution twice and 10 ml of a saturated aqueous solution of sodium bicarbonate once, then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: 1,2-dichloroethane:methanol=100:0 to 98:2 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 128 mg of the title compound (yield: 58%) as a white foam.


Mass spectrum (CI, m/z): 488 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.35-11.70 (m, 1H), 9.84-9.41 (m, 1H), 7.38-7.29 (m, 1H), 7.21-7.15 (m, 2H), 7.05-6.98 (m, 1H), 6.21 (br s, 1H), 4.92 (t, J=5.8 Hz, 1H), 4.83-4.74 (m, 1H), 4.58-4.45 (m, 2H), 3.67-3.55 (m, 2H), 2.49-2.42 (m, 2H), 2.26-2.15 (m, 2H), 1.89-1.73 (m, 2H), 1.60 (s, 3H), 1.53 (s, 3H), 0.09 (s, 9H).


Example 28
(S)—N-[1-(4-Fluorophenyl)-2-hydroxyethyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound No. IV-527)



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To a solution of 201 mg (0.456 mmol) of ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2 (4H)-carboxylate synthesized in the similar manner as in Reference Example 3 in 5.0 ml of 1,4-dioxane, 0.23 ml (1.4 mmol) of DIPEA and 212 mg (1.37 mmol) of (S)-2-amino-2-(4-fluorophenyl)ethanol [purchased from Amatek Chemical Co., Ltd.] were added at room temperature in an argon atmosphere and then reacted at 100° C. for 1 hour. The reaction solution was concentrated under reduced pressure, and then, 4 ml of methanol and 1 ml of triethylamine were added to the concentration residue and reacted at room temperature for 15 hours.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained concentration residue was dissolved in 5 ml of ethyl acetate, washed with 10 ml of a 5% aqueous potassium dihydrogen phosphate solution twice and 10 ml of a saturated aqueous solution of sodium bicarbonate once, then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: 1,2-dichloroethane:methanol=100:0 to 98:2 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was subjected again to silica gel column chromatography (DIOL silica gel, elution solvent: 1,2-dichloroethane:methanol=100:0 to 98:2 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 139 mg of the title compound (yield: 63%) as a pale yellow foam.


Mass spectrum (CI, m/z): 488 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.20 & 11.71 (br s, total 1H), 9.75-9.43 (m, 1H), 7.42-7.33 (m, 2H), 7.15-7.06 (m, 2H), 6.28-6.02 (m, 1H), 4.89 (t, J=5.8 Hz, 1H), 4.81-4.72 (m, 1H), 4.51 (br s, 2H), 3.66-3.53 (m, 2H), 2.49-2.42 (m, 2H), 2.26-2.15 (m, 2H), 1.90-1.74 (m, 2H), 1.60 (br s, 3H), 1.53 (br s, 3H), 0.09 (s, 9H).


Example 29
N-[2-Hydroxy-1-(pyridin-2-yl)ethyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound No. IV-534)



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To a solution of 152 mg (0.344 mmol) of ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2 (4H)-carboxylate synthesized in the similar manner as in Reference Example 3 and 223 mg (1.06 mmol) of 2-amino-2-(pyridin-2-yl)ethanol dihydrochloride [purchased from J&W PharmLab, LLC] in 4 ml of 1,4-dioxane, 0.60 ml (3.4 mmol) of DIPEA was added at room temperature in an argon atmosphere, then applied to a microwave reaction apparatus, and reacted at 100° C. for 1 hour.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure, and a saturated aqueous solution of sodium bicarbonate was added to the concentration residue, followed by extraction with dichloromethane. The obtained organic layer was dried over anhydrous sodium sulfate and filtered, and then, the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (DNH silica gel, elution solvent: 1,2-dichloroethane:methanol=100:0 to 93:7 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained residue was subjected again to silica gel column chromatography (DIOL silica gel, elution solvent: ethyl acetate:methanol=100:0 to 78:22 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 78 mg of the title compound (yield: 48%) as a white foam.


Mass spectrum (DUIS, m/z): 469 [M−1]−.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.22 & 11.78 (br s, total 1H), 9.79-9.45 (m, 1H), 8.54-8.49 (m, 1H), 7.74 (dt, J=1.7, 7.7 Hz, 1H), 7.42-7.36 (m, 1H), 7.28-7.21 (m, 1H), 6.19-6.00 (m, 1H), 4.92-4.82 (m, 2H), 4.62-4.43 (m, 2H), 3.76-3.65 (m, 2H), 2.49-2.42 (m, 2H), 2.27-2.15 (m, 2H), 1.92-1.72 (m, 2H), 1.68-1.50 (m, 6H), 0.10 (s, 9H).


Example 30
N-[2-Hydroxy-1-(pyridin-3-yl)ethyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound No. IV-542)



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To a solution of 150 mg (0.341 mmol) of ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 3 and 218 mg (1.03 mmol) of 2-amino-2-(pyridin-3-yl)ethanol dihydrochloride [purchased from J&W PharmLab, LLC] in 4 ml of 1,4-dioxane, 0.60 ml (3.4 mmol) of DIPEA was added at room temperature in an argon atmosphere and then stirred at 100° C. for 1 hour.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure, and a saturated aqueous solution of sodium bicarbonate was added to the concentration residue, followed by extraction with dichloromethane. The obtained organic layer was dried over anhydrous magnesium sulfate and filtered, and then, the filtrate was concentrated under reduced pressure. 4 ml of methanol and 1 ml of triethylamine were added to the obtained concentration residue, applied to a microwave reaction apparatus, and reacted at 80° C. for 1 hour.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure, the obtained concentration residue was subjected to silica gel column chromatography (DNH silica gel, elution solvent: 1,2-dichloroethane:methanol=95:5 to 88:12 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained residue was subjected again to silica gel column chromatography (DNH silica gel, elution solvent: ethyl acetate:methanol=96:4 to 70:30 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained residue was subjected again to silica gel column chromatography (DIOL silica gel, elution solvent: ethyl acetate:methanol=99:1 to 73:27 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 27 mg of the title compound (yield: 17%) as a white foam.


Mass spectrum (DUIS, m/z): 471 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.20 & 11.77 (br s, total 1H), 9.75-9.47 (m, 1H), 8.54 (d, J=2.0 Hz, 1H), 8.41 (dd, J=2.0, 4.7 Hz, 1H), 7.75 (ddd, J=2.0, 2.0, 7.6 Hz, 1H), 7.32 (dd, J=4.7, 7.6 Hz, 1H), 6.39-6.13 (m, 1H), 4.97 (t, J=5.8 Hz, 1H), 4.84-4.76 (m, 1H), 4.61-4.42 (m, 2H), 3.71-3.59 (m, 2H), 2.49-2.42 (m, 2H), 2.27-2.14 (m, 2H), 1.89-1.72 (m, 2H), 1.60 (br s, 3H), 1.52 (br s, 3H), 0.09 (s, 9H).


Example 31
N-[1-(Benzo[d][1,3]dioxol-4-yl)-2-hydroxyethyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound No. IV-502)



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To a solution of 240 mg (0.815 mmol) of 1-(benzo[d][1,3]dioxol-4-yl)-2-[(tert-butyldimethylsilyl)oxy]ethanamine synthesized in the similar manner as in Reference Example 32 in 10 ml of dichloromethane, 1 ml (4 mmol) of 4 N hydrogen chloride/1,4-dioxane solution was added at room temperature and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and 3 ml of THF, 0.210 ml (1.24 mmol) of DIPEA, and 93.0 mg (0.211 mmol) of ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarbox amido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 3 were added to the obtained residue at room temperature and stirred at 60° C. for 8 hours.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure, and ethyl acetate, a saturated aqueous solution of sodium chloride, and water were added thereto and then the aqueous layer and the organic layer were separated. The obtained organic layer was dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. 2 ml of methanol and 2 ml of triethylamine were added to the obtained concentration residue, applied to a microwave reaction apparatus, and reacted at 80° C. for 30 minutes.


After the completion of the reaction, the concentration residue obtained by concentration under reduced pressure was subjected to silica gel column chromatography (elution solvent: ethyl acetate: a mixed solution of 28% aqueous ammonia solution/ethanol [1:5 (V/V)]=98:2 to 95:5 (V/V)), and a fraction containing N-{1-(benzo[d][1,3]dioxol-4-yl)-2-[(tert-butyldimethylsilyl)oxy]ethyl}-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide was concentrated under reduced pressure to obtain a concentration residue.


To a solution of 119 mg (0.190 mmol) of the obtained concentration residue in 3.5 ml of dehydrated dichloromethane, 0.18 ml (1.0 mmol) of trimethylsilyl trifluoromethanesulfonate was added at 0° C. and stirred at the same temperature as above for 5 minutes, and then, 0.17 ml (1.5 mmol) of 2,6-lutidine and 0.18 ml (1.0 mmol) of trimethylsilyl trifluoromethanesulfonate were added at 0° C. and stirred at the same temperature as above for 5 minutes. Subsequently, 1 ml of methanol and 0.17 ml (1.5 mmol) of 2,6-lutidine were added, and then, the reaction solution was concentrated under reduced pressure. To a solution of the obtained concentration residue in 1 ml of dehydrated dichloromethane, 0.18 ml (1.0 mmol) of trimethylsilyl trifluoromethanesulfonate was added at 0° C. and stirred at the same temperature as above for 5 minutes, and then, 1.0 ml of dehydrated acetonitrile was added at 0° C. and stirred at the same temperature as above for 10 minutes.


After the completion of the reaction, 1 ml of methanol and 0.17 ml (1.5 mmol) of 2,6-lutidine were added to the reaction solution and then concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: ethyl acetate:a mixed solution of 28% aqueous ammonia solution/ethanol [1:5 (V/V)]=98:2 to 95:5 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was subjected again to silica gel column chromatography (DIOL silica gel, elution solvent: ethyl acetate:methanol=100:0 to 95:5 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 52 mg of the title compound (yield: 48%) as a white solid.


Mass spectrum (DUIS, m/z): 514 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.21 & 11.72 (br s, total 1H), 9.69-9.50 (m, 1H), 6.89-6.83 (m, 1H), 6.81-6.76 (m, 2H), 6.12-5.94 (m, 3H), 4.96-4.90 (m, 2H), 4.59-4.43 (m, 2H), 3.62-3.56 (m, 2H), 2.49-2.42 (m, 2H), 2.26-2.15 (m, 2H), 1.90-1.74 (m, 2H), 1.60 (br s, 3H), 1.54 (br s, 3H), 0.10 (s, 9H).


Example 32
(S)—N-(1-Cyclohexyl-2-hydroxyethyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound No. IV-495)



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To a solution of 326 mg (0.739 mmol) of ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 3 in 4 ml of dehydrated THF, 0.33 ml (1.9 mmol) of DIPEA and 304 mg (2.12 mmol) of (S)-2-amino-2-cyclohexylethanol [synthesized according to the method described in Bioorg. Med. Chem. Lett., 2009, 19, 926-929] were added at room temperature in a nitrogen atmosphere and then stirred for 1.5 hours while heated to reflux. Subsequently, 0.90 ml (6.5 mmol) of triethylamine and 0.90 ml (22 mmol) of methanol were added to the reaction solution and then stirred for 1.5 hours while heated to reflux.


After the completion of the reaction, water was added to the reaction solution, followed by extraction with dichloromethane three times. All of the obtained organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. 85 μl of acetic acid was added to the obtained concentration residue and then subjected to silica gel column chromatography (DIOL silica gel, elution solvent: dichloromethane:methanol=100:0 to 97:3 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. For the obtained concentration residue, crystallization was performed with dichloromethane/n-hexane, and the deposited solid was collected by filtration, washed by sousing with n-hexane, and then dried under reduced pressure to obtain 295 mg of the title compound (yield: 84%) as a white solid.


Mass spectrum (CI, m/z): 476 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.20 & 11.71 (br s, total 1H), 9.70-9.44 (m, 1H), 5.46-5.15 (m, 1H), 4.54 (t, J=5.0 Hz, 1H), 4.49-4.21 (m, 2H), 3.53-3.40 (m, 3H), 2.48-2.40 (m, 2H), 2.27-2.10 (m, 2H), 1.88-1.45 (m, 14H), 1.28-1.03 (m, 3H), 1.03-0.83 (m, 2H), 0.08 (s, 9H).


Example 33
(S)—N-(1-Hydroxy-3-methylbutan-2-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound No. IV-475)



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To a solution of 201 mg (0.456 mmol) of ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 3 in 4.5 ml of 1,4-dioxane, 235 mg (2.27 mmol) of (S)-2-amino-3-methylbutan-1-ol and 0.16 ml (0.91 mmol) of DIPEA were added at room temperature in a nitrogen atmosphere and then stirred at 100° C. for 1 hour.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure, and ethyl acetate, water, and a saturated aqueous solution of sodium chloride were added to the concentration residue and then the aqueous layer and the organic layer were separated. The aqueous layer was subjected to extraction with ethyl acetate, all of the obtained organic layers were dried over anhydrous magnesium sulfate and filtered, and then, the filtrate was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: 1,2-dichloroethane:methanol=99:1 to 96:4 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. Acetone was added to the obtained concentration residue and then ultrasonicated, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 129 mg of the title compound (yield: 65%) as a white solid.


Mass spectrum (CI, m/z): 436 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.20 & 11.67 (br s, total 1H), 9.60-9.48 (m, 1H), 5.45-5.20 (m, 1H), 4.62-4.24 (m, 3H), 3.52-3.39 (m, 3H), 2.49-2.41 (m, 2H), 2.24-2.13 (m, 2H), 1.91-1.73 (m, 3H), 1.60 (br s, 6H), 0.92-0.82 (m, 6H), 0.08 (s, 9H).


Example 34
(S)—N-(1-Hydroxypropan-2-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound No. IV-455)



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To a solution of 200 mg (0.454 mmol) of ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 3 in 4.5 ml of 1,4-dioxane, 170 mg (2.26 mmol) of (S)-2-aminopropan-1-ol and 0.16 ml (0.91 mmol) of DIPEA were added at room temperature, then applied to a microwave reaction apparatus, and reacted at 100° C. for 1 hour.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure, and ethyl acetate, water, and a saturated aqueous solution of sodium chloride were added to the concentration residue and then the aqueous layer and the organic layer were separated. The aqueous layer was subjected to extraction with ethyl acetate, all of the obtained organic layers were dried over anhydrous magnesium sulfate and filtered, and then, the filtrate was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: 1,2-dichloroethane:methanol=99:1 to 95:5 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. Ethyl acetate was added to the obtained concentration residue and ultrasonicated, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 145 mg of the title compound (yield: 78%) as a white solid.


Mass spectrum (CI, m/z): 408 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.18 & 11.64 (br s, total 1H), 9.52 (s, 1H), 5.70-5.32 (m, 1H), 4.65 (t, J=5.6 Hz, 1H), 4.44-4.28 (m, 2H), 3.77-3.64 (m, 1H), 3.41-3.34 (m, 1H), 3.30-3.23 (m, 1H), 2.49-2.40 (m, 2H), 2.24-2.13 (m, 2H), 1.88-1.72 (m, 2H), 1.60 (s, 6H), 1.05 (d, J=6.7 Hz, 3H), 0.08 (s, 9H).


Example 35
N-(2-Hydroxyethyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound No. IV-438)



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To a solution of 200 mg (0.454 mmol) of ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 3 in 3 ml of dehydrated THF, 0.16 ml (0.92 mmol) of DIPEA and 0.14 ml (2.3 mmol) of 2-aminoethanol were added at room temperature in an argon atmosphere and stirred at 60° C. for 3 hours.


After the completion of the reaction, water was added to the reaction solution, followed by extraction from the mixed solution with ethyl acetate. The obtained organic layer was washed with a saturated aqueous solution of sodium chloride, then dried by adding anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=90:10 to 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 135 mg of the title compound (yield: 76%) as a white solid.


Mass spectrum (DUIS, m/z): 394 [M+1]+



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.19 & 11.60 (br s, total 1H), 9.54 (s, 1H), 6.05-5.85 (m, 1H), 4.66 (t, J=5.5 Hz, 1H), 4.42-4.28 (m, 2H), 3.45-3.36 (in 2H), 3.17-3.02 (m, 2H), 2.48-2.39 (m, 2H), 2.25-2.12 (m, 2H), 1.91-1.71 (m, 2H), 1.67-1.52 (m, 6H), 0.08 (s, 9H).


Example 36
N-(2-Hydroxy-2-phenylethyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound No. IV-450)



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To a solution of 100 mg (0.227 mmol) of ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 3 in 2 ml of dehydrated 1,4-dioxane, 0.20 ml (1.1 mmol) of DIPEA and 160 mg (1.17 mmol) of 2-amino-1-phenylethanol were added at room temperature in an argon atmosphere and stirred at the same temperature as above for 1 hour.


After the completion of the reaction, water was added to the reaction solution, followed by extraction from the mixed solution with ethyl acetate. The obtained organic layer was washed with a saturated aqueous solution of sodium chloride, then dried by adding anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=50:50 to 0:100 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 82.0 mg of the title compound (yield: 77%) as a white solid.


Mass spectrum (CI, m/z): 470 [M+1]+



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.38-11.74 (m, 1H), 9.59 (br s, 1H), 7.36-7.29 (m, 4H), 7.26-7.20 (m, 1H), 6.14-5.98 (m, 1H), 5.58 (d, J=4.0 Hz, 1H), 4.70-4.62 (m, 1H), 4.42-4.28 (m, 2H), 3.29-3.23 (m, 1H), 3.10 (ddd, J=4.8, 8.0, 13.2 Hz, 1H), 2.48-2.40 (m, 2H), 2.23-2.14 (m, 2H), 1.88-1.74 (m, 2H), 1.60 (s, 6H), 0.08 (s, 9H).


Example 37
N-(2-Hydroxypropyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound No. IV-442)



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To a solution of 100 mg (0.227 mmol) of ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 3 and 85 μl (1.1 mmol) of 1-amino-2-propanol in 2 ml of dehydrated 1,4-dioxane, 0.20 ml (1.1 mmol) of DIPEA was added at room temperature in an argon atmosphere and stirred at the same temperature as above for 1.5 hours.


After the completion of the reaction, water was added to the reaction solution, followed by extraction from the mixed solution with ethyl acetate. The obtained organic layer was washed with a saturated aqueous solution of sodium chloride, then dried by adding anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=50:50 to 0:100 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 61.1 mg of the title compound (yield: 66%) as a white solid.


Mass spectrum (CI, m/z): 408 [M+1]+



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.19 & 11.78 (br s, total 1H), 9.71-9.46 (m, 1H), 6.05-5.78 (m, 1H), 4.76 (d, J=4.4 Hz, 1H), 4.38 (br s, 2H), 3.71-3.61 (m, 1H), 3.09-2.99 (m, 1H), 2.97-2.88 (m, 1H), 2.49-2.39 (m, 2H), 2.25-2.13 (m, 2H), 1.88-1.71 (m, 2H), 1.60 (br s, 6H), 1.01 (d, J=6.3 Hz, 3H), 0.08 (s, 9H).


Example 38
N-[(2S)-1-Hydroxy-3-methyl-1-phenylbutan-2-yl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (compound No. IV-487)



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To a solution of 1.25 g (6.21 mmol) of (S)-tert-butyl (3-methyl-1-oxobutan-2-yl)carbamate [synthesized according to the method described in J. Am. Chem. Soc., 2004, 126, 11440-11441] in 15 ml of dehydrated THF, 6.60 ml (6.60 mmol) of 1 M phenyl magnesium bromide/THF solution was added dropwise at an internal temperature of 15° C. or lower in an argon atmosphere and, after the completion of the dropwise addition, stirred at room temperature for 1.5 hours.


After the completion of the reaction, the reaction solution was cooled in ice water, and 20 ml of a saturated aqueous solution of ammonium chloride was added and stirred at room temperature. Ethyl acetate and a saturated aqueous solution of sodium chloride were further added thereto and then the aqueous layer and the organic layer were separated. The obtained organic layer was dried over anhydrous magnesium sulfate and filtered, and then, the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=90:10 to 70:30 (V/V)), and a fraction containing tert-butyl[(2S)-1-hydroxy-3-methyl-1-phenylbutan-2-yl]carbamate was concentrated under reduced pressure to obtain a concentration residue.


To a solution of 0.90 g of the obtained concentration residue in 10 ml of dichloromethane, 1.2 ml (10 mmol) of 2,6-lutidine and 1.8 ml (10 mmol) of trimethylsilyl trifluoromethanesulfonate were added dropwise at 0° C. in a nitrogen atmosphere and stirred at the same temperature as above for 2 hours.


After the completion of the reaction, 50 ml of a saturated aqueous solution of sodium bicarbonate was added thereto, stirred, and then the aqueous layer and the organic layer were separated. The aqueous layer was subjected to extraction with dichloromethane, all of the obtained organic layers were dried over anhydrous sodium sulfate and filtered, and then, the filtrate was concentrated under reduced pressure. The operation of adding toluene to the obtained concentration residue and concentrating the resultant under reduced pressure was repeated several times. The obtained concentration residue was subjected to silica gel column chromatography (DNH silica gel, elution solvent: 1,2-dichloroethane:methanol=100:0 to 95:5 (V/V)), and a fraction containing (2S)-2-amino-3-methyl-1-phenylbutan-1-ol was concentrated under reduced pressure. The obtained concentration residue was subjected again to silica gel column chromatography (DIOL silica gel, elution solvent: 1,2-dichloroethane:methanol=100:0 to 95:5 (V/V)), and a fraction containing (2S)-2-amino-3-methyl-1-phenylbutan-1-ol was concentrated under reduced pressure to obtain a concentration residue.


To a solution of 111 mg (0.251 mmol) of ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2 (4H)-carboxylate synthesized in the similar manner as in Reference Example 3 in 4.0 ml of 1,4-dioxane, 97 mg of the concentration residue of (2S)-2-amino-3-methyl-1-phenylbutan-1-ol described above and 0.11 ml (0.63 mmol) of DIPEA were added at room temperature, then applied to a microwave reaction apparatus, and reacted at 100° C. for 1 hour. After the reaction, the reaction solution was concentrated under reduced pressure, and 4 ml of methanol and 1 ml of triethylamine were added to the obtained concentration residue, applied to a microwave reaction apparatus, and reacted at 80° C. for 1 hour.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure, the obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: 1,2-dichloroethane:methanol=100:0 to 95:5 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. Diethyl ether and n-hexane were added to the obtained concentration residue and ultrasonicated, and the deposited solid was collected by filtration. The obtained solid was subjected again to silica gel column chromatography (DIOL silica gel, elution solvent: 1,2-dichloroethane:methanol=100:0 to 95:5 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. For the obtained concentration residue, crystallization was performed with acetone/n-heptane, and the deposited solid was collected by filtration. The obtained solid was subjected again to silica gel column chromatography (elution solvent: hexane:ethyl acetate=38:62 to 17:83 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. n-Hexane was added to the obtained concentration residue, and after ultrasonication, the deposited solid was collected by filtration and dried under reduced pressure to obtain 55 mg of the title compound (yield: 42%) as a white solid.


Mass spectrum (CI, m/z): 512 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.15 & 11.74 (br s, total 1H), 9.85-9.20 (m, 1H), 7.33-7.19 (m, 4H), 7.17-7.10 (m, 1H), 5.68 (d, J=5.8 Hz, 1H), 5.32-5.16 (m, 1H), 4.82 (dd, J=2.6, 5.8 Hz, 1H), 4.37-4.23 (m, 2H), 3.52 (ddd, J=2.6, 8.7, 8.7 Hz, 1H), 2.49-2.39 (m, 2H), 2.26-2.13 (m, 2H), 2.00-1.72 (m, 3H), 1.52 (br s, 3H), 1.31 (br s, 3H), 1.03 (d, J=6.7 Hz, 3H), 0.90 (d, J=6.7 Hz, 3H), 0.09 (s, 9H).


Example 39
N-(4-Hydroxy-1-phenyl-2-butyn-1-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound No. IV-378)



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To a solution of 106 mg (0.240 mmol) of ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarbox amido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 3 in 3 ml of dehydrated 1,4-dioxane, 0.24 ml (1.4 mmol) of DIPEA and 146 mg (0.739 mmol) of 4-amino-4-phenyl-2-butyn-1-ol hydrochloride synthesized in the similar manner as in Reference Example 33 were added in an argon atmosphere and stirred at 100° C. for 2 hours. Subsequently, 1 ml of triethylamine and 1 ml of methanol were added to the reaction solution and stirred at 80° C. for 1 hour.


After the completion of the reaction, water was added to the reaction solution, followed by extraction from the mixed solution with ethyl acetate. The obtained organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel chromatography (DIOL column, elution solvent: dichloromethane:methanol=100:0 to 90:10 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was subjected again to silica gel chromatography (elution solvent: dichloromethane:methanol=100:0 to 90:10 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 79.6 mg of the title compound (yield: 67%) as a light brown solid.


Mass spectrum (CI, m/z): 494 [M+1]+



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.21 & 11.70 (br s, total 1H), 9.54 (br s, 1H), 7.53-7.47 (m, 2H), 7.38-7.32 (m, 2H), 7.29-7.23 (m, 1H), 7.20-6.97 (m, 1H), 5.89-5.84 (m, 1H), 5.20 (t, J=5.9 Hz, 1H), 4.45 (br s, 2H), 4.15 (dd, J=1.9, 5.9 Hz, 2H), 2.48-2.40 (m, 2H), 2.24-2.12 (m, 2H), 1.87-1.73 (m, 2H), 1.63 (s, 3H), 1.59 (s, 3H), 0.08 (s, 9H).


Example 40
(S)-2-{6,6-Dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylethyl acetate (Compound No. V-1442)



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To a solution of 360 mg (0.816 mmol) of ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 3 in 10 ml of THF, 883 mg (4.09 mmol) of (S)-2-amino-2-phenylethyl acetate hydrochloride synthesized in the similar manner as in Reference Example 35 and 2.0 ml (12 mmol) of DIPEA were added at room temperature, applied to a microwave reaction apparatus, and reacted at 100° C. for 2 hours. Subsequently, 1.1 ml (27 mmol) of methanol was added, then applied to a microwave reaction apparatus, and reacted at 80° C. for 1 hour. 2.0 ml (49 mmol) of methanol and 1.0 ml (7.2 mmol) of triethylamine were further added, then applied to a microwave reaction apparatus, and reacted at 80° C. for 1 hour.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure, and 15 ml of ethyl acetate and 15 ml of a saturated aqueous solution of sodium chloride were added to the obtained concentration residue and then the aqueous layer and the organic layer were separated. The aqueous layer was subjected to extraction with 15 ml of dichloromethane. All of the obtained organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: 1,2-dichloroethane:methanol=100:0 to 90:10 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. Ethyl acetate and diethyl ether were added in small amounts to the obtained concentration residue, then ultrasonicated, cooled in ice water, and then filtered. The obtained solid was subjected again to silica gel column chromatography (DIOL silica gel, elution solvent: ethyl acetate:methanol=100:0 to 99:1 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. Ethyl acetate and diethyl ether were added in small amounts to the obtained concentration residue, then ultrasonicated, cooled in ice water, and then filtered to obtain white solid A. The filtrate was concentrated under reduced pressure, the obtained concentration residue was subjected to silica gel column chromatography (elution solvent: ethyl acetate:methanol=100:0 to 99:1 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. Ethyl acetate and diethyl ether were added in small amounts to the obtained concentration residue, then ultrasonicated, cooled in ice water, and then filtered to obtain white solid B. The white solids A and B were dissolved in ethyl acetate, then diethyl ether was added, and the deposited solid was filtered and dried under reduced pressure to obtain 142 mg of the title compound (yield: 34%) as a white solid.


Mass spectrum (DUIS, m/z): 512 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.21 & 11.71 (br s, total 1H), 9.76-9.33 (m, 1H), 7.43-7.37 (m, 2H), 7.37-7.31 (m, 2H), 7.28-7.22 (m, 1H), 6.65-6.38 (m, 1H), 5.12-5.03 (m, 1H), 4.49 (br s, 2H), 4.30-4.19 (m, 2H), 2.49-2.41 (m, 2H), 2.25-2.14 (m, 2H), 1.98 (s, 3H), 1.89-1.74 (m, 2H), 1.61 (br s, 3H), 1.53 (br s, 3H), 0.09 (s, 9H).


Example 41
(S)-2-{6,6-Dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylethyl propionate (Compound No. V-1446)



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To a solution of 200 mg (0.369 mmol) of (S)-ethyl 5-[(2-hydroxy-1-phenylethyl)carbamoyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 38 and 0.10 ml (0.74 mmol) of triethylamine in 3 ml of dehydrated dichloromethane, 0.071 ml (0.55 mmol) of propionic anhydride and 9.7 mg (0.079 mmol) of 4-dimethylaminopyridine were added in this order at room temperature in an argon atmosphere and then reacted at room temperature for 5 hours. Subsequently, 1 ml of methanol and 0.5 ml of triethylamine were added and reacted at room temperature for 2 hours.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure, and 10 ml of ethyl acetate, 0.5 ml of water, and 10 ml of a saturated aqueous solution of sodium chloride were added to the obtained concentration residue, and then the aqueous layer and the organic layer were separated. The aqueous layer was subjected to extraction with 10 ml of dichloromethane twice, and all of the obtained organic layers were dried over anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: 1,2-dichloroethane:methanol=100:0 to 95:5 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. Diethyl ether was added to the obtained concentration residue, and after ultrasonication, insoluble matter was filtered and dried under reduced pressure to obtain 138 mg of the title compound (yield: 71%) as a white solid.


Mass spectrum (CI, m/z): 526 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.20 & 11.66 (br s, total 1H), 9.70-9.39 (m, 1H), 7.45-7.30 (m, 4H), 7.28-7.21 (m, 1H), 6.64-6.39 (m, 1H), 5.16-5.03 (m, 1H), 4.57-4.39 (m, 2H), 4.32-4.19 (m, 2H), 2.49-2.41 (m, 2H), 2.27 (q, J=7.5 Hz, 2H), 2.24-2.14 (m, 2H), 1.91-1.72 (m, 2H), 1.67-1.47 (m, 6H), 0.99 (t, J=7.5 Hz, 3H), 0.09 (s, 9H).


Example 42
(S)-2-{6,6-Dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylethyl butanoate (Compound No. V-1450)



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To a solution of 250 mg (0.461 mmol) of a mixture of (S)-ethyl 5-[(2-hydroxy-1-phenylethyl)carbamoyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-carboxylate synthesized in the similar manner as in Reference Example and (S)-ethyl 5-[(2-hydroxy-1-phenylethyl)carbamoyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate and 0.10 ml (0.74 mmol) of triethylamine in 4.5 ml of 1,4-dioxane, 0.09 ml (0.6 mmol) of butyric anhydride and 9.0 mg (0.074 mmol) of 4-dimethylaminopyridine were added in this order at room temperature in an argon atmosphere and then reacted at 100° C. for 1.5 hours. Subsequently, 1.5 ml (37 mmol) of methanol and 0.75 ml (5.4 mmol) of triethylamine were added, applied to a microwave reaction apparatus, and reacted at 80° C. for 2 hours.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure, and 8 ml of ethyl acetate, 0.4 ml of water, and 8 ml of a saturated aqueous solution of sodium chloride were added to the obtained concentration residue, and then the aqueous layer and the organic layer were separated. The aqueous layer was subjected to extraction with 10 ml of dichloromethane twice, and all of the obtained organic layers were dried over anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: 1,2-dichloroethane:methanol=100:0 to 95:5 (V/V)), a fraction containing the compound of interest was concentrated under reduced pressure, then the obtained concentration residue was subjected again to silica gel column chromatography (DIOL silica gel, elution solvent: 1,2-dichloroethane:ethyl acetate=100:0 to 51:49 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. Water was added to the concentration residue, and after ultrasonication, insoluble matter was filtered and dried under reduced pressure to obtain 80 mg of the title compound (yield: 32%) as a white solid.


Mass spectrum (CI, m/z): 540 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.20 & 11.65 (br s, total 1H), 9.69-9.40 (m, 1H), 7.45-7.37 (m, 2H), 7.37-7.29 (m, 2H), 7.28-7.21 (m, 1H), 6.64-6.39 (m, 1H), 5.15-5.04 (m, 1H), 4.57-4.38 (m, 2H), 4.31-4.20 (m, 2H), 2.49-2.41 (m, 2H), 2.28-2.14 (m, 4H), 1.92-1.73 (m, 2H), 1.64-1.44 (m, 8H), 0.83 (t, J=7.4 Hz, 3H), 0.09 (s, 9H).


Example 43
(S)-2-{6,6-Dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylethyl pentanoate (Compound No. V-1458)



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To a solution of 200 mg (0.369 mmol) of (S)-ethyl 5-[(2-hydroxy-1-phenylethyl)carbamoyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 38 and 0.10 ml (0.74 mmol) of triethylamine in 3 ml of 1,4-dioxane, 0.09 ml (0.5 mmol) of valeric anhydride and 9.0 mg (0.074 mmol) of 4-dimethylaminopyridine were added at room temperature in an argon atmosphere and then reacted at 100° C. for 1 hour. Subsequently, 1 ml of methanol and 0.5 ml of triethylamine were added, applied to a microwave reaction apparatus, and reacted at 80° C. for 1 hour.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure, and 10 ml of ethyl acetate and 10 ml of 10% potassium dihydrogen phosphate were added to the obtained concentration residue, and then the aqueous layer and the organic layer were separated. The aqueous layer was subjected to extraction with 10 ml of dichloromethane twice, and all of the obtained organic layers were washed with 10 ml of water, 10 ml of a saturated aqueous solution of sodium bicarbonate, and 10 ml of a saturated aqueous solution of sodium chloride in this order, then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: 1,2-dichloroethane:ethyl acetate=100:0 to 51:49 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. Purified water was added to the obtained concentration residue, and after ultrasonication, insoluble matter was filtered and dried under reduced pressure to obtain 39 mg of the title compound (yield: 19%) as a white solid.


Mass spectrum (CI, m/z): 554 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.20 & 11.63 (br s, total 1H), 9.54 (s, 1H), 7.44-7.37 (m, 2H), 7.36-7.30 (m, 2H), 7.28-7.21 (m, 1H), 6.66-6.39 (m, 1H), 5.14-5.04 (m, 1H), 4.59-4.40 (m, 2H), 4.25 (d, J=7.5 Hz, 2H), 2.49-2.41 (m, 2H), 2.29-2.14 (m, 4H), 1.92-1.73 (m, 2H), 1.61 (br s, 3H), 1.56-1.41 (m, 5H), 1.29-1.18 (m, 2H), 0.80 (t, J=7.3 Hz, 3H), 0.09 (s, 9H).


Example 44
(S)-2-{6,6-Dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylethyl octanoate (Compound No. V-1470)



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To a solution of 183 mg (0.329 mmol) of a mixture of (S)-ethyl 5-[(2-hydroxy-1-phenylethyl)carbamoyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-carboxylate synthesized in the similar manner as in Reference Example 38 and (S)-ethyl 5-[(2-hydroxy-1-phenylethyl)carbamoyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate in a 3 ml of dehydrated dichloromethane, 0.10 ml (0.72 mmol) of triethylamine, 0.15 ml (0.51 mmol) of n-octanoic anhydride, and 10.6 mg (0.087 mmol) of 4-dimethylaminopyridine were added in this order at room temperature in a nitrogen atmosphere and then stirred at the same temperature as above for 2 hours. Subsequently, 1.0 ml (7.2 mmol) of triethylamine and 1.0 ml (25 mmol) of methanol were added to the reaction solution and then stirred at room temperature for 20.5 hours. 1.0 ml (7.2 mmol) of triethylamine and 1.0 ml (25 mmol) of methanol were added to the reaction solution, stirred at 50° C. for 2 hours, and then stirred for 4 hours after the temperature was raised to 60° C.


After the completion of the reaction, water was added to the reaction solution, followed by extraction with dichloromethane three times. All of the obtained organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: dichloromethane:methanol=100:0 to 97:3 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. n-Hexane was added to the obtained concentration residue, and after ultrasonication, the deposited solid was collected by filtration, washed by sousing with n-hexane, and then dried under reduced pressure to obtain 115 mg of the title compound (yield: 58%) as a white solid.


Mass spectrum (CI, m/z): 596 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.16 & 11.77 (br s, total 1H), 9.55 (br s, 1H), 7.47-7.37 (m, 2H), 7.37-7.29 (m, 2H), 7.29-7.20 (m, 1H), 6.64-6.43 (m, 1H), 5.16-5.02 (m, 1H), 4.49 (s, 2H), 4.34-4.18 (m, 2H), 2.49-2.41 (m, 2H), 2.28-2.14 (m, 4H), 1.89-1.73 (m, 2H), 1.60 (s, 3H), 1.53 (s, 3H), 1.50-1.43 (m, 2H), 1.24-1.13 (m, 8H), 0.83-0.75 (m, 3H), 0.09 (s, 9H).


Example 45
(S)-2-{6,6-Dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylethyl dodecanoate (Compound No. V-1474)



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To a solution of 202 mg (0.373 mmol) of (S)-ethyl 5-[(2-hydroxy-1-phenylethyl)carbamoyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 38, 0.11 ml (0.79 mmol) of triethylamine, and 10 mg (0.082 mmol) of 4-dimethylaminopyridine in 2 ml of dehydrated dichloromethane, 224 mg (0.585 mmol) of dodecanoic anhydride was added at room temperature in an argon atmosphere and stirred at room temperature for 1 hour. Subsequently, 1 ml of triethylamine and 1 ml of methanol were added to the reaction solution and stirred at room temperature for 16 hours.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel chromatography (elution solvent: n-hexane:ethyl acetate=95:5 to 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 139 mg of the title compound (yield: 57%) as a white solid.


Mass spectrum (CI, m/z): 652 [M+1]+



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.18 & 11.66 (br s, total 1H), 9.83-9.28 (m, 1H), 7.42-7.37 (m, 2H), 7.37-7.30 (m, 2H), 7.28-7.21 (m, 1H), 6.67-6.35 (m, 1H), 5.14-5.03 (m, 1H), 4.56-4.42 (m, 2H), 4.30-4.20 (m, 2H), 2.49-2.42 (m, 2H), 2.28-2.13 (m, 4H), 1.89-1.73 (m, 2H), 1.60 (br s, 3H), 1.57-1.43 (m, 5H), 1.30-1.14 (m, 16H), 0.85 (t, J=6.9 Hz, 3H), 0.09 (s, 9H).


Example 46
(S)-2-{6,6-Dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylethyl palmitate (Compound No. V-1478)



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To a solution of 220 mg (0.406 mmol) of (S)-ethyl 5-[(2-hydroxy-1-phenylethyl)carbamoyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 38, 0.115 ml (0.825 mmol) of triethylamine, and 300 mg (0.606 mmol) of palmitic anhydride in 3 ml of dichloromethane, 10 mg (0.082 mmol) of 4-dimethylaminopyridine was added at room temperature in an argon atmosphere and stirred at the same temperature as above for 1.5 hours. Subsequently, 1.0 ml of methanol and 0.5 ml of triethylamine were added to the reaction solution and stirred at room temperature for 15 hours.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel chromatography (elution solvent: n-hexane:ethyl acetate=90:10 to 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 195 mg of the title compound (yield: 68%) as a white solid.


Mass spectrum (DUIS, m/z): 708 [M+1]+



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.18 & 11.64 (br s, total 1H), 9.64-9.50 (m, 1H), 7.43-7.38 (m, 2H), 7.36-7.30 (m, 2H), 7.27-7.21 (m, 1H), 6.63-6.39 (m, 1H), 5.13-5.04 (m, 1H), 4.55-4.42 (m, 2H), 4.30-4.20 (m, 2H), 2.48-2.40 (m, 2H), 2.29-2.14 (m, 4H), 1.89-1.74 (m, 2H), 1.60 (br s, 3H), 1.57-1.43 (m, 5H), 1.29-1.14 (m, 24H), 0.89-0.81 (m, 3H), 0.09 (s, 9H).


Example 47
(S)-2-{6,6-Dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylethyl isobutanoate (Compound No. V-1454)



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To a solution of 247 mg (0.456 mmol) of (S)-ethyl 5-[(2-hydroxy-1-phenylethyl)carbamoyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2 (4H)-carboxylate synthesized in the similar manner as in Reference Example 38 in 3 ml of dehydrated dichloromethane, 0.15 ml (1.1 mmol) of triethylamine and 0.060 ml (0.57 mmol) of isobutyryl chloride were added in this order at room temperature in a nitrogen atmosphere and then stirred at the same temperature as above for 100 minutes. Subsequently, 1.0 ml (7.2 mmol) of triethylamine and 1.0 ml (25 mmol) of methanol were added to the reaction solution and then stirred at room temperature for 4.5 hours.


After the completion of the reaction, water was added to the reaction solution, followed by extraction with dichloromethane three times. All of the obtained organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: dichloromethane:methanol=100:0 to 99:1 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. For the obtained concentration residue, crystallization was performed with ethyl acetate/n-hexane, and the obtained solid was collected by filtration, washed by sousing with n-hexane, and then dried under reduced pressure to obtain 202 mg of the title compound (yield: 82%) as a white solid.


Mass spectrum (CI, m/z): 540 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.20 & 11.61 (br s, total 1H), 9.53 (s, 1H), 7.47-7.38 (m, 2H), 7.38-7.29 (m, 2H), 7.29-7.20 (m, 1H), 6.71-6.34 (m, 1H), 5.20-5.03 (m, 1H), 4.57-4.38 (m, 2H), 4.33-4.15 (m, 2H), 2.48-2.42 (m, 3H), 2.27-2.13 (m, 2H), 1.92-1.73 (m, 2H), 1.65-1.47 (m, 6H), 1.08-0.99 (m, 6H), 0.14-0.05 (m, 9H).


Example 48
(S)-2-{6,6-Dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylethyl pivalate (Compound No. V-1462)



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To a solution of 210 mg (0.387 mmol) of (S)-ethyl 5-[(2-hydroxy-1-phenylethyl)carbamoyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 38 and 0.11 ml (0.79 mmol) of triethylamine in 3 ml of dehydrated dichloromethane, 0.12 ml (0.59 mmol) of pivalic anhydride and 10.5 mg (0.086 mmol) of 4-dimethylaminopyridine were added in an argon atmosphere and stirred at room temperature for 4.5 hours. Subsequently, 0.5 ml of triethylamine and 1 ml of methanol were added to the reaction solution and reacted at room temperature for 14 hours.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel chromatography (elution solvent: n-hexane:ethyl acetate=90:10 to 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure. Diisopropyl ether was added to the obtained concentration residue, and after ultrasonication, insoluble matter was collected by filtration and dried under reduced pressure to obtain 144 mg of the title compound (yield: 67%) as a white solid.


Mass spectrum (CI, m/z): 554 [M+1]+



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.20 & 11.66 (br s, total 1H), 9.55 (s, 1H), 7.45-7.38 (m, 2H), 7.37-7.31 (m, 2H), 7.28-7.22 (m, 1H), 6.68-6.40 (m, 1H), 5.20-5.09 (m, 1H), 4.48 (br s, 2H), 4.29-4.19 (m, 2H), 2.49-2.41 (m, 2H), 2.26-2.14 (m, 2H), 1.90-1.74 (m, 2H), 1.59 (s, 3H), 1.55 (s, 3H), 1.08 (s, 9H), 0.09 (s, 9H).


Example 49
(S)-2-{6,6-Dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylethyl 3-methylbutanoate (Compound No. V-1466)



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To a solution of 201 mg (0.371 mmol) of a mixture of (S)-ethyl 5-[(2-hydroxy-1-phenylethyl)carbamoyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-carboxylate synthesized in the similar manner as in Reference Example and (S)-ethyl 5-[(2-hydroxy-1-phenylethyl)carbamoyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate and 0.10 ml (0.74 mmol) of triethylamine in 3 ml of dichloromethane, 0.11 ml (0.56 mmol) of isovaleric anhydride and 10.6 mg (0.087 mmol) of 4-dimethylaminopyridine were added at room temperature in an argon atmosphere and then reacted at the same temperature as above for 3 hours. Subsequently, 1.0 ml of methanol and 0.5 ml of triethylamine were added and reacted at room temperature for 15.5 hours, then the reaction solution was concentrated under reduced pressure, and 1.0 ml of methanol and 0.5 ml of triethylamine were added again to the obtained concentration residue and reacted at 40° C. for 6 hours.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure, and 8 ml of ethyl acetate, 0.4 ml of water, and 8 ml of a saturated aqueous solution of sodium chloride were added to the obtained concentration residue, and then the aqueous layer and the organic layer were separated. The aqueous layer was subjected to extraction with 10 ml of dichloromethane twice, and all of the obtained organic layers were dried over anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: 1,2-dichloroethane:methanol=100:0 to 95:5 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. Diethyl ether was added to the obtained concentration residue, ultrasonicated, and then concentrated under reduced pressure. Water was added to the obtained concentration residue, ultrasonicated, and left standing overnight, and then, insoluble matter was filtered and dried under reduced pressure to obtain 97 mg of the title compound (yield: 47%) as a white solid.


Mass spectrum (CI, m/z): 554 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.50-11.49 (m, 1H), 9.55 (s, 1H), 7.44-7.38 (m, 2H), 7.37-7.30 (m, 2H), 7.29-7.22 (m, 1H), 6.84-6.25 (m, 1H), 5.13-5.06 (m, 1H), 4.55-4.41 (m, 2H), 4.31-4.21 (m, 2H), 2.49-2.42 (m, 2H), 2.26-2.11 (m, 4H), 2.01-1.87 (m, 1H), 1.87-1.74 (m, 2H), 1.59 (s, 3H), 1.53 (s, 3H), 0.87-0.82 (m, 6H), 0.09 (s, 9H).


Example 50
(S)-2-{6,6-Dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylethyl benzoate (Compound No. V-1482)



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To a solution of 132 mg (0.244 mmol) of (S)-ethyl 5-[(2-hydroxy-1-phenylethyl)carbamoyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 38 and 0.068 ml (0.49 mmol) of triethylamine in 2.5 ml of dehydrated dichloromethane, 0.042 ml (0.36 mmol) of benzoyl chloride was added at room temperature in an argon atmosphere and stirred at the same temperature as above for 1 hour. Subsequently, 0.5 ml of triethylamine and 0.5 ml of methanol were added to the reaction solution and stirred at room temperature for 20 hours.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel chromatography (elution solvent: n-hexane:ethyl acetate=90:10 to 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 94 mg of the title compound (yield: 67%) as a white solid.


Mass spectrum (CI, m/z): 574 [M+1]+



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.19 & 11.71 (br s, total 1H), 9.55 (br s, 1H), 7.95-7.91 (m, 2H), 7.66-7.60 (m, 1H), 7.52-7.46 (m, 4H), 7.39-7.33 (m, 2H), 7.30-7.24 (m, 1H), 6.73-6.59 (m, 1H), 5.35-5.26 (m, 1H), 4.57-4.44 (m, 4H), 2.48-2.42 (m, 2H), 2.23-2.15 (m, 2H), 1.87-1.73 (m, 2H), 1.57 (s, 3H), 1.55 (s, 3H), 0.08 (s, 9H).


Example 51
(S)-2-{6,6-Dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylethyl ethyl carbonate (Compound No. V-1486)



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To a solution of 265 mg (0.490 mmol) of (S)-ethyl 5-[(2-hydroxy-1-phenylethyl)carbamoyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 38 in 4 ml of dehydrated dichloromethane, 0.14 ml (1.0 mmol) of triethylamine and 0.060 ml (0.63 mmol) of ethyl chloroformate were added in this order at room temperature in a nitrogen atmosphere and then stirred at the same temperature as above for 2 hours. Then, 0.20 ml (1.4 mmol) of triethylamine and 0.10 ml (1.1 mmol) of ethyl chloroformate were added at room temperature and stirred at the same temperature as above for 1.5 hours. 0.20 ml (1.4 mmol) of triethylamine and 0.10 ml (1.1 mmol) of ethyl chloroformate were further added again at room temperature and stirred at the same temperature as above for 1 hour. Subsequently, 1.0 ml (7.2 mmol) of triethylamine and 1.0 ml (25 mmol) of methanol were added to the reaction solution and then stirred at room temperature for 4 hours.


After the completion of the reaction, water was added to the reaction solution, followed by extraction with dichloromethane three times. All of the obtained organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: dichloromethane:methanol=100:0 to 98:2 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was subjected to preparative HPLC (column: X-Bridge (trade name) ODS, elution solvent: acetonitrile:1 mM aqueous dipotassium hydrogen phosphate solution=45:55 (V/V)), a fraction containing the compound of interest was concentrated under reduced pressure, and acetonitrile was distilled off. The deposited solid was collected by filtration, washed by sousing with pure water, and then dried under reduced pressure to obtain 60 mg of the title compound (yield: 23%) as a white solid.


Mass spectrum (ESI, m/z): 542 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.20 & 11.65 (br s, total 1H), 9.62-9.49 (m, 1H), 7.44-7.31 (m, 4H), 7.28-7.21 (m, 1H), 6.68-6.45 (m, 1H), 5.21-4.99 (m, 1H), 4.59-4.40 (m, 2H), 4.38-4.22 (m, 2H), 4.10 (q, J=7.0 Hz, 2H), 2.56-2.42 (m, 2H), 2.27-2.14 (m, 2H), 1.93-1.73 (m, 2H), 1.69-1.45 (m, 6H), 1.18 (t, J=7.0 Hz, 3H), 0.17-0.04 (m, 9H).


Example 52
Sodium
(S)-4-(2-{6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylethoxy)-4-oxobutanoate (Sodium Salt of Compound No. V-1490)



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To a solution of 201 mg (0.456 mmol) of ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 3 in 7.0 ml of 1,4-dioxane, 628 mg of (S)-2-amino-2-phenylethyl benzyl succinate trifluoroacetate (containing impurities) synthesized in the similar manner as in Reference Example 40 and 1.0 ml (5.7 mmol) of DIPEA were added, applied to a microwave reaction apparatus, and reacted at 100° C. for 1 hour. Subsequently, 1 ml of methanol and 1 ml of triethylamine were added, applied to a microwave reaction apparatus, and reacted at 80° C. for 3 hours.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure, ethyl acetate was added to the obtained concentration residue, washed with a 10% aqueous potassium dihydrogen phosphate solution, water, a saturated aqueous solution of sodium bicarbonate, and a saturated aqueous solution of sodium chloride in this order, then dried over anhydrous magnesium sulfate, and filtered, and then, the filtrate was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: 1,2-dichloroethane:ethyl acetate=100:0 to 70:30 (V/V)), and a fraction containing (S)-benzyl (2-{6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylethyl)succinate was concentrated under reduced pressure to obtain a concentration residue.


To a solution of 171 mg of the obtained concentration residue in 20 ml of ethanol, 25.4 mg of palladium/carbon (ASCA2 (trade name), manufactured by N.E. Chemcat Corp., containing 52% water) was added in a nitrogen atmosphere and then, after replacement with a hydrogen atmosphere under reduced pressure, stirred at room temperature for 2 hours.


After the completion of the reaction, replacement with an argon atmosphere was performed, and the reaction solution was filtered through celite. 0.26 ml (0.26 mmol) of a 1 N aqueous sodium hydroxide solution was added to the filtrate and concentrated under reduced pressure. Diethyl ether was added to the obtained residue and then ultrasonicated, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 147 mg of the title compound (yield: 54% [2 steps]) as a white solid.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 13.32 (br s, 1H), 10.75 (br s, 1H), 7.44-7.38 (m, 2H), 7.36-7.29 (m, 2H), 7.28-7.19 (m, 1H), 6.47 (d, J=7.3 Hz, 1H), 5.11-5.02 (m, 1H), 4.57-4.41 (m, 2H), 4.28 (dd, J=5.6, 10.8 Hz, 1H), 4.17 (dd, J=8.0, 10.8 Hz, 1H), 2.49-2.42 (m, 2H), 2.35 (t, J=7.2 Hz, 2H), 2.25-2.16 (m, 2H), 2.11 (t, J=7.2 Hz, 2H), 1.87-1.71 (m, 2H), 1.58 (s, 3H), 1.51 (s, 3H), 0.08 (s, 9H).


Example 53
(S)-(2-{6,6-Dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylethoxy) methyl pivalate (Compound No. VI-474)



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To a solution of 272 mg (1.08 mmol) of (S)-(2-amino-2-phenylethoxy)methyl pivalate synthesized in the similar manner as in Reference Example 42 in 2 ml of dehydrated THF, 0.15 ml (0.86 mmol) of DIPEA and 162 mg (0.368 mmol) of ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 3 were added in this order at room temperature in a nitrogen atmosphere and then stirred for 130 minutes while heated to reflux. Subsequently, 1.0 ml of triethylamine and 0.8 ml of methanol were added to the reaction solution and then stirred for 70 minutes while heated to reflux.


After the completion of the reaction, water was added to the reaction solution, followed by extraction with dichloromethane three times. All of the obtained organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DNH silica gel, elution solvent: dichloromethane:methanol=100:0 to 98:2 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. For the obtained concentration residue, crystallization was performed with ethyl acetate/n-hexane, and the deposited solid was collected by filtration, washed by sousing with n-hexane, and then dried under reduced pressure to obtain 176 mg of the title compound (yield: 82%) as a white solid.


Mass spectrum (CI, m/z): 584 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.20 & 11.64 (br s, total 1H), 9.59-9.49 (m, 1H), 7.41-7.35 (m, 2H), 7.35-7.27 (m, 2H), 7.25-7.19 (m, 1H), 6.42 & 6.28 (d, J=8.0 Hz, total 1H), 5.29 (d, J=6.2 Hz, 1H), 5.22 (d, J=6.2 Hz, 1H), 5.02-4.94 (m, 1H), 4.57-4.37 (m, 2H), 3.91-3.83 (m, 1H), 3.79 (dd, J=6.0, 10.0 Hz, 1H), 2.49-2.40 (m, 2H), 2.28-2.13 (m, 2H), 1.92-1.73 (m, 2H), 1.67-1.45 (m, 6H), 1.13 (s, 9H), 0.14-0.06 (m, 9H).


Example 54
(S)-2-Acetoxy-1-phenylethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate (Compound No. V-1250)



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To a solution of 412 mg of ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate (containing impurities) synthesized in the similar manner as in Reference Example 3 by using 506 mg (1.06 mmol) of 5-tert-butyl 2-ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]pyrrolo[3,4-c]pyrazole-2,5(4H,6H)-dicarboxylate synthesized in the similar manner as in Reference Example 84 in 4 ml of dehydrated THF, 0.70 ml (4.0 mmol) of DIPEA and 1.30 g (3.84 mmol) of (S)-2-({[(2,5-dioxopyrrolidin-1-yl)oxy]carbonyl}oxy)-2-phenylethyl acetate synthesized in the similar manner as in Reference Example 43 were added in this order at room temperature in a nitrogen atmosphere and then stirred for 1.5 hours while heated to reflux. Subsequently, 2.0 ml (14 mmol) of triethylamine and 1.5 ml (37 mmol) of methanol were added to the reaction solution and then stirred for 3.5 hours while heated to reflux.


After the completion of the reaction, water was added to the reaction solution, followed by extraction with dichloromethane three times. All of the obtained organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=80:20 to 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 225 mg of a concentration residue.


Approximately 50 mg of the obtained concentration residue was subjected to preparative HPLC (column: X-Bridge (trade name) ODS, elution solvent: acetonitrile:1 mM aqueous dipotassium hydrogen phosphate solution=50:50 (V/V)), a fraction containing the compound of interest was concentrated under reduced pressure, and acetonitrile was distilled off. The concentration residue was subjected to extraction with ethyl acetate twice, and all of the obtained organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. For the obtained concentration residue, crystallization was performed with ethyl acetate/diisopropyl ether/n-hexane, and the deposited solid was collected by filtration, washed by sousing with n-hexane, and then dried under reduced pressure to obtain 11.6 mg of the title compound (yield: 2% [2 steps]) as a white solid.


Mass spectrum (CI, m/z): 513 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.35-12.21 & 11.97-11.83 (m, total 1H), 9.87-9.45 (m, 1H), 7.47-7.24 (m, 5H), 5.99-5.85 (m, 1H), 4.65-4.17 (m, 4H), 2.48-2.36 (m, 2H), 2.28-2.10 (m, 2H), 2.05-1.95 (m, 3H), 1.92-1.72 (m, 2H), 1.71-1.43 (m, 6H), 0.16-0.02 (m, 9H).


Example 55
(S)-Benzyl
2-{6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylacetate (Compound No. IV-411)



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To a solution of 195 mg (0.442 mmol) of ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2 (4H)-carboxylate synthesized in the similar manner as in Reference Example 3 in 7 ml of 1,4-dioxane, 565 mg of (S)-benzyl 2-amino-2-phenylacetate trifluoroacetate (containing impurities) synthesized in the similar manner as in Reference Example 45 and 0.50 ml (2.9 mmol) of DIPEA were added at room temperature in an argon atmosphere, then applied to a microwave reaction apparatus, and stirred at 100° C. for 1 hour. After the reaction, the reaction solution was concentrated under reduced pressure, and 4 ml of methanol and 1 ml of triethylamine were added to the obtained concentration residue, applied to a microwave reaction apparatus, and reacted at 80° C. for 1 hour.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure, ethyl acetate was added to the obtained concentration residue, the organic layer after washing with a 10% aqueous potassium dihydrogen phosphate solution, a saturated aqueous solution of sodium bicarbonate, and a saturated aqueous solution of sodium chloride in this order was dried over anhydrous magnesium sulfate and filtered, and then, the filtrate was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: 1,2-dichloroethane:ethyl acetate=100:0 to 55:45 (V/V)), and a fraction composed mainly of the title compound and a fraction composed mainly of a by-product [(S)-methyl 2-{6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylacetate] were each concentrated under reduced pressure. The concentration residue of the fraction composed mainly of the title compound was subjected again to silica gel column chromatography (DIOL silica gel, elution solvent: 1,2-dichloroethane:ethyl acetate=100:0 to 55:45 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 99 mg of the title compound (yield: 39%) as a white foam.


Mass spectrum (DUIS, m/z): 574 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.21 & 11.70 (br s, total 1H), 9.63-9.44 (m, 1H), 7.51-7.41 (m, 2H), 7.38-7.23 (m, 8H), 6.81-6.47 (m, 1H), 5.42 (d, J=7.2 Hz, 1H), 5.17 (d, J=12.7 Hz, 1H), 5.11 (d, J=12.7 Hz, 1H), 4.61-4.39 (m, 2H), 2.49-2.38 (m, 2H), 2.25-2.12 (m, 2H), 1.91-1.72 (m, 2H), 1.68-1.52 (m, 6H), 0.07 (s, 9H).


Example 56
(S)-Methyl 2-{6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylacetate (Compound No. IV-419)



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The concentration residue of the fraction composed mainly of the title compound collected at the time of the first purification of silica gel column chromatography in the operational steps of Example 55 was subjected again to silica gel column chromatography (DIOL silica gel, elution solvent: 1,2-dichloroethane:ethyl acetate=100:0 to 55:45 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 29 mg of the title compound (yield: 13%) as a white foam.


Mass spectrum (DUIS, m/z): 498 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.21 & 11.71 (br s, total 1H), 9.63-9.46 (m, 1H), 7.48-7.41 (m, 2H), 7.40-7.28 (m, 3H), 6.73-6.56 (m, 1H), 5.36 (d, J=7.2 Hz, 1H), 4.61-4.38 (m, 2H), 3.62 (s, 3H), 2.49-2.38 (m, 2H), 2.27-2.10 (m, 2H), 1.92-1.71 (m, 2H), 1.67-1.51 (m, 6H), 0.08 (s, 9H).


Example 57
N-(2,2-Difluoro-3-hydroxy-1-phenylpropyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound No. IV-362)



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To a solution of 249 mg (1.33 mmol) of 3-amino-2,2-difluoro-3-phenylpropan-1-ol synthesized in the similar manner as in Reference Example 48 in 2 ml of dehydrated 1,4-dioxane, 0.30 ml (1.7 mmol) of DIPEA and 178 mg (0.403 mmol) of ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 3 were added in this order at room temperature in a nitrogen atmosphere and then stirred at 80° C. for 7 hours. Subsequently, 0.10 ml (1.7 mmol) of 2-aminoethanol was added to the reaction solution allowed to cool to room temperature, and then stirred at room temperature for 1.5 hours.


After the completion of the reaction, a saturated aqueous solution of sodium bicarbonate was added to the reaction solution and stirred, followed by extraction with dichloromethane three times. All of the organic layers were dried over anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=60:40 to 30:70 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in ethyl acetate, then n-hexane was added, and the deposited solid was collected by filtration, washed with n-hexane, and then dried under reduced pressure to obtain 155 mg of the title compound (yield: 74%) as a white solid.


Mass spectrum (CI, m/z): 520 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.43-11.84 (m, 1H), 10.02-9.36 (m, 1H), 7.56-7.50 (m, 2H), 7.40-7.27 (m, 3H), 6.61 (br s, 1H), 5.71 (br s, 1H), 5.49-5.34 (m, 1H), 4.70-4.56 (m, 1H), 4.47 (br d, J=12.0 Hz, 1H), 3.73-3.45 (m, 2H), 2.57-2.42 (m, 2H), 2.26-2.15 (m, 2H), 1.90-1.74 (m, 2H), 1.61 (s, 3H), 1.51 (s, 3H), 0.09 (s, 9H).


Example 58
N-(2-Isopropoxy-1-phenylethyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound No. IV-146)



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To a solution of 0.102 g (0.231 mmol) of ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2 (4H)-carboxylate synthesized in the similar manner as in Reference Example 3 and 0.127 g (0.709 mmol) of 2-isopropoxy-1-phenylethanamine synthesized in the similar manner as in Reference Example 50 in 2.5 ml of dehydrated 1,4-dioxane, 0.200 ml (1.15 mmol) of DIPEA was added at room temperature in a nitrogen atmosphere and then heated and stirred at 100° C. for 1 hour. After standing to cool, 0.50 ml (12 mmol) of methanol and 0.070 ml (1.2 mmol) of 2-aminoethanol were added to the reaction solution and stirred at room temperature for 1 hour.


After the completion of the reaction, ethyl acetate was added to the residue obtained by concentration under reduced pressure, the organic layer after washing with a 10% aqueous potassium dihydrogen phosphate solution, a saturated aqueous solution of sodium bicarbonate, and a saturated aqueous solution of sodium chloride in this order was dried over anhydrous magnesium sulfate and filtered, and then, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: 1,2-dichloroethane:ethyl acetate=100:0 to 50:50 (V/V)), a fraction containing the compound of interest was concentrated under reduced pressure, the residue was dissolved in a small amount of dichloromethane, and after addition of n-hexane and ultrasonication, the deposited solid was collected by filtration and dried under reduced pressure to obtain 0.106 g of the title compound (yield: 90%) as a white solid.


Mass spectrum (CI, m/z): 512 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.21 & 11.76 (br s, total 1H), 9.68-9.50 (m, 1H), 7.42-7.16 (m, 5H), 6.31-6.08 (m, 1H), 4.94-4.84 (m, 1H), 4.56-4.37 (m, 2H), 3.67-3.51 (m, 3H), 2.51-2.40 (m, 2H), 2.27-2.13 (m, 2H), 1.92-1.71 (m, 2H), 1.65-1.48 (m, 6H), 1.08-1.03 (m, 6H), 0.09 (s, 9H).


Example 59
6,6-Dimethyl-N-(2-phenoxy-1-phenylethyl)-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound No. IV-162)



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To a solution of 0.101 g (0.230 mmol) of ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 3 and 0.145 g (0.681 mmol) of 2-phenoxy-1-phenylethanamine synthesized in the similar manner as in Reference Example 52 in 2.5 ml of dehydrated 1,4-dioxane, 0.200 ml (1.15 mmol) of DIPEA was added at room temperature in a nitrogen atmosphere and then stirred at 100° C. for 1 hour. After standing to cool, 0.50 ml (12 mmol) of methanol and 0.070 ml (1.2 mmol) of 2-aminoethanol were added and stirred at room temperature for 1 hour.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure, ethyl acetate was added, the organic layer after washing with a 10% aqueous potassium dihydrogen phosphate solution, a saturated aqueous solution of sodium bicarbonate, and a saturated aqueous solution of sodium chloride in this order was dried over anhydrous magnesium sulfate and filtered, and then, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: 1,2-dichloroethane:ethyl acetate=100:0 to 67:33 (V/V)), a fraction containing the compound of interest was concentrated under reduced pressure, the residue was dissolved in a small amount of dichloromethane, and after addition of n-hexane and ultrasonication, the deposited solid was collected by filtration and dried under reduced pressure to obtain 0.112 g of the title compound (yield: 89%) as a white solid.


Mass spectrum (CI, m/z): 546 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.21 & 11.70 (br s, total 1H), 9.57 (br s, 1H), 7.51-7.18 (m, 7H), 7.03-6.86 (m, 3H), 6.68-6.40 (m, 1H), 5.23-5.11 (m, 1H), 4.57-4.38 (m, 2H), 4.34-4.22 (m, 1H), 4.16 (dd, J=5.9, 9.8 Hz, 1H), 2.57-2.39 (m, 2H), 2.25-2.11 (m, 2H), 1.90-1.71 (m, 2H), 1.62 (br s, 3H), 1.54 (br s, 3H), 0.08 (s, 9H).


Example 60
(S)—N-[1-(2-Chlorophenyl)-2-hydroxyethyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound No. IV-959)



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To a solution of 0.105 g (0.238 mmol) of ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 3 and 0.124 g (0.723 mmol) of (S)-2-amino-2-(2-chlorophenyl)ethanol [purchased from Amatek Chemical Co., Ltd.] in 2.5 ml of dehydrated 1,4-dioxane, 0.200 ml (1.15 mmol) of DIPEA was added at room temperature in a nitrogen atmosphere and then stirred at 100° C. for 1 hour. After standing to cool, 0.50 ml (12 mmol) of methanol and 0.070 ml (1.2 mmol) of 2-aminoethanol were added and stirred at room temperature for 1 hour.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, the organic layer after washing with a 10% aqueous potassium dihydrogen phosphate solution, a saturated aqueous solution of sodium bicarbonate, and a saturated aqueous solution of sodium chloride in this order was dried over anhydrous magnesium sulfate and filtered, and then, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: 1,2-dichloroethane:ethyl acetate=84:16 to 33:67 (V/V)), a fraction containing the compound of interest was concentrated under reduced pressure, the residue was dissolved in a small amount of dichloromethane, and after addition of n-hexane and ultrasonication, the deposited solid was collected by filtration and dried under reduced pressure to obtain 0.0958 g of the title compound (yield: 80%) as a white solid.


Mass spectrum (DUIS, m/z): 504 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.21 & 11.75 (br s, total 1H), 9.71-9.52 (m, 1H), 7.51 (dd, J=1.6, 7.7 Hz, 1H), 7.38 (dd, J=1.2, 7.8 Hz, 1H), 7.33-7.20 (m, 2H), 6.36-6.14 (m, 1H), 5.21-5.12 (m, 1H), 5.04 (t, J=6.0 Hz, 1H), 4.66-4.45 (m, 2H), 3.64-3.48 (m, 2H), 2.57-2.41 (m, 2H), 2.28-2.13 (m, 2H), 1.91-1.72 (m, 2H), 1.66-1.42 (m, 6H), 0.10 (s, 9H).


Example 61
(S)—N-[2-Hydroxy-1-(o-tolyl)ethyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound No. IV-1067)



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To a solution of 0.104 g (0.235 mmol) of ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 3 and 0.131 g (0.696 mmol) of (S)-2-amino-2-(o-tolyl)ethanol hydrochloride [purchased from Acesys Pharmatech Ltd.] in 2.5 ml of dehydrated 1,4-dioxane, 0.400 ml (2.30 mmol) of DIPEA was added at room temperature in a nitrogen atmosphere and then heated and stirred at 100° C. for 1 hour. After standing to cool, 0.50 ml (12 mmol) of methanol and 0.070 ml (1.2 mmol) of 2-aminoethanol were added and stirred at room temperature for 1 hour.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure, ethyl acetate was added, the organic layer after washing with a 10% aqueous potassium dihydrogen phosphate solution, a saturated aqueous solution of sodium bicarbonate, and a saturated aqueous solution of sodium chloride in this order was dried over anhydrous magnesium sulfate and filtered, and then, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: 1,2-dichloroethane:ethyl acetate=84:16 to 33:67 (V/V)), a fraction containing the compound of interest was concentrated under reduced pressure, the residue was dissolved in a small amount of dichloromethane, and after addition of n-hexane and ultrasonication, the deposited solid was collected by filtration and dried under reduced pressure to obtain 0.0738 g of the title compound (yield: 65%) as a white solid.


Mass spectrum (CI, m/z): 484 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.20 & 11.66 (br s, total 1H), 9.63-9.50 (m, 1H), 7.40 (d, J=7.4 Hz, 1H), 7.18-7.03 (m, 3H), 6.28-6.05 (m, 1H), 5.04-4.95 (m, 1H), 4.89 (t, J=6.0 Hz, 1H), 4.58-4.41 (m, 2H), 3.61-3.43 (m, 2H), 2.56-2.41 (m, 2H), 2.36 (s, 3H), 2.27-2.11 (m, 2H), 1.93-1.70 (m, 2H), 1.69-1.41 (m, 6H), 0.10 (s, 9H).


Example 62
(S)—N-(1-Hydroxy-3-phenylpropan-2-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound No. IV-862)



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To a solution of 101 mg (0.229 mmol) of ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 3 in 3 ml of 1,4-dioxane, 0.115 ml (0.673 mmol) of DIPEA and 102 mg (0.675 mmol) of (S)-2-amino-3-phenylpropan-1-ol were added in this order in an argon atmosphere and then stirred at 100° C. for 1 hour. Subsequently, the reaction solution was concentrated under reduced pressure, and 2 ml of methanol and 0.5 ml of triethylamine were added in this order at room temperature and stirred at 80° C. for 1 hour in a microwave reaction apparatus.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure, the concentration residue was dissolved in 5 ml of ethyl acetate and washed with a 5% aqueous potassium dihydrogen phosphate solution twice, and then, the organic layer was washed with 5 ml of a saturated aqueous solution of sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: ethyl acetate:methanol=100:0 to 86:14 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and subsequently dried under reduced pressure at 50° C. to obtain 88.5 mg of the title compound (yield: 80%) as a white solid.


Mass spectrum (CI, m/z): 484 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.19 & 11.71 (br s, total 1H), 9.54 (br s, 1H), 7.28-7.18 (m, 4H), 7.18-7.12 (m, 1H), 5.72-5.45 (m, 1H), 4.77 (t, J=5.5 Hz, 1H), 4.46-4.17 (m, 2H), 3.90-3.77 (m, 1H), 3.44-3.28 (m, 2H), 2.87-2.70 (m, 2H), 2.54-2.40 (m, 2H), 2.25-2.13 (m, 2H), 1.92-1.70 (m, 2H), 1.58 (br s, 3H), 1.50 (br s, 3H), 0.09 (s, 9H).


Example 63
N-(2-Hydroxy-3-methylbutyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound No. IV-446)



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To a solution of 103 mg (0.234 mmol) of ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2 (4H)-carboxylate synthesized in the similar manner as in Reference Example 3 in 3 ml of 1,4-dioxane, 69.8 mg (0.677 mmol) of 1-amino-3-methylbutan-2-ol [purchased from Life Chemicals Inc.] and 0.115 ml (0.673 mmol) of DIPEA were added in this order at room temperature in an argon atmosphere and then stirred at 100° C. for 2.5 hours.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure, the concentration residue was dissolved in 5 ml of ethyl acetate and washed with a 5% aqueous potassium dihydrogen phosphate solution twice, and then, the organic layer was washed with 5 ml of a saturated aqueous solution of sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: ethyl acetate:methanol=100:0 to 86:14 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in dichloromethane, n-hexane was added, and then, the deposited solid was collected by filtration and dried under reduced pressure to obtain 71.9 mg of the title compound (yield: 71%) as a white solid.


Mass spectrum (CI, m/z): 436 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.20 & 11.72 (br s, total 1H), 9.56 (br s, 1H), 6.03-5.75 (m, 1H), 4.79 (d, J=4.5 Hz, 1H), 4.48-4.27 (m, 2H), 3.29-3.17 (m, 2H), 2.96-2.85 (m, 1H), 2.56-2.39 (m, 2H), 2.25-2.12 (m, 2H), 1.91-1.72 (m, 2H), 1.68-1.50 (m, 7H), 0.86 (d, J=6.8 Hz, 6H), 0.08 (s, 9H).


Example 64
(R)—N-(1-Hydroxy-3-phenylpropan-2-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound No. IV-861)



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To a solution of 0.102 g (0.232 mmol) of ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 3 and 0.110 g (0.729 mmol) of (R)-2-amino-3-phenylpropan-1-ol in 2.5 ml of dehydrated 1,4-dioxane, 0.20 ml (1.1 mmol) of DIPEA was added at room temperature in an argon atmosphere and then heated and stirred at 100° C. for 1.5 hours. After standing to cool, the resultant was concentrated under reduced pressure, and 4 ml of methanol and 1 ml of triethylamine were added to the residue, applied to a microwave reaction apparatus, and reacted at 80° C. for 1 hour.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure, ethyl acetate was added, the organic layer after washing with a 10% aqueous potassium dihydrogen phosphate solution, a saturated aqueous solution of sodium bicarbonate, and a saturated aqueous solution of sodium chloride in this order was dried over anhydrous magnesium sulfate and filtered, and then, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: ethyl acetate:methanol=100:0 to 90:10 (V/V)), a fraction containing the compound of interest was concentrated under reduced pressure, small amounts of dichloromethane and n-hexane were added to the residue, and after ultrasonication, the deposited solid was collected by filtration and dried under reduced pressure to obtain 0.0454 g of the title compound (yield: 40%) as a white solid.


Mass spectrum (CI, m/z): 484 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.19 & 11.65 (br s, total 1H), 9.54 (s, 1H), 7.28-7.18 (m, 4H), 7.18-7.12 (m, 1H), 5.70-5.47 (m, 1H), 4.77 (t, J=5.5 Hz, 1H), 4.45-4.19 (m, 2H), 3.90-3.77 (m, 1H), 3.46-3.29 (m, 2H), 2.87-2.70 (m, 2H), 2.56-2.38 (m, 2H), 2.26-2.11 (m, 2H), 1.92-1.71 (m, 2H), 1.65-1.40 (m, 6H), 0.09 (s, 9H).


Example 65
(R)—N-(2-Hydroxy-2-phenylethyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound No. IV-786)



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To a solution of 101 mg (0.229 mmol) of ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 3 in 2 ml of dehydrated THF, 0.20 ml (1.1 mmol) of DIPEA and 151 mg (1.10 mmol) of (R)-2-amino-1-phenylethanol were added in this order at room temperature in a nitrogen atmosphere and then stirred for 3 hours then with the temperature unchanged.


After the completion of the reaction, a saturated aqueous solution of sodium bicarbonate was added to the reaction solution and stirred, followed by extraction with dichloromethane three times. All of the organic layers were dried over anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=70:30 to 20:80 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was subjected to preparative HPLC (column: X-Bridge (trade name) ODS, elution solvent: acetonitrile:1 mM aqueous dipotassium hydrogen phosphate solution=40:60 (V/V)), a fraction containing the compound of interest was concentrated under reduced pressure, and acetonitrile was distilled off. The solid deposited in the course of concentration was collected by filtration, washed with pure water, and then dried under reduced pressure to obtain 55 mg of the title compound (yield: 51%) as a white solid.


Mass spectrum (EI, m/z): 469 [M]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.21 & 11.67 (br s, total 1H), 9.56 (s, 1H), 7.36-7.28 (m, 4H), 7.27-7.19 (m, 1H), 6.19-5.94 (m, 1H), 5.59 (d, J=4.0 Hz, 1H), 4.66 (td, J=4.0, 8.0 Hz, 1H), 4.48-4.24 (m, 2H), 3.44-3.22 (m, 1H), 3.09 (ddd, J=4.8, 8.0, 13.2 Hz, 1H), 2.56-2.38 (m, 2H), 2.26-2.12 (m, 2H), 1.90-1.72 (m, 2H), 1.60 (br s, 6H), 0.08 (s, 9H).


Example 66
(S)—N-(2-Hydroxy-2-phenylethyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound No. IV-787)



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To a solution of 102 mg (0.231 mmol) of ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 3 in 2 ml of dehydrated THF, 0.20 ml (1.1 mmol) of DIPEA and 129 mg (0.943 mmol) of (S)-2-amino-1-phenylethanol were added in this order at room temperature in a nitrogen atmosphere and then stirred for 4 hours with the temperature unchanged.


After the completion of the reaction, a saturated aqueous solution of sodium bicarbonate was added to the reaction solution and stirred, followed by extraction with dichloromethane three times. All of the organic layers were dried over anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: dichloromethane:methanol=100:0 to 98:2 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was subjected to preparative HPLC (column: X-Bridge (trade name) ODS, elution solvent: acetonitrile:1 mM aqueous dipotassium hydrogen phosphate solution=45:55 (V/V)), a fraction containing the compound of interest was concentrated under reduced pressure, and acetonitrile was distilled off. The solid deposited in the course of concentration was collected by filtration, washed with pure water, and then dried under reduced pressure. Ethyl acetate was added to the obtained solid, then insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained concentration residue was dissolved in ethyl acetate, then n-hexane was added, and the deposited solid was collected by filtration, washed with n-hexane, and then dried under reduced pressure to obtain 52 mg of the title compound (yield: 48%) as a white solid.


Mass spectrum (EI, m/z): 469 [M]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.21 & 11.70 (br s, total 1H), 9.63-9.53 (m, 1H), 7.36-7.28 (m, 4H), 7.27-7.19 (m, 1H), 6.19-5.94 (m, 1H), 5.59 (d, J=4.0 Hz, 1H), 4.66 (td, J=4.0, 8.0 Hz, 1H), 4.48-4.24 (m, 2H), 3.44-3.22 (m, 1H), 3.15-3.04 (m, 1H), 2.56-2.38 (m, 2H), 2.26-2.12 (m, 2H), 1.90-1.72 (m, 2H), 1.60 (br s, 6H), 0.08 (s, 9H).


Example 67
2-Hydroxy-2-phenylethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate (Compound No. IV-670)



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To a solution of 0.125 g of 2-[(2-methoxypropan-2-yl)oxy]-2-phenylethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate (containing impurities) synthesized in Reference Example 56 in 3 ml of methanol, 0.0077 g (0.031 mmol) of pyridinium p-toluenesulfonate was added at 0° C. in a nitrogen atmosphere and stirred at the same temperature as above for 3.5 hours, and then, 0.020 ml of triethylamine was added and concentrated under reduced pressure.


The residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: 1,2-dichloroethane:ethyl acetate=77:23 to 26:74 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 0.0837 g of the title compound (yield: 66% [2 steps]) as a white foam.


Mass spectrum (CI, m/z): 471 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.25 & 12.19 & 11.83 (br s, total 1H), 9.73-9.49 (m, 1H), 7.47-7.19 (m, 5H), 5.58 (d, J=4.5 Hz, 1H), 4.89-4.74 (m, 1H), 4.50-4.23 (m, 2H), 4.21-3.91 (m, 2H), 2.57-2.35 (m, 2H), 2.27-2.09 (m, 2H), 1.93-1.68 (m, 2H), 1.66-1.30 (m, 6H), 0.17-0.01 (m, 9H).


Example 68
(R)—N-[6,6-Dimethyl-5-(2-phenoxypropanoyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide (Compound No. IV-1258)



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To a solution of 58.3 mg (0.351 mmol) of (R)-2-phenoxypropanoic acid in 2 ml of dehydrated DMF, 0.12 ml (0.69 mmol) of DIPEA and 152 mg (0.354 mmol) of (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate [COMU (trade name)] were added in this order at 0° C. in a nitrogen atmosphere and then stirred for 20 minutes with the temperature unchanged. Subsequently, 104 mg (0.274 mmol) of ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-carboxylate synthesized in the similar manner as in Reference Example 5 was added at 0° C. and then stirred at room temperature for 15.5 hours. Subsequently, 0.10 ml (1.7 mmol) of 2-aminoethanol was added to the reaction solution at room temperature and then stirred for 2.5 hours with the temperature unchanged.


After the completion of the reaction, a saturated aqueous solution of sodium bicarbonate was added to the reaction solution and stirred, followed by extraction with dichloromethane three times. All of the obtained organic layers were dried over anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The operation of adding toluene to the obtained concentration residue, followed by concentration under reduced pressure again was repeated twice, then the resultant was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=75:25 to 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in ethyl acetate, then n-hexane was added, and the deposited solid was collected by filtration, washed with n-hexane, and then dried under reduced pressure to obtain 75 mg of the title compound (yield: 60%) as a white solid.


Mass spectrum (EI, m/z): 454 [M]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.53-11.80 (m, 1H), 9.69 (br s, 1H), 7.30-7.21 (m, 2H), 6.94-6.87 (m, 1H), 6.85-6.78 (m, 2H), 4.90 (q, J=6.5 Hz, 1H), 4.87-4.78 (m, 1H), 4.67-4.57 (m, 1H), 2.56-2.38 (m, 2H), 2.25-2.12 (m, 2H), 1.87-1.74 (m, 2H), 1.67-1.58 (m, 6H), 1.46 (d, J=6.5 Hz, 3H), 0.06 (s, 9H).


Example 69
(S)—N-[6,6-Dimethyl-5-(2-phenoxypropanoyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide (Compound No. IV-1259)



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To a solution of 58.6 mg (0.353 mmol) of (S)-2-phenoxypropanoic acid in 2 ml of dehydrated DMF, 0.12 ml (0.69 mmol) of DIPEA and 153 mg (0.356 mmol) of (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate [COMU (trade name)] were added in this order at 0° C. in a nitrogen atmosphere and then stirred for 20 minutes with the temperature unchanged. Subsequently, 104 mg (0.275 mmol) of ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-carboxylate synthesized in the similar manner as in Reference Example 5 was added at 0° C. and then stirred at room temperature for 3 hours. Subsequently, 0.10 ml (1.7 mmol) of 2-aminoethanol was added to the reaction solution at room temperature and then stirred for 2 hours with the temperature unchanged.


After the completion of the reaction, a saturated aqueous solution of sodium bicarbonate was added to the reaction solution and stirred, followed by extraction with dichloromethane three times. All of the obtained organic layers were dried over anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The operation of adding toluene to the obtained concentration residue, followed by concentration under reduced pressure again was repeated twice, then the resultant was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=75:25 to 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in ethyl acetate, then n-hexane was added, and the deposited solid was collected by filtration, washed with n-hexane, and then dried under reduced pressure to obtain 75 mg of the title compound (yield: 60%) as a white solid.


Mass spectrum (EI, m/z): 454 [M]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.32 & 11.92 (br s, total 1H), 9.81-9.55 (m, 1H), 7.30-7.21 (m, 2H), 6.94-6.87 (m, 1H), 6.85-6.78 (m, 2H), 4.96-4.74 (m, 2H), 4.71-4.54 (m, 1H), 2.56-2.38 (m, 2H), 2.26-2.10 (m, 2H), 1.91-1.72 (m, 2H), 1.69-1.54 (m, 6H), 1.46 (d, J=6.5 Hz, 3H), 0.06 (br s, 9H).


Example 70
N-[6,6-Dimethyl-5-(2-phenoxyacetyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide (Compound No. IV-1238)



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To a solution of 0.143 g (0.279 mmol) of ethyl 6,6-dimethyl-5-(2-phenoxyacetyl)-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 57 in 3 ml of methanol, 0.150 ml (1.38 mmol) of N,N-dimethylethane-1,2-diamine was added at room temperature in a nitrogen atmosphere and then stirred at room temperature for 30 minutes.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, the organic layer after washing with a 10% aqueous potassium dihydrogen phosphate solution, a saturated aqueous solution of sodium bicarbonate, and a saturated aqueous solution of sodium chloride in this order was dried over anhydrous magnesium sulfate and filtered, and then, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: 1,2-dichloroethane:ethyl acetate=100:0 to 62:38 (V/V)), a fraction containing the compound of interest was concentrated under reduced pressure, the residue was dissolved in a small amount of dichloromethane, and after addition of n-hexane and ultrasonication, the deposited solid was collected by filtration and dried under reduced pressure to obtain 0.0876 g of the title compound (yield: 71%) as a white solid.


Mass spectrum (CI, m/z): 441 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.29 & 11.89 (br s, total 1H), 9.84-9.56 (m, 1H), 7.30-7.24 (m, 2H), 6.95-6.89 (m, 3H), 4.78 (s, 2H), 4.73-4.56 (m, 2H), 2.56-2.35 (m, 2H), 2.27-2.08 (m, 2H), 1.93-1.54 (m, 8H), 0.08 (s, 9H).


Example 71
(R)—N-[6,6-Dimethyl-5-(2-phenoxypropanoyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclopropanecarboxamide (Compound No. III-1140)



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To a solution of 143 mg (0.861 mmol) of (R)-2-phenoxypropanoic acid in 3 ml of dehydrated dichloromethane, 0.12 ml (1.4 mmol) of oxalyl chloride and 0.0050 ml (0.065 mmol) of dehydrated DMF were added in this order at 0° C. in a nitrogen atmosphere and then stirred for 2 hours with the temperature unchanged.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a concentration residue.


To a solution of 154 mg (0.424 mmol) of ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 46 and 0.38 ml (2.2 mmol) of DIPEA in 2 ml of dehydrated dichloromethane, a solution of the obtained concentration residue in 1 ml of dehydrated dichloromethane was added at 0° C. in a nitrogen atmosphere and then stirred for 1.5 hours with the temperature unchanged. Subsequently, 0.24 ml (2.2 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction solution at 0° C. and then stirred at room temperature for 2 hours.


After the completion of the reaction, the reaction solution diluted with dichloromethane was washed with a 5% aqueous potassium bisulfate solution and then separated into an aqueous layer and an organic layer. The aqueous layer was subjected to extraction with dichloromethane twice, and then, all of the obtained organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=80:20 to 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in ethyl acetate, then n-hexane was added, and the deposited solid was collected by filtration, washed with n-hexane, and then dried under reduced pressure to obtain 155 mg of the title compound (yield: 83%) as a white solid.


Mass spectrum (CI, m/z): 441 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.33 & 12.02 (br s, total 1H), 10.03-9.76 (m, 1H), 7.30-7.22 (m, 2H), 6.94-6.87 (m, 1H), 6.85-6.78 (m, 2H), 4.95-4.70 (m, 2H), 4.67-4.51 (m, 1H), 1.70-1.52 (m, 6H), 1.45 (d, J=6.4 Hz, 3H), 0.98 (br s, 2H), 0.80-0.59 (m, 2H), 0.01 (br s, 9H).


Example 72
N-{5-[3-(Benzyloxy)-2-phenoxypropanoyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide (Compound No. IV-1354)



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To a solution of 340 mg of 3-(benzyloxy)-2-phenoxypropanoic acid (containing impurities) synthesized in the similar manner as in Reference Example 60 in 3 ml of dehydrated dichloromethane, 0.005 ml (0.07 mmol) of DMF and 0.140 ml (1.63 mmol) of oxalyl chloride were added dropwise with stirring at 0° C. in an argon atmosphere and stirred at the same temperature as above for 2 hours.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a concentration residue.


To a solution of 236 mg (0.625 mmol) of ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 84 and 0.550 ml (3.16 mmol) of DIPEA in 3 ml of dehydrated dichloromethane, a solution of the obtained concentration residue in 1 ml of dehydrated dichloromethane was added dropwise with stirring at 0° C. in an argon atmosphere and stirred at the same temperature as above for 1 hour. Subsequently, 0.340 ml (3.12 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction solution at room temperature and then reacted with stirring at room temperature for 16 hours.


After the completion of the reaction, a saturated aqueous solution of sodium bicarbonate was added to the reaction solution, followed by extraction with dichloromethane. The obtained organic layer was washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=60:40 to 30:70 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was subjected again to silica gel column chromatography (DNH silica gel, elution solvent: 1,2-dichloroethane:methanol=100:0 to 90:10), and some fractions containing the compound of interest at high purity were concentrated under reduced pressure. The obtained concentration residue was dissolved by adding methanol and then added to water, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 11.7 mg of the title compound (yield: 3.3%) as a white solid. Also, the remaining fractions containing the compound of interest obtained by silica gel column chromatography were combined, concentrated under reduced pressure, and dried under reduced pressure to obtain 162 mg of the title compound (yield: 46%) as a white solid.


Mass spectrum (CI, m/z): 561 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.30 & 11.92 (br s, total 1H), 9.82-9.54 (m, 1H), 7.38-7.20 (m, 7H), 6.97-6.88 (m, 1H), 6.88-6.80 (m, 2H), 5.03-4.66 (m, 3H), 4.60 (s, 2H), 3.93-3.81 (m, 2H), 2.57-2.39 (m, 2H), 2.29-2.11 (m, 2H), 1.91-1.71 (m, 2H), 1.70-1.50 (m, 6H), 0.07 (s, 9H).


Example 73
N-[5-(3-Hydroxy-2-phenoxypropanoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide (Compound No. IV-1330)



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To a solution of 162 mg (0.289 mmol) of N-{5-[3-(benzyloxy)-2-phenoxypropanoyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide synthesized in the similar manner as in Example 72 in 5 ml of ethanol, 30 mg of 20% palladium hydroxide/carbon (containing 50 wt % water) was added in an argon atmosphere and after replacement with a hydrogen atmosphere under reduced pressure, stirred at room temperature for 5 hours.


After the completion of the reaction, replacement with an argon atmosphere was performed, and the reaction solution was filtered through celite. The solid on the celite was washed with ethanol, and all of the filtrates were concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: 1,2-dichloroethane:methanol=100:0 to 95:5 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved by adding methanol and then added to water, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 61 mg of the title compound (yield: 45%) as a white solid.


Mass spectrum (CI, m/z): 471 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.39-11.82 (m, 1H), 9.70 (br s, 1H), 7.32-7.22 (m, 2H), 6.95-6.88 (m, 1H), 6.85-6.78 (m, 2H), 5.34-5.23 (m, 1H), 4.92-4.82 (m, 1H), 4.81-4.69 (m, 2H), 3.85-3.71 (m, 2H), 2.60-2.39 (m, 2H), 2.26-2.12 (m, 2H), 1.89-1.71 (m, 2H), 1.62 (s, 3H), 1.60 (s, 3H), 0.08 (s, 9H).


Example 74
N-{5-[2-(4-Chlorophenoxy)propanoyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide (Compound No. IV-1270)



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To a solution of 150 mg (0.748 mmol) of 2-(4-chlorophenoxy)propanoic acid [purchased from AK Scientific, Inc.] in 3 ml of dehydrated dichloromethane, 0.080 ml (0.93 mmol) of oxalyl chloride and 0.004 ml (0.05 mmol) of DMF were added dropwise with stirring at 0° C. in an argon atmosphere and stirred at the same temperature as above for 2 hours.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a concentration residue.


To a solution of 129 mg (0.341 mmol) of ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 84 and 0.300 ml (1.72 mmol) of DIPEA in 3 ml of dehydrated dichloromethane, a solution of the obtained concentration residue in 1 ml of dehydrated dichloromethane was added dropwise with stirring at 0° C. in an argon atmosphere and stirred at the same temperature as above for 3 hours. Subsequently, 0.200 ml (1.84 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction solution at room temperature and then reacted with stirring at room temperature for 16 hours.


After the completion of the reaction, a saturated aqueous solution of sodium bicarbonate was added to the reaction solution, followed by extraction with dichloromethane. The obtained organic layer was washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=60:40 to 30:70 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved by adding methanol and then added to water, and the deposited solid was collected by filtration and dried under reduced pressure to obtain a solid. The obtained solid was subjected again to silica gel column chromatography (DNH silica gel, elution solvent: n-hexane:ethyl acetate=50:50 to 0:100 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved by adding methanol and then added to water, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 39 mg of the title compound (yield: 23%) as a white solid.


Mass spectrum (CI, m/z): 489 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.32 & 11.89 (br s, total 1H), 9.79-9.53 (m, 1H), 7.34-7.24 (m, 2H), 6.90-6.77 (m, 2H), 4.93 (q, J=6.4 Hz, 1H), 4.90-4.72 (m, 1H), 4.70-4.50 (m, 1H), 2.60-2.36 (m, 2H), 2.28-2.10 (m, 2H), 1.93-1.70 (m, 2H), 1.70-1.53 (m, 6H), 1.46 (d, J=6.4 Hz, 3H), 0.06 (s, 9H).


Example 75
N-{5-[2-(2-Chlorophenoxy)propanoyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide (Compound No. IV-1266)



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To a solution of 150 mg (0.748 mmol) of 2-(2-chlorophenoxy)propanoic acid in 3 ml of dehydrated dichloromethane, 0.080 ml (0.93 mmol) of oxalyl chloride and 0.004 ml (0.05 mmol) of DMF were added dropwise with stirring at 0° C. in an argon atmosphere and stirred at the same temperature as above for 2 hours.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a concentration residue.


To a solution of 129 mg (0.341 mmol) of ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 84 and 0.300 ml (1.72 mmol) of DIPEA in 3 ml of dehydrated dichloromethane, a solution of the obtained concentration residue in 1 ml of dehydrated dichloromethane was added dropwise with stirring at 0° C. in an argon atmosphere and stirred at the same temperature as above for 3 hours. Subsequently, 0.200 ml (1.84 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction solution at room temperature and then reacted with stirring at room temperature for 16 hours.


After the completion of the reaction, a saturated aqueous solution of sodium bicarbonate was added to the reaction solution, followed by extraction with dichloromethane. The obtained organic layer was washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=60:40 to 30:70 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved by adding methanol and then added to water, and the deposited solid was collected by filtration and dried under reduced pressure to obtain a solid. The obtained solid was subjected again to silica gel column chromatography (DNH silica gel, elution solvent: n-hexane:ethyl acetate=100:0 to 0:100 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved by adding methanol and then added to water, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 16 mg of the title compound (yield: 10%) as a white solid.


Mass spectrum (CI, m/z): 489 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.32 & 11.92 (br s, total 1H), 9.80-9.54 (m, 1H), 7.45-7.38 (m, 1H), 7.29-7.20 (m, 1H), 6.96-6.89 (m, 1H), 6.89-6.83 (m, 1H), 5.01 (q, J=6.5 Hz, 1H), 4.92-4.74 (m, 1H), 4.72-4.52 (m, 1H), 2.58-2.37 (m, 2H), 2.27-2.10 (m, 2H), 1.93-1.71 (m, 2H), 1.71-1.55 (m, 6H), 1.51 (d, J=6.5 Hz, 3H), 0.06 (s, 9H).


Example 76
N-{5-[2-(Cyclohexyloxy)propanoyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide (Compound No. IV-1255)



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To a solution of 120 mg (0.697 mmol) of 2-(cyclohexyloxy)propanoic acid [purchased from Enamine Ltd.] in 3 ml of dehydrated dichloromethane, 0.080 ml (0.93 mmol) of oxalyl chloride and 0.005 ml (0.07 mmol) of DMF were added dropwise with stirring at 0° C. in an argon atmosphere and stirred at the same temperature as above for 2 hours.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a concentration residue.


To a solution of 129 mg (0.341 mmol) of ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 84 and 0.300 ml (1.72 mmol) of DIPEA in 3 ml of dehydrated dichloromethane, a solution of the obtained concentration residue in 1 ml of dehydrated dichloromethane was added dropwise with stirring at 0° C. in an argon atmosphere and stirred at the same temperature as above for 2 hours. Subsequently, 0.200 ml (1.84 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction solution at room temperature and then reacted with stirring at room temperature for 16 hours.


After the completion of the reaction, a saturated aqueous solution of sodium bicarbonate was added to the reaction solution, followed by extraction with dichloromethane. The obtained organic layer was washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=60:40 to 30:70 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved by adding methanol and then added to water, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 37 mg of the title compound (yield: 24%) as a white solid.


Mass spectrum (CI, m/z): 461 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.39-11.73 (m, 1H), 9.63 (br s, 1H), 4.78-4.55 (m, 2H), 4.23 (q, J=6.5 Hz, 1H), 3.41-3.26 (m, 1H), 2.58-2.37 (m, 2H), 2.25-2.12 (m, 2H), 1.90-1.72 (m, 4H), 1.71-1.55 (m, 8H), 1.50-1.39 (m, 1H), 1.28-1.05 (m, 8H), 0.07 (s, 9H).


Example 77
N-{5-[2-(3-Chlorophenoxy)propanoyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide (Compound No. IV-1268)



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To a solution of 150 mg (0.748 mmol) of 2-(3-chlorophenoxy)propanoic acid [purchased from Combi-Blocks Inc.] in 3 ml of dehydrated dichloromethane, 0.080 ml (0.93 mmol) of oxalyl chloride and 0.005 ml (0.07 mmol) of DMF were added dropwise with stirring at 0° C. in an argon atmosphere and stirred at the same temperature as above for 2 hours.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a concentration residue.


To a solution of 129 mg (0.341 mmol) of ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 84 and 0.300 ml (1.72 mmol) of DIPEA in 3 ml of dehydrated dichloromethane, a solution of the obtained concentration residue in 1 ml of dehydrated dichloromethane was added dropwise with stirring at 0° C. in an argon atmosphere and stirred at the same temperature as above for 2 hours. Subsequently, 0.200 ml (1.84 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction solution at room temperature and then reacted with stirring at room temperature for 16 hours.


After the completion of the reaction, a saturated aqueous solution of sodium bicarbonate was added to the reaction solution, followed by extraction with dichloromethane. The obtained organic layer was washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=60:40 to 30:70 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved by adding methanol and then added to water, and the deposited solid was collected by filtration and dried under reduced pressure. The obtained solid was subjected again to silica gel column chromatography (DNH silica gel, elution solvent: n-hexane:ethyl acetate=100:0 to 0:100 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved by adding methanol and then added to water, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 30 mg of the title compound (yield: 18%) as a white solid.


Mass spectrum (CI, m/z): 489 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.32 & 11.93 (br s, total 1H), 9.79-9.56 (m, 1H), 7.29 (t, J=8.3 Hz, 1H), 7.00-6.94 (m, 1H), 6.86 (t, J=2.1 Hz, 1H), 6.83-6.77 (m, 1H), 5.00 (q, J=6.4 Hz, 1H), 4.90-4.73 (m, 1H), 4.71-4.51 (m, 1H), 2.57-2.37 (m, 2H), 2.27-2.10 (m, 2H), 1.92-1.71 (m, 2H), 1.70-1.53 (m, 6H), 1.47 (d, J=6.4 Hz, 3H), 0.06 (s, 9H).


Example 78
N-[5-(2-Methoxypropanoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide (Compound No. IV-1241)



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To a solution of 65.0 mg (0.624 mmol) of 2-methoxypropanoic acid [purchased from Combi-Blocks Inc.] in 3 ml of dehydrated dichloromethane, 0.200 ml (1.15 mmol) of DIPEA and 220 mg (0.514 mmol) of (1-cyano-2-ethoxy-2-oxoethylideneaininooxy)dimethylaminomorpholinocarbenium hexafluorophosphate [COMU (trade name)] were added in this order with stirring at 0° C. in an argon atmosphere and then stirred at the same temperature as above for 15 minutes. Subsequently, 129 mg (0.341 mmol) of ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 84 was added at 0° C. and stirred at room temperature for 16 hours. Subsequently, 0.220 ml (2.02 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction solution at room temperature and then reacted with stirring at room temperature for 4 hours.


The reaction solution was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=60:40 to 30:70 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 61 mg of the title compound (yield: 46%) as a white solid.


Mass spectrum (CI, m/z): 393 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.28 & 11.86 (br s, total 1H), 9.80-9.53 (m, 1H), 4.82-4.44 (m, 2H), 4.06 (q, J=6.4 Hz, 1H), 3.20 (s, 3H), 2.57-2.37 (m, 2H), 2.29-2.10 (m, 2H), 1.93-1.55 (m, 8H), 1.21 (d, J=6.4 Hz, 3H), 0.08 (s, 9H).


Example 79
N-[5-(3-Methoxy-2-phenoxypropanoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide (Compound No. IV-1348)



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To a solution of 116 mg of 3-methoxy-2-phenoxypropanoic acid (containing impurities) synthesized in the similar manner as in Reference Example 63 in 3 ml of dehydrated dichloromethane, 0.004 ml (0.05 mmol) of DMF and 0.070 ml (0.82 mmol) of oxalyl chloride were added dropwise with stirring at 0° C. in an argon atmosphere and stirred at the same temperature as above for 2 hours.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a concentration residue.


To a solution of 124 mg (0.329 mmol) of ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 84 and 0.300 ml (1.72 mmol) of DIPEA in 3 ml of dehydrated dichloromethane, a solution of the obtained concentration residue in 1 ml of dehydrated dichloromethane was added dropwise with stirring at 0° C. in an argon atmosphere and stirred at the same temperature as above for 2 hours. Subsequently, 0.200 ml (1.84 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction solution at room temperature and then reacted with stirring at room temperature for 16 hours.


The reaction solution was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=60:40 to 30:70 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved by adding methanol and then added to water, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 75 mg of the title compound (yield: 47%) as a white solid.


Mass spectrum (CI, m/z): 485 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.32 & 11.94 (br s, total 1H), 9.85-9.57 (m, 1H), 7.34-7.21 (m, 2H), 6.97-6.89 (m, 1H), 6.88-6.78 (m, 2H), 4.98-4.79 (m, 2H), 4.78-4.59 (m, 1H), 3.83-3.68 (m, 2H), 3.34 (s, 3H), 2.58-2.37 (m, 2H), 2.28-2.10 (m, 2H), 1.92-1.71 (m, 2H), 1.69-1.49 (m, 6H), 0.08 (s, 9H).


Example 80
N-{6,6-Dimethyl-5-[2-(pyridin-3-yloxy)propanoyl]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide (Compound No. IV-1274)



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To a solution of 114 mg (0.682 mmol) of 2-(pyridin-3-yloxy)propanoic acid [purchased from Enamine Ltd.] in 3 ml of dehydrated dichloromethane, 0.200 ml (1.15 mmol) of DIPEA and 250 mg (0.584 mmol) of (1-cyano-2-ethoxy-2-oxoethylideneaininooxy)dimethylaminomorpholinocarbenium hexafluorophosphate [COMU (trade name)] were added in this order with stirring at 0° C. in an argon atmosphere and then stirred at the same temperature as above for 15 minutes. Subsequently, 172 mg (0.454 mmol) of ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 84 was added at 0° C. and stirred at room temperature for 16 hours. Subsequently, 0.250 ml (2.30 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction solution at room temperature and then reacted with stirring at room temperature for 4 hours.


The reaction solution was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=60:40 to 30:70 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved by adding methanol and then added to water, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 89 mg of the title compound (yield: 43%) as a white solid.


Mass spectrum (CI, m/z): 456 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.32 & 11.88 (s, total 1H), 9.76-9.60 (m, 1H), 8.24-8.17 (m, 1H), 8.17-8.09 (m, 1H), 7.33-7.27 (m, 1H), 7.25-7.20 (m, 1H), 5.06 (q, J=6.3 Hz, 1H), 4.93-4.79 (m, 1H), 4.70-4.54 (m, 1H), 2.57-2.38 (m, 2H), 2.27-2.13 (m, 2H), 1.91-1.71 (m, 2H), 1.69-1.54 (m, 6H), 1.50 (d, J=6.3 Hz, 3H), 0.13-0.02 (m, 9H).


Example 81
N-{5-[3-(Dimethylamino)-2-phenoxypropanoyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide (Compound No. IV-1372)



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To a solution of 70.0 mg (0.335 mmol) of 3-(dimethylamino)-2-phenoxypropanoic acid synthesized in the similar manner as in Reference Example 66 in 3 ml of dehydrated DMF, 0.150 ml (0.861 mmol) of DIPEA and 200 mg (0.467 mmol) of (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate [COMU (trade name)] were added in this order with stirring at 0° C. in an argon atmosphere and then stirred at the same temperature as above for 15 minutes. Subsequently, 115 mg (0.304 mmol) of ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 84 was added at 0° C. and stirred at room temperature for 3 hours. Subsequently, 0.200 ml (1.84 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction solution at room temperature and then reacted with stirring at room temperature for 16 hours.


After the completion of the reaction, a saturated aqueous solution of sodium bicarbonate was added to the reaction solution, followed by extraction with dichloromethane. The obtained organic layer was washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: 1,2-dichloroethane:methanol=100:0 to 90:10 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved by adding methanol and then added to water, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 57 mg of the title compound (yield: 38%) as a white solid.


Mass spectrum (CI, m/z): 498 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.48-11.69 (m, 1H), 9.67 (br s, 1H), 7.32-7.23 (m, 2H), 6.96-6.88 (m, 1H), 6.84-6.77 (m, 2H), 4.87 (br d, J=12.0 Hz, 1H), 4.81 (dd, J=4.5, 6.6 Hz, 1H), 4.66 (br d, J=12.0 Hz, 1H), 2.82-2.70 (m, 2H), 2.57-2.39 (m, 2H), 2.26 (s, 6H), 2.24-2.12 (m, 2H), 1.89-1.73 (m, 2H), 1.62 (s, 3H), 1.61 (s, 3H), 0.07 (s, 9H).


Example 82
N-[6,6-Dimethyl-5-(2-phenoxy-2-phenylacetyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide (Compound No. IV-1211)



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To a solution of 140 mg (0.613 mmol) of 2-phenoxy-2-phenylacetic acid [purchased from Enamine Ltd.] in 3 ml of dehydrated dichloromethane, 0.080 ml (0.93 mmol) of oxalyl chloride and 0.005 ml (0.07 mmol) of DMF were added dropwise with stirring at 0° C. in an argon atmosphere and stirred at the same temperature as above for 2 hours.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a concentration residue.


To a solution of 129 mg (0.341 mmol) of ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 84 and 0.300 ml (1.72 mmol) of DIPEA in 3 ml of dehydrated dichloromethane, a solution of the obtained concentration residue in 1 ml of dehydrated dichloromethane was added dropwise with stirring at 0° C. in an argon atmosphere and stirred at the same temperature as above for 3 hours. Subsequently, 0.200 ml (1.84 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction solution at room temperature and then reacted with stirring at room temperature for 16 hours.


The reaction solution was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=60:40 to 30:70 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved by adding methanol and then added to water, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 94 mg of the title compound (yield: 53%) as a white solid.


Mass spectrum (CI, m/z): 517 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.30 & 11.91 (br s, total 1H), 9.57 (br s, 1H), 7.57-7.50 (m, 2H), 7.48-7.36 (m, 3H), 7.31-7.23 (m, 2H), 6.97-6.88 (m, 3H), 5.91 (s, 1H), 4.98-4.72 (m, 1H), 4.40-4.21 (m, 1H), 2.48-2.35 (m, 2H), 2.27-2.08 (m, 2H), 1.91-1.73 (m, 2H), 1.67 (s, 3H), 1.60 (s, 3H), 0.04 (s, 9H).


Example 83
N-{5-[3-(3,3-Difluoropyrrolidin-1-yl)-2-phenoxypropanoyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide (Compound No. IV-1378)



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To a solution of 170 mg of 3-(3,3-difluoropyrrolidin-1-yl)-2-phenoxypropanoic acid (containing impurities) synthesized in the similar manner as in Reference Example 69 in 3 ml of dehydrated DMF, 0.250 ml (1.44 mmol) of DIPEA and 300 mg (0.700 mmol) of (1-cyano-2-ethoxy-2-oxoethylideneaininooxy)dimethylaminomorpholinocarbenium hexafluorophosphate [COMU (trade name)] were added in this order with stirring at 0° C. in an argon atmosphere and then stirred at the same temperature as above for 15 minutes. Subsequently, 129 mg (0.341 mmol) of ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 84 was added at 0° C. and stirred at room temperature for 16 hours. Subsequently, 0.200 ml (1.84 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction solution at room temperature and then reacted with stirring at room temperature for 64 hours.


The reaction solution was subjected to silica gel column chromatography (elution solvent: 1,2-dichloroethane:methanol=100:0 to 90:10 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was subjected to preparative HPLC (column: X-Bridge (trade name) ODS, elution solvent: acetonitrile:1 mM aqueous potassium dihydrogen phosphate solution=50:50 (V/V)), and ethyl acetate and water were added to a fraction containing the compound of interest, then an organic layer and an aqueous layer were separated. The obtained organic layer was concentrated under reduced pressure. The obtained concentration residue was dissolved by adding methanol and then added to water, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 49 mg of the title compound (yield: 26%) as a white solid.


Mass spectrum (CI, m/z): 560 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.32 & 11.94 (br s, total 1H), 9.84-9.59 (m, 1H), 7.32-7.23 (m, 2H), 6.97-6.89 (m, 1H), 6.85-6.78 (m, 2H), 4.97-4.80 (m, 2H), 4.74-4.57 (m, 1H), 3.14-2.80 (m, 6H), 2.58-2.37 (m, 2H), 2.29-2.10 (m, 4H), 1.92-1.72 (m, 2H), 1.70-1.52 (m, 6H), 0.14-0.03 (m, 9H).


Example 84
N-[5-(3-Hydroxy-2-phenylpropanoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide (Compound No. IV-632)



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To a solution of 139 mg (0.540 mmol) of 3-(benzyloxy)-2-phenylpropanoic acid synthesized according to the method described in Tetrahedron Lett., 2002 (43), 9691-9693] in 3 ml of dehydrated DMF, 0.18 ml (1.0 mmol) of DIPEA and 233 mg (0.544 mmol) of (1-cyano-2-ethoxy-2-oxoethylideneaininooxy)dimethylaminomorpholinocarbenium hexafluorophosphate [COMU (trade name)] were added in this order at 0° C. in a nitrogen atmosphere and then stirred for 15 minutes with the temperature unchanged. Subsequently, 158 mg (0.418 mmol) of ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-carboxylate synthesized in the similar manner as in Reference Example 5 was added at 0° C. and then stirred at room temperature for 3.5 hours.


After the completion of the reaction, a saturated aqueous solution of sodium bicarbonate was added to the reaction solution and stirred, followed by extraction with ethyl acetate three times. All of the obtained organic layers were dried over anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure to obtain a concentration residue.


To a solution of the obtained concentration residue in 4 ml of THF, 0.25 ml (1.8 mmol) of triethylamine and 0.10 ml (1.7 mmol) of 2-aminoethanol were added in this order at room temperature in a nitrogen atmosphere and then stirred for 1.5 hours with the temperature unchanged.


After the completion of the reaction, a saturated aqueous solution of sodium bicarbonate was added to the reaction solution and stirred, followed by extraction with dichloromethane three times. All of the obtained organic layers were dried over anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=70:30 to 50:50 (V/V)), subsequently concentrated under reduced pressure, and dried under reduced pressure to obtain a concentration residue.


To a solution of the obtained concentration residue in 2 ml of ethanol, 25.4 mg of 20% palladium hydroxide/carbon [containing 50 wt % water] was added at room temperature in a nitrogen atmosphere and then, after replacement with a hydrogen atmosphere under reduced pressure, stirred at room temperature for 1.5 hours. The inside of the reaction container was replaced with a nitrogen atmosphere under reduced pressure, and subsequently, 68.3 mg of 20% palladium hydroxide/carbon [containing 50 wt % water] was added at room temperature and then, after replacement with a hydrogen atmosphere again under reduced pressure, stirred at room temperature for 3.5 hours.


After the completion of the reaction, the inside of the reaction container was replaced with a nitrogen atmosphere under reduced pressure. The reaction solution was filtered using a celite filter, subsequently the removed solid was washed with ethanol, and then, the filtrate was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=70:30 to 30:70 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in ethyl acetate, then n-hexane was added, and the deposited solid was collected by filtration, washed with n-hexane, and then dried under reduced pressure to obtain 104 mg of the title compound (yield: 55% [2 steps]) as a white solid.


Mass spectrum (EI, m/z): 454 [M]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.45-11.70 (m, 1H), 9.58 (br s, 1H), 7.35-7.20 (m, 5H), 4.81-4.64 (m, 2H), 4.23 (d, J=12.0 Hz, 1H), 3.98-3.89 (m, 1H), 3.84 (dd, J=5.4, 8.2 Hz, 1H), 3.52-3.44 (m, 1H), 2.58-2.37 (m, 2H), 2.24-2.12 (m, 2H), 1.87-1.73 (m, 2H), 1.69 (s, 3H), 1.58 (s, 3H), 0.05 (s, 9H).


Example 85
(S)—N-[5-(3-Hydroxy-2-phenylpropanoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide (Compound No. IV-633)



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To a solution of 139 mg (0.256 mmol) of (S)—N-{5-[3-(benzyloxy)-2-phenylpropanoyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide synthesized in the similar manner as in Reference Example 70 in 2 ml of ethanol, 58.4 mg of 20% palladium hydroxide/carbon [containing 50 wt % water] was added at room temperature in a nitrogen atmosphere and then, after replacement with a hydrogen atmosphere under reduced pressure, stirred at room temperature for 3 hours.


After the completion of the reaction, the inside of the reaction container was replaced with a nitrogen atmosphere under reduced pressure. The reaction solution was filtered using a celite filter, subsequently the removed solid was washed with ethyl acetate, and then, the filtrate was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=85:15 to 35:65 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in ethyl acetate, then n-hexane was added, and the deposited solid was collected by filtration, washed with n-hexane, and then dried under reduced pressure to obtain 55 mg of the title compound (yield: 47%) as a white solid.


Mass spectrum (CI, m/z): 455 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.24 & 11.85 (br s, total 1H), 9.73-9.44 (m, 1H), 7.35-7.20 (m, 5H), 4.81-4.63 (m, 2H), 4.33-4.11 (m, 1H), 3.98-3.89 (m, 1H), 3.88-3.80 (m, 1H), 3.52-3.44 (m, 1H), 2.60-2.36 (m, 2H), 2.26-2.10 (m, 2H), 1.89-1.64 (m, 5H), 1.58 (br s, 3H), 0.05 (s, 9H).


Example 86
(R)—N-{5-[3-(Benzyloxy)-2-phenylpropanoyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide (Compound No. IV-1221)



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To a solution of 1.22 g (4.76 mmol) of (R)-3-(benzyloxy)-2-phenylpropanoic acid [synthesized according to the method described in Tetrahedron Lett., 2002, 43, 9691-9693] in 20 ml of dehydrated dichloromethane, 0.55 ml (6.4 mmol) of oxalyl chloride and 0.030 ml (0.39 mmol) of dehydrated DMF were added in this order at 0° C. in a nitrogen atmosphere and then stirred for 2 hours with the temperature unchanged.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a concentration residue.


To a solution of 903 mg (2.39 mmol) of ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 84 and 1.70 ml (9.76 mmol) of DIPEA in 15 ml of dehydrated dichloromethane, a solution of the obtained concentration residue in 5 ml of dehydrated dichloromethane was added at 0° C. in a nitrogen atmosphere and then stirred for 2 hours with the temperature unchanged. Subsequently, 1.0 ml (9.2 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction solution at 0° C. and then stirred at room temperature for 1.5 hours.


After the completion of the reaction, the reaction solution diluted with dichloromethane was washed with a 5% aqueous potassium bisulfate solution and then the aqueous layer and the organic layer were separated. The aqueous layer was subjected to extraction with dichloromethane twice, and then, all of the obtained organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=85:15 to 50:50 (V/V)), and some fractions containing the compound of interest at high purity were concentrated under reduced pressure. The obtained concentration residue was dissolved in ethyl acetate, then n-hexane was added, and the deposited solid was collected by filtration, washed with n-hexane, and then dried under reduced pressure to obtain 43 mg of the title compound (yield: 3%) as a white solid. Also, the remaining fractions containing the compound of interest obtained by silica gel column chromatography were concentrated under reduced pressure and dried under reduced pressure to obtain 1.10 g of the title compound (yield: 85%) as a pale yellow foam.


Mass spectrum (CI, m/z): 545 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.25 & 11.85 (s, total 1H), 9.65-9.47 (m, 1H), 7.38-7.20 (m, 10H), 4.79-4.62 (m, 1H), 4.52 (d, J=12.6 Hz, 1H), 4.47 (d, J=12.6 Hz, 1H), 4.31-4.15 (m, 1H), 4.07-3.94 (m, 2H), 3.57-3.47 (m, 1H), 2.57-2.36 (m, 2H), 2.25-2.09 (m, 2H), 1.89-1.64 (m, 5H), 1.63-1.50 (m, 3H), 0.09-0.02 (m, 9H).


Example 87
(R)—N-[5-(3-Hydroxy-2-phenylpropanoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide (Compound No. IV-1215)



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To a solution of 1.10 g (2.02 mmol) of (R)—N-{5-[3-(benzyloxy)-2-phenylpropanoyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide synthesized in the similar manner as in Example 86 in 15 ml of ethanol, 326 mg of 20% palladium hydroxide/carbon [containing 50 wt % water] was added at room temperature in a nitrogen atmosphere and then, after replacement with a hydrogen atmosphere under reduced pressure, stirred at room temperature for 3.5 hours.


After the completion of the reaction, the inside of the reaction container was replaced with a nitrogen atmosphere under reduced pressure. The reaction solution was filtered using a celite filter, subsequently the removed solid was washed with ethyl acetate, and then, the filtrate was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=70:30 to 10:90 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was subjected again to silica gel column chromatography (elution solvent: dichloromethane:methanol=100:0 to 96:4 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in ethyl acetate, then n-hexane was added, and the deposited solid was collected by filtration, washed with n-hexane, and then dried under reduced pressure to obtain 708 mg of the title compound (yield: 77%) as a white solid.


Mass spectrum (CI, m/z): 455 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.25 & 11.82 (s, total 1H), 9.66-9.47 (m, 1H), 7.36-7.20 (m, 5H), 4.83-4.62 (m, 2H), 4.32-4.13 (m, 1H), 3.99-3.90 (m, 1H), 3.89-3.79 (m, 1H), 3.53-3.42 (m, 1H), 2.57-2.35 (m, 2H), 2.25-2.09 (m, 2H), 1.91-1.64 (m, 5H), 1.63-1.52 (m, 3H), 0.13-0.01 (m, 9H).


Example 88
(R)—N-[5-(2-Methoxy-2-phenylacetyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide (Compound No. IV-1175)



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To a solution of 263 mg (1.58 mmol) of (R)-2-methoxy-2-phenylacetic acid in 5 ml of dehydrated dichloromethane, 0.24 ml (2.8 mmol) of oxalyl chloride and 0.025 ml (0.32 mmol) of DMF were added in this order at 0° C. in an argon atmosphere and then stirred for 3 hours with the temperature unchanged.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure at room temperature to obtain a concentration residue.


To a solution of 300 mg (0.793 mmol) of ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 84 and 0.55 ml (3.2 mmol) of DIPEA in 5 ml of dehydrated dichloromethane, a solution of the obtained concentration residue in 3 ml of dehydrated dichloromethane was added dropwise at 0° C. in an argon atmosphere and then stirred at room temperature for 15 hours. Subsequently, 0.37 ml (4.0 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction solution at room temperature and then stirred for 3 hours with the temperature unchanged.


After the completion of the reaction, a saturated aqueous solution of sodium bicarbonate was added to the reaction solution, followed by extraction with ethyl acetate. All of the obtained organic layers were washed with a saturated aqueous solution of ammonium chloride and a saturated aqueous solution of sodium chloride in this order, dried over anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=50:50 to 35:65 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved by adding ethyl acetate, then n-hexane was added, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 224 mg of the title compound (yield: 62%) as a white solid.


Mass spectrum (CI, m/z): 455 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.26 & 11.86 (br s, total 1H), 9.71-9.47 (m, 1H), 7.44-7.27 (m, 5H), 4.96 (s, 1H), 4.74-4.52 (m, 1H), 4.39-4.21 (m, 1H), 3.31 (s, 3H), 2.48-2.36 (m, 2H), 2.26-2.07 (m, 2H), 1.92-1.53 (m, 8H), 0.05 (s, 9H).


Example 89
(S)—N-[5-(2-Methoxy-2-phenylacetyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide (Compound No. IV-1176)



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To a solution of 263 mg (1.58 mmol) of (S)-2-methoxy-2-phenylacetic acid in 5 ml of dehydrated dichloromethane, 0.24 ml (2.8 mmol) of oxalyl chloride and 0.025 ml (0.32 mmol) of DMF were added in this order at 0° C. in an argon atmosphere and then stirred for 3 hours with the temperature unchanged.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure at room temperature to obtain a concentration residue.


To a solution of 300 mg (0.793 mmol) of ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 84 and 0.55 ml (3.2 mmol) of DIPEA in 5 ml of dehydrated dichloromethane, a solution of the obtained concentration residue in 3 ml of dehydrated dichloromethane was added dropwise at 0° C. in an argon atmosphere and then stirred at room temperature for 15 hours. Subsequently, 0.37 ml (4.0 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction solution at room temperature and then stirred for 3 hours with the temperature unchanged.


After the completion of the reaction, a saturated aqueous solution of sodium bicarbonate was added to the reaction solution, followed by extraction with ethyl acetate. All of the obtained organic layers were washed with a saturated aqueous solution of ammonium chloride and a saturated aqueous solution of sodium chloride in this order, dried over anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=50:50 to 35:65 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved by adding ethyl acetate, then n-hexane was added, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 206 mg of the title compound (yield: 57%) as a white solid.


Mass spectrum (CI, m/z): 455 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.26 & 11.86 (br s, total 1H), 9.71-9.45 (m, 1H), 7.46-7.26 (m, 5H), 4.96 (s, 1H), 4.73-4.53 (m, 1H), 4.30 (br d, J=12.3 Hz, 1H), 3.31 (s, 3H), 2.47-2.36 (m, 2H), 2.24-2.11 (m, 2H), 1.89-1.53 (m, 8H), 0.05 (s, 9H).


Example 90
N-[5-(3-Methoxy-2-phenylpropanoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide (Compound No. IV-634)



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To a solution of 212 mg (1.18 mmol) of 3-methoxy-2-phenylpropanoic acid synthesized in the similar manner as in Reference Example 72 in 6 ml of dehydrated dichloromethane, 0.14 ml (1.6 mmol) of oxalyl chloride and 0.0060 ml (0.077 mmol) of dehydrated DMF were added in this order at 0° C. in a nitrogen atmosphere and then stirred for 2.5 hours with the temperature unchanged.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a concentration residue.


To a solution of 156 mg (0.413 mmol) of ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 84 and 0.36 ml (2.1 mmol) of DIPEA in 3 ml of dehydrated dichloromethane, a solution of the obtained concentration residue in 1 ml of dehydrated dichloromethane was added at 0° C. in a nitrogen atmosphere and then stirred for 1.5 hours with the temperature unchanged. Subsequently, 0.23 ml (2.1 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction solution at 0° C. and then stirred at room temperature for 2 hours.


After the completion of the reaction, the reaction solution diluted with dichloromethane was washed with a 5% aqueous potassium bisulfate solution, and then the aqueous layer and the organic layer were separated. The aqueous layer was subjected to extraction with dichloromethane twice, and then, all of the obtained organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=70:30 to 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was subjected again to silica gel column chromatography (elution solvent: dichloromethane:methanol=100:0 to 95:5 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was subjected to preparative HPLC (column: X-Bridge (trade name) ODS, elution solvent: acetonitrile:1 mM aqueous dipotassium hydrogen phosphate solution=40:60 (V/V)), a fraction containing the compound of interest was concentrated under reduced pressure, and acetonitrile was distilled off. The obtained concentration residue was subjected to extraction with ethyl acetate three times, and then, all of the obtained organic layers were washed with a saturated aqueous solution of sodium chloride, subsequently dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was dissolved in ethyl acetate, then n-hexane was added, and the deposited solid was collected by filtration, washed with n-hexane, and then dried under reduced pressure to obtain 101 mg of the title compound (yield: 52%) as a white solid.


Mass spectrum (CI, m/z): 469 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.50-11.61 (m, 1H), 9.57 (br s, 1H), 7.36-7.22 (m, 5H), 4.70 (d, J=12.3 Hz, 1H), 4.22 (d, J=12.3 Hz, 1H), 3.99-3.92 (m, 1H), 3.90-3.83 (m, 1H), 3.40 (dd, J=5.7, 8.8 Hz, 1H), 3.23 (s, 3H), 2.57-2.37 (m, 2H), 2.22-2.12 (m, 2H), 1.86-1.74 (m, 2H), 1.68 (s, 3H), 1.57 (s, 3H), 0.05 (s, 9H).


Example 91
N-[5-(4-Methoxy-2-phenylbutanoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide (Compound No. IV-1224)



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To a solution of 154 mg (0.793 mmol) of 4-methoxy-2-phenylbutanoic acid synthesized in the similar manner as in Reference Example 74 in 3 ml of dehydrated dichloromethane, 0.14 ml (1.6 mmol) of oxalyl chloride and 0.0092 ml (0.12 mmol) of DMF were added in this order at 0° C. in an argon atmosphere and then stirred for 1 hour with the temperature unchanged.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure at room temperature to obtain a concentration residue.


To a solution of 150 mg (0.396 mmol) of ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 84 and 0.28 ml (1.6 mmol) of DIPEA in 3 ml of dehydrated dichloromethane, a solution of the obtained concentration residue in 3 ml of dehydrated dichloromethane was added dropwise at 0° C. in an argon atmosphere and then stirred at room temperature for 3 hours. Subsequently, 0.185 ml (1.98 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction solution at room temperature and then stirred for 14 hours with the temperature unchanged.


After the completion of the reaction, a saturated aqueous solution of sodium bicarbonate was added to the reaction solution, followed by extraction with ethyl acetate. All of the obtained organic layers were washed with a saturated aqueous solution of ammonium chloride and a saturated aqueous solution of sodium chloride in this order, dried over anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=60:40 to 40:60 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was subjected to preparative HPLC (column: XSelect (trade name) HSS C18, elution solvent: acetonitrile:1 mM aqueous potassium dihydrogen phosphate solution=50:50 (V/V)), a fraction containing the compound of interest was concentrated under reduced pressure, and acetonitrile was distilled off. The obtained concentration residue was subjected to extraction with ethyl acetate, and all of the obtained organic layers were washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The obtained concentration residue was dissolved by adding ethyl acetate, then n-hexane was added, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 78 mg of the title compound (yield: 41%) as a white solid.


Mass spectrum (CI, m/z): 483 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.24 & 11.95 (br s, total 1H), 9.78-9.46 (m, 1H), 7.39-7.18 (m, 5H), 4.79-4.57 (m, 1H), 4.24 (br d, J=12.2 Hz, 1H), 3.92-3.75 (m, 1H), 3.29-3.21 (m, 2H), 3.20 (s, 3H), 2.59-2.37 (m, 2H), 2.25-2.11 (m, 3H), 1.88-1.62 (m, 6H), 1.57 (br s, 3H), 0.05 (s, 9H).


Example 92
(S)—N-[5-(3-Hydroxy-2-phenylpropanoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclopropanecarboxamide (Compound No. III-592)



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To a solution of 45.8 mg (0.0864 mmol) of (S)—N-{5-[3-(benzyloxy)-2-phenylpropanoyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclopropanecarboxamide synthesized in the similar manner as in Reference Example 75 in 1 ml of ethanol, 13.6 mg of 20% palladium hydroxide/carbon [containing 50 wt % water] was added at room temperature in a nitrogen atmosphere and then, after replacement with a hydrogen atmosphere under reduced pressure, stirred at room temperature for 2.5 hours.


After the completion of the reaction, the inside of the reaction container was replaced with a nitrogen atmosphere under reduced pressure. The reaction solution was filtered using a celite filter, subsequently the removed solid was washed with ethyl acetate, and then, the filtrate was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=70:30 to 30:70 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was subjected again to silica gel column chromatography (elution solvent: dichloromethane:methanol=99:1 to 95:5 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in ethyl acetate, then n-hexane was added, and the deposited solid was collected by filtration, washed with n-hexane, and then dried under reduced pressure to obtain 19 mg of the title compound (yield: 50%) as a white solid.


Mass spectrum (CI, m/z): 441 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.25 & 11.96 (br s, total 1H), 9.98-9.65 (m, 1H), 7.37-7.19 (m, 5H), 4.80-4.58 (m, 2H), 4.33-4.10 (m, 1H), 3.98-3.88 (m, 1H), 3.88-3.80 (m, 1H), 3.52-3.43 (m, 1H), 1.68 (br s, 3H), 1.57 (br s, 3H), 1.05-0.91 (m, 2H), 0.80-0.56 (m, 2H), 0.01 (s, 9H).


Example 93
(R)—N-[5-(2-Methoxy-2-phenylacetyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclopropanecarboxamide (Compound No. III-1059)



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To a solution of 182 mg (1.10 mmol) of (R)-2-methoxy-2-phenylacetic acid in 5 ml of dehydrated dichloromethane, 0.165 ml (1.92 mmol) of oxalyl chloride and 0.017 ml (0.22 mmol) of DMF were added in this order at 0° C. in an argon atmosphere and then stirred for 1 hour with the temperature unchanged.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure at room temperature to obtain a concentration residue.


To a solution of 200 mg (0.549 mmol) of ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 46 and 0.38 ml (2.2 mmol) of DIPEA in 5 ml of dehydrated dichloromethane, a solution of the obtained concentration residue in 3 ml of dehydrated dichloromethane was added dropwise at 0° C. in an argon atmosphere and then stirred at room temperature for 1.5 hours. Subsequently, 0.26 ml (2.7 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction solution at room temperature and then stirred for 1 hour with the temperature unchanged.


After the completion of the reaction, a saturated aqueous solution of sodium bicarbonate was added to the reaction solution, followed by extraction with ethyl acetate. All of the obtained organic layers were washed with a saturated aqueous solution of ammonium chloride and a saturated aqueous solution of sodium chloride in this order, dried over anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=70:30 to 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was subjected again to silica gel column chromatography (elution solvent: 1,2-dichloroethane:methanol=97:3 to 90:10 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 191 mg of the title compound (yield: 79%) as a white solid.


Mass spectrum (CI, m/z): 441 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.38-11.88 (m, 1H), 9.97-9.65 (m, 1H), 7.45-7.27 (m, 5H), 4.96 (s, 1H), 4.71-4.49 (m, 1H), 4.29 (br d, J=12.8 Hz, 1H), 3.31 (s, 3H), 1.68 (br s, 3H), 1.59 (s, 3H), 1.05-0.91 (m, 2H), 0.78-0.58 (m, 2H), 0.01 (s, 9H).


Example 94
(R)—N-{5-[2-(Difluoromethoxy)-2-phenylacetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide (Compound No. IV-1180)



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To a solution of 1.01 g (4.17 mmol) of (R)-benzyl 2-hydroxy-2-phenylacetate and 158 mg (0.83 mmol) of copper(I) iodide in 15 ml of acetonitrile, a solution of 2.2 ml (17 mmol) of 2,2-difluoro-2-(fluorosulfonyl)acetic acid in 20 ml of acetonitrile was dividedly added (2 ml each) every 5 minutes at 60° C. in an argon atmosphere and stirred for 2 hours with the temperature unchanged.


After the completion of the reaction, the reaction solution allowed to cool to room temperature was concentrated under reduced pressure and diluted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in this order, then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=90:10 to 70:30 (V/V)), and subsequently, a fraction containing the compound of interest was concentrated under reduced pressure to obtain 0.67 g of a concentration residue as a colorless oil.


To a solution of 0.67 g of the obtained concentration residue in 20 ml of methanol, 70 mg of palladium/carbon (ASCA2 (trade name), manufactured by N.E. Chemcat Corp., containing 54% water) was added in an argon atmosphere and then, after replacement with a hydrogen atmosphere under reduced pressure, stirred at room temperature for 2 hours.


After the completion of the reaction, replacement with a nitrogen atmosphere was performed, the reaction solution was filtered through celite, the solid component was washed with methanol, and then, the filtrate was concentrated under reduced pressure to obtain 0.42 g of a concentration residue as a pale yellow solid.


To a solution of 115 mg of the obtained concentration residue in 3 ml of dehydrated dichloromethane, 0.072 ml (0.82 mmol) of oxalyl chloride and 0.010 ml (0.13 mmol) of dehydrated DMF were added in this order at room temperature in an argon atmosphere and then stirred for 15 minutes with the temperature unchanged.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a concentration residue.


To a solution of 103 mg (0.273 mmol) of ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 84 and 0.24 ml (1.4 mmol) of DIPEA in 3 ml of dehydrated dichloromethane, a solution of the obtained concentration residue in 1 ml of dehydrated dichloromethane was added at room temperature in an argon atmosphere and then stirred for 3.5 hours with the temperature unchanged. Subsequently, 0.15 ml (1.4 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction solution at room temperature and then stirred at room temperature for 1 hour.


After the completion of the reaction, a 5% aqueous potassium bisulfate solution was added, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in this order, dried by adding anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=50:50 to 0:100 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in ethyl acetate, and n-hexane was added. The deposited solid was collected by filtration and dried under reduced pressure to obtain 48.1 mg of the title compound (yield: 36%) as a white solid.


Mass spectrum (CI, m/z): 491 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.30 & 11.86 (br s, total 1H), 9.67-9.51 (m, 1H), 7.48-7.37 (m, 5H), 6.83 (t, J=76.0 Hz, 1H), 5.78 (s, 1H), 4.83-4.61 (m, 1H), 4.24-4.07 (m, 1H), 2.56-2.35 (m, 2H), 2.24-2.10 (m, 2H), 1.91-1.50 (m, 8H), 0.04 (s, 9H).


Example 95
(R)—N-[5-(2-Ethoxy-2-phenylacetyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide (Compound No. IV-1188)



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To a solution of 128 mg (0.710 mmol) of (R)-2-ethoxy-2-phenylacetic acid obtained in the similar manner as in Reference Example 77 in 3 ml of dehydrated dichloromethane, 0.090 ml (1.0 mmol) of oxalyl chloride and 0.010 ml (0.13 mmol) of dehydrated DMF were added in this order at 0° C. in an argon atmosphere and then stirred for 1 hour with the temperature unchanged.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a concentration residue.


To a solution of 112 mg (0.295 mmol) of ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 84 and 0.30 ml (1.7 mmol) of DIPEA in 3 ml of dehydrated dichloromethane, a solution of the obtained concentration residue in 1 ml of dehydrated dichloromethane was added at 0° C. in an argon atmosphere and then stirred for 30 minutes with the temperature unchanged. Subsequently, 0.11 ml (1.01 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction solution at 0° C. and then stirred at room temperature for 1 hour.


After the completion of the reaction, water was added, followed by extraction with ethyl acetate. The organic layer was washed with a 5% aqueous potassium bisulfate solution and a saturated aqueous solution of sodium chloride in this order, dried by adding anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=50:50 to 0:100 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in ethyl acetate, n-hexane was added, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 69.7 mg of the title compound (yield: 50%) as a white solid.


Mass spectrum (CI, m/z): 469 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.26 & 11.85 (br s, total 1H), 9.67-9.48 (m, 1H), 7.43-7.27 (m, 5H), 5.04 (s, 1H), 4.73-4.47 (m, 1H), 4.44-4.24 (m, 1H), 3.62-3.40 (m, 2H), 2.58-2.36 (m, 2H), 2.25-2.10 (m, 2H), 1.90-1.53 (m, 8H), 1.14 (t, J=7.0 Hz, 3H), 0.05 (s, 9H).


Example 96
(R)-1-(Ethyldimethylsilyl)-N-[5-(2-methoxy-2-phenylacetyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl] cyclobutanecarboxamide (Compound No. IV-1178)



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To a solution of 107 mg (0.646 mmol) of (R)-2-methoxy-2-phenylacetic acid in 2 ml of dehydrated dichloromethane, 0.080 ml (0.93 mmol) of oxalyl chloride and 0.0050 ml (0.065 mmol) of dehydrated DMF were added in this order at 0° C. in a nitrogen atmosphere and then stirred for 3 hours with the temperature unchanged.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a concentration residue.


To a solution of 117 mg (0.299 mmol) of ethyl 3-[1-(ethyldimethylsilyl)cyclobutanecarboxamido]-6,6-dimethyl-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 12 and 0.21 ml (1.2 mmol) of DIPEA in 1 ml of dehydrated dichloromethane, a solution of the obtained concentration residue in 1 ml of dehydrated dichloromethane was added at 0° C. in a nitrogen atmosphere and then stirred for 2.5 hours with the temperature unchanged. Subsequently, 0.16 ml (1.5 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction solution at 0° C. and then stirred at room temperature for 1.5 hours.


After the completion of the reaction, the reaction solution diluted with dichloromethane was washed with a 5% aqueous potassium bisulfate solution and then the aqueous layer and the organic layer were separated. The aqueous layer was subjected to extraction with dichloromethane twice, and then, all of the obtained organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=80:20 to 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in ethyl acetate, then n-hexane was added, and the deposited solid was collected by filtration, washed with n-hexane, and then dried under reduced pressure to obtain 115 mg of the title compound (yield: 82%) as a white solid.


Mass spectrum (CI, m/z): 469 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.26 & 11.84 (s, total 1H), 9.67-9.48 (m, 1H), 7.42-7.27 (m, 5H), 4.95 (s, 1H), 4.71-4.52 (m, 1H), 4.35-4.23 (m, 1H), 3.30 (s, 3H), 2.56-2.37 (m, 2H), 2.26-2.11 (m, 2H), 1.90-1.52 (m, 8H), 0.88 (t, J=7.8 Hz, 3H), 0.53 (q, J=7.8 Hz, 2H), 0.09-0.01 (m, 6H).


Example 97
(R)—N-[5-(2-Cyclopropoxy-2-phenylacetyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide (Compound No. IV-1208)



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To a solution of 140 mg (0.728 mmol) of (R)-2-cyclopropoxy-2-phenylacetic acid synthesized in the similar manner as in Reference Example 86 in 2 ml of dehydrated dichloromethane, 0.006 ml (0.08 mmol) of DMF and 0.083 ml (0.95 mmol) of oxalyl chloride were added with stirring at 0° C. in an argon atmosphere and stirred at room temperature for 1.5 hours.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a concentration residue.


To a solution of 150 mg (0.396 mmol) of ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 84 and 0.350 ml (2.00 mmol) of DIPEA in 2 ml of dehydrated dichloromethane, a solution of the obtained concentration residue in 3 ml of dehydrated dichloromethane was added dropwise with stirring at 0° C. in an argon atmosphere and stirred at room temperature for 2 hours.


After the completion of the reaction, a saturated aqueous solution of sodium bicarbonate was added to the reaction solution, followed by extraction with dichloromethane. The obtained organic layer was washed with water, then dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=100:0 to 70:30 (V/V)), subsequently concentrated under reduced pressure, and dried under reduced pressure to obtain a concentration residue.


To a solution of the obtained concentration residue in 2 ml of dehydrated dichloromethane, 0.130 ml (1.19 mmol) of N,N-dimethylethane-1,2-diamine was added at room temperature in an argon atmosphere and then stirred at room temperature for 16 hours.


After the completion of the reaction, a 5% aqueous potassium bisulfate solution was added to the reaction solution and stirred, followed by extraction with dichloromethane. The obtained organic layer was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in this order, then dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=100:0 to 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in ethyl acetate and then added to n-hexane, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 80 mg of the title compound (yield: 42%) as a white solid.


Mass spectrum (CI, m/z): 481 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.37-11.83 (m, 1H), 9.59 (br s, 1H), 7.42-7.28 (m, 5H), 5.10 (s, 1H), 4.73-4.54 (m, 1H), 4.35 (d, J=12.4 Hz, 1H), 3.40 (tt, J=3.0, 6.1 Hz, 1H), 2.59-2.37 (m, 2H), 2.24-2.12 (m, 2H), 1.90-1.74 (m, 2H), 1.70 (s, 3H), 1.61 (s, 3H), 0.69-0.53 (m, 2H), 0.51-0.39 (m, 2H), 0.05 (s, 9H).


Example 98
(R)—N-[5-(2-Isopropoxy-2-phenylacetyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide (Compound No. IV-1204)



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To a solution of 165 mg (0.849 mmol) of (R)-2-isopropoxy-2-phenylacetic acid synthesized in the similar manner as in Reference Example 87 in 2 ml of dehydrated dichloromethane, 0.10 ml (1.2 mmol) of oxalyl chloride and 0.0050 ml (0.065 mmol) of dehydrated DMF were added in this order at 0° C. in an argon atmosphere and then stirred for 2.5 hours with the temperature unchanged.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure and dried under reduced pressure to obtain a concentration residue.


To a solution of 128 mg (0.338 mmol) of ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 84 and 0.30 ml (1.7 mmol) of DIPEA in 1 ml of dehydrated dichloromethane, a solution of the obtained concentration residue in 1 ml of dehydrated dichloromethane was added at 0° C. in an argon atmosphere and then stirred for 1.5 hours with the temperature unchanged.


After the completion of the reaction, ethyl acetate and a saturated aqueous solution of sodium bicarbonate were added to the reaction solution and stirred. After separation into an aqueous layer and an organic layer, the aqueous layer was subjected to extraction with ethyl acetate twice. All of the organic layers were dried over anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=80:20 to 60:40 (V/V)), subsequently concentrated under reduced pressure, and dried under reduced pressure to obtain a concentration residue.


To a solution of the obtained concentration residue in 2 ml of THF, 0.15 ml (1.4 mmol) of N,N-dimethylethane-1,2-diamine was added at room temperature in an argon atmosphere and then stirred at room temperature for 2 hours.


After the completion of the reaction, a 5% aqueous potassium bisulfate solution was added to the reaction solution and stirred, followed by extraction with ethyl acetate three times. All of the obtained organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=80:20 to 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in ethyl acetate, then n-hexane was added, and the deposited solid was collected by filtration, washed with n-hexane, and then dried under reduced pressure to obtain 135 mg of the title compound (yield: 83%) as a white solid.


Mass spectrum (CI, m/z): 483 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.40-11.82 (m, 1H), 9.75-9.42 (m, 1H), 7.40-7.27 (m, 5H), 5.11 (s, 1H), 4.65-4.38 (m, 2H), 3.68 (spt, J=6.0 Hz, 1H), 2.47-2.35 (m, 2H), 2.23-2.09 (m, 2H), 1.87-1.71 (m, 2H), 1.67 (s, 3H), 1.61 (s, 3H), 1.16 (d, J=6.0 Hz, 3H), 1.13 (d, J=6.0 Hz, 3H), 0.04 (s, 9H).


Example 99
(R)—N-{6,6-Dimethyl-5-[2-phenyl-2-(trifluoromethoxy)acetyl]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide (Compound No. Iv-1184)



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To a solution of 160 mg of (R)-2-phenyl-2-(trifluoromethoxy)acetic acid (containing impurities) synthesized in the similar manner as in Reference Example 89 in 2 ml of dehydrated dichloromethane, 0.083 ml (0.95 mmol) of oxalyl chloride and 0.006 ml (0.08 mmol) of DMF were added with stirring at 0° C. in an argon atmosphere and stirred at room temperature for 1.5 hours.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a concentration residue.


To a solution of 150 mg (0.396 mmol) of ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 84 and 0.350 ml (2.00 mmol) of DIPEA in 2 ml of dehydrated dichloromethane, a solution of the obtained concentration residue in 3 ml of dehydrated dichloromethane was added dropwise with stirring at 0° C. in an argon atmosphere and stirred at room temperature for 2 hours.


After the completion of the reaction, a saturated aqueous solution of sodium bicarbonate was added to the reaction solution, followed by extraction with dichloromethane. The obtained organic layer was washed with water, then dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=100:0 to 70:30 (V/V)), subsequently concentrated under reduced pressure, and dried under reduced pressure to obtain a concentration residue.


To a solution of the obtained concentration residue in 2 ml of dehydrated dichloromethane, 0.130 ml (1.19 mmol) of N,N-dimethylethane-1,2-diamine was added at room temperature in an argon atmosphere and then stirred at room temperature for 2 hours.


After the completion of the reaction, a 5% aqueous potassium bisulfate solution was added to the reaction solution and stirred, followed by extraction with dichloromethane. The obtained organic layer was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in this order, then dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=100:0 to 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in ethyl acetate and then added to n-hexane, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 97.6 mg of the title compound (yield: 48%) as a white solid.


Mass spectrum (CI, m/z): 509 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.39-11.84 (m, 1H), 9.58 (br s, 1H), 7.54-7.41 (m, 5H), 6.06 (s, 1H), 4.78 (br d, J=11.9 Hz, 1H), 4.08 (br d, J=11.9 Hz, 1H), 2.58-2.35 (m, 2H), 2.23-2.10 (m, 2H), 1.88-1.73 (m, 2H), 1.70 (s, 3H), 1.60 (s, 3H), 0.04 (s, 9H).


Example 100
(R)—N-[6,6-Dimethyl-5-(2-phenyl-2-propoxyacetyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide (Compound No. Iv-1196)



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To a solution of 146 mg (0.753 mmol) of (R)-2-phenyl-2-propoxyacetic acid synthesized in the similar manner as in Reference Example 91 in 2 ml of dehydrated dichloromethane, 0.10 ml (1.2 mmol) of oxalyl chloride and 0.0050 ml (0.065 mmol) of dehydrated DMF were added in this order at 0° C. in an argon atmosphere and then stirred for 1.5 hours with the temperature unchanged.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure and dried under reduced pressure to obtain a concentration residue.


To a solution of 144 mg (0.380 mmol) of ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 84 and 0.33 ml (1.9 mmol) of DIPEA in 1 ml of dehydrated dichloromethane, a solution of the obtained concentration residue in 1 ml of dehydrated dichloromethane was added at 0° C. in an argon atmosphere and then stirred for 1.5 hours with the temperature unchanged.


After the completion of the reaction, ethyl acetate and a saturated aqueous solution of sodium bicarbonate were added to the reaction solution and stirred. After separation into an aqueous layer and an organic layer, the aqueous layer was subjected to extraction with ethyl acetate twice. All of the organic layers were dried over anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=85:15 to 60:40 (V/V)), subsequently concentrated under reduced pressure, and dried under reduced pressure to obtain a concentration residue.


To a solution of the obtained concentration residue in 2 ml of THF, 0.17 ml (1.6 mmol) of N,N-dimethylethane-1,2-diamine was added at room temperature in an argon atmosphere and then stirred at room temperature for 3 hours.


After the completion of the reaction, a 5% aqueous potassium bisulfate solution was added to the reaction solution and stirred, followed by extraction with ethyl acetate three times. All of the obtained organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=85:15 to 60:40 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in ethyl acetate, then n-hexane was added, and the deposited solid was collected by filtration, washed with n-hexane, and then dried under reduced pressure to obtain 144 mg of the title compound (yield: 80%) as a white solid.


Mass spectrum (CI, m/z): 483 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.43-11.75 (m, 1H), 9.56 (br s, 1H), 7.43-7.27 (m, 5H), 5.03 (s, 1H), 4.71-4.47 (m, 1H), 4.39 (br d, J=12.5 Hz, 1H), 3.51-3.43 (m, 1H), 3.41-3.24 (m, 1H), 2.60-2.36 (m, 2H), 2.25-2.10 (m, 2H), 1.88-1.72 (m, 2H), 1.68 (s, 3H), 1.65-1.48 (m, 5H), 0.87 (t, J=7.4 Hz, 3H), 0.04 (s, 9H).


Example 101
N-{5-[2-(4-Fluorophenyl)-2-methoxyacetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide (Compound No. IV-1427)



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To a suspension of 229 mg of 2-(4-fluorophenyl)-2-methoxyacetic acid (containing impurities) synthesized in the similar manner as in Reference Example 93 in 2 ml of dehydrated dichloromethane, 0.150 ml (1.71 mmol) of oxalyl chloride and 0.011 ml (0.14 mmol) of DMF were added with stirring at 0° C. in an argon atmosphere and stirred at room temperature for 1.5 hours.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a concentration residue.


To a solution of 265 mg (0.700 mmol) of ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 84 and 0.620 ml (3.55 mmol) of DIPEA in 2 ml of dehydrated dichloromethane, a solution of the obtained concentration residue in 3 ml of dehydrated dichloromethane was added dropwise with stirring at 0° C. in an argon atmosphere and stirred at room temperature for 1 hour.


After the completion of the reaction, a saturated aqueous solution of sodium bicarbonate was added to the reaction solution, followed by extraction with dichloromethane. The obtained organic layer was washed with water, then dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=100:0 to 70:30 (V/V)), subsequently concentrated under reduced pressure, and dried under reduced pressure to obtain a concentration residue.


To a solution of the obtained concentration residue in 2 ml of dehydrated dichloromethane, 0.230 ml (2.11 mmol) of N,N-dimethylethane-1,2-diamine was added at room temperature in an argon atmosphere and then stirred at room temperature for 1 hour.


After the completion of the reaction, a 5% aqueous potassium bisulfate solution was added to the reaction solution and stirred, followed by extraction with dichloromethane. The obtained organic layer was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in this order, then dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=100:0 to 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in dichloromethane, and then, a 5% aqueous potassium bisulfate solution was added thereto, stirred, and separated into an aqueous layer and an organic layer. The obtained organic layer was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in this order, then dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The obtained concentration residue was dissolved in ethyl acetate and then added to n-hexane, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 174 mg of the title compound (yield: 53%) as a white solid.


Mass spectrum (CI, m/z): 473 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.27 & 11.91 (br s, total 1H), 9.58 (br s, 1H), 7.47-7.36 (m, 2H), 7.26-7.14 (m, 2H), 4.99 (s, 1H), 4.76-4.53 (m, 1H), 4.32 (br d, J=12.4 Hz, 1H), 3.29 (s, 3H), 2.58-2.36 (m, 2H), 2.25-2.10 (m, 2H), 1.88-1.72 (m, 2H), 1.69 (br s, 3H), 1.60 (s, 3H), 0.05 (s, 9H).


Example 102
N-{5-[2-(3-Fluorophenyl)-2-methoxyacetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide (Compound No. IV-1404)



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To a suspension of 146 mg of 2-(3-fluorophenyl)-2-methoxyacetic acid (containing impurities) synthesized in the similar manner as in Reference Example 96 in 2 ml of dehydrated dichloromethane, 0.080 ml (0.91 mmol) of oxalyl chloride and 0.010 ml (0.13 mmol) of DMF were added with stirring at 0° C. in an argon atmosphere and stirred at room temperature for 1.5 hours.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a concentration residue.


To a solution of 200 mg (0.528 mmol) of ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 84 and 0.462 ml (2.65 mmol) of DIPEA in 2 ml of dehydrated dichloromethane, a solution of the obtained concentration residue in 3 ml of dehydrated dichloromethane was added dropwise with stirring at room temperature in an argon atmosphere and stirred at room temperature for 1 hour.


After the completion of the reaction, a saturated aqueous solution of sodium bicarbonate was added to the reaction solution, followed by extraction with dichloromethane. The obtained organic layer was washed with water, then dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=100:0 to 70:30 (V/V)), subsequently concentrated under reduced pressure, and dried under reduced pressure to obtain a concentration residue.


To a solution of the obtained concentration residue in 2 ml of dehydrated dichloromethane, 0.173 ml (1.59 mmol) of N,N-dimethylethane-1,2-diamine was added at room temperature in an argon atmosphere and then stirred at room temperature for 16 hours.


After the completion of the reaction, a 5% aqueous potassium bisulfate solution was added to the reaction solution and stirred, followed by extraction with dichloromethane. The obtained organic layer was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in this order, then dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=100:0 to 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in methanol and then added to water, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 187 mg of the title compound (yield: 75%) as a white solid.


Mass spectrum (CI, m/z): 473 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.40-11.81 (m, 1H), 9.60 (br s, 1H), 7.48-7.38 (m, 1H), 7.24-7.13 (m, 3H), 5.03 (s, 1H), 4.75-4.54 (m, 1H), 4.39 (br d, J=12.7 Hz, 1H), 3.32 (s, 3H), 2.59-2.36 (m, 2H), 2.24-2.10 (m, 2H), 1.88-1.72 (m, 2H), 1.69 (s, 3H), 1.60 (s, 3H), 0.05 (s, 9H).


Example 103
(R)—N-{5-[2-(2-Fluorophenyl)-2-methoxyacetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide (Compound No. IV-1383)



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To a suspension of 200 mg (1.09 mmol) of (R)-2-(2-fluorophenyl)-2-methoxyacetic acid synthesized in the similar manner as in Reference Example 98 in 2 ml of dehydrated dichloromethane, 0.111 ml (1.27 mmol) of oxalyl chloride and 0.010 ml (0.13 mmol) of DMF were added with stirring at 0° C. in an argon atmosphere and stirred at room temperature for 1.5 hours.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a concentration residue.


To a solution of 200 mg (0.528 mmol) of ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 84 and 0.500 ml (2.86 mmol) of DIPEA in 2 ml of dehydrated dichloromethane, a solution of the obtained concentration residue in 3 ml of dehydrated dichloromethane was added dropwise with stirring at room temperature in an argon atmosphere and stirred at room temperature for 2 hours.


After the completion of the reaction, a saturated aqueous solution of sodium bicarbonate was added to the reaction solution, followed by extraction with dichloromethane. The obtained organic layer was washed with water, then dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=100:0 to 70:30 (V/V)), subsequently concentrated under reduced pressure, and dried under reduced pressure to obtain a concentration residue.


To a solution of the obtained concentration residue in 2 ml of dehydrated dichloromethane, 0.173 ml (1.59 mmol) of N,N-dimethylethane-1,2-diamine was added at room temperature in an argon atmosphere and then stirred at room temperature for 3 hours.


After the completion of the reaction, a 5% aqueous potassium bisulfate solution was added to the reaction solution and stirred, followed by extraction with dichloromethane. The obtained organic layer was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in this order, then dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=100:0 to 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in methanol and then added to water, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 164 mg of the title compound (yield: 66%) as a white solid.


Mass spectrum (CI, m/z): 473 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.42-11.83 (m, 1H), 9.60 (br s, 1H), 7.46-7.34 (m, 2H), 7.27-7.18 (m, 2H), 5.22 (s, 1H), 4.75 (d, J=12.3 Hz, 1H), 4.20 (d, J=12.3 Hz, 1H), 3.32 (s, 3H), 2.58-2.37 (m, 2H), 2.25-2.11 (m, 2H), 1.88-1.73 (m, 2H), 1.70 (s, 3H), 1.60 (s, 3H), 0.05 (s, 9H).


Example 104
N-{5-[2-Methoxy-2-(thiophen-2-yl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide (Compound No. IV-1546)



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To a suspension of 60 mg of 2-methoxy-2-(thiophen-2-yl)acetic acid (containing impurities) synthesized in the similar manner as in Reference Example 101 in 2 ml of dehydrated dichloromethane, 0.036 ml (0.41 mmol) of oxalyl chloride and 0.005 ml (0.07 mmol) of DMF were added with stirring at 0° C. in an argon atmosphere and stirred at room temperature for 1.5 hours.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a concentration residue.


To a solution of 120 mg (0.317 mmol) of ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 84 and 0.166 ml (0.950 mmol) of DIPEA in 2 ml of dehydrated dichloromethane, a solution of the obtained concentration residue in 3 ml of dehydrated dichloromethane was added dropwise with stirring at 0° C. in an argon atmosphere and stirred at room temperature for 2 hours.


After the completion of the reaction, a saturated aqueous solution of sodium bicarbonate was added to the reaction solution, followed by extraction with dichloromethane. The obtained organic layer was washed with water, then dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=100:0 to 70:30 (V/V)), subsequently concentrated under reduced pressure, and dried under reduced pressure to obtain a concentration residue.


To a solution of the obtained concentration residue in 2 ml of dehydrated dichloromethane, 0.104 ml (0.954 mmol) of N,N-dimethylethane-1,2-diamine was added at room temperature in an argon atmosphere and then stirred at room temperature for 16 hours.


After the completion of the reaction, a 5% aqueous potassium bisulfate solution was added to the reaction solution and stirred, followed by extraction with dichloromethane. The obtained organic layer was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in this order, then dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=100:0 to 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in methanol and then added to water, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 62 mg of the title compound (yield: 42%) as a white solid.


Mass spectrum (CI, m/z): 461 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.41-11.86 (m, 1H), 9.82-9.47 (m, 1H), 7.57 (dd, J=1.3, 5.0 Hz, 1H), 7.13-7.06 (m, 1H), 7.01 (dd, J=3.5, 5.0 Hz, 1H), 5.26 (s, 1H), 4.84-4.64 (m, 1H), 4.41 (br d, J=12.4 Hz, 1H), 3.28 (s, 3H), 2.58-2.37 (m, 2H), 2.26-2.10 (m, 2H), 1.89-1.73 (m, 2H), 1.70 (s, 3H), 1.62 (s, 3H), 0.06 (s, 9H).


Example 105
(−)-N-{5-[2-Methoxy-2-(thiophen-2-yl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide (Compound No. IV-1548)

0.041 g (0.089 mmol) of N-{5-[2-methoxy-2-(thiophen-2-yl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide synthesized in the similar manner as in Example 104 was subjected to optical resolution preparative chromatography (column: CHIRALPAK (trade name) ID, elution solvent: n-hexane:ethanol=85:15 (V/V)), and a fraction containing an optically active form eluted first was concentrated under reduced pressure to obtain 17 mg of the title compound (yield: 41%) as a white solid.


Specific optical rotation: [α]D20=−51° (c=0.20, methanol).


Mass spectrum (CI, m/z): 461 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.23 (br s, 1H), 9.67 (br s, 1H), 7.57 (dd, J=1.2, 5.0 Hz, 1H), 7.13-7.06 (m, 1H), 7.01 (dd, J=3.5, 5.0 Hz, 1H), 5.26 (s, 1H), 4.74 (br d, J=12.5 Hz, 1H), 4.41 (d, J=12.5 Hz, 1H), 3.28 (s, 3H), 2.58-2.37 (m, 2H), 2.24-2.11 (m, 2H), 1.89-1.74 (m, 2H), 1.70 (s, 3H), 1.62 (s, 3H), 0.06 (s, 9H).


HPLC analysis:


Column: CHIRALPAK (trade name) ID 4.6×250 mm


Eluent: n-hexane/ethanol=85/15 (V/V)


Flow rate: 1.0 ml/min


Temperature: 40° C.


Detection wavelength: 254 nm


Retention time: 7.6 min.


Optical purity: >99% ee


Example 106
(+)-N-{5-[2-Methoxy-2-(thiophen-2-yl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide (Compound No. IV-1547)

A fraction containing an optically active form eluted later in the optical resolution preparative chromatography operation of Example 105 was concentrated under reduced pressure to obtain 14 mg of the title compound (yield: 34%) as a white solid.


Specific optical rotation: [α]D20=+66° (c=0.20, methanol).


Mass spectrum (CI, m/z): 461 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.23 (br s, 1H), 9.66 (br s, 1H), 7.57 (dd, J=1.2, 5.0 Hz, 1H), 7.14-7.06 (m, 1H), 7.01 (dd, J=3.5, 5.0 Hz, 1H), 5.26 (s, 1H), 4.74 (br d, J=12.4 Hz, 1H), 4.41 (d, J=12.4 Hz, 1H), 3.28 (s, 3H), 2.58-2.37 (m, 2H), 2.26-2.10 (m, 2H), 1.89-1.74 (m, 2H), 1.70 (s, 3H), 1.62 (s, 3H), 0.06 (s, 9H).


HPLC analysis:


Column: CHIRALPAK (trade name) ID 4.6×250 mm


Eluent: n-hexane/ethanol=85/15 (V/V)


Flow rate: 1.0 ml/min


Temperature: 40° C.


Detection wavelength: 254 nm


Retention time: 9.7 min.


Optical purity: >99% ee


Example 107
N-{[1-(Hydroxymethyl)cyclobutyl](phenyl)methyl}-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound No. IV-718)



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To a solution of a mixture of 131 mg (0.243 mmol) of 2-ethyl 5-(trichloromethyl) 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]pyrrolo[3,4-c]pyrazole-2,5(4H,6H)-dicarboxylate synthesized in the similar manner as in Reference Example 102 and 79 mg (0.18 mmol) of ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate in 3 ml of dehydrated 1,4-dioxane, 0.34 ml (2.0 mmol) of DIPEA and 235 mg (1.23 mmol) of {1-[amino(phenyl)methyl] cyclobutyl}methanol synthesized in the similar manner as in Reference Example 103 were added in this order at room temperature in an argon atmosphere and then stirred at 90° C. for 1.5 hours. After standing to cool until the reaction solution becomes room temperature, 0.21 ml (1.9 mmol) of N,N-dimethylethane-1,2-diamine was added at room temperature and stirred for 2 hours with the temperature unchanged.


After the completion of the reaction, a 5% aqueous potassium bisulfate solution was added to the reaction solution and stirred, followed by extraction with ethyl acetate three times. All of the organic layers were dried over anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=60:40 to 30:70 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in ethyl acetate, then n-hexane was added, and the deposited solid was collected by filtration, washed with n-hexane, and then dried under reduced pressure to obtain 187 mg of a white solid. The obtained solid was subjected to preparative HPLC (column: X-Bridge (trade name) ODS, elution solvent: acetonitrile:1 mM aqueous potassium dihydrogen phosphate solution=50:50 (V/V)), a fraction containing the compound of interest was concentrated under reduced pressure, and acetonitrile was distilled off. The solid deposited in the course of concentration was collected by filtration, washed with water, and then dried under reduced pressure to obtain 156 mg of the title compound (yield: 70%) as a white solid.


Mass spectrum (CI, m/z): 524 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.34-11.78 (m, 1H), 9.87-9.34 (m, 1H), 7.35-7.27 (m, 4H), 7.24-7.16 (m, 1H), 6.75 (d, J=7.9 Hz, 1H), 5.49 (br s, 1H), 4.95 (d, J=7.9 Hz, 1H), 4.47-4.20 (m, 2H), 3.49-3.41 (m, 1H), 3.26-3.18 (m, 1H), 2.57-2.39 (m, 2H), 2.26-2.14 (m, 2H), 2.11-1.99 (m, 2H), 1.98-1.74 (m, 5H), 1.61 (s, 3H), 1.53 (s, 3H), 1.26-1.13 (m, 1H), 0.08 (s, 9H).


Example 108
(R)—N-[2-(1-Hydroxycyclopropyl)-1-phenylethyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound No. IV-743)



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To a solution of 128 mg of (R)-1-(2-amino-2-phenylethyl)cyclopropanol (containing impurities) synthesized in the similar manner as in Reference Example 105 in 2 ml of dehydrated 1,4-dioxane, 0.26 ml (1.5 mmol) of DIPEA and 154 mg (0.349 mmol) of ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 3 were added in this order at room temperature in an argon atmosphere and then stirred at 90° C. for 2 hours. After standing to cool until the reaction solution becomes room temperature, 0.16 ml (1.5 mmol) of N,N-dimethylethane-1,2-diamine was added at room temperature and stirred for 2 hours with the temperature unchanged.


After the completion of the reaction, a 5% aqueous potassium bisulfate solution was added to the reaction solution and stirred, followed by extraction with ethyl acetate twice. All of the obtained organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=70:30 to 40:60 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was suspended in an ethyl acetate/n-hexane mixed solvent and stirred, and then, insoluble matter was collected by filtration, washed with n-hexane, and then dried under reduced pressure to obtain 139 mg of the title compound (yield: 79%) as a white solid.


Mass spectrum (CI, m/z): 510 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.23 & 11.80 (br s, total 1H), 9.75-9.47 (m, 1H), 7.43-7.37 (m, 2H), 7.34-7.27 (m, 2H), 7.23-7.17 (m, 1H), 6.51-6.33 (m, 1H), 5.54-5.37 (m, 1H), 5.14-5.05 (m, 1H), 4.66-4.29 (m, 2H), 2.61-2.39 (m, 2H), 2.26-2.06 (m, 3H), 1.90-1.50 (m, 9H), 0.55-0.37 (m, 3H), 0.18-0.04 (m, 10H).


Example 109
(R)—N-(3-Ethyl-3-Hydroxy-1-phenylpentyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound No. IV-759)



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To a solution of 118 mg (0.568 mmol) of (R)-1-amino-3-ethyl-1-phenylpentan-3-ol synthesized in the similar manner as in Reference Example 107 in 2 ml of dehydrated 1,4-dioxane, 0.20 ml (1.1 mmol) of DIPEA and 128 mg (0.290 mmol) of ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 3 were added in this order at room temperature in an argon atmosphere and then stirred at 90° C. for 2 hours.


After the completion of the reaction, a saturated aqueous solution of sodium bicarbonate was added to the reaction solution and stirred, followed by extraction with ethyl acetate three times. All of the organic layers were dried over anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=75:25 to 40:60 (V/V)), subsequently concentrated under reduced pressure, and dried under reduced pressure to obtain a concentration residue.


To a solution of the obtained concentration residue in 2 ml of THF, 0.13 ml (1.2 mmol) of N,N-dimethylethane-1,2-diamine was added at room temperature in an argon atmosphere and then stirred at room temperature for 2 hours.


After the completion of the reaction, a 5% aqueous potassium bisulfate solution was added to the reaction solution and stirred, followed by extraction with ethyl acetate three times. All of the obtained organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=70:30 to 30:70 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was suspended in an ethyl acetate/n-hexane mixed solvent and stirred at room temperature, and then, insoluble matter was collected by filtration, washed with n-hexane, and then dried under reduced pressure to obtain 123 mg of the title compound (yield: 79%) as a white solid.


Mass spectrum (CI, m/z): 540 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.35-11.68 (m, 1H), 9.56 (br s, 1H), 7.37-7.24 (m, 4H), 7.19-7.13 (m, 1H), 6.56 (d, J=5.8 Hz, 1H), 4.91-4.81 (m, 1H), 4.54-4.31 (m, 3H), 2.58-2.41 (m, 2H), 2.26-2.13 (m, 2H), 1.95-1.73 (m, 3H), 1.63-1.55 (m, 4H), 1.53 (s, 3H), 1.49-1.33 (m, 4H), 0.82 (t, J=7.4 Hz, 3H), 0.77 (t, J=7.4 Hz, 3H), 0.09 (s, 9H).


Example 110
(R)—N-[1-(4-Fluorophenyl)-3-hydroxy-3-methylbutyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound No. IV-939)



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To a solution of 599 mg (1.36 mmol) of ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 3 in 3 ml of 1,4-dioxane, 134 mg of (R)-4-amino-4-(4-fluorophenyl)-2-methylbutan-2-ol (containing impurities) synthesized in the similar manner as in Reference Example 111 and 0.602 ml (3.40 mmol) of DIPEA were added in this order at room temperature under argon stream and then stirred at 100° C. for 1 hour. Subsequently, 0.318 ml (3.40 mmol) of N,N-dimethylethane-1,2-diamine was added at room temperature and stirred for 2 hours with the temperature unchanged.


After the completion of the reaction, a 5% aqueous potassium bisulfate solution was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous solution of sodium chloride in this order, dried over anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: ethyl acetate:methanol=100:0 to 90:10 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was subjected to preparative HPLC (column: X-Bridge (trade name) ODS, elution solvent: acetonitrile:1 mM aqueous potassium dihydrogen phosphate solution=30:70 to 50:50 (V/V)), a fraction containing the compound of interest was concentrated under reduced pressure, and acetonitrile was distilled off, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, then filtered, concentrated under reduced pressure, and dried under reduced pressure to obtain 48 mg of the title compound (yield: 8% [2 steps]) as a white solid.


Mass spectrum (CI, m/z): 530 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.20 & 11.77 (br s, total 1H), 9.74-9.41 (m, 1H), 7.40-7.32 (m, 2H), 7.14-7.05 (m, 2H), 6.66-6.44 (m, 1H), 4.94-4.84 (m, 1H), 4.75-4.60 (m, 1H), 4.52-4.31 (m, 2H), 2.59-2.39 (m, 2H), 2.27-2.11 (m, 2H), 2.04-1.73 (m, 3H), 1.70-1.45 (m, 7H), 1.15 (s, 3H), 1.13 (s, 3H), 0.09 (s, 9H).


Example 111
(R)—N-[1-(3-Fluorophenyl)-3-hydroxy-3-methylbutyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound No. IV-911)



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To a solution of 149 mg (0.248 mmol) of (R)-ethyl 5-{[1-(3-fluorophenyl)-3-hydroxy-3-methylbutyl]carbamoyl}-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 116 in 3 ml of dichloromethane, 0.108 ml (0.992 mmol) of N,N-dimethylethane-1,2-diamine was added in one portion with stirring at room temperature under argon stream and stirred at room temperature for 1 hour.


After the completion of the reaction, a 5% aqueous potassium bisulfate solution was added to the reaction solution, followed by extraction from the mixed solution with ethyl acetate twice. The organic layer was washed with a 5% aqueous potassium bisulfate solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=70:30 to 17:83 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in a small amount of ethyl acetate, and a solid was deposited by adding n-hexane. The solid was collected by filtration, washed with n-hexane, and dried under reduced pressure at 50° C. to obtain 101 mg of the title compound (yield: 77%) as a white solid.


Mass spectrum (CI, m/z): 530 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.21 & 11.77 (br s, total 1H), 9.71-9.47 (m, 1H), 7.37-7.26 (m, 1H), 7.22-7.11 (m, 2H), 7.02-6.92 (m, 1H), 6.65-6.51 (m, 1H), 4.95-4.87 (m, 1H), 4.76-4.60 (m, 1H), 4.55-4.35 (m, 2H), 2.57-2.40 (m, 2H), 2.27-2.12 (m, 2H), 2.03-1.74 (m, 3H), 1.66 (dd, J=3.1, 14.2 Hz, 1H), 1.59 (br s, 3H), 1.54 (br s, 3H), 1.16 (s, 3H), 1.13 (s, 3H), 0.09 (s, 9H).


Example 112
(R)—N-[1-(2-Fluorophenyl)-3-hydroxy-3-methylbutyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound No. IV-883)



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To a solution of 150 mg (0.249 mmol) of (R)-ethyl 5-{[1-(2-fluorophenyl)-3-hydroxy-3-methylbutyl]carbamoyl}-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 121 in 3 ml of dichloromethane, 0.109 ml (1.00 mmol) of N,N-dimethylethane-1,2-diamine was added in one portion with stirring at room temperature under argon stream and stirred at room temperature for 1 hour.


After the completion of the reaction, a 5% aqueous potassium bisulfate solution was added to the reaction solution, followed by extraction from the mixed solution with ethyl acetate twice. The organic layer was washed with a 5% aqueous potassium bisulfate solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=70:30 to 17:83 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in a small amount of ethyl acetate, and a solid was deposited by adding n-hexane. The solid was collected by filtration, washed with n-hexane, and dried under reduced pressure at 50° C. to obtain 112 mg of the title compound (yield: 85%) as a white solid.


Mass spectrum (CI, m/z): 530 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.20 & 11.76 (br s, total 1H), 9.72-9.46 (m, 1H), 7.54-7.43 (m, 1H), 7.26-7.17 (m, 1H), 7.17-7.04 (m, 2H), 6.62-6.47 (m, 1H), 5.23-5.14 (m, 1H), 4.78-4.62 (m, 1H), 4.55-4.35 (m, 2H), 2.58-2.40 (m, 2H), 2.27-2.12 (m, 2H), 2.02-1.73 (m, 3H), 1.67-1.45 (m, 7H), 1.18 (s, 3H), 1.15 (s, 3H), 0.09 (s, 9H)


Example 113
(R)—N-(5-Hydroxy-2,5-dimethylhexan-3-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound No. IV-815)



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To a solution of 99 mg (0.18 mmol) of (R)-ethyl 5-[(5-hydroxy-2,5-dimethylhexan-3-yl)carbamoyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 125 in 3 ml of dichloromethane, 0.078 ml (0.72 mmol) of N,N-dimethylethane-1,2-diamine was added in one portion with stirring at room temperature under argon stream and stirred at room temperature for 1 hour.


After the completion of the reaction, a 5% aqueous potassium bisulfate solution was added to the reaction solution, followed by extraction from the mixed solution with ethyl acetate twice. The organic layer was washed with a 5% aqueous potassium bisulfate solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=50:50 to 16:84 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in a small amount of ethyl acetate, and a solid was deposited by adding n-hexane. The solid was collected by filtration, washed with n-hexane, and dried under reduced pressure at 50° C. to obtain 72 mg of the title compound (yield: 84%) as a white solid.


Mass spectrum (CI, m/z): 478 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.19 & 11.81 (br s, total 1H), 9.71-9.44 (m, 1H), 5.63 (br s, 1H), 4.47-4.25 (m, 3H), 3.71-3.60 (m, 1H), 2.57-2.39 (m, 2H), 2.27-2.11 (m, 2H), 1.90-1.66 (m, 3H), 1.65-1.52 (m, 7H), 1.49-1.42 (m, 1H), 1.10 (s, 3H), 1.09 (s, 3H), 0.82 (d, J=6.8 Hz, 6H), 0.08 (s, 9H).


Example 114
N-[1-(4-Fluorophenyl)-3-hydroxy-2,2-dimethylpropyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound No. IV-946)



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To a solution of 0.745 g (1.69 mmol) of ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 3 in 8 ml of 1,4-dioxane, 1.47 ml (8.44 mmol) of DIPEA and 1.00 g (5.07 mmol) of 3-amino-3-(4-fluorophenyl)-2,2-dimethylpropan-1-ol synthesized in the similar manner as in Reference Example 127 were added in this order with stirring at room temperature under argon stream and stirred at 90° C. for 1.5 hours. Subsequently, the reaction solution was allowed to cool to room temperature, and then, 0.738 ml (6.78 mmol) of N,N-dimethylethane-1,2-diamine was added dropwise at room temperature and stirred at room temperature for 4 hours.


After the completion of the reaction, a 5% aqueous potassium bisulfate solution was added to the reaction solution, followed by extraction from the mixed solution with ethyl acetate twice. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=70:30 to 19:81 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The concentration residue was dissolved in 60 ml of ethyl acetate and washed with 10 ml of a 5% aqueous potassium bisulfate solution three times. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was dissolved in a small amount of ethyl acetate, and a solid was deposited by adding n-hexane. The solid was collected by filtration, washed with n-hexane, and dried under reduced pressure at 50° C. to obtain 509 mg of the title compound (yield: 57%) as a white solid.


Mass spectrum (ESI, m/z): 530 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.21 & 11.80 (br s, total 1H), 9.68-9.44 (m, 1H), 7.39-7.32 (m, 2H), 7.17-7.09 (m, 2H), 6.91-6.78 (m, 1H), 5.46 (br s, 1H), 4.65 (d, J=7.9 Hz, 1H), 4.45-4.28 (m, 2H), 3.23 (dd, J=4.2, 10.6 Hz, 1H), 3.08-2.99 (m, 1H), 2.60-2.39 (m, 2H), 2.27-2.14 (m, 2H), 1.91-1.73 (m, 2H), 1.65-1.49 (m, 6H), 1.05 (s, 3H), 0.64 (s, 3H), 0.09 (s, 9H).


Example 115
N-[1-(3-Fluorophenyl)-3-hydroxy-2,2-dimethylpropyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound No. IV-918)



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To a solution of 162 mg (0.367 mmol) of ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 3 in 4 ml of 1,4-dioxane, 0.32 ml (1.9 mmol) of DIPEA and 227 mg (1.15 mmol) of 3-amino-3-(3-fluorophenyl)-2,2-dimethylpropan-1-ol synthesized in the similar manner as in Reference Example 129 were added at room temperature in an argon atmosphere and then reacted at 100° C. for 2.5 hours. After standing to cool, 0.12 ml (1.1 mmol) of N,N-dimethyl-1,2-diamine was added and stirred at room temperature for 1 hour.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure, 20 ml of ethyl acetate was added to the residue, the organic layer after washing with 10 ml of a 5% aqueous potassium bisulfate solution, 10 ml of a saturated aqueous solution of sodium bicarbonate, and 10 ml of a saturated aqueous solution of sodium chloride in this order was dried over anhydrous magnesium sulfate and filtered, and then, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: 1,2-dichloroethane:ethyl acetate=81:19 to 30:70 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in a small amount of dichloromethane, then n-hexane was added, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 159 mg of the title compound (yield: 82%) as a white solid.


Mass spectrum (CI, m/z): 530 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.22 & 11.89 (br s, total 1H), 9.79-9.40 (m, 1H), 7.39-7.29 (m, 1H), 7.22-7.13 (m, 2H), 7.08-7.01 (m, 1H), 6.86 (d, J=8.0 Hz, 1H), 5.56-5.41 (m, 1H), 4.67 (d, J=8.0 Hz, 1H), 4.49-4.27 (m, 2H), 3.25 (dd, J=4.0, 10.6 Hz, 1H), 3.05 (dd, J=4.0, 10.6 Hz, 1H), 2.56-2.40 (m, 2H), 2.29-2.13 (m, 2H), 1.92-1.72 (m, 2H), 1.60 (br s, 3H), 1.52 (br s, 3H), 1.05 (s, 3H), 0.67 (s, 3H), 0.09 (s, 9H).


Example 116
(−)-N-[1-(3-Fluorophenyl)-3-hydroxy-2,2-dimethylpropyl]-6,6-dimethyl-3-[1-(trimethyl silyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound No. IV-920)

0.129 g (0.244 mmol) of N-[1-(3-fluorophenyl)-3-hydroxy-2,2-dimethylpropyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide synthesized in the similar manner as in Example 115 was subjected to optical resolution preparative chromatography (column: CHIRALPAK (trade name) ID, elution solvent: n-hexane:ethanol:methanol=95:5:1 (V/V)), and a fraction containing an optically active form eluted first was concentrated under reduced pressure to obtain 47 mg of the title compound (yield: 36%) as a white solid.


Specific optical rotation: [α]D20=−53° (c=0.23, methanol).


Mass spectrum (CI, m/z): 530 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.21 & 11.88 (br s, total 1H), 9.78-9.41 (m, 1H), 7.38-7.30 (m, 1H), 7.21-7.13 (m, 2H), 7.08-7.01 (m, 1H), 6.86 (br d, J=8.3 Hz, 1H), 5.56-5.40 (m, 1H), 4.67 (d, J=8.3 Hz, 1H), 4.47-4.30 (m, 2H), 3.25 (br dd, J=3.9, 10.5 Hz, 1H), 3.05 (br dd, J=3.9, 10.5 Hz, 1H), 2.60-2.40 (m, 2H), 2.26-2.13 (m, 2H), 1.90-1.73 (m, 2H), 1.60 (br s, 3H), 1.52 (s, 3H), 1.05 (s, 3H), 0.67 (s, 3H), 0.09 (s, 9H).


HPLC analysis:


Column: CHIRALPAK (trade name) ID 4.6×250 mm


Eluent: n-hexane/ethanol/methanol=95/5/1 (V/V)


Flow rate: 1.0 ml/min


Temperature: 40° C.


Detection wavelength: 254 nm


Retention time: 8.8 min.


Optical purity: >99% ee


Example 117
(+)-N-[1-(3-Fluorophenyl)-3-hydroxy-2,2-dimethylpropyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound No. IV-919)

A fraction containing an optically active form eluted later in the optical resolution preparative chromatography operation of Example 116 was concentrated under reduced pressure to obtain 45 mg of the title compound (yield: 35%) as a white solid.


Specific optical rotation: [α]D20=+59° (c=0.22, methanol).


Mass spectrum (CI, m/z): 530 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.21 & 11.94 (br s, total 1H), 9.78-9.41 (m, 1H), 7.38-7.30 (m, 1H), 7.21-7.13 (m, 2H), 7.08-7.01 (m, 1H), 6.86 (br d, J=8.1 Hz, 1H), 5.56-5.39 (m, 1H), 4.67 (d, J=8.1 Hz, 1H), 4.47-4.30 (m, 2H), 3.25 (br dd, J=3.8, 10.5 Hz, 1H), 3.05 (br dd, J=3.8, 10.5 Hz, 1H), 2.59-2.40 (m, 2H), 2.27-2.13 (m, 2H), 1.90-1.73 (m, 2H), 1.60 (br s, 3H), 1.52 (s, 3H), 1.05 (s, 3H), 0.67 (s, 3H), 0.09 (s, 9H).


HPLC analysis:


Column: CHIRALPAK (trade name) ID 4.6×250 mm


Elution solvent: n-hexane/ethanol/methanol=95/5/1 (V/V)


Flow rate: 1.0 ml/min


Temperature: 40° C.


Detection wavelength: 254 nm


Retention time: 11.6 min


Optical purity: >98% ee


Example 118
N-[1-(2-Fluorophenyl)-3-hydroxy-2,2-dimethylpropyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound No. IV-890)



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To a solution of 225 mg (1.14 mmol) of 3-amino-3-(2-fluorophenyl)-2,2-dimethylpropan-1-ol synthesized in the similar manner as in Reference Example 130 in 4 ml of 1,4-dioxane, 0.32 ml (1.9 mmol) of DIPEA and 166 mg (0.376 mmol) of ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2 (4H)-carboxylate synthesized in the similar manner as in Reference Example 3 were added at room temperature in an argon atmosphere and then reacted at 100° C. for 2.5 hours. After standing to cool, 0.12 ml (1.1 mmol) of N,N-dimethylethane-1,2-diamine was added and stirred at room temperature for 1 hour.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure, 20 ml of ethyl acetate was added to the residue, the organic layer after washing with 10 ml of a 5% aqueous potassium bisulfate solution, 10 ml of a saturated aqueous solution of sodium bicarbonate, and 10 ml of a saturated aqueous solution of sodium chloride in this order was dried over anhydrous magnesium sulfate and filtered, and then, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: 1,2-dichloroethane:ethyl acetate=81:19 to 30:70 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in a small amount of dichloromethane, then n-hexane was added, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 154 mg of the title compound (yield: 77%) as a white solid.


Mass spectrum (CI, m/z): 530 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.22 & 11.87 (br s, total 1H), 9.75-9.42 (m, 1H), 7.53-7.44 (m, 1H), 7.32-7.24 (m, 1H), 7.23-7.17 (m, 1H), 7.17-7.08 (m, 1H), 6.96-6.85 (m, 1H), 5.53 (br s, 1H), 5.03 (d, J=7.9 Hz, 1H), 4.46-4.26 (m, 2H), 3.40-3.28 (m, 1H), 3.08 (dd, J=4.0, 10.5 Hz, 1H), 2.56-2.39 (m, 2H), 2.27-2.12 (m, 2H), 1.92-1.72 (m, 2H), 1.65-1.47 (m, 6H), 1.10 (s, 3H), 0.69-0.60 (m, 3H), 0.09 (s, 9H).


Example 119
N-(1-Hydroxy-2,2,4-trimethylpentan-3-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound No. IV-822)



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To a solution of a mixture of 133 mg (0.246 mmol) of 2-ethyl 5-(trichloromethyl) 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]pyrrolo[3,4-c]pyrazole-2,5(4H,6H)-dicarboxylate synthesized in the similar manner as in Reference Example 102 and 80 mg (0.18 mmol) of ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate in 3 ml of dehydrated 1,4-dioxane, 0.37 ml (2.1 mmol) of DIPEA and 189 mg (1.30 mmol) of 3-amino-2,2,4-trimethylpentan-1-ol synthesized in the similar manner as in Reference Example 132 were added in this order at room temperature in an argon atmosphere and then stirred at 90° C. for 2.5 hours. After standing to cool until the reaction solution becomes room temperature, 0.23 ml (2.1 mmol) of N,N-dimethylethane-1,2-diamine was added at room temperature and stirred for 14 hours with the temperature unchanged.


After the completion of the reaction, a 5% aqueous potassium bisulfate solution was added to the reaction solution and stirred, followed by extraction with ethyl acetate three times. All of the organic layers were dried over anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=60:40 to 30:70 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in ethyl acetate, then n-hexane was added, and the deposited solid was collected by filtration, washed with n-hexane, and then dried under reduced pressure to obtain 107 mg of the title compound (yield: 52%) as a white solid.


Mass spectrum (CI, m/z): 478 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.42-11.70 (m, 1H), 9.86-9.33 (m, 1H), 5.48 (br d, J=9.2 Hz, 1H), 5.13-4.93 (m, 1H), 4.48-4.22 (m, 2H), 3.55-3.48 (m, 1H), 3.45 (dd, J=3.9, 10.7 Hz, 1H), 3.04 (dd, J=5.4, 10.7 Hz, 1H), 2.58-2.38 (m, 2H), 2.26-2.12 (m, 2H), 2.05-1.92 (m, 1H), 1.88-1.73 (m, 2H), 1.61 (br s, 3H), 1.59 (br s, 3H), 0.93 (s, 3H), 0.89 (d, J=6.7 Hz, 6H), 0.79 (s, 3H), 0.07 (s, 9H).


Example 120
(R)—N-(3-Hydroxy-3-methyl-1-phenylbutyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound No. III-298)



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To a solution of 1.53 g (4.19 mmol) of ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 46 in 20 ml of dehydrated dichloromethane, 2.60 ml (14.9 mmol) of DIPEA was added at room temperature in an argon atmosphere. Subsequently, a solution of 700 mg (2.36 mmol) of bis(trichloromethyl) carbonate in 5 ml of dehydrated dichloromethane was added dropwise at −78° C. and then stirred for 0.5 hours with the temperature unchanged and further for 2 hours after the temperature was raised to room temperature.


After the completion of the reaction, a saturated aqueous solution of sodium bicarbonate and dichloromethane were added to the reaction solution at −78° C. and then stirred for 1.5 hours while the temperature was raised to room temperature for a while. The reaction solution was separated into an aqueous layer and an organic layer, and then, the aqueous layer was subjected to extraction with ethyl acetate twice. All of the organic layers were washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=85:15 to 75:25 (V/V)), subsequently concentrated under reduced pressure, and dried under reduced pressure to obtain 1.75 g of a white solid.


To a solution of 97.1 mg (0.542 mmol) of (R)-4-amino-2-methyl-4-phenylbutan-2-ol synthesized in the similar manner as in Reference Example 23 in 2 ml of dehydrated 1,4-dioxane, 0.18 ml (1.0 mmol) of DIPEA and 130 mg of a portion of the solid obtained by the operation described above were added in this order at room temperature in an argon atmosphere and then stirred at 90° C. for 1.5 hours.


After the completion of the reaction, a saturated aqueous solution of sodium bicarbonate was added to the reaction solution and stirred, followed by extraction with ethyl acetate three times. All of the organic layers were dried over anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=70:30 to 30:70 (V/V)), subsequently concentrated under reduced pressure, and dried under reduced pressure to obtain a concentration residue.


To a solution of the obtained concentration residue in 2 ml of THF, 0.12 ml (1.1 mmol) of N,N-dimethylethane-1,2-diamine was added at room temperature in an argon atmosphere and then stirred for 2 hours with the temperature unchanged.


After the completion of the reaction, a 5% aqueous potassium bisulfate solution was added to the reaction solution and stirred, followed by extraction with ethyl acetate three times. All of the organic layers were dried over anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=50:50 to 25:75 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in ethyl acetate, then n-hexane was added, and the deposited solid was collected by filtration, washed with n-hexane, and then dried under reduced pressure to obtain 96 mg of the title compound (yield: 62% [2 steps]) as a white solid.


Mass spectrum (CI, m/z): 498 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.35-11.77 (m, 1H), 9.95-9.67 (m, 1H), 7.36-7.23 (m, 4H), 7.19-7.11 (m, 1H), 6.58-6.44 (m, 1H), 4.94-4.84 (m, 1H), 4.64 (br s, 1H), 4.40 (br s, 2H), 2.00-1.88 (m, 1H), 1.65 (dd, J=3.2, 14.2 Hz, 1H), 1.57 (br s, 3H), 1.52 (br s, 3H), 1.16 (s, 3H), 1.13 (s, 3H), 0.97 (br s, 2H), 0.98 (br s, 2H), 0.03 (s, 9H).


Example 121
N-(3-Hydroxy-2,2-dimethyl-1-phenylpropyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound No. III-353)



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To a solution of 1.53 g (4.19 mmol) of ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 46 in 20 ml of dehydrated dichloromethane, 2.60 ml (14.9 mmol) of DIPEA was added at room temperature in an argon atmosphere. Subsequently, a solution of 700 mg (2.36 mmol) of bis(trichloromethyl) carbonate in 5 ml of dehydrated dichloromethane was added dropwise at −78° C. and then stirred for 0.5 hours with the temperature unchanged and further for 2 hours after the temperature was raised to room temperature.


After the completion of the reaction, a saturated aqueous solution of sodium bicarbonate and dichloromethane were added to the reaction solution at −78° C. and then stirred for 1.5 hours while the temperature was raised to room temperature for a while. The reaction solution was separated into an aqueous layer and an organic layer, and then, the aqueous layer was subjected to extraction with ethyl acetate twice. All of the organic layers were washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=85:15 to 75:25 (V/V)), subsequently concentrated under reduced pressure, and dried under reduced pressure to obtain 1.75 g of a white solid.


To a solution of 109 mg (0.608 mmol) of 3-amino-2,2-dimethyl-3-phenylpropan-1-ol [synthesized according to the method described in Synthetic Communications 1994, 24 (7), 899-906] in 2 ml of dehydrated 1,4-dioxane, 0.20 ml (1.1 mmol) of DIPEA and 142 mg of a portion of the solid obtained by the operation described above were added in this order at room temperature in an argon atmosphere and then stirred at 90° C. for 2.5 hours. After standing to cool until the reaction solution becomes room temperature, 0.13 ml (1.2 mmol) of N,N-dimethylethane-1,2-diamine was added at room temperature and stirred for 2 hours with the temperature unchanged.


After the completion of the reaction, a 5% aqueous potassium bisulfate solution was added to the reaction solution and stirred, followed by extraction with ethyl acetate three times. All of the organic layers were dried over anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=60:40 to 40:60 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in ethyl acetate, then n-hexane was added, and the deposited solid was collected by filtration, washed with n-hexane, and then dried under reduced pressure to obtain 112 mg of the title compound (yield: 66% [2 steps]) as a white solid. Mass spectrum (CI, m/z): 498 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.40-11.84 (m, 1H), 10.11-9.58 (m, 1H), 7.37-7.26 (m, 4H), 7.25-7.18 (m, 1H), 6.85 (br d, J=8.2 Hz, 1H), 5.53-5.39 (m, 1H), 4.63 (d, J=8.2 Hz, 1H), 4.45-4.25 (m, 2H), 3.29-3.22 (m, 1H), 3.07-2.98 (m, 1H), 1.58 (s, 3H), 1.51 (s, 3H), 1.06 (s, 3H), 1.03-0.94 (m, 2H), 0.76-0.58 (m, 5H), 0.03 (s, 9H).


Example 122
(−)-N-(3-Hydroxy-2,2-dimethyl-1-phenylpropyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound No. IV-673)

To a solution of a mixture of 545 mg (1.16 mmol) of 2-ethyl 5-(trichloromethyl) 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]pyrrolo[3,4-c]pyrazole-2,5(4H,6H)-dicarboxylate synthesized in the similar manner as in Reference Example 102 and 329 mg (0.853 mmol) of ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate in 7 ml of dehydrated 1,4-dioxane, 1.80 ml (10.3 mmol) of DIPEA and 1.16 g (6.47 mmol) of 3-amino-2,2-dimethyl-3-phenylpropan-1-ol [synthesized according to the method described in Synthetic Communications 1994, 24 (7), 899-906] were added in this order at room temperature in an argon atmosphere and then stirred at 90° C. for 2 hours. After standing to cool until the reaction solution becomes room temperature, 0.90 ml (8.3 mmol) of N,N-dimethylethane-1,2-diamine was added at room temperature and stirred for 2.5 hours with the temperature unchanged.


After the completion of the reaction, a 5% aqueous potassium bisulfate solution was added to the reaction solution and stirred, followed by extraction with ethyl acetate three times. All of the organic layers were dried over anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=60:40 to 40:60 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was subjected again to silica gel column chromatography (DIOL silica gel, elution solvent: 1,2-dichloroethane:ethyl acetate=100:0 to 85:15 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in an ethyl acetate/ethanol mixed solvent, then n-hexane was added, and the deposited solid was collected by filtration, washed with n-hexane, and then dried under reduced pressure to obtain 802 mg of a white solid.


0.50 g of a portion of the obtained solid was subjected to optical resolution preparative chromatography (column: CHIRALPAK (trade name) ID, elution solvent: n-hexane:ethanol=90:10 (V/V)), and a fraction containing an optically active form eluted first was concentrated under reduced pressure. The obtained concentration residue was dissolved in an acetonitrile/water mixed solvent and then freeze-dried to obtain 225 mg of the title compound (yield: 35%) as a white solid.


Specific optical rotation: [α]D20=−66° (c=0.50, methanol).


Mass spectrum (CI, m/z): 512 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.35-11.77 (m, 1H), 9.86-9.35 (m, 1H), 7.36-7.27 (m, 4H), 7.25-7.17 (m, 1H), 6.86 (br d, J=8.2 Hz, 1H), 5.45 (br s, 1H), 4.64 (d, J=8.2 Hz, 1H), 4.46-4.30 (m, 2H), 3.45-3.23 (m, 1H), 3.06-2.99 (m, 1H), 2.58-2.40 (m, 2H), 2.26-2.14 (m, 2H), 1.90-1.73 (m, 2H), 1.60 (s, 3H), 1.52 (s, 3H), 1.06 (s, 3H), 0.64 (s, 3H), 0.09 (s, 9H).


SFC (supercritical fluid chromatography) analysis:


Column: CHIRALPAK (trade name) ID 2.1×150 mm (particle size: 3 um)


Eluent: CO2/methanol=90/10 (V/V)


Flow rate: 0.85 ml/min


Temperature: 40° C.


Detection wavelength: 240 nm


Retention time: 5.3 min.


Optical purity: >99% ee


Example 123
(+)-N-(3-Hydroxy-2,2-dimethyl-1-phenylpropyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound No. IV-672)

A fraction containing an optically active form eluted later in the optical resolution preparative chromatography operation of Example 122 was concentrated under reduced pressure. The obtained concentration residue was dissolved in an acetonitrile/water mixed solvent and then freeze-dried to obtain 223 mg of the title compound (yield: 35%) as a white solid.


Specific optical rotation: [α]D20=+60° (c=0.50, methanol).


Mass spectrum (CI, m/z): 512 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.42-11.76 (m, 1H), 9.57 (br s, 1H), 7.35-7.27 (m, 4H), 7.25-7.18 (m, 1H), 6.86 (br d, J=8.2 Hz, 1H), 5.45 (br s, 1H), 4.64 (d, J=8.2 Hz, 1H), 4.44-4.30 (m, 2H), 3.44-3.23 (m, 1H), 3.06-2.98 (m, 1H), 2.59-2.40 (m, 2H), 2.26-2.14 (m, 2H), 1.89-1.74 (m, 2H), 1.60 (s, 3H), 1.52 (s, 3H), 1.06 (s, 3H), 0.64 (s, 3H), 0.09 (s, 9H).


SFC (supercritical fluid chromatography) analysis:


Column: CHIRALPAK (trade name) ID 2.1×150 mm (particle size: 3 um)


Eluent: CO2/methanol=90/10 (V/V)


Flow rate: 0.85 ml/min


Temperature: 40° C.


Detection wavelength: 240 nm


Retention time: 6.5 min.


Optical purity: >99% ee


Example 124
(R)—N-[5-(2-Butoxy-2-phenylacetyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide (Compound No. IV-1200)



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To a solution of 1.65 g (5.53 mmol) of (R)-benzyl 2-butoxy-2-phenylacetate synthesized in the similar manner as in Reference Example 133 in 8 ml of methanol/8 ml of water, 300 mg (7.15 mmol) of lithium hydroxide monohydrate was added at room temperature and then reacted with stirring at room temperature for 3 hours.


After the completion of the reaction, diethyl ether was added to the reaction solution and separated into an aqueous layer and an organic layer. The aqueous layer was adjusted to pH 2 by adding 2 N hydrochloric acid, followed by extraction with ethyl acetate three times. All of the obtained organic layers were washed with saturated saline, then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 1.34 g of a concentration residue.


To a solution of 150 mg of a portion of the obtained concentration residue in 2 ml of dehydrated dichloromethane, 0.006 ml (0.08 mmol) of DMF and 0.083 ml (0.95 mmol) of oxalyl chloride were added with stirring at 0° C. in an argon atmosphere and stirred at room temperature for 1.5 hours.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a concentration residue.


To a solution of 150 mg (0.396 mmol) of ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 84 and 0.350 ml (2.00 mmol) of DIPEA in 2 ml of dehydrated dichloromethane, a solution of the obtained concentration residue in 3 ml of dehydrated dichloromethane was added dropwise with stirring at 0° C. in an argon atmosphere and stirred at room temperature for 3 hours.


After the completion of the reaction, a saturated aqueous solution of sodium bicarbonate was added to the reaction solution, followed by extraction with dichloromethane. The obtained organic layer was washed with water, then dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=100:0 to 70:30 (V/V)) and subsequently concentrated under reduced pressure to obtain a concentration residue.


To a solution of the obtained concentration residue in 2 ml of dehydrated dichloromethane, 0.130 ml (1.19 mmol) of N,N-dimethylethane-1,2-diamine was added at room temperature in an argon atmosphere and then stirred at room temperature for 16 hours.


After the completion of the reaction, a 5% aqueous potassium bisulfate solution was added to the reaction solution and stirred, followed by extraction with dichloromethane. The obtained organic layer was washed with a saturated aqueous solution of sodium bicarbonate and saturated saline in this order, then dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=100:0 to 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was subjected to preparative HPLC (column: X-Bridge (trade name) ODS, elution solvent: acetonitrile:1 mM aqueous potassium dihydrogen phosphate solution=50:50 (V/V)), and ethyl acetate and water were added to a fraction containing the compound of interest to separate an organic layer and an aqueous layer. The obtained organic layer was concentrated under reduced pressure. The obtained concentration residue was dissolved in ethyl acetate and then added to n-hexane, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 77 mg of the title compound (yield: 39%) as a white solid.


Mass spectrum (CI, m/z): 497 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.34-11.89 (m, 1H), 9.56 (br s, 1H), 7.45-7.25 (m, 5H), 5.02 (s, 1H), 4.68-4.49 (m, 1H), 4.40 (br d, J=12.7 Hz, 1H), 3.57-3.39 (m, 2H), 2.59-2.35 (m, 2H), 2.24-2.09 (m, 2H), 1.87-1.73 (m, 2H), 1.68 (s, 3H), 1.61 (s, 3H), 1.56-1.45 (m, 2H), 1.40-1.28 (m, 2H), 0.86 (t, J=7.3 Hz, 3H), 0.05 (s, 9H).


Example 125
N-(3-Methoxy-2,2-dimethyl-1-phenylpropyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide (Compound No. IV-676)



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To a solution of 131 mg (0.219 mmol) of ethyl 5-[(3-methoxy-2,2-dimethyl-1-phenylpropyl)carbamoyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 137 in 3 ml of dichloromethane, 0.095 ml (0.87 mol) of N,N-dimethylethane-1,2-diamine was added in one portion with stirring at room temperature under argon stream and stirred at room temperature for 1 hour.


After the completion of the reaction, a 5% aqueous potassium bisulfate solution was added to the reaction solution, followed by extraction from the mixed solution with ethyl acetate twice. The organic layer was washed with a 5% aqueous potassium bisulfate solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=70:30 to 13:87 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was dissolved in a small amount of ethyl acetate, and a solid was deposited by adding n-hexane. The solid was collected by filtration, washed with n-hexane, and dried under reduced pressure at 50° C. to obtain 62 mg of the title compound (yield: 54%) as a white solid.


Mass spectrum (CI, m/z): 526 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.21 & 11.76 (br s, total 1H), 9.58 (br s, 1H), 7.38-7.18 (m, 5H), 6.75-6.52 (m, 1H), 4.59 (d, J=7.7 Hz, 1H), 4.52-4.30 (m, 2H), 3.38 (s, 3H), 3.13 (d, J=9.3 Hz, 1H), 2.92 (d, J=9.3 Hz, 1H), 2.58-2.40 (m, 2H), 2.29-2.12 (m, 2H), 1.91-1.74 (m, 2H), 1.59 (br s, 3H), 1.50 (s, 3H), 1.12 (s, 3H), 0.68 (s, 3H), 0.09 (s, 9H).


Reference Example 1
1-(Trimethylsilyl)cyclobutanecarboxylic acid



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To 200 ml of dehydrated THF, 214 ml (428 mmol) of 2 M lithium diisopropylamide/THF solution was added in an argon atmosphere, and then, 10.1 ml (107 mmol) of cyclobutanecarboxylic acid was added dropwise with stirring under cooling in ice water and stirred for 4 hours while the temperature was raised to room temperature for a while. Subsequently, 20 ml (116 mmol) of hexamethylphosphoric acid triamide was added, and 51 ml (490 mmol) of chlorotrimethylsilane was added dropwise with stirring while the internal temperature was kept at −60° C. or lower under cooling in a dry ice/acetone coolant, and then stirred at −78° C. for 16.5 hours.


After the completion of the reaction, 67 ml of methanol was added to the reaction solution, and 134 ml of cold water was added after the temperature was raised to 0° C. The pH was adjusted to 2.1 by adding 2 N hydrochloric acid, 268 ml of diethyl ether was added thereto and then the aqueous layer and the organic layer were separated, and the organic layer was washed with 268 ml of a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. 50 ml of a 2 N aqueous sodium hydroxide solution and 267 ml of n-hexane were added to the obtained concentration residue and then the aqueous layer and the organic layer were separated. Subsequently, the aqueous layer was adjusted to pH 2.7 by adding 1 N hydrochloric acid, and 267 ml of ethyl acetate was added to this solution and then the aqueous layer and the organic layer were separated. The obtained organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. n-Hexane was added to the obtained concentration residue and cooled in an ice water bath. The resulting solid was filtered, washed by sousing with cooled n-hexane, and then dried under reduced pressure to obtain 6.24 g of the title compound (yield: 34%) as a white solid. The filtrate was further concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (elution solvent: 1,2-dichloroethane:methanol=100:0 to 95:5 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 4.33 g of the title compound (yield: 23%) as a white solid.


Mass spectrum (CI, m/z): 173 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 11.64 (br s, 1H), 2.45-2.34 (m, 2H), 2.17-2.06 (m, 2H), 1.91-1.70 (m, 2H), 0.06 (s, 9H).


Reference Example 2
5-tert-Butyl 2-ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]pyrrolo[3,4-c]pyrazole-2,5(4H,6H)-dicarboxylate



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To a solution of 13.9 g (80.4 mmol) of 1-(trimethylsilyl)cyclobutanecarboxylic acid synthesized in the similar manner as in Reference Example 1 in 105 ml of dehydrated dichloromethane, 6.96 ml (81.2 mmol) of oxalyl chloride and 0.32 ml (4.14 mmol) of DMF were added dropwise in this order between −25° C. and −10° C. in an argon atmosphere and then stirred for 2 hours after the temperature was raised to 0° C. To a solution of 8.74 g (26.9 mmol) of 5-tert-butyl 2-ethyl 3-amino-6,6-dimethylpyrrolo[3,4-c]pyrazole-2,5(4H,6H)-dicarboxylate [synthesized according to the method described in Journal of Medicinal Chemistry 2012, 55 (10), 4728-4739] and 23.5 ml (135 mmol) of DIPEA in 122 ml of dehydrated dichloromethane, the resulting reaction solution was added dropwise at 0° C. in an argon atmosphere and stirred at the same temperature as above for 16 hours.


After the completion of the reaction, 486 ml of a 5% aqueous potassium bisulfate solution was added to the reaction solution and then the aqueous layer and the organic layer were separated. The aqueous layer was subjected to extraction with 200 ml of dichloromethane twice. All of the obtained organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=86:14 to 53:47 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 8.30 g of the title compound (yield: 64%) as a white foam.


Mass spectrum (CI, m/z): 479 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 9.98 & 9.72 & 9.71 (s, total 1H), 4.50-4.37 (m, 4H), 2.53-2.43 (m, 2H), 2.32-2.07 (m, 2H), 2.02-1.72 (m, 2H), 1.65-1.55 (m, 6H), 1.51-1.42 (m, 9H), 1.38-1.31 (m, 3H), 0.10 & 0.06 & 0.01 (s, total 9H).


Reference Example 3
Ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate



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To a solution of 8.30 g (17.3 mmol) of 5-tert-butyl 2-ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]pyrrolo[3,4-c]pyrazole-2,5(4H,6H)-dicarboxylate synthesized in the similar manner as in Reference Example 2 in 81 ml of dehydrated dichloromethane, 6.0 ml (52 mmol) of 2,6-lutidine and 9.2 ml (51 mmol) of trimethylsilyl trifluoromethanesulfonate were added dropwise in this order at 0° C. in an argon atmosphere and stirred at the same temperature as above for 2 hours.


After the completion of the reaction, 64 ml of a saturated aqueous solution of sodium bicarbonate and 64 ml of dichloromethane were added to the reaction solution and then the aqueous layer and the organic layer were separated. The aqueous layer was subjected to extraction with 72 ml of dichloromethane twice, and then, all of the obtained organic layers were washed with 72 ml of a saturated aqueous solution of sodium bicarbonate and 72 ml of a saturated aqueous solution of sodium chloride in this order, subsequently dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The operation of adding 5 ml of toluene to the obtained concentration residue and concentrating the resultant under reduced pressure was repeated five times to obtain crude ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate.


To a solution of 6.70 g of the obtained crude ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate in 235 ml of dehydrated dichloromethane, 8.8 ml (51 mmol) of DIPEA was added at room temperature in an argon atmosphere, and then, a solution of 3.79 g (12.8 mmol) of bis(trichloromethyl)carbonate in 38 ml of dehydrated dichloromethane was added dropwise at −78° C. and stirred at the same temperature as above for 3 hours. At each point in time of 1 hour, 2 hours, and 2.6 hours after the start of this reaction, 1.0 ml (5.7 mmol) of DIPEA was added thereto.


After the completion of the reaction, 150 ml of a saturated aqueous solution of sodium bicarbonate was added to the reaction solution and stirred while the temperature was raised to room temperature for a while. After separation into an aqueous layer and an organic layer, the aqueous layer was subjected to extraction with 130 ml of dichloromethane twice. All of the obtained organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=78:22 to 57:43 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. n-Hexane was added to the obtained concentration residue and ultrasonicated. After cooling in a refrigerator, the deposited solid was filtered and dried under reduced pressure to obtain 3.51 g of the title compound (yield: 46% [2 steps]) as a white solid.


Mass spectrum (CI, m/z): 441 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 9.83-9.65 (m, 1H), 4.84 (s, 2H), 4.49-4.37 (m, 2H), 2.54-2.43 (m, 2H), 2.31-2.21 (m, 2H), 1.95-1.83 (m, 2H), 1.71-1.58 (m, 6H), 1.35 (t, J=7.1 Hz, 3H), 0.13-0.08 (m, 9H).


Reference Example 4
5-tert-Butyl 1-ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]pyrrolo[3,4-c]pyrazole-1,5(4H,6H)-dicarboxylate



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To a solution of 24.52 g (142 mmol) of 1-(trimethylsilyl)cyclobutanecarboxylic acid synthesized in the similar manner as in Reference Example 1 in 180 ml of dehydrated dichloromethane, 0.55 ml (7.1 mmol) of DMF and 12.2 ml (142 mmol) of oxalyl chloride were added dropwise at 0° C. in an argon atmosphere and stirred at the same temperature as above for 2 hours.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure (hot water bath temperature: 30° C.) to obtain a concentration residue.


To a solution of 15.39 g (47.4 mmol) of 5-tert-butyl 1-ethyl 3-amino-6,6-dimethylpyrrolo[3,4-c]pyrazole-1,5(4H,6H)-dicarboxylate [synthesized according to the method described in Journal of Medicinal Chemistry 2012, 55 (10), 4728-4739] and 40.6 ml (238 mmol) of DIPEA in 180 ml of dehydrated dichloromethane, a solution of the obtained concentration residue in 120 ml of dehydrated dichloromethane was added dropwise at 0° C. in an argon atmosphere and stirred at the same temperature as above for 20 hours.


After the completion of the reaction, the reaction solution was poured to 800 ml of a 5% aqueous potassium bisulfate solution, stirred, and then the aqueous layer and the organic layer were separated. The aqueous layer was subjected to extraction with 250 ml of dichloromethane twice. All of the obtained organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=91:9 to 70:30 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 14.6 g of the title compound (yield: 64%) as a white foam.


Mass spectrum (EI, m/z): 478 [M]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 10.32-10.20 (m, 1H), 4.46-4.32 (m, 4H), 2.48-2.39 (m, 2H), 2.24-2.14 (m, 2H), 1.84-1.68 (m, 8H), 1.52-1.40 (m, 9H), 1.32 (t, J=7.1 Hz, 3H), 0.07 (s, 9H).


Reference Example 5
Ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-carboxylate



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To a solution of 10.02 g (20.9 mmol) of 5-tert-butyl 1-ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]pyrrolo[3,4-c]pyrazole-1,5(4H,6H)-dicarboxylate synthesized in the similar manner as in Reference Example 4 in 100 ml of dehydrated dichloromethane, 7.26 ml (62.7 mmol) of 2,6-lutidine and 11.3 ml (62.7 mmol) of trimethylsilyl trifluoromethanesulfonate were added dropwise at 0° C. in an argon atmosphere and stirred at the same temperature as above for 1.5 hours.


After the completion of the reaction, 60 ml of a saturated aqueous solution of sodium bicarbonate and 60 ml of dichloromethane were added to the reaction solution. After separation into an aqueous layer and an organic layer, the aqueous layer was subjected to extraction with 60 ml of dichloromethane twice. All of the obtained organic layers were washed with 60 ml of a saturated aqueous solution of sodium bicarbonate and 60 ml of a saturated aqueous solution of sodium chloride in this order, then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The operation of adding toluene to the obtained concentration residue and concentrating it under reduced pressure was repeated three times to obtain 7.43 g of the title compound (yield: 94%) as a pale yellow solid.


Mass spectrum (EI, m/z): 378 [M]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 10.03 (s, 1H), 4.37 (q, J=7.1 Hz, 2H), 3.85 (s, 2H), 2.48-2.38 (m, 2H), 2.23-2.12 (m, 2H), 1.85-1.72 (m, 2H), 1.41 (s, 6H), 1.31 (t, J=7.1 Hz, 3H), 0.06 (s, 9H).


Reference Example 6
5-tert-Butyl 2-ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]pyrrolo[3,4-c]pyrazole-2,5(4H,6H)-dicarboxylate



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To a solution of 1.05 g (6.63 mmol) of 1-(trimethylsilyl)cyclopropanecarboxylic acid [synthesized according to the method described in J. Org. Chem., 1982, 47 (5), 893-895] in 20 ml of dehydrated dichloromethane, 0.70 ml (8.2 mmol) of oxalyl chloride and 0.020 ml (0.26 mmol) of DMF were added at 0° C. in a nitrogen atmosphere and stirred at the same temperature as above for 3 hours.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure (hot water bath temperature: 25° C.) to obtain a concentration residue.


To a solution of the obtained concentration residue in 15 ml of dehydrated dichloromethane, 1.80 ml (10.3 mmol) of DIPEA and 839 mg (2.59 mmol) of 5-tert-butyl 2-ethyl 3-amino-6,6-dimethylpyrrolo[3,4-c]pyrazole-2,5(4H,6H)-dicarboxylate [synthesized according to the method described in Journal of Medicinal Chemistry 2012, 55 (10), 4728-4739] were added at 0° C. in a nitrogen atmosphere and stirred at the same temperature as above for 20.5 hours.


After the completion of the reaction, a saturated aqueous solution of sodium bicarbonate was added to the reaction solution, followed by extraction with dichloromethane twice. All of the obtained organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=90:10 to 75:25 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 1.19 g of the title compound (containing impurities) as a pale yellow foam.


Mass spectrum (CI, m/z): 465 [M+1]+.



1H-NMR spectrum (400 MHz, CDCl3) δ: 10.09 & 9.92 (s, total 1H), 4.70-4.46 (m, 4H), 1.72 (s, 3H), 1.65 (s, 3H), 1.54-1.44 (m, 12H), 1.15-1.07 (m, 2H), 0.84-0.78 (m, 2H), 0.17-0.07 (m, 9H).


Reference Example 7
Ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate hydrochloride



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To a solution of 1.19 g of 5-tert-butyl 2-ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]pyrrolo[3,4-c]pyrazole-2,5(4H,6H)-dicarboxylate (containing impurities) synthesized in the similar manner as in Reference Example 6 in 20 ml of ethyl acetate, 4.0 ml (16 mmol) of 4 N hydrogen chloride/ethyl acetate was added at room temperature in a nitrogen atmosphere and stirred at the same temperature as above for 6.5 hours. Then, 2.0 ml (8.0 mmol) of 4 N hydrogen chloride/ethyl acetate was added thereto and further stirred at room temperature for 14.5 hours.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained concentration residue was suspended in diisopropyl ether and stirred at room temperature. Insoluble matter was collected by filtration, and the obtained solid was washed by sousing with diisopropyl ether and then dried under reduced pressure to obtain 0.91 g of the title compound (yield: 88% [2 steps]) as a white solid.


Mass spectrum (CI, m/z): 365 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 9.99 (br s, 2H), 9.91 (s, 1H), 4.51-4.39 (m, 4H), 1.63 (s, 6H), 1.35 (t, J=7.2 Hz, 3H), 1.08 (dd, J=4.2, 6.0 Hz, 2H), 0.87 (dd, J=4.2, 6.0 Hz, 2H), 0.08 (s, 9H).


Reference Example 8
2-Methyl-2-(trimethylsilyl)propanoic acid



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To 100 ml of dehydrated THF, 200 ml (400 mmol) of 2 M lithium diisopropylamide/THF solution was added in an argon atmosphere, and subsequently, 4.7 ml (51 mmol) of isobutanoic acid was added dropwise at 0° C. and then stirred at room temperature for 4 hours. 10 ml (58 mmol) of hexamethylphosphoric acid triamide was added thereto, and then, 29 ml (230 mmol) of chlorotrimethylsilane was added thereto dropwise at −78° C. and stirred for 24 hours while the temperature was gradually raised to room temperature.


After the completion of the reaction, 25 ml of methanol and 50 ml of water were added to the reaction solution. Subsequently, the solution was rendered acidic by adding 2 N hydrochloric acid, followed by extraction with diethyl ether. All of the obtained organic layers were washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was dissolved in a 2 N aqueous sodium hydroxide solution and washed with ethyl acetate. After separation into an aqueous layer and an organic layer, the aqueous layer was rendered acidic by adding 1 N hydrochloric acid, followed by extraction with ethyl acetate. All of the obtained organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was suspended in n-hexane, and after ultrasonication, insoluble matter was collected by filtration. The filtrate was concentrated under reduced pressure, the obtained concentration residue was subjected to silica gel column chromatography (elution solvent: 1,2-dichloroethane:methanol=100:0 to 99:1 (V/V)), and a fraction containing the compound of interest and the aforementioned solid collected by filtration were combined, concentrated under reduced pressure, and dried under reduced pressure to obtain 2.66 g of the title compound (yield: 32%) as a white solid.


Mass spectrum (CI, m/z): 161 [M+1]+.



1H-NMR spectrum (400 MHz, CDCl3) δ: 1.22 (s, 6H), 0.08 (s, 9H).


Reference Example 9
5-tert-Butyl 1-ethyl 6,6-dimethyl-3-[2-methyl-2-(trimethylsilyl)propanamido]pyrrolo[3,4-c]pyrazole-1,5(4H,6H)-dicarboxylate



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To a solution of 1.30 g (8.11 mmol) of 2-methyl-2-(trimethylsilyl)propanoic acid synthesized in the similar manner as in Reference Example 8 in 25 ml of dehydrated dichloromethane, 0.85 ml (9.9 mmol) of oxalyl chloride and 0.040 ml (0.52 mmol) of DMF were added in this order at 0° C. in a nitrogen atmosphere and stirred at the same temperature as above for 3.5 hours.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure (hot water bath temperature: 25° C.) to obtain a concentration residue.


To a solution of the obtained concentration residue in 15 ml of dehydrated dichloromethane, 2.30 ml (13.2 mmol) of DIPEA and 1.08 g (3.33 mmol) of 5-tert-butyl 1-ethyl 3-amino-6,6-dimethylpyrrolo[3,4-c]pyrazole-1,5(4H,6H)-dicarboxylate [synthesized according to the method described in Journal of Medicinal Chemistry 2012, 55 (10), 4728-4739] were added in this order at 0° C. in a nitrogen atmosphere and stirred at the same temperature as above for 17.5 hours.


After the completion of the reaction, a saturated aqueous solution of sodium bicarbonate was added to the reaction solution and stirred, followed by extraction with dichloromethane three times. All of the organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=93:7 to 80:20 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 1.28 g of the title compound (yield: 82%) as a pale yellow foam.


Mass spectrum (CI, m/z): 467 [M+1]+.



1H-NMR spectrum (400 MHz, CDCl3) δ: 7.87-7.74 (m, 1H), 4.60-4.47 (m, 4H), 1.84 & 1.78 (s, total 6H), 1.55-1.48 (m, 9H), 1.47 (t, J=7.2 Hz, 3H), 1.31-1.25 (m, 6H), 0.10-0.04 (m, 9H).


Reference Example 10
1-(Ethyldimethylsilyl)cyclobutanecarboxylic acid



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To 200 ml of dehydrated THF, 214 ml (428 mmol) of 2 M lithium diisopropylamide/THF solution was added in an argon atmosphere, and then, 10.7 ml (112 mmol) of cyclobutanecarboxylic acid was added dropwise under cooling in ice water and stirred while the temperature was raised to room temperature for a while. Subsequently, 20 ml (120 mmol) of hexamethylphosphoric acid triamide was added. After cooling in a dry ice/ethanol coolant, 67.6 ml (485 mmol) of chloro(ethyl)dimethylsilane was added dropwise at −75° C. to −69° C. and stirred overnight at a temperature of −60° C. or lower.


After the completion of the reaction, 67 ml of methanol and subsequently 134 ml of cold water were added dropwise to the reaction solution and then brought to room temperature. 240 ml of 2 N hydrochloric acid was added for acidity (pH 2.0), and 200 ml of diethyl ether was added thereto and then the aqueous layer and the organic layer were separated. The obtained organic layer was washed with 250 ml of a saturated aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. 41 ml of a 2 N aqueous sodium hydroxide solution was added to the obtained concentration residue and washed with 250 ml of n-hexane. The aqueous layer was rendered acidic (pH 2.0) again by adding 82 ml of 1 N hydrochloric acid. This solution was subjected to extraction with 250 ml of ethyl acetate, and the organic layer was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (elution solvent: 1,2-dichloroethane:methanol=100:0 to 95:5 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 11.7 g of the title compound (yield: 59%) as a white solid.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 11.71 (br s, 1H), 2.44-2.33 (m, 2H), 2.19-2.08 (m, 2H), 1.91-1.73 (m, 2H), 0.92 (t, J=7.9 Hz, 3H), 0.55 (q, J=7.9 Hz, 2H), 0.05 (s, 6H).


Reference Example 11
5-tert-Butyl 2-ethyl 3-[1-(ethyldimethylsilyl)cyclobutanecarboxamido]-6,6-dimethylpyrrolo[3,4-c]pyrazole-2,5(4H,6H)-dicarboxylate



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To a solution of 11.7 g (62.8 mmol) of 1-(ethyldimethylsilyl)cyclobutanecarboxylic acid synthesized in the similar manner as in Reference Example 10 in 81 ml of dehydrated dichloromethane, 5.3 ml (62 mmol) of oxalyl chloride and 0.24 ml (3.1 mmol) of DMF were added in this order under cooling in ice water in an argon atmosphere and stirred at the same temperature as above for 2 hours.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure at room temperature to obtain a concentration residue.


To a solution of 6.73 g (20.7 mmol) of 5-tert-butyl 2-ethyl 3-amino-6,6-dimethylpyrrolo[3,4-c]pyrazole-2,5(4H,6H)-dicarboxylate [synthesized according to the method described in Journal of Medicinal Chemistry 2012, 55 (10), 4728-4739] and 18 ml (100 mmol) of DIPEA in 94 ml of dehydrated dichloromethane, a solution of the obtained concentration residue in 5 ml of dehydrated dichloromethane was added dropwise under cooling in ice water in a nitrogen atmosphere and stirred at the same temperature as above for 16 hours.


After the completion of the reaction, 350 ml of a 5% aqueous potassium bisulfate solution was added to the reaction solution and separated into an aqueous layer and an organic layer, and then, the aqueous layer was subjected to extraction with 150 ml of dichloromethane twice. All of the obtained organic layers were dried over anhydrous magnesium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=86:14 to 53:47 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 7.51 g of the title compound (yield: 74%) as a pale yellow oil.


Mass spectrum (DUIS, m/z): 493 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 9.82-9.69 (m, 1H), 4.51-4.36 (m, 4H), 2.49-2.42 (m, 2H), 2.32-2.23 (m, 2H), 1.95-1.84 (m, 2H), 1.62-1.55 (m, 6H), 1.49-1.42 (m, 9H), 1.38-1.31 (m, 3H), 0.91 (t, J=7.9 Hz, 3H), 0.57 (q, J=7.9 Hz, 2H), 0.09 (s, 6H).


Reference Example 12
Ethyl 3-[1-(ethyldimethylsilyl)cyclobutanecarboxamido]-6,6-dimethyl-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate



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To a solution of 7.27 g (14.8 mmol) of 5-tert-butyl 2-ethyl 3-[1-(ethyl dimethylsilyl)cyclobutanecarboxamido]-6,6-dimethylpyrrolo[3,4-c]pyrazole-2,5(4H,6H)-dicarboxylate synthesized in the similar manner as in Reference Example 11 in 70 ml of dehydrated dichloromethane, 5.1 ml (44 mmol) of 2,6-lutidine and 7.8 ml (43 mmol) of trimethylsilyl trifluoromethanesulfonate were added dropwise in this order under ice cooling in an argon atmosphere and stirred at the same temperature as above for 2 hours.


After the completion of the reaction, 57 ml of a saturated aqueous solution of sodium bicarbonate and 57 ml of dichloromethane were added to the reaction solution, and then the aqueous layer and the organic layer were separated. The aqueous layer was subjected to extraction with 60 ml of dichloromethane twice, all of the obtained organic layers were washed with 60 ml of a saturated aqueous solution of sodium bicarbonate and 60 ml of a saturated aqueous solution of sodium chloride in this order, then dried over anhydrous magnesium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The operation of adding toluene to the obtained concentration residue and concentrating the resultant under reduced pressure was performed five times to obtain 5.92 g of the title compound (containing impurities) as a yellow oil.


Mass spectrum (DUIS, m/z): 393 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 9.68 (s, 1H), 4.39 (q, J=7.0 Hz, 2H), 3.92 (s, 2H), 2.48-2.40 (m, 2H), 2.29-2.22 (m, 2H), 1.93-1.82 (m, 2H), 1.33 (t, J=7.0 Hz, 3H), 1.29 (s, 6H), 0.91 (t, J=8.1 Hz, 3H), 0.56 (q, J=8.1 Hz, 2H), 0.08 (s, 6H).


Reference Example 13
Ethyl 5-(chlorocarbonyl)-3-[1-(ethyldimethylsilyl)cyclobutanecarboxamido]-6,6-dimethyl-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate



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To a solution of 5.92 g of ethyl 3-[1-(ethyldimethylsilyl)cyclobutanecarboxamido]-6,6-dimethyl-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate (containing impurities) synthesized in the similar manner as in Reference Example 12 by using 7.27 g (14.8 mmol) of 5-tert-butyl 2-ethyl 3-[1-(ethyldimethylsilyl)cyclobutanecarboxamido]-6,6-dimethylpyrrolo[3,4-c]pyrazole-2,5(4H,6H)-dicarboxylate synthesized in the similar manner as in Reference Example 11 in 200 ml of dehydrated dichloromethane, 7.3 ml (43 mmol) of DIPEA was added at room temperature in an argon atmosphere, and then, a solution of 3.24 g (10.9 mmol) of bis(trichloromethyl)carbonate in 33 ml of dehydrated dichloromethane was added dropwise at −60° C. or lower and stirred at the same temperature as above for 2 hours.


After the completion of the reaction, 130 ml of a saturated aqueous solution of sodium bicarbonate was added to the reaction solution, and the temperature was raised to room temperature for a while with stirring. After separation into an aqueous layer and an organic layer, the aqueous layer was subjected to extraction with 100 ml of dichloromethane twice. All of the obtained organic layers were dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=78:22 to 57:43 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. n-Hexane was added to the concentration residue and concentrated again under reduced pressure to obtain 5.13 g of the title compound (yield: 76% [2 steps]) as a white solid.


Mass spectrum (CI, m/z): 455 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 9.85-9.76 (m, 1H), 4.88-4.81 & 4.53-4.48 (m, total 2H), 4.44 (q, J=7.1 Hz, 2H), 2.55-2.44 (m, 2H), 2.35-2.24 (m, 2H), 1.96-1.85 (m, 2H), 1.69-1.61 (m, 6H), 1.34 (t, J=7.1 Hz, 3H), 0.92 (t, J=7.9 Hz, 3H), 0.58 (q, J=7.9 Hz, 2H), 0.13-0.07 (m, 6H).


Reference Example 14
2-(Ethyldimethylsilyl)-2-methylpropanoic acid



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To 100 ml of dehydrated THF, 100 ml (200 mmol) of 2 M lithium diisopropylamide/THF solution was added in an argon atmosphere, and then, 4.7 ml (51 mmol) of isobutanoic acid was added dropwise at 0° C. and stirred for 4 hours after the temperature was raised to room temperature. Subsequently, 10 ml (58 mmol) of hexamethylphosphoric acid triamide was added thereto, and then, 32 ml (230 mmol) of chloro(ethyl)dimethylsilane was added thereto dropwise at −78° C. After the completion of the dropwise addition, the resultant was stirred for 1 day while the temperature was raised to room temperature for a while.


After the completion of the reaction, 25 ml of methanol and subsequently 50 ml of water were added under cooling in ice water. Then, 2 N hydrochloric acid was added for acidity, followed by extraction with diethyl ether. The obtained organic layer was washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. A 2 N aqueous sodium hydroxide solution was added to the concentration residue, and it was washed with ethyl acetate. Subsequently, the aqueous layer was rendered acidic by adding a 1 N aqueous hydrochloric acid solution, followed by extraction with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (elution solvent: 1,2-dichloroethane:methanol=100:0 to 99:1 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 2.24 g of the title compound (yield: 25%) as a white solid.


Mass spectrum (CI, m/z): 175 [M+1]+.



1H-NMR spectrum (400 MHz, CDCl3) δ: 11.57 (br s, 1H), 1.23 (s, 6H), 0.95 (t, J=8.0 Hz, 3H), 0.62 (q, J=8.0 Hz, 2H), 0.06 (s, 6H).


Reference Example 15
5-tert-Butyl 1-ethyl 3-[2-(ethyldimethylsilyl)-2-methylpropanamido]-6,6-dimethylpyrrolo[3,4-c]pyrazole-1,5(4H,6H)-dicarboxylate



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To a solution of 4.7 g (27 mmol) of 2-(ethyldimethylsilyl)-2-methylpropanoic acid synthesized in the similar manner as in Reference Example 14 in 40 ml of dehydrated dichloromethane, 2.3 ml (27 mmol) of oxalyl chloride was added dropwise at 0° C. in an argon atmosphere and stirred at the same temperature as above for 10 minutes. Subsequently, 0.10 ml (1.3 mmol) of DMF was added at 0° C. and stirred at the same temperature as above for 4 hours.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure at room temperature to obtain a concentration residue.


To a solution of 2.9 g (8.9 mmol) of 5-tert-butyl 1-ethyl 3-amino-6,6-dimethylpyrrolo[3,4-c]pyrazole-1,5(4H,6H)-dicarboxylate [synthesized according to the method described in Journal of Medicinal Chemistry 2012, 55 (10), 4728-4739] in 10 ml of dehydrated dichloromethane, a solution of the obtained concentration residue in 20 ml of dehydrated dichloromethane was added dropwise at 0° C. in an argon atmosphere, and subsequently, 7.9 ml (45 mmol) of DIPEA was added and stirred at 0° C. for 24 hours.


After the completion of the reaction, water was added to the reaction solution, followed by extraction with dichloromethane. The obtained organic layer was washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=98:2 to 80:20 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 3.18 g of the title compound (yield: 74%) as a pale yellow oil.


Mass spectrum (CI, m/z): 481 [M+1]+.



1H-NMR spectrum (400 MHz, CDCl3) δ: 7.88-7.73 (m, 1H), 4.62-4.46 (m, 4H), 1.87-1.75 (m, 6H), 1.55-1.41 (m, 12H), 1.31-1.26 (m, 6H), 0.99-0.88 (m, 3H), 0.66-0.53 (m, 2H), 0.09-0.02 (m, 6H).


Reference Example 16
Ethyl 3-[2-(ethyldimethylsilyl)-2-methylpropanamido]-6,6-dimethyl-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-carboxylate



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To a solution of 3.18 g (6.62 mmol) of 5-tert-butyl 1-ethyl 3-[2-(ethyldimethylsilyl)-2-methylpropanamido]-6,6-dimethylpyrrolo[3,4-c]pyrazole-1,5(4H,6H)-dicarboxylate synthesized in the similar manner as in Reference Example 15 in 30 ml of dehydrated dichloromethane, 2.3 ml (20 mmol) of 2,6-lutidine and 3.6 ml (20 mmol) of trimethylsilyl trifluoromethanesulfonate were added dropwise in this order at 0° C. in an argon atmosphere and stirred at the same temperature as above for 1 hour.


After the completion of the reaction, a saturated aqueous solution of sodium bicarbonate was added to the reaction solution, followed by extraction with dichloromethane. The obtained organic layer was washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. Toluene was added to the residue, and then, concentration under reduced pressure was performed to obtain 2.44 g of the title compound (yield: 97%) as a pale yellow solid.


Mass spectrum (CI, m/z): 381 [M+1]+.



1H-NMR spectrum (400 MHz, CDCl3) δ: 7.77 (s, 1H), 4.50 (q, J=7.2 Hz, 2H), 4.15 (s, 2H), 1.55 (s, 6H), 1.46 (t, J=7.2 Hz, 3H), 1.32-1.25 (m, 6H), 0.93 (t, J=8.0 Hz, 3H), 0.60 (q, J=8.0 Hz, 2H), 0.05 (s, 6H).


Reference Example 17
(S)-2-[(2-Methoxypropan-2-yl)oxy]-1-phenylethanol



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To a solution of 664 mg (2.63 mmol) of (S)-2-[(tert-butyldimethylsilyl)oxy]-2-phenylethanol [synthesized according to the method described in Angew. Chem. Int. Ed., 2012, 51 (31), 7825-7829] in 15 ml of dichloromethane, 0.33 ml (3.5 mmol) of 2-methoxy-1-propene and 68.3 mg (0.272 mmol) of pyridinium p-toluenesulfonate were added at 0° C. in a nitrogen atmosphere and stirred at the same temperature as above for 2 hours.


After the completion of the reaction, a saturated aqueous solution of sodium bicarbonate was added to the reaction solution and stirred, followed by extraction with dichloromethane twice. All of the organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=98:2 to 97:3 (V/V)), and a fraction containing (S)-3,3,8,8,9,9-hexamethyl-6-phenyl-2,4,7-trioxa-8-siladecane was concentrated under reduced pressure and dried under reduced pressure to obtain a concentration residue.


To a solution of 347 mg of the obtained concentration residue in 10 ml of THF, 428 mg (1.64 mmol) of tetrabutylammonium fluoride was added at 0° C. in a nitrogen atmosphere and stirred at the same temperature as above for 3.5 hours.


After the completion of the reaction, a saturated aqueous solution of sodium bicarbonate was added to the reaction solution and stirred, followed by extraction with an ethyl acetate/n-hexane mixed solvent twice. All of the obtained organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=90:10 to 85:15 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 160 mg of the title compound (yield: 29% [2 steps]) as a colorless oil.



1H-NMR spectrum (400 MHz, CDCl3) δ: 7.43-7.27 (m, 5H), 4.89-4.83 (m, 1H), 3.59 (dd, J=3.2, 9.8 Hz, 1H), 3.45 (dd, J=9.0, 9.8 Hz, 1H), 3.19 (s, 3H), 2.82 (d, J=2.4 Hz, 1H), 1.38 (s, 3H), 1.37 (s, 3H).


Reference Example 18
(S)-2,5-Dioxopyrrolidin-1-yl {2-[(2-methoxypropan-2-yl)oxy]-1-phenylethyl}carbonate



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To a solution of 157 mg (0.747 mmol) of (S)-2-[(2-methoxypropan-2-yl)oxy]-1-phenylethanol synthesized in the similar manner as in Reference Example 17 in 4 ml of dehydrated acetonitrile, 0.16 ml (1.2 mmol) of triethylamine and 233 mg (0.908 mmol) of N,N′-disuccinimidyl carbonate were added at room temperature in a nitrogen atmosphere and stirred at the same temperature as above for 6 hours.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure. The obtained concentration residue was dissolved in ethyl acetate, and it was washed with water. After separation into an aqueous layer and an organic layer, the aqueous layer was subjected to extraction with ethyl acetate twice. All of the obtained organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=90:10 to 65:35 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 190 mg of the title compound (yield: 72%) as a colorless oil.



1H-NMR spectrum (400 MHz, CDCl3) δ: 7.42-7.33 (m, 5H), 5.86 (dd, J=3.4, 8.8 Hz, 1H), 3.83 (dd, J=8.8, 11.0 Hz, 1H), 3.64 (dd, J=3.4, 11.0 Hz, 1H), 3.20 (s, 3H), 2.81 (s, 4H), 1.38 (s, 3H), 1.34 (s, 3H).


Reference Example 19
Ethyl 4-(benzyloxy)-3-phenylbutanoate



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To a solution of 8.9 mg (0.023 mmol) of bis(acetonitrile)(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate in 3 ml of 1,4-dioxane/0.3 ml of water, 23 mg (0.41 mmol) of potassium hydroxide, 128 mg (1.05 mmol) of phenylboronic acid, and 120 mg (0.545 mmol) of (E)-ethyl 4-(benzyloxy)-2-butenoate [synthesized according to the method described in Tetrahedron Lett., 1982, 37, 9033-9036] were added in this order with stirring at room temperature in an argon atmosphere, stirred at the same temperature as above for 30 minutes, and then stirred at 60° C. for 6 hours.


After the completion of the reaction, water was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography (elution solvent: n-hexane:ethyl acetate=95:5 to 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 160 mg of the title compound (yield: 98%) as a pale yellow oil.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 7.36-7.18 (m, 10H), 4.45 (s, 2H), 3.97-3.89 (m, 2H), 3.59-3.52 (m, 2H), 3.39-3.33 (m, 1H), 2.81 (dd, J=6.3, 15.6 Hz, 1H), 2.59 (dd, J=8.5, 15.6 Hz, 1H), 1.04 (t, J=7.1 Hz, 3H).


Reference Example 20
Ethyl 6,6-dimethyl-5-(3-oxo-3-phenylpropanoyl)-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate and (Z)-ethyl 5-(3-hydroxy-3-phenylacryloyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate as tautomer



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To a solution of 487 mg (2.39 mmol) of 3-oxo-3-phenylpropanoic acid [synthesized according to the method described in Chem. Pharm. Bull., 29 (10), 2762 (1981)] and 10 μl (0.13 mmol) of DMF in 5 ml of dehydrated dichloromethane, 205 μl (2.39 mmol) of oxalyl chloride was added dropwise with stirring at 0° C. in an argon atmosphere and stirred for 1.5 hours after the temperature was raised to room temperature.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure at room temperature to obtain a concentration residue.


To a solution of 299 mg (0.790 mmol) of ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 84 and 0.70 ml (4.1 mmol) of DIPEA in 5 ml of 1,2-dichloroethane, a solution of the obtained concentration residue in 5 ml of 1,2-dichloroethane was added dropwise with stirring at room temperature in an argon atmosphere and stirred at the same temperature as above for 5 hours.


After the completion of the reaction, 5 ml of 2-propanol was added and stirred at room temperature for 14 hours, and then, the reaction solution was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=87:13 to 0:100 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 293 mg of the title compound (yield: 71%) (containing the tautomer) as a pale yellow solid.


Mass spectrum (DUIS, m/z): 525 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 15.71 (s, 0.3H), 9.79 (s, 0.3H), 9.75 (s, 0.7H), 8.01-7.42 (m, total 5H), 5.82 (s, 0.3H), 4.85 (s, 0.6H), 4.78 (s, 1.4H), 4.47-4.38 (m, total 2H), 4.18 (s, 1.4H), 2.57-2.41 (m, total 2H), 2.33-2.12 (m, total 2H), 1.93-1.81 (m, total 2H), 1.75 & 1.64 (s, total 6H), 1.38-1.31 (m, total 3H), 0.11 & 0.08 (s, total 9H)


Reference Example 21
(R)-Methyl 3-amino-3-phenylpropanoate hydrochloride



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To a solution of 2.01 g (12.2 mmol) of (R)-3-amino-3-phenylpropanoic acid [purchased from Shanghai HC Biotech Co., Ltd.] in 100 ml of dehydrated methanol, 1.32 ml (18.2 mmol) of thionyl chloride was added dropwise with stirring at room temperature in a nitrogen atmosphere and then stirred at the same temperature as above for 24 hours. Then, the temperature was raised to 65° C., and the resultant was stirred for 9.5 hours.


After standing to cool, the reaction solution was concentrated under reduced pressure, diethyl ether was added to the obtained concentration residue and ultrasonicated, and the deposited solid was collected by filtration and dried under reduced pressure to obtain 2.55 g of the title compound (yield: 97%) as a white solid.


Mass spectrum (DUIS, m/z): 180 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 8.67 (br s, 3H), 7.57-7.50 (m, 2H), 7.45-7.36 (m, 3H), 4.58 (dd, J=6.0, 8.6 Hz, 1H), 3.35 (br s, 3H), 3.20 (dd, J=6.0, 16.3 Hz, 1H), 3.00 (dd, J=8.6, 16.3 Hz, 1H).


Reference Example 22
(R)-Methyl 3-phenyl-3-(2,2,2-trifluoroacetamido)propanoate



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To a solution of 2.55 g (11.8 mmol) of (R)-methyl 3-amino-3-phenylpropanoate hydrochloride synthesized in the similar manner as in Reference Example 21 in 50 ml of dichloromethane, 10.5 ml (60.3 mmol) of DIPEA and 1.75 ml (12.4 mmol) of trifluoroacetic anhydride were added dropwise in this order with stirring at 0° C. in an argon atmosphere, stirred at the same temperature as above for 2 hours, and further stirred overnight at room temperature.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure. Ethyl acetate was added to the concentration residue, washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in this order, then dried over anhydrous magnesium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=91:9 to 70:30 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 2.75 g of the title compound (yield: 85%) as a white solid.


Mass spectrum (DUIS, m/z): 276 [M+1]+.



1H-NMR spectrum (400 MHz, CDCl3) δ: 7.80-7.64 (m, 1H), 7.39-7.25 (m, 5H), 5.46-5.39 (m, 1H), 3.65 (s, 3H), 3.00 (dd, J=5.5, 16.2 Hz, 1H), 2.93 (dd, J=5.5, 16.2 Hz, 1H).


Reference Example 23
(R)-4-Amino-2-methyl-4-phenylbutan-2-ol



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To a solution of 506 mg (1.84 mmol) of (R)-methyl 3-phenyl-3-(2,2,2-trifluoroacetamido)propanoate synthesized in the similar manner as in Reference Example 22 in 5 ml of dehydrated THF, 6.60 ml (9.24 mmol) of 1.4 M methyl magnesium bromide/THF solution was added dropwise with stirring at room temperature in an argon atmosphere and stirred at room temperature for 3.5 hours.


After the completion of the reaction, 10 ml of a saturated aqueous solution of ammonium chloride was added dropwise to the reaction solution under ice cooling, brought back to room temperature, and stirred for a while. Dichloromethane and water, and further an aqueous solution of dilute sodium hydroxide were added to the reaction solution to adjust the pH of the aqueous layer to 10, followed by separation into an aqueous layer and an organic layer. The aqueous layer was subjected to extraction with dichloromethane, all of the obtained organic layers were dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (DNH silica gel, elution solvent: 1,2-dichloroethane:methanol=100:0 to 95:5 (V/V)), and a fraction containing (R)-2,2,2-trifluoro-N-(3-hydroxy-3-methyl-1-phenylbutyl)acetamide was concentrated under reduced pressure to obtain a concentration residue.


To a solution of 427 mg of the obtained concentration residue in 5 ml of ethanol, 64.6 mg (1.71 mmol) of sodium borohydride was added in several divided portions at room temperature and then stirred at room temperature for 14 hours. 77.0 mg (2.04 mmol) of sodium borohydride was further added in several divided portions, stirred at room temperature for 2 hours, and then stirred at 75° C. for 2 hours.


After the completion of the reaction, the reaction solution was cooled in ice, and 10 ml of a saturated aqueous solution of ammonium chloride was added thereto dropwise and then stirred at room temperature. Dichloromethane and water were added thereto, and an aqueous solution of dilute sodium hydroxide was added thereto to adjust the pH of the aqueous layer to 10, followed by separation into an aqueous layer and an organic layer. The aqueous layer was subjected to extraction with dichloromethane, all of the obtained organic layers were dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The concentration residue was subjected to silica gel column chromatography (DNH silica gel, elution solvent: 1,2-dichloroethane:methanol=100:0 to 95:5 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 160 mg of the title compound (yield: 49%) as a colorless oil.


Mass spectrum (DUIS, m/z): 180 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 7.37-7.26 (m, 4H), 7.21-7.15 (m, 1H), 4.05 (dd, J=2.8, 10.7 Hz, 1H), 1.66 (dd, J=10.7, 14.0 Hz, 1H), 1.52 (dd, J=2.8, 14.0 Hz, 1H), 1.22 (s, 3H), 1.10 (s, 3H).


Reference Example 24
(S)-tert-Butyl [2-(difluoromethoxy)-1-phenylethyl]carbamate



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To a solution of 1.00 g (4.21 mmol) of (S)-tert-butyl (2-hydroxy-1-phenylethyl)carbamate [purchased from Novo Cherry Ltd.] in 30 ml of dehydrated acetonitrile, 165 mg (0.866 mmol) of copper(I) iodide was added at room temperature in an argon atmosphere and stirred at the same temperature as above for 30 minutes. Subsequently, a solution of 0.87 ml (8.4 mmol) of 2-(fluorosulfonyl)difluoroacetic acid in 10 ml of dehydrated acetonitrile was dividedly added (1 ml each) at 45° C. over 40 minutes and stirred at the same temperature as above for 1 hour.


After the completion of the reaction, the reaction solution allowed to cool to room temperature was concentrated under reduced pressure. Water and ethyl acetate were added to the obtained concentration residue, followed by extraction from the mixed solution with ethyl acetate. The obtained organic layer was washed with water, then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel chromatography (elution solvent: n-hexane:ethyl acetate=95:5 to 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained concentration residue was subjected again to silica gel chromatography (elution solvent: n-hexane:ethyl acetate=95:5 to 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 213 mg of the title compound (yield: 18%) as a yellow solid.


Mass spectrum (CI, m/z): 288 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 7.55 (d, J=8.7 Hz, 1H), 7.37-7.24 (m, 5H), 6.67 (t, J=75.9 Hz, 1H), 4.83-4.73 (m, 1H), 3.95-3.86 (m, 2H), 1.42-1.23 (m, 9H).


Reference Example 25
(S)-2-(Difluoromethoxy)-1-phenylethanamine trifluoroacetate



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To a solution of 210 mg (0.731 mmol) of (S)-tert-butyl [2-(difluoromethoxy)-1-phenylethyl]carbamate synthesized in the similar manner as in Reference Example 24 in 4 ml of dehydrated dichloromethane, 1 ml of trifluoroacetic acid was added at room temperature in an argon atmosphere and stirred at the same temperature as above for 2 hours.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure and dried under reduced pressure to obtain 210 mg of the title compound (yield: 95%) as a yellow oil.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 8.59 (br s, 3H), 7.54-7.40 (m, 5H), 6.76 (t, J=74.8 Hz, 1H), 4.70-4.59 (m, 1H), 4.19-4.11 (m, 2H).


Reference Example 26
(S)-2-Ethoxy-1-phenylethanamine



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To a solution of 1.40 g (10.2 mmol) of (S)-2-amino-2-phenylethanol and 3.0 ml (15 mmol) of 1,4,7,10,13-pentaoxacyclopentadecane in 10 ml of dehydrated THF, 481 mg (11.0 mmol) of 55% sodium hydride was dividedly added with stirring at room temperature in an argon atmosphere and stirred at the same temperature as above until foaming settled. Subsequently, 0.82 ml (10 mmol) of ethyl iodide was added dropwise at room temperature and stirred at the same temperature as above for 24 hours.


After the completion of the reaction, water and diethyl ether were added to the reaction solution and then the aqueous layer and the organic layer were separated. The aqueous layer was subjected to extraction with diethyl ether, then all of the organic layers were washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (DNH silica gel, elution solvent: 1,2-dichloroethane:methanol=100:0 to 95:5 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 1.17 g of the title compound (yield: 69%) as a pale yellow oil.


Mass spectrum (CI, m/z): 166 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 7.39-7.33 (m, 2H), 7.33-7.25 (m, 2H), 7.25-7.19 (m, 1H), 4.01 (dd, J=4.9, 8.0 Hz, 1H), 3.53-3.35 (m, 3H), 3.28 (dd, J=8.0, 9.3 Hz, 1H), 1.82 (br s, 2H), 1.09 (t, J=7.0 Hz, 3H).


Reference Example 27
(R)-3-Methoxy-1-phenylpropan-1-amine



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To a solution of 1.53 g (10.1 mmol) of (R)-3-amino-3-phenylpropan-1-ol [purchased from Ark Pharm, Inc.] and 3.0 ml (15 mmol) of 1,4,7,10,13-pentaoxacyclopentadecane in 10 ml of dehydrated THF, 473 mg (10.9 mmol) of 55% sodium hydride was dividedly added with stirring at room temperature in an argon atmosphere and stirred at the same temperature as above until foaming settled. Subsequently, 0.62 ml (10 mmol) of methyl iodide was added thereto dropwise at 0° C. and then stirred at room temperature for 17 hours.


After the completion of the reaction, water and diethyl ether were added to the reaction solution and then the aqueous layer and the organic layer were separated. The aqueous layer was subjected to extraction with diethyl ether, then all of the organic layers were washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (DNH silica gel, elution solvent: 1,2-dichloroethane:methanol=100:0 to 95:5 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 1.49 g of the title compound (yield: 89%) as a colorless oil.


Mass spectrum (CI, m/z): 166 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 7.35-7.26 (m, 4H), 7.24-7.15 (m, 1H), 3.85 (dd, J=6.4, 7.4 Hz, 1H), 3.38-3.20 (m, 2H), 3.19 (s, 3H), 1.93-1.63 (m, 4H).


Reference Example 28
2-(Benzo[d][1,3]dioxol-4-yl)-2-[(tert-butoxycarbonyl)amino]acetic acid



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To a solution of 7.09 g (47.2 mmol) of benzo[d][1,3]dioxole-4-carbaldehyde in 15 ml of methanol, 67.5 ml (472 mmol) of 7 M aqueous ammonia solution/methanol solution was gradually added at room temperature and then stirred at room temperature for 18 minutes. The reaction solution was cooled in ice water, and 14.1 ml (113 mmol) of trimethylsilane carbonitrile was added dropwise. After the completion of the dropwise addition, the resultant was stirred overnight at room temperature.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a concentration residue.


To 9.30 g of the obtained concentration residue, 17 ml of acetic acid and 66.7 ml (776 mmol) of concentrated hydrochloric acid were added and stirred for 9 hours while heated to reflux.


After standing to cool, the reaction solution was concentrated under reduced pressure to obtain a concentration residue.


To 8.33 g of the obtained concentration residue, 35.2 ml (141 mmol) of a 4 N aqueous sodium hydroxide solution, 65 ml of 1,4-dioxane, and 14.7 ml (64.1 mmol) of di-tert-butyl dicarbonate were added in this order at room temperature and stirred at room temperature.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure, 100 ml of dichloromethane was added thereto, and then, the pH was adjusted to 1.75 by using concentrated hydrochloric acid. Methanol was added thereto until insoluble matter was dissolved, and then the aqueous layer and the organic layer were separated. The aqueous layer was subjected to extraction with 100 ml of dichloromethane twice, all of the obtained organic layers were dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (elution solvent: ethyl acetate), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained residue was subjected again to silica gel column chromatography (elution solvent: ethyl acetate), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 10.22 g of the title compound (yield: 73% [3 steps]) as a black viscous liquid.


Mass spectrum (DUIS, m/z): 296 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 13.24-12.32 (m, 1H), 7.48 (d, J=8.5 Hz, 1H), 6.88-6.77 (m, 3H), 6.04-6.01 (m, 2H), 5.22 (d, J=8.5 Hz, 1H), 1.38 (s, 9H).


Reference Example 29
Methyl 2-(benzo[d][1,3]dioxol-4-yl)-2-[(tert-butoxycarbonyl)amino]acetate



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To a solution of 3.93 g (13.3 mmol) of 2-(benzo[d][1,3]dioxol-4-yl)-2-[(tert-butoxycarbonyl)amino]acetic acid synthesized in the similar manner as in Reference Example 28 in 8 ml of DMF, 3.86 g (27.9 mmol) of potassium carbonate and 1.3 ml (21 mmol) of methyl iodide were added in this order at room temperature, stirred at the same temperature as above for 1 hour, and then left standing overnight.


After the completion of the reaction, the reaction solution was poured to 100 ml of a saturated aqueous solution of sodium chloride, and water was added until insoluble matter was dissolved, followed by extraction with toluene twice. The obtained organic layer was dried over anhydrous sodium sulfate and filtered, and then, the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (elution solvent: hexane:ethyl acetate=95:5 to 70:30 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 2.83 g of the title compound (yield: 69%) as a white solid.


Mass spectrum (EL m/z): 309 [M]+.



1H-NMR spectrum (400 MHz, CDCl3) δ: 6.85-6.76 (m, 3H), 6.03-5.97 (m, 2H), 5.71-5.61 (m, 1H), 5.49-5.39 (m, 1H), 3.73 (s, 3H), 1.47-1.39 (m, 9H).


Reference Example 30
tert-Butyl [1-(benzo[d][1,3]dioxol-4-yl)-2-hydroxyethyl]carbamate



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To a solution of 2.82 g (9.13 mmol) of methyl 2-(benzo[d][1,3]dioxol-4-yl)-2-[(tert-butoxycarbonyl)amino]acetate synthesized in the similar manner as in Reference Example 29 in 30 ml of dehydrated THF, 716 mg (32.9 mmol) of lithium borohydride was added under cooling in ice water and stirred at room temperature.


After the completion of the reaction, the reaction solution was poured to 150 ml of a saturated aqueous solution of ammonium chloride, followed by extraction with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. Diethyl ether and n-hexane were added to the concentration residue, and the formed solid was filtered, washed by sousing with diethyl ether, and then dried under reduced pressure to obtain 1.54 g of the title compound (yield: 60%) as a white solid.


Mass spectrum (CI, m/z): 282 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 7.13 (d, J=8.3 Hz, 1H), 6.84-6.75 (m, 3H), 6.02-5.96 (m, 2H), 4.82 (t, J=5.6 Hz, 1H), 4.74-4.64 (m, 1H), 3.54-3.40 (m, 2H), 1.37 (s, 9H).


Reference Example 31
2-Amino-2-(benzo[d][1,3] dioxol-4-yl)ethanol



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To a solution of 1.04 g (3.69 mmol) of tert-butyl[1-(benzo[d][1,3]dioxol-4-yl)-2-hydroxyethyl]carbamate synthesized in the similar manner as in Reference Example 30 in 17 ml of dichloromethane, 1.3 ml (11 mmol) of 2,6-lutidine and 2.0 ml (11 mmol) of trimethylsilyl trifluoromethanesulfonate were added in this order under cooling in ice water and stirred at the same temperature as above for 3 hours.


After the completion of the reaction, 14 ml of a saturated aqueous solution of sodium bicarbonate and 14 ml of dichloromethane were added to the reaction solution. The pH was adjusted to 10 to 11 by further adding a 4 N aqueous sodium hydroxide solution, followed by separation into an aqueous layer and an organic layer. The aqueous layer was subjected to extraction with dichloromethane twice, all of the obtained organic layers were dried over anhydrous sodium carbonate and filtered, and then, the filtrate was concentrated under reduced pressure. 2.5 ml of methanol and 2.5 ml of triethylamine were added to the obtained residue and stirred at room temperature for 7 hours. 5 ml of methanol was further added, then applied to a microwave reaction apparatus, and reacted at 80° C. for 1 hour. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain 0.696 g of the title compound (containing impurities) as a pale yellow solid.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 6.95-6.91 (m, 1H), 6.81-6.75 (m, 2H), 5.98 (d, J=0.9 Hz, 1H), 5.95 (d, J=0.9 Hz, 1H), 4.86-4.63 (m, 1H), 3.96 (dd, J=4.4, 7.9 Hz, 1H), 3.51 (dd, J=4.4, 10.2 Hz, 1H), 3.40-3.21 (m, 1H), 1.98-1.72 (m, 2H).


Reference Example 32
1-(Benzo[d][1,3]dioxol-4-yl)-2-[(tert-butyldimethylsilyl)oxy]ethanamine



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To a solution of 0.691 g of 2-amino-2-(benzo[d][1,3]dioxol-4-yl)ethanol (containing impurities) synthesized in the similar manner as in Reference Example 31 by using 1.04 g (3.69 mmol) of tert-butyl [1-(benzo[d][1,3]dioxol-4-yl)-2-hydroxyethyl] carbamate synthesized in the similar manner as in Reference Example 30, and 95.9 mg (0.785 mmol) of 4-(N,N-dimethylamino)pyridine in 7 ml of dichloromethane, 1.10 ml (7.89 mmol) of triethylamine and 580 mg (3.85 mmol) of chloro(tert-butyl)dimethylsilane were added and stirred at room temperature for 14 hours.


After the completion of the reaction, water and dichloromethane were added to the reaction solution, and then the aqueous layer and the organic layer were separated. The aqueous layer was subjected to extraction with dichloromethane twice, all of the obtained organic layers were dried over anhydrous sodium carbonate and filtered, and then, the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (DNH silica gel, elution solvent: 1,2-dichloroethane:methanol=100:0 to 95:5 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained residue was subjected again to silica gel column chromatography (elution solvent: 1,2-dichloroethane:methanol=100:0 to 95:5 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 0.810 g of the title compound (74% [2 steps]) as a pale yellow oil.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 6.95-6.91 (m, 1H), 6.81-6.76 (m, 2H), 5.97 (d, J=0.9 Hz, 1H), 5.95 (d, J=0.9 Hz, 1H), 3.99 (dd, J=5.5, 7.0 Hz, 1H), 3.64 (dd, J=5.5, 9.7 Hz, 1H), 3.53 (dd, J=7.0, 9.7 Hz, 1H), 1.81 (br s, 2H), 0.82 (s, 9H), −0.04 (s, 3H), −0.05 (s, 3H).


Reference Example 33
4-Amino-4-phenyl-2-butyn-1-ol hydrochloride



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To a solution of 1.01 ml (7.28 mmol) of 2-(2-propynyloxy)tetrahydro-2H-pyran in 20 ml of dehydrated THF, 5.65 ml (7.35 mmol) of 1.3 mol/1 lithium bis(trimethylsilyl)amide/THF solution was added with stirring at −78° C. in an argon atmosphere and stirred at the same temperature as above for 15 minutes. Subsequently, 1.02 g (4.87 mmol) of (E)-N-benzylidene-2-methylpropane-2-sulfinamide [synthesized according to the method described in Org. Lett., 2005, 7, 5493-5496] was added at −78° C., stirred at the same temperature as above for 1 hour, and then stirred for 1 hour after the temperature was raised to room temperature.


After the completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction from the mixed solution with ethyl acetate. The obtained organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a concentration residue.


To a solution of 2.10 g of the obtained concentration residue in 20 ml of methanol, 4.85 ml (19.4 mmol) of 4 N hydrogen chloride/1,4-dioxane solution was added with stirring at 0° C. in an argon atmosphere and stirred for 3 hours after the temperature was raised to room temperature.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure. For the obtained concentration residue, crystallization was performed with diisopropyl ether/methanol, and the deposited solid was collected by filtration, washed by sousing with diisopropyl ether, and then dried under reduced pressure to obtain 0.93 g of the title compound (yield: 97% [2 steps]) as a brown solid.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 8.97 (br s, 3H), 7.66-7.60 (m, 2H), 7.51-7.40 (m, 3H), 5.78-5.07 (m, 2H), 4.19 (d, J=1.8 Hz, 2H).


Reference Example 34
(S)-2-[(tert-Butoxycarbonyl)amino]-2-phenylethyl acetate



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To 10 g (42 mmol) of (S)-tert-butyl(2-hydroxy-1-phenylethyl)carbamate [purchased from Novo Chemy Ltd.] and 7.1 ml (51 mmol) of triethylamine in 100 ml of dehydrated dichloromethane, 4.80 ml (50.8 mmol) of acetic anhydride was added dropwise at 0° C. in an argon atmosphere and stirred for 20 hours after the temperature was raised to room temperature.


After the completion of the reaction, 100 ml of a saturated aqueous solution of sodium bicarbonate was added to the reaction solution and then the aqueous layer and the organic layer were separated. The aqueous layer was subjected to extraction with dichloromethane (100 ml) twice, and all of the obtained organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=93:7 to 72:28 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 10.5 g of the title compound (yield: 89%) as a white solid.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 7.53 (d, J=8.9 Hz, 1H), 7.38-7.31 (m, 4H), 7.30-7.22 (m, 1H), 4.87-4.74 (m, 1H), 4.15 (dd, J=4.8, 11.0 Hz, 1H), 4.02 (dd, J=8.8, 11.0 Hz, 1H), 1.98 (s, 3H), 1.43-1.20 (m, 9H).


Reference Example 35
(S)-2-Amino-2-phenylethyl acetate hydrochloride



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To a solution of 10.5 g (37.6 mmol) of (S)-2-[(tert-butoxycarbonyl)amino]-2-phenylethyl acetate synthesized in the similar manner as in Reference Example 34 in 110 ml of dehydrated dichloromethane, 47 ml (188 mmol) of 4 N hydrogen chloride/1,4-dioxane solution was added at room temperature in an argon atmosphere and stirred for 14 hours.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure. Diethyl ether was added to the obtained concentration residue, ultrasonicated, then filtered, and dried under reduced pressure to obtain 6.78 g of the title compound (yield: 84%) as a white solid.


Mass spectrum (DUIS, m/z): 180 [M (Free form)+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 8.80 (br s, 3H), 7.59-7.52 (m, 2H), 7.49-7.38 (m, 3H), 4.58 (dd, J=6.1, 6.1 Hz, 1H), 4.39-4.29 (m, 2H), 2.06 (s, 3H).


Reference Example 36
(S)-tert-Butyl [2-(benzyloxy)-1-phenylethyl]carbamate



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To a solution of 10.01 g (42.2 mmol) of (S)-tert-butyl (2-hydroxy-1-phenylethyl)carbamate [purchased from Novo Chemy Ltd.] in 200 ml of dehydrated DMF, 2.58 g (64.5 mmol) of 60% sodium hydride was added at 0° C. in an argon atmosphere and stirred at the same temperature as above for 20 minutes. Subsequently, 5.50 ml (46.3 mmol) of benzyl bromide was added at 0° C. and stirred at the same temperature as above for 1 hour.


After the completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction from the mixed solution with ethyl acetate. The obtained organic layer was washed with water three times, and a saturated aqueous solution of sodium chloride once, then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel chromatography (elution solvent: n-hexane:ethyl acetate=95:5 to 80:20 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 9.94 g of the title compound (yield: 72%) as a white solid.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 7.44 (d, J=8.7 Hz, 1H), 7.37-7.21 (m, 10H), 4.84-4.73 (m, 1H), 4.49 (s, 2H), 3.61-3.46 (m, 2H), 1.46-1.15 (m, 9H).


Reference Example 37
(S)-Ethyl 5-{[2-(benzyloxy)-1-phenylethyl]carbamoyl}-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate



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To a solution of 9.94 g (30.4 mmol) of (S)-tert-butyl[2-(benzyloxy)-1-phenylethyl]carbamate synthesized in the similar manner as in Reference Example 36 in 120 ml of dichloromethane, 30 ml of trifluoroacetic acid was added at room temperature in an argon atmosphere and stirred at the same temperature as above for 1 hour.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure and dried under reduced pressure to obtain 10.25 g of a concentration residue.


To a solution of 3.02 g of a portion of the obtained concentration residue and 3.10 ml (17.8 mmol) of DIPEA in 50 ml of dehydrated 1,4-dioxane, 1.95 g (4.42 mmol) of ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 3 was added at room temperature in an argon atmosphere and stirred at 60° C. for 8 hours.


After the completion of the reaction, water was added to the reaction solution, followed by extraction from the mixed solution with ethyl acetate. The obtained organic layer was washed with water and a saturated aqueous solution of sodium chloride in this order, then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel chromatography (elution solvent: n-hexane:ethyl acetate=90:10 to 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 1.86 g of the title compound (yield: 67%) as a white foam.


Mass spectrum (DUIS, m/z): 632 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 9.80 (s, 1H), 7.43-7.18 (m, 10H), 6.56 (d, J=8.2 Hz, 1H), 5.11-5.03 (m, 1H), 4.66 (d, J=13.8 Hz, 1H), 4.60 (d, J=13.8 Hz, 1H), 4.52 (s, 2H), 4.42 (q, J=7.1 Hz, 2H), 3.74 (dd, J=8.0, 10.0 Hz, 1H), 3.63 (dd, J=6.0, 10.0 Hz, 1H), 2.58-2.52 (m, 2H), 2.31-2.22 (m, 2H), 1.95-1.84 (m, 2H), 1.62 (s, 3H), 1.55 (s, 3H), 1.34 (t, J=7.1 Hz, 3H), 0.12 (s, 9H).


Reference Example 38
(S)-Ethyl 5-[(2-hydroxy-1-phenylethyl)carbamoyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2 (4H)-carboxylate



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To a solution of 1.86 g (2.94 mmol) of (S)-ethyl 5-{[2-(benzyloxy)-1-phenylethyl]carbamoyl}-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2 (4H)-carboxylate synthesized in the similar manner as in Reference Example 37 in 30 ml of 2-propanol, 0.19 g of 20% palladium hydroxide/carbon (containing 50 wt % water) was added at room temperature in an argon atmosphere and then, after replacement with a hydrogen atmosphere under reduced pressure, stirred at room temperature for 1.5 hours. After replacement with an argon atmosphere, the reaction solution was filtered through celite. The solid on the celite was washed with ethyl acetate, and then, the filtrate was concentrated under reduced pressure. To a solution of the obtained concentration residue in 30 ml of 2-propanol, 0.19 g of 20% palladium hydroxide/carbon (containing 50 wt % water) was added at room temperature in an argon atmosphere and after replacement with a hydrogen atmosphere under reduced pressure, stirred at room temperature for 3.5 hours.


After the completion of the reaction, replacement with an argon atmosphere was performed, and then, the reaction solution was filtered through celite. The solid on the celite was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel chromatography (elution solvent: n-hexane:ethyl acetate=80:20 to 60:40 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 1.34 g of the title compound (yield: 84%) as a white foam.


Mass spectrum (DUIS, m/z): 542 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 9.81 (s, 1H), 7.38-7.26 (m, 4H), 7.23-7.17 (m, 1H), 6.36 (d, J=7.5 Hz, 1H), 4.87 (t, J=6.0 Hz, 1H), 4.82-4.75 (m, 1H), 4.66 (s, 2H), 4.42 (q, J=7.2 Hz, 2H), 3.67-3.55 (m, 2H), 2.60-2.52 (m, 2H), 2.31-2.21 (m, 2H), 1.96-1.85 (m, 2H), 1.62 (s, 3H), 1.54 (s, 3H), 1.34 (t, J=7.2 Hz, 3H), 0.13 (s, 9H).


Reference Example 39
(S)-Benzyl {2-[(tert-butoxycarbonyl)amino]-2-phenylethyl}succinate



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To a solution of 496 mg (2.09 mmol) of (S)-tert-butyl (2-hydroxy-1-phenylethyl)carbamate [purchased from Novo Chemy Ltd.] and 227 mg (2.26 mmmol) of succinic anhydride in 3 ml of dehydrated DMF, 26.2 mg (0.214 mmol) of 4-dimethylaminopyridine was added at room temperature in a nitrogen atmosphere and stirred at room temperature for 3 hours. Subsequently, 0.270 ml (2.27 mmol) of benzyl bromide was added at room temperature and stirred at room temperature for 15 hours.


After the completion of the reaction, toluene was added to the reaction solution, the organic layer obtained after washing with water twice and a saturated aqueous solution of sodium chloride once was dried over anhydrous magnesium sulfate and filtered, and then, the filtrate was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=86:14 to 65:35 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 872 mg of the title compound (yield: 98%) as a white solid.


Mass spectrum (CI, m/z): 428 [M+1]+.



1H-NMR spectrum (400 MHz, CDCl3) δ: 7.39-7.25 (m, 10H), 5.21-5.08 (m, 3H), 5.04-4.90 (m, 1H), 4.39-4.21 (m, 2H), 2.70-2.59 (m, 4H), 1.42 (br s, 9H).


Reference Example 40
(S)-2-Amino-2-phenylethyl benzyl succinate trifluoroacetate



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To a solution of 608 mg (1.42 mmol) of (S)-benzyl{2-[(tert-butoxycarbonyl)amino]-2-phenylethyl}succinate synthesized in the similar manner as in Reference Example 39 in 10 ml of dichloromethane, 2.0 ml (26 mmol) of trifluoroacetic acid was added at room temperature in a nitrogen atmosphere and stirred at room temperature for 1 hour.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the operation of adding toluene to the obtained concentration residue and concentrating the resultant under reduced pressure was repeated several times to obtain 813 mg of the title compound (containing impurities).



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 8.57 (br s, 3H), 7.53-7.30 (m, 10H), 5.09 (s, 2H), 4.67-4.55 (m, 1H), 4.38-4.27 (m, 2H), 2.66 (s, 4H).


Reference Example 41
(S)-{2-[(tert-Butoxycarbonyl)amino]-2-phenylethoxy}methyl pivalate



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To a solution of 4.09 g (17.2 mmol) of (S)-tert-butyl (2-hydroxy-1-phenylethyl)carbamate [purchased from Novo Chemy Ltd.] in 80 ml of dehydrated THF, 0.762 g (19.1 mmol) of 60 wt % sodium hydride was added at 0° C. in a nitrogen atmosphere and stirred at the same temperature as above for 1 hour. Subsequently, 2.65 ml (18.3 mmol) of chloromethyl pivalate was added at 0° C. and stirred at the same temperature as above for 25 minutes and further for 2.5 hours after the temperature was raised to room temperature.


After the completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution and stirred, followed by extraction with a mixed solvent of ethyl acetate and n-hexane twice. All of the obtained organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=95:5 to 75:25 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 3.32 g of the title compound (yield: 55%) as a white solid.


Mass spectrum (CI, m/z): 352 [M+1]+.



1H-NMR spectrum (400 MHz, CDCl3) δ: 7.36-7.23 (m, 5H), 5.27 (d, J=6.3 Hz, 1H), 5.33-5.21 (m, 1H), 5.19 (d, J=6.3 Hz, 1H), 4.80 (br s, 1H), 3.91 (dd, J=4.4, 9.6 Hz, 1H), 3.87-3.77 (m, 1H), 1.41 (br s, 9H), 1.18 (s, 9H).


Reference Example 42
(S)-(2-Amino-2-phenylethoxy)methyl pivalate



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To a solution of 3.32 g (9.45 mmol) of (S)-{2-[(tert-butoxycarbonyl)amino]-2-phenylethoxy}methyl pivalate synthesized in the similar manner as in Reference Example 41 in 50 ml of dehydrated dichloromethane, 6.0 ml (78 mmol) of trifluoroacetic acid was added at 0° C. in a nitrogen atmosphere, stirred at the same temperature as above for 2 hours, and then stirred for 70 minutes after the temperature was raised to room temperature.


After the completion of the reaction, the reaction solution was poured to a saturated aqueous solution of sodium bicarbonate for neutralization, followed by extraction with dichloromethane three times. All of the obtained organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DNH silica gel, elution solvent: n-hexane:ethyl acetate=95:5 to 80:20 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 1.83 g of the title compound (yield: 77%) as a colorless oil.


Mass spectrum (CI, m/z): 252 [M+1]+.



1H-NMR spectrum (400 MHz, CDCl3) δ: 7.40-7.24 (m, 5H), 5.36 (d, J=6.1 Hz, 1H), 5.26 (d, J=6.1 Hz, 1H), 4.21 (dd, J=3.8, 8.8 Hz, 1H), 3.78 (dd, J=3.8, 9.6 Hz, 1H), 3.59 (dd, J=8.8, 9.6 Hz, 1H), 1.21 (s, 9H).


Reference Example 43
(S)-2-({[(2,5-Dioxopyrrolidin-1-yl)oxy]carbonyl}oxy)-2-phenylethyl acetate



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To a solution of 0.84 g (4.7 mmol) of (S)-2-hydroxy-2-phenylethyl acetate [synthesized according to the method described in J. Org. Chem., 2013, 78 (22), 11618-11622] in 30 ml of dehydrated acetonitrile, 0.90 ml (6.4 mmol) of triethylamine and 1.33 g (5.19 mmol) of N,N′-disuccinimidyl carbonate were added in this order at room temperature in a nitrogen atmosphere and stirred at the same temperature as above for 15 hours.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure. The obtained concentration residue was dissolved in ethyl acetate, and it was washed with water. An organic layer and an aqueous layer were separated, and then, the aqueous layer was subjected to extraction with ethyl acetate once. All of the obtained organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=85:15 to 60:40 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 1.28 g of the title compound (yield: 85%) as a colorless oil.


Mass spectrum (CI, m/z): 322 [M+1]+.



1H-NMR spectrum (400 MHz, CDCl3) δ: 7.45-7.34 (m, 5H), 5.95 (dd, J=5.2, 7.2 Hz, 1H), 4.39 (d, J=5.2 Hz, 1H), 4.38 (d, J=7.2 Hz, 1H), 2.83 (s, 4H), 2.12 (s, 3H).


Reference Example 44
(S)-Benzyl 2-[(tert-butoxycarbonyl)amino]-2-phenylacetate



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To a solution of 2.50 g (9.95 mmol) of (S)-2-[(tert-butoxycarbonyl)amino]-2-phenylacetic acid in 30 ml of DMF, 1.47 g (10.6 mmol) of potassium carbonate was dividedly added with stirring at room temperature in a nitrogen atmosphere, and subsequently, 1.20 ml (10.1 mmol) of benzyl bromide was added dropwise at room temperature, stirred at the same temperature as above for 7 hours, and then left at room temperature for 3 days.


After the completion of the reaction, toluene was added to the reaction solution and washed with water twice. All of the obtained organic layers were washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=100:0 to 79:21 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 3.24 g of the title compound (yield: 95%) as a white solid.


Mass spectrum (CI, m/z): 342 [M+1]+.



1H-NMR spectrum (400 MHz, CDCl3) δ: 7.37-7.27 (m, 8H), 7.23-7.15 (m, 2H), 5.61-5.50 (m, 1H), 5.40-5.33 (m, 1H), 5.23-5.08 (m, 2H), 1.49-1.29 (m, 9H).


Reference Example 45
(S)-Benzyl 2-amino-2-phenylacetate trifluoroacetate



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To a solution of 462 mg (1.35 mmol) of (S)-benzyl 2-[(tert-butoxycarbonyl)amino]-2-phenylacetate synthesized in the similar manner as in Reference Example 44 in 10 ml of dichloromethane, 2.0 ml (26 mmol) of trifluoroacetic acid was added at room temperature and stirred at room temperature for 24 hours.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure. The operation of adding dichloromethane to the obtained concentration residue and concentrating the resultant under reduced pressure was repeated several times to obtain 572 mg of the title compound (containing impurities).



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 8.93 (br s, 3H), 7.54-7.44 (m, 5H), 7.38-7.31 (m, 3H), 7.27-7.21 (m, 2H), 5.40 (br s, 1H), 5.27 (d, J=12.5 Hz, 1H), 5.21 (d, J=12.5 Hz, 1H).


Reference Example 46
Ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate



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To a solution of 9.70 g (61.3 mmol) of 1-(trimethylsilyl)cyclopropanecarboxylic acid [synthesized according to the method described in J. Org. Chem., 1982 (47) 5, 893-895] in 120 ml of dehydrated dichloromethane, 6.60 ml (76.9 mmol) of oxalyl chloride and 0.25 ml (3.2 mmol) of dehydrated DMF were added in this order at 0° C. in a nitrogen atmosphere and then stirred for 2.5 hours with the temperature unchanged.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure and dried under reduced pressure to obtain a concentration residue.


To a solution of 19.0 ml (109 mmol) of DIPEA and 9.94 g (30.6 mmol) of 5-tert-butyl 2-ethyl 3-amino-6,6-dimethylpyrrolo[3,4-c]pyrazole-2,5(4H,6H)-dicarboxylate [synthesized according to the method described in Journal of Medicinal Chemistry 2012, 55 (10), 4728-4739] in 170 ml of dehydrated dichloromethane, a solution of the obtained concentration residue in 30 ml of dehydrated dichloromethane was added at 0° C. in a nitrogen atmosphere and then stirred for 24 hours with the temperature unchanged.


After the completion of the reaction, a saturated aqueous solution of sodium bicarbonate was added to the reaction solution and stirred, followed by extraction with dichloromethane once and ethyl acetate twice. All of the obtained organic layers were dried over anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=90:10 to 70:30 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. A concentration residue of a fraction containing impurities was subjected again to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=90:10 to 75:25 (V/V)), combined with the purified form obtained above, concentrated under reduced pressure, and dried under reduced pressure to obtain 10.63 g of a concentration residue.


To a solution of the obtained concentration residue in 100 ml of ethyl acetate, 60.0 ml (240 mmol) of 4 N hydrogen chloride/ethyl acetate was added at room temperature in a nitrogen atmosphere and then stirred for 5 hours with the temperature unchanged.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure. The obtained concentration residue was suspended in diisopropyl ether, and the suspension was stirred at room temperature. Insoluble matter was collected by filtration, and the obtained solid was washed with diisopropyl ether. The obtained solid was dissolved in water, and then, a saturated aqueous solution of sodium bicarbonate and dichloromethane were added and stirred at room temperature for 5 minutes. After separation into an aqueous layer and an organic layer, the aqueous layer was subjected to extraction with dichloromethane twice. All of the organic layers were washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and dried under reduced pressure to obtain 8.27 g of the title compound (yield: 73% [2 steps]) as a light orange solid.


Mass spectrum (DUIS, m/z): 365 [M+1]+.



1H-NMR spectrum (400 MHz, CDCl3) δ: 10.02 (s, 1H), 4.53 (q, J=7.2 Hz, 2H), 4.16 (s, 2H), 1.50-1.43 (m, 9H), 1.14-1.08 (m, 2H), 0.84-0.77 (m, 2H), 0.12 (s, 9H).


Reference Example 47
N-(2,2-Difluoro-3-hydroxy-1-phenylpropyl)-2-methylpropane-2-sulfinamide



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To 32 ml of degassed dehydrated THF, 3.29 g (50.3 mmol) of an active zinc powder was added at room temperature in an argon atmosphere and then heated to 40° C. Subsequently, 8.60 ml (66.1 mmol) of ethyl bromodifluoroacetate was dividedly added to the reaction solution at 40° C. and then stirred at 40° C. for 1 hour. To the reaction solution allowed to cool to room temperature, a solution of 3.47 g (16.6 mmol) of N-benzylidene-2-methylpropane-2-sulfinamide [synthesized according to the method described in Org. Lett., 2005, 7, 5493-5496] in 18 ml of dehydrated THF was added at room temperature and then stirred at room temperature for 23 hours.


After the completion of the reaction, ethyl acetate and a saturated aqueous solution of sodium bicarbonate were added to the reaction solution and then stirred at room temperature for 10 minutes. The obtained suspension was filtered using a celite filter, subsequently the removed solid was washed with ethyl acetate, and then, the filtrate was separated into an aqueous layer and an organic layer. The aqueous layer was subjected to extraction with ethyl acetate twice, and then, all of the obtained organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=85:15 to 65:35 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 4.08 g of a concentration residue.


To a solution of 1.01 g of a portion of the obtained concentration residue in 20 ml of dehydrated THF, 136 mg (6.23 mmol) of lithium borohydride was added at room temperature in a nitrogen atmosphere and then stirred for 1.5 hours with the temperature unchanged.


After the completion of the reaction, a saturated aqueous solution of ammonium chloride was added dropwise to the reaction solution until foaming settled, and then, an excessive amount of a saturated aqueous solution of ammonium chloride was further added and stirred at room temperature for 10 minutes. Subsequently, extraction was performed with ethyl acetate three times. All of the obtained organic layers were dried over anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=80:20 to 50:50 (V/V)), subsequently concentrated under reduced pressure, and dried under reduced pressure to obtain 573 mg of the title compound (yield: 48% [2 steps]) as a colorless oil.


Mass spectrum (CI, m/z): 292 [M+1]+.



1H-NMR spectrum (400 MHz, CDCl3) δ: 7.42-7.33 (m, 5H), 4.97-4.85 (m, 1H), 4.37 (d, J=6.8 Hz, 1H), 4.03-3.74 (m, 3H), 1.25 (s, 9H).


Reference Example 48
3-Amino-2,2-difluoro-3-phenylpropan-1-ol



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To a solution of 568 mg (1.95 mmol) of N-(2,2-difluoro-3-hydroxy-1-phenylpropyl)-2-methylpropane-2-sulfinamide synthesized in the similar manner as in Reference Example 47 in 5 ml of ethanol, 2.0 ml (8.0 mmol) of 4 N hydrogen chloride/1,4-dioxane was added at room temperature in a nitrogen atmosphere and then stirred for 1.5 hours with the temperature unchanged.


After the completion of the reaction, the reaction solution was neutralized by adding a saturated aqueous solution of sodium bicarbonate, followed by extraction with dichloromethane three times. All of the obtained organic layers were dried over anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=70:30 to 30:70 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 254 mg of the title compound (yield: 70%) as a white solid.


Mass spectrum (CI, m/z): 188 [M+1]+.



1H-NMR spectrum (400 MHz, CDCl3) δ: 7.46-7.32 (m, 5H), 4.44 (dd, J=9.8, 13.1 Hz, 1H), 3.88 (ddd, J=8.6, 12.4, 17.8 Hz, 1H), 3.79-3.67 (m, 1H).


Reference Example 49
2-(2-Isopropoxy-1-phenylethyl)isoindolin-1,3-dione



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To a solution of 0.500 g (2.78 mmol) of 2-isopropoxy-1-phenylethanol [synthesized according to the method described in J. Fluorine Chem., 2004, 125, 1779-1790], 0.818 g (5.56 mmol) of isoindolin-1,3-dione, and 1.46 g (5.57 mmol) of triphenylphosphine in 20 ml of dehydrated dichloromethane, 1.10 ml (5.66 mmol) of diisopropyl azodicarboxylate was added with stirring at 0° C. in an argon atmosphere, then brought back to room temperature, and stirred at room temperature for 16 hours.


A 5% aqueous potassium bisulfate solution was added to the reaction solution and separated into an aqueous layer and an organic layer. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate, and filtered, and then, the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=93:7 to 72:28 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 0.677 g of the title compound (yield: 79%) as a colorless oil.


Mass spectrum (CI, m/z): 310 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 7.93-7.83 (m, 4H), 7.47-7.41 (m, 2H), 7.39-7.27 (m, 3H), 5.44 (dd, J=6.0, 9.9 Hz, 1H), 4.33 (t, J=9.9 Hz, 1H), 4.01 (dd, J=6.0, 9.9 Hz, 1H), 3.61 (spt, J=6.1 Hz, 1H), 1.02 (d, J=6.1 Hz, 3H), 0.98 (d, J=6.1 Hz, 3H).


Reference Example 50
2-Isopropoxy-1-phenylethanamine



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To a solution of 0.670 g (2.17 mmol) of 2-(2-isopropoxy-1-phenylethyl)isoindolin-1,3-dione synthesized in the similar manner as in Reference Example 49 in 10 ml of ethanol, 0.37 ml (6.5 mmol) of acetic acid and 0.32 ml (6.6 mmol) of hydrazine monohydrate were added in an argon atmosphere and heated to reflux for 3 hours.


After standing to cool, ethanol was added and filtered, and the filtrate was concentrated under reduced pressure. Dichloromethane and a 5% aqueous sodium carbonate solution were added to the residue and stirred at room temperature. After separation into an aqueous layer and an organic layer, the organic layer was dried over anhydrous sodium sulfate and filtered, and then, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: 1,2-dichloroethane:methanol=100:0 to 95:5 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 0.348 g of the title compound (yield: 90%) as a colorless oil.


Mass spectrum (CI, m/z): 180 [M+1]+.



1H-NMR spectrum (400 MHz, CDCl3) δ: 7.43-7.37 (m, 2H), 7.37-7.30 (m, 2H), 7.29-7.23 (m, 1H), 4.17 (dd, J=3.6, 9.2 Hz, 1H), 3.66-3.55 (m, 2H), 3.31 (t, J=9.2 Hz, 1H), 1.20-1.14 (m, 6H).


Reference Example 51
2-(2-Phenoxy-1-phenylethyl)isoindolin-1,3-dione



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To a solution of 1.04 g (4.85 mmol) of 2-phenoxy-1-phenylethanol [synthesized according to the method described in J. Org. Chem., 2011, 76, 1883-1886], 1.40 g (9.52 mmol) of isoindolin-1,3-dione, and 2.45 g (9.34 mmol) of triphenylphosphine in 40 ml of dehydrated dichloromethane, 1.90 ml (9.77 mmol) of diisopropyl azodicarboxylate was added with stirring at 0° C. in an argon atmosphere, then brought back to room temperature, and stirred at room temperature for 20 hours.


A 5% aqueous potassium bisulfate solution was added to the reaction solution and separated into an aqueous layer and an organic layer. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate, and filtered, and then, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=93:7 to 72:28 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 1.15 g of the title compound (containing impurities) as a colorless viscous liquid.


Mass spectrum (CI, m/z): 344[M+1]+.


Reference Example 52
2-Phenoxy-1-phenylethanamine



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To a solution of 1.14 g of 2-(2-phenoxy-1-phenylethyl)isoindolin-1,3-dione (containing impurities) synthesized in Reference Example 51 in 15 ml of ethanol, 0.60 ml (10 mmol) of acetic acid was added with stirring in a nitrogen atmosphere, and subsequently, 0.50 ml (10 mmol) of hydrazine monohydrate was added at room temperature and then heated to reflux for 2.5 hours.


After standing to cool, ethanol was added and filtered, and the filtrate was concentrated under reduced pressure. 50 ml of dichloromethane and 50 ml of a 5% aqueous sodium carbonate solution were added to the residue and stirred at room temperature. After separation into an aqueous layer and an organic layer, the organic layer was dried over anhydrous sodium sulfate and filtered, and then, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: 1,2-dichloroethane:methanol=100:0 to 95:5 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 0.59 g of the title compound (yield: 58% [2 steps]) as a colorless oil.


Mass spectrum (CI, m/z): 214 [M+1]+.



1H-NMR spectrum (400 MHz, CDCl3) δ: 7.49-7.43 (m, 2H), 7.41-7.24 (m, 5H), 6.98-6.88 (m, 3H), 4.43 (dd, J=3.7, 9.0 Hz, 1H), 4.09 (dd, J=3.7, 9.0 Hz, 1H), 3.92 (t, J=9.0 Hz, 1H).


Reference Example 53
3,3,8,8,9,9-Hexamethyl-5-phenyl-2,4,7-trioxa-8-siladecane



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A solution of 1.78 g (7.05 mmol) of 2-[(tert-butyldimethylsilyl)oxy]-1-phenylethanol [synthesized according to the method described in WO 2011/19090, page 43] in 35 ml of dehydrated dichloromethane was cooled in ice, and 0.86 ml (9.1 mmol) of 2-methoxy-1-propene and subsequently 0.180 g (0.716 mmol) of pyridinium p-toluenesulfonate were added thereto in a nitrogen atmosphere and stirred at the same temperature as above for 3 hours.


20 ml of a saturated aqueous solution of sodium bicarbonate was added to the reaction solution, stirred, and then separated into an aqueous layer and an organic layer. The aqueous layer was subjected to extraction with dichloromethane, all of the obtained organic layers were dried over anhydrous magnesium sulfate and filtered, and then, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=99:1 to 94:6 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 1.38 g of the title compound (yield: 60%) as a colorless oil.



1H-NMR spectrum (400 MHz, CDCl3) δ: 7.39-7.18 (m, 5H), 4.74 (dd, J=5.4, 7.3 Hz, 1H), 3.75 (dd, J=7.3, 10.4 Hz, 1H), 3.54 (dd, J=5.4, 10.4 Hz, 1H), 3.15 (s, 3H), 1.42 (s, 3H), 1.12 (s, 3H), 0.84 (s, 9H), −0.04 (s, 3H), −0.07 (s, 3H).


Reference Example 54
2-[(2-Methoxypropan-2-yl)oxy]-2-phenylethanol



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To a solution of 1.36 g (4.19 mmol) of 3,3,8,8,9,9-hexamethyl-5-phenyl-2,4,7-trioxa-8-siladecane synthesized in the similar manner as in Reference Example 53 in 24 ml of dehydrated THF, 6.3 ml (6.3 mmol) of 1 M tetra-n-butylammonium fluoride/THF solution was added dropwise with stirring at 0° C. in a nitrogen atmosphere and stirred at the same temperature as above for 2 hours.


A saturated aqueous solution of sodium bicarbonate was added to the reaction solution, followed by extraction with a n-hexane/ethyl acetate mixed solution (1:1 (V/V)) three times. The extracts were dried over anhydrous magnesium sulfate and filtered, and then, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=84:16 to 63:37 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 0.697 g of the title compound (yield: 79%) as a colorless oil.



1H-NMR spectrum (400 MHz, CDCl3) δ: 7.37-7.23 (m, 5H), 4.84 (dd, J=4.8, 7.0 Hz, 1H), 3.70-3.58 (m, 2H), 3.18 (s, 3H), 2.34-2.20 (m, 1H), 1.44 (s, 3H), 1.21 (s, 3H).


Reference Example 55
2,5-Dioxopyrrolidin-1-yl{2-[(2-methoxypropan-2-yl)oxy]-2-phenylethyl}carbonate



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To a solution of 0.685 g (3.26 mmol) of 2-[(2-methoxypropan-2-yl)oxy]-2-phenylethanol synthesized in the similar manner as in Reference Example 54 in 20 ml of dehydrated acetonitrile, 1.00 g (3.90 mmol) of bis(2,5-dioxopyrrolidin-1-yl)carbonate and 0.70 ml (5.0 mmol) of triethylamine were added with stirring at room temperature in a nitrogen atmosphere and stirred at room temperature for 3 hours.


The reaction solution was concentrated under reduced pressure, and water was added to the residue, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered, and then, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=71:29 to 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 0.636 g of the title compound (yield: 56%) as a colorless viscous liquid.



1H-NMR spectrum (400 MHz, CDCl3) δ: 7.42-7.27 (m, 5H), 5.04 (dd, J=3.7, 8.8 Hz, 1H), 4.41 (dd, J=8.8, 11.1 Hz, 1H), 4.24 (dd, J=3.7, 11.1 Hz, 1H), 3.17 (s, 3H), 2.83 (s, 4H), 1.45 (s, 3H), 1.13 (s, 3H).


Reference Example 56
2-[(2-Methoxypropan-2-yl)oxy]-2-phenylethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5-(1H)-carboxylate



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To a solution of 0.102 g (0.269 mmol) of ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-carboxylate synthesized in the similar manner as in Reference Example 5 and 0.145 g (0.411 mmol) of 2,5-dioxopyrrolidin-1-yl {2-[(2-methoxypropan-2-yl)oxy]-2-phenylethyl}carbonate synthesized in the similar manner as in Reference Example 55 in 3 ml of dehydrated dichloromethane, 0.14 ml (0.80 mmol) of DIPEA was added at room temperature in a nitrogen atmosphere and stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, and 2.5 ml of methanol and 0.080 ml (1.3 mmol) of 2-aminoethanol were added at room temperature and stirred at room temperature for 14 hours.


The reaction solution was concentrated under reduced pressure, water was added, the organic layer after extraction with ethyl acetate was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and filtered, and then, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: 1,2-dichloroethane:ethyl acetate=100:0 to 84:16 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 0.127 g of the title compound (containing impurities) as a white foam.


Mass spectrum (DUIS, m/z): 541 [M−1]−.


Reference Example 57
Ethyl 6,6-dimethyl-5-(2-phenoxyacetyl)-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate



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To a solution of 0.180 g (1.19 mmol) of 2-phenoxyacetic acid in 3 ml of dehydrated dichloromethane, 0.005 ml (0.07 mmol) of DMF was added at room temperature in a nitrogen atmosphere and then cooled in ice. Subsequently, 0.102 ml (1.19 mmol) of oxalyl chloride was added dropwise at 0° C. and after the completion of the dropwise addition, stirred at room temperature for 2 hours. Then, the reaction solution was concentrated under reduced pressure at room temperature.


To a solution of 0.171 g (0.388 mmol) of ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 84 in 3.5 ml of dehydrated dichloromethane, 0.35 ml (2.0 mmol) of DIPEA was added at room temperature in a nitrogen atmosphere, and subsequently, a solution of the concentration residue obtained by the operation described above in 3 ml of dehydrated dichloromethane was added with stirring at 0° C. and then stirred at room temperature for 2 hours. Subsequently, 5 ml of 2-propanol was added and stirred at room temperature for 18 hours.


The reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (elution solvent: 1,2-dichloroethane:ethyl acetate=100:0 to 0:100 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 0.148 g of the title compound (yield: 74%) as a pale yellow foam.


Mass spectrum (DUIS, m/z): 513 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 9.78 (s, 1H), 7.30-7.24 (m, 2H), 6.99-6.90 (m, 3H), 4.89-4.75 (m, 4H), 4.43 (q, J=7.1 Hz, 2H), 2.56-2.44 (m, 2H), 2.32-2.20 (m, 2H), 1.96-1.83 (m, 2H), 1.66 (s, 6H), 1.35 (t, J=7.1 Hz, 3H), 0.12 (s, 9H).


Reference Example 58
Ethyl 3-(benzyloxy)-2-bromopropanoate



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To a solution of 2.00 g (7.72 mmol) of 3-(benzyloxy)-2-bromopropanoic acid [synthesized according to the method described in WO 2008/128942, page 38] in 20 ml of ethanol, 1.00 ml (18.8 mmol) of concentrated sulfuric acid was added with stirring at room temperature in an argon atmosphere and stirred at 80° C. for 5 hours.


After the completion of the reaction, the reaction solution allowed to cool to room temperature was concentrated under reduced pressure. The obtained concentration residue was neutralized by adding a 1 N aqueous sodium hydroxide solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate, and filtered, and the filtrate was concentrated under reduced pressure to obtain 2.00 g of the title compound (containing impurities) as a colorless oil.


Mass spectrum (CI, m/z): 287, 289 [M+1]+.



1H-NMR spectrum (400 MHz, CDCl3) δ: 7.38-7.27 (m, 5H), 4.59 (s, 2H), 4.32 (dd, J=5.9, 8.4 Hz, 1H), 4.29-4.21 (m, 2H), 3.97 (dd, J=8.4, 10.2 Hz, 1H), 3.79 (dd, J=5.9, 10.2 Hz, 1H), 1.30 (t, J=7.2 Hz, 3H).


Reference Example 59
Ethyl 3-(benzyloxy)-2-phenoxypropanoate



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To a solution of 1.31 g (13.9 mmol) of phenol in 20 ml of dehydrated DMF, 608 mg (13.9 mmol) of 55% sodium hydride was dividedly added with stirring at 0° C. in an argon atmosphere and stirred at the same temperature as above for 30 minutes. Subsequently, a solution of 2.00 g of ethyl 3-(benzyloxy)-2-bromopropanoate (containing impurities) synthesized in the similar manner as in Reference Example 58 in 5 ml of dehydrated DMF was added dropwise at 0° C. and then stirred at room temperature for 1 hour.


After the completion of the reaction, ice water was added to the reaction solution and neutralized with 1 N hydrochloric acid, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography (elution solvent: n-hexane:ethyl acetate=100:0 to 80:20 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 1.10 g of the title compound (yield: 53%) as a colorless oil.


Mass spectrum (CI, m/z): 301 [M+1]+.



1H-NMR spectrum (400 MHz, CDCl3) δ: 7.42-7.21 (m, 7H), 7.02-6.89 (m, 3H), 4.91-4.78 (m, 1H), 4.68 (d, J=12.2 Hz, 1H), 4.64 (d, J=12.2 Hz, 1H), 4.23 (q, J=7.1 Hz, 2H), 3.99-3.91 (m, 2H), 1.24 (t, J=7.1 Hz, 3H).


Reference Example 60
3-(Benzyloxy)-2-phenoxypropanoic acid



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To a solution of 400 mg (1.33 mmol) of ethyl 3-(benzyloxy)-2-phenoxypropanoate synthesized in the similar manner as in Reference Example 59 in 10 ml of THF, 12 ml (12 mmol) of a 1 N aqueous sodium hydroxide solution was added with stirring at room temperature and stirred at 80° C. for 3 hours.


After the completion of the reaction, 1 N hydrochloric acid was added to the reaction solution at 0° C. to adjust the pH to 2, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate, and filtered, and the filtrate was concentrated under reduced pressure to obtain 341 mg of the title compound (containing impurities) as a white solid.


Mass spectrum (CI, m/z): 273 [M+1]+.



1H-NMR spectrum (400 MHz, CDCl3) δ: 7.42-7.21 (m, 7H), 7.08-6.90 (m, 3H), 4.91-4.85 (m, 1H), 4.67 (d, J=12.3 Hz, 1H), 4.63 (d, J=12.3 Hz, 1H), 4.03-3.90 (m, 2H).


Reference Example 61
Methyl 2-bromo-3-methoxypropanoate



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To a solution prepared by adding 20 ml of dehydrated methanol to 2.50 g (13.0 mmol) of a solution of 28% sodium methoxide in methanol, a solution of 3.00 g (11.5 mmol) of ethyl 2,3-dibromopropanoate in 20 ml of dehydrated methanol was added dropwise with stirring at 0° C. in an argon atmosphere and then stirred at room temperature for 2 hours.


After the completion of the reaction, 1 N hydrochloric acid was added thereto for neutralization and then concentrated under reduced pressure. The operation of adding toluene to the obtained concentration residue and concentrating the resultant under reduced pressure was repeated several times. Toluene was added, precipitates were filtered off, and the filtrate was concentrated under reduced pressure and dried under reduced pressure to obtain 580 mg of the title compound (yield: 26%) as an orange oil.


Mass spectrum (CI, m/z): 197 [M+1]+.



1H-NMR spectrum (400 MHz, CDCl3) δ: 4.33 (dd, J=5.8, 8.2 Hz, 1H), 3.90 (dd, J=8.2, 10.2 Hz, 1H), 3.81 (s, 3H), 3.72 (dd, J=5.8, 10.2 Hz, 1H), 3.41 (s, 3H).


Reference Example 62
Methyl 3-methoxy-2-phenoxypropanoate



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To a solution of 555 mg (5.90 mmol) of phenol in 10 ml of dehydrated DMF, 260 mg (5.96 mmol) of 55% sodium hydride was dividedly added with stirring at 0° C. in an argon atmosphere and stirred at the same temperature as above for 30 minutes. Subsequently, a solution of 580 mg (2.94 mmol) of methyl 2-bromo-3-methoxypropanoate synthesized in the similar manner as in Reference Example 61 in 10 ml of dehydrated DMF was added dropwise at 0° C. and then stirred at room temperature for 16 hours.


After the completion of the reaction, ice water was added to the reaction solution and then neutralized by adding 1 N hydrochloric acid, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography (elution solvent: n-hexane:ethyl acetate=100:0 to 80:20 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 380 mg of the title compound (yield: 61%) as a colorless oil.


Mass spectrum (CI, m/z): 211 [M+1]+.



1H-NMR spectrum (400 MHz, CDCl3) δ: 7.33-7.23 (m, 2H), 7.03-6.96 (m, 1H), 6.95-6.88 (m, 2H), 4.84 (dd, J=3.8, 5.3 Hz, 1H), 3.91 (dd, J=5.3, 10.5 Hz, 1H), 3.86 (dd, J=3.8, 10.5 Hz, 1H), 3.78 (s, 3H), 3.46 (s, 3H).


Reference Example 63
3-Methoxy-2-phenoxypropanoic acid



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To a solution of 120 mg (0.571 mmol) of methyl 3-methoxy-2-phenoxypropanoate synthesized in the similar manner as in Reference Example 62 in 2 ml of THF, 0.700 ml (0.700 mmol) of a 1 N aqueous sodium hydroxide solution was added with stirring at room temperature and stirred at the same temperature as above for 3 hours.


After the completion of the reaction, the reaction solution was adjusted to pH 2 by adding 1 N hydrochloric acid, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate, and filtered, and the filtrate was concentrated under reduced pressure to obtain 116 mg of the title compound (containing impurities) as a brown solid.


Mass spectrum (CI, m/z): 197 [M+1]+.



1H-NMR spectrum (400 MHz, CDCl3) δ: 7.34-7.25 (m, 2H), 7.06-7.00 (m, 1H), 6.99-6.91 (m, 2H), 4.90-4.81 (m, 1H), 3.98-3.84 (m, 2H), 3.46 (s, 3H).


Reference Example 64
Ethyl 3-hydroxy-2-phenoxypropanoate



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To a solution of 3.00 g (9.99 mmol) of ethyl 3-(benzyloxy)-2-phenoxypropanoate synthesized in the similar manner as in Reference Example 59 in 20 ml of ethanol, 200 mg of 20% palladium hydroxide/carbon (containing 50% water) was added in an argon atmosphere and after replacement with a hydrogen atmosphere, stirred at room temperature for 2 hours.


After the completion of the reaction, replacement with an argon atmosphere was performed, and the reaction solution was filtered through celite. The solid on the celite was washed with ethanol, and all of the filtrates were concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=80:20 to 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 1.89 g of the title compound (yield: 90%) as a colorless oil.


Mass spectrum (CI, m/z): 211 [M+1]+.



1H-NMR spectrum (400 MHz, CDCl3) δ: 7.35-7. 25 (m, 2H), 7.05-6.97 (m, 1H), 6.95-6.88 (m, 2H), 4.78 (dd, J=3.8, 5.3 Hz, 1H), 4.29-4.22 (m, 2H), 4.15-4.01 (m, 2H), 2.22 (t, J=7.0 Hz, 1H), 1.26 (t, J=7.1 Hz, 3H).


Reference Example 65
Ethyl 3-(dimethylamino)-2-phenoxypropanoate



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To a solution of 470 mg (2.24 mmol) of ethyl 3-hydroxy-2-phenoxypropanoate synthesized in the similar manner as in Reference Example 64 in 12 ml of dehydrated dichloromethane, 1.10 g (2.59 mmol) of Dess-Martin periodinane was added at 0° C. in an argon atmosphere and stirred at room temperature for 1 hour.


After the completion of the reaction, an aqueous sodium thiosulfate solution and a saturated aqueous solution of sodium bicarbonate were added to the reaction solution and stirred for 30 minutes, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate, and filtered, and then, the filtrate was concentrated under reduced pressure.


To a solution of 470 mg of the obtained concentration residue in 6 ml of dehydrated dichloromethane, 0.260 ml (4.54 mmol) of acetic acid and 4.50 ml (9.00 mmol) of a solution of dimethylamine in THF were added in this order with stirring at room temperature in an argon atmosphere and then stirred at room temperature for 30 minutes. Subsequently, 720 mg (3.40 mmol) of sodium triacetoxyborohydride was dividedly added at 0° C. and stirred at room temperature for 16 hours.


After the completion of the reaction, a saturated aqueous solution of sodium bicarbonate was added to the reaction solution, followed by extraction with dichloromethane. The obtained organic layer was washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=100:0 to 80:20 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure.


To a solution of 162 mg of the obtained concentration residue in 4 ml of ethanol, 75 mg of 10% palladium/carbon (containing 54% water, PE-type manufactured by N.E. Chemcat Corp.) was added in an argon atmosphere and after replacement with a hydrogen atmosphere, stirred at room temperature for 3 hours.


After the completion of the reaction, replacement with an argon atmosphere was performed, and the reaction solution was filtered through celite. The solid on the celite was washed with ethanol, and all of the filtrates were concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=50:50 to 0:100 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 94 mg of the title compound (yield: 18% [3 steps]) as a colorless oil.


Mass spectrum (CI, m/z): 238 [M+1]+.



1H-NMR spectrum (400 MHz, CDCl3) δ: 7.32-7.22 (m, 2H), 7.01-6.94 (m, 1H), 6.94-6.85 (m, 2H), 4.79 (dd, J=4.4, 7.2 Hz, 1H), 4.22 (q, J=7.1 Hz, 2H), 2.94 (dd, J=7.2, 13.2 Hz, 1H), 2.85 (dd, J=4.4, 13.2 Hz, 1H), 2.36 (s, 6H), 1.24 (t, J=7.1 Hz, 3H).


Reference Example 66
3-(Dimethylamino)-2-phenoxypropanoic acid



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To a solution of 129 mg (0.544 mmol) of ethyl 3-(dimethylamino)-2-phenoxypropanoate synthesized in the similar manner as in Reference Example 65 in 4 ml of THF, 0.700 ml (0.700 mmol) of a 1 N aqueous sodium hydroxide solution was added with stirring at room temperature and stirred at the same temperature as above for 3 hours.


After the completion of the reaction, 1 N hydrochloric acid was added for neutralization and concentrated under reduced pressure. The operation of adding toluene to the obtained concentration residue and concentrating the resultant under reduced pressure was repeated several times. Dichloromethane was added to the obtained concentration residue and ultrasonicated, then the deposited solid was filtered off, and the filtrate was concentrated under reduced pressure to obtain 75 mg of the title compound (yield: 66%) as a white solid.


Mass spectrum (CI, m/z): 210 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 7.31-7.22 (m, 2H), 6.96-6.86 (m, 3H), 4.75 (dd, J=5.3, 6.7 Hz, 1H), 3.01 (dd, J=6.7, 13.0 Hz, 1H), 2.95 (dd, J=5.3, 13.0 Hz, 1H), 2.45 (s, 6H).


Reference Example 67
Ethyl 2-bromo-3-(3,3-difluoropyrrolidin-1-yl)propanoate



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To a solution of 0.900 g (6.27 mmol) of 3,3-difluoropyrrolidine hydrochloride in 20 ml of dehydrated THF, 1.70 ml (12.1 mmol) of triethylamine was added with stirring at room temperature in an argon atmosphere, and subsequently, a solution of 1.50 g (5.77 mmol) of ethyl 2,3-dibromopropanoate in 20 ml of dehydrated THF was added dropwise at 0° C. and stirred at room temperature for 16 hours.


After the completion of the reaction, precipitates were filtered off, the filtrate was washed with water, then dried over anhydrous magnesium sulfate, and filtered, and the filtrate was dried under reduced pressure to obtain 1.30 g of the title compound (yield: 79%) as an orange oil.


Mass spectrum (CI, m/z): 286 [M+1]+.



1H-NMR spectrum (400 MHz, CDCl3) δ: 4.25 (q, J=7.1 Hz, 2H), 4.18 (dd, J=5.8, 9.5 Hz, 1H), 3.27-3.19 (m, 1H), 3.12-2.77 (m, 5H), 2.31-2.16 (m, 2H), 1.30 (t, J=7.1 Hz, 3H).


Reference Example 68
Ethyl 3-(3,3-difluoropyrrolidin-1-yl)-2-phenoxypropanoate



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To a solution of 860 mg (9.14 mmol) of phenol in 15 ml of dehydrated DMF, 400 mg (9.17 mmol) of 55% sodium hydride was dividedly added with stirring at 0° C. in an argon atmosphere and stirred at the same temperature as above for 30 minutes. Subsequently, a solution of 1.30 g (4.54 mmol) of ethyl 2-bromo-3-(3,3-difluoropyrrolidin-1-yl)propanoate synthesized in the similar manner as in Reference Example 67 in 10 ml of dehydrated DMF was added dropwise at 0° C. and then stirred at room temperature for 16 hours.


After the completion of the reaction, ice water was added to the reaction solution and then neutralized with 1 N hydrochloric acid, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=100:0 to 70:30 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 476 mg of the title compound (containing impurities) as a pale yellow oil.


Mass spectrum (CI, m/z): 300 [M+1]+.


Reference Example 69
3-(3,3-Difluoropyrrolidin-1-yl)-2-phenoxypropanoic acid



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To a solution of 476 mg of ethyl 3-(3,3-difluoropyrrolidin-1-yl)-2-phenoxypropanoate (containing impurities) synthesized in Reference Example 68 in 6 ml of THF, 2.00 ml of a 1 N aqueous sodium hydroxide solution was added with stirring at room temperature and stirred at the same temperature as above for 3 hours.


After the completion of the reaction, 1 N hydrochloric acid was added to the reaction solution to adjust the pH to 2, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate, and filtered, and the filtrate was concentrated under reduced pressure to obtain 393 mg of the title compound (containing impurities) as a white foam.


Mass spectrum (CI, m/z): 272 [M+1]+.


Reference Example 70
(S)—N-{5-[3-(Benzyloxy)-2-phenylpropanoyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide



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To a solution of 168 mg (0.657 mmol) of (S)-3-(benzyloxy)-2-phenylpropanoic acid [synthesized according to the method described in Tetrahedron Lett., 2002 (43), 9691-9693] in 3 ml of dehydrated dichloromethane, 0.10 ml (1.2 mmol) of oxalyl chloride and 0.010 ml (0.13 mmol) of dehydrated DMF were added in this order at 0° C. in a nitrogen atmosphere and then stirred for 3.5 hours with the temperature unchanged.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a concentration residue.


To a solution of 127 mg (0.335 mmol) of ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 84 and 0.23 ml (1.3 mmol) of DIPEA in 3 ml of dehydrated dichloromethane, a solution of the obtained concentration residue in 1 ml of dehydrated dichloromethane was added at 0° C. in a nitrogen atmosphere and then stirred for 1 hour with the temperature unchanged. Subsequently, 1.0 ml (7.2 mmol) of triethylamine and 1.0 ml (25 mmol) of methanol were added to the reaction solution at room temperature and then stirred for 19 hours with the temperature unchanged.


After the completion of the reaction, a saturated aqueous solution of sodium bicarbonate was added to the reaction solution and stirred, followed by extraction with dichloromethane three times. All of the obtained organic layers were dried over anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=80:20 to 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 142 mg of the title compound (yield: 78%) as a pale yellow foam.


Mass spectrum (CI, m/z): 545 [M+1]+.



1H-NMR spectrum (400 MHz, CDCl3) δ: 7.43-7.37 (m, 2H), 7.35-7.16 (m, 10H), 4.89 (d, J=12.0 Hz, 1H), 4.59 (d, J=12.0 Hz, 1H), 4.50-4.39 (m, 2H), 4.19-4.12 (m, 1H), 4.05 (dd, J=5.3, 8.6 Hz, 1H), 3.61 (dd, J=5.3, 8.8 Hz, 1H), 2.62-2.49 (m, 2H), 2.33-2.23 (m, 2H), 2.00-1.89 (m, 2H), 1.86 (s, 3H), 1.73 (s, 3H), 0.14 (s, 9H).


Reference Example 71
3-(3-Methoxy-2-phenylpropanoyl)oxazolidin-2-one



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To a solution of 506 mg (2.46 mmol) of 3-(2-phenylacetyl)oxazolidin-2-one [synthesized according to the method described in Tetrahedron, 1998 (54) 2697-2708] in 10 ml of dehydrated dichloromethane, 0.33 ml (3.0 mmol) of titanium tetrachloride was added at 0° C. in a nitrogen atmosphere and then stirred for 5 minutes with the temperature unchanged. Subsequently, 0.52 ml (3.0 mmol) of DIPEA was added thereto at 0° C. and then stirred for 1 hour with the temperature unchanged. Subsequently, 0.37 ml (4.9 mmol) of chloromethyl methyl ether was added thereto dropwise at 0° C. and then stirred for 2 hours with the temperature unchanged.


After the completion of the reaction, water was added to the reaction solution at 0° C. and stirred, followed by extraction with dichloromethane three times. All of the obtained organic layers were washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in this order, then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=75:25 to 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 522 mg of the title compound (yield: 85%) as an orange oil.


Mass spectrum (CI, m/z): 250 [M+1]+.



1H-NMR spectrum (400 MHz, CDCl3) δ: 7.44-7.38 (m, 2H), 7.35-7.27 (m, 3H), 5.38 (dd, J=4.6, 10.2 Hz, 1H), 4.44-4.27 (m, 2H), 4.18-4.07 (m, 2H), 3.95 (ddd, J=6.8, 9.2, 11.0 Hz, 1H), 3.50 (dd, J=4.6, 9.2 Hz, 1H), 3.37 (s, 3H).


Reference Example 72
3-Methoxy-2-phenylpropanoic acid



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To a solution of 517 mg (2.07 mmol) of 3-(3-methoxy-2-phenylpropanoyl)oxazolidin-2-one synthesized in the similar manner as in Reference Example 71 in 12 ml of THF/4 ml of water, 1.0 ml (9.7 mmol) of an aqueous hydrogen peroxide solution [30%] at room temperature and 111 mg (4.63 mmol) of lithium hydroxide at 0° C. were added in this order in a nitrogen atmosphere and then stirred for 2.5 hours with the temperature unchanged. Subsequently, 10 ml of a 10% aqueous sodium thiosulfate solution and 10 ml of a saturated aqueous solution of sodium bicarbonate were added in small portions at 0° C. and then stirred at room temperature for 1 hour.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure, and THF was distilled off. The concentration residue was washed with dichloromethane twice and then adjusted to pH 2 by adding 6 N hydrochloric acid, and subsequently, this solution was subjected to extraction with ethyl acetate three times. All of the obtained organic layers were washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=80:20 to 65:35 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 331 mg of the title compound (yield: 89%) as a colorless oil.


Mass spectrum (CI, m/z): 181 [M+1]+.



1H-NMR spectrum (400 MHz, CDCl3) δ: 7.38-7.27 (m, 5H), 4.01-3.95 (m, 1H), 3.91 (dd, J=4.8, 9.2 Hz, 1H), 3.63 (dd, J=4.8, 8.7 Hz, 1H), 3.39 (s, 3H).


Reference Example 73
Benzyl 4-methoxy-2-phenylbutanoate



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To a solution of 0.45 ml (2.2 mmol) of benzyl phenylacetate in 6 ml of dehydrated DMF, 139 mg (3.19 mmol) of 55% sodium hydride was added at 0° C. in an argon atmosphere and then stirred for 30 minutes with the temperature unchanged. Subsequently, 0.35 ml (3.7 mmol) of 2-bromoethyl methyl ether was added to the reaction solution at 0° C. and then stirred at room temperature for 2 hours.


After the completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction with ethyl acetate. All of the obtained organic layers were washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=100:0 to 95:5 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 528 mg of the title compound (yield: 84%) as a colorless oil.


Mass spectrum (ESI, m/z): 285 [M+1]+.



1H-NMR spectrum (400 MHz, CDCl3) δ: 7.34-7.21 (m, 10H), 5.15 (d, J=12.5 Hz, 1H), 5.05 (d, J=12.5 Hz, 1H), 3.83 (t, J=7.7 Hz, 1H), 3.38-3.30 (m, 1H), 3.29-3.20 (m, 4H), 2.45-2.34 (m, 1H), 2.06-1.95 (m, 1H)


Reference Example 74
4-Methoxy-2-phenylbutanoic acid



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To a solution of 528 mg (1.86 mmol) of benzyl 4-methoxy-2-phenylbutanoate synthesized in the similar manner as in Reference Example 73 in 7 ml of ethanol, 130 mg of 10% Pd—C (containing 54.33% water, PE-type manufactured by N.E. Chemcat Corp.) was added at room temperature in an argon atmosphere. After replacement with a hydrogen atmosphere, the resultant was stirred at room temperature for 2 hours.


After the completion of the reaction, the reaction solution was filtered through celite and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=60:40 to 40:60 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 304 mg of the title compound (yield: 84%) as a white solid.


Mass spectrum (CI, m/z): 195 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.37 (br s, 1H), 7.38-7.20 (m, 5H), 3.61 (t, J=7.7 Hz, 1H), 3.29-3.16 (m, 5H), 2.26-2.14 (m, 1H), 1.88-1.77 (m, 1H)


Reference Example 75
(S)—N-{5-[3-(Benzyloxy)-2-phenylpropanoyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclopropanecarboxamide



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To a solution of 51.9 mg (0.202 mmol) of (S)-3-(benzyloxy)-2-phenylpropanoic acid [synthesized according to the method described in Tetrahedron Lett., 2002 (43), 9691-9693] in 2 ml of dehydrated dichloromethane, 0.040 ml (0.47 mmol) of oxalyl chloride and 0.0050 ml (0.065 mmol) of dehydrated DMF were added in this order at 0° C. in a nitrogen atmosphere and then stirred for 2.5 hours with the temperature unchanged.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a concentration residue.


To a solution of 47.0 mg (0.129 mmol) of ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 46 and 0.10 ml (0.57 mmol) of DIPEA in 1 ml of dehydrated dichloromethane, a solution of the obtained concentration residue in 1 ml of dehydrated dichloromethane was added at 0° C. in a nitrogen atmosphere and then stirred for 2 hours with the temperature unchanged. Subsequently, 0.10 ml (0.92 mmol) of N,N-dimethylethane-1,2-diamine was added to the reaction solution at 0° C. and then stirred at room temperature for 3 hours.


After the completion of the reaction, the reaction solution diluted with dichloromethane was washed with a 5% aqueous potassium bisulfate solution and then separated into an aqueous layer and an organic layer. The aqueous layer was subjected to extraction with dichloromethane twice, and then, all of the obtained organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=80:20 to 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 48 mg of the title compound (yield: 70%) as a pale yellow foam.


Mass spectrum (DUIS, m/z): 531 [M+1]+.



1-NMR spectrum (400 MHz, CDCl3) δ: 7.55 (s, 1H), 7.41-7.37 (m, 2H), 7.34-7.20 (m, 9H), 4.84 (d, J=12.0 Hz, 1H), 4.60 (d, J=12.0 Hz, 1H), 4.47 (d, J=12.0 Hz, 1H), 4.42 (d, J=12.0 Hz, 1H), 4.16 (t, J=8.8 Hz, 1H), 4.02 (dd, J=5.4, 8.8 Hz, 1H), 3.61 (dd, J=5.4, 8.8 Hz, 1H), 1.85 (s, 3H), 1.72 (s, 3H), 1.09-1.04 (m, 2H), 0.81-0.76 (m, 2H), 0.10 (s, 9H).


Reference Example 76
(R)-Benzyl 2-ethoxy-2-phenylacetate



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To a solution of 1.01 g (4.17 mol) of (R)-benzyl 2-hydroxy-2-phenylacetate in 20 ml (0.25 mol) of iodoethane, 1.93 g (8.33 mmol) of silver oxide was added at room temperature in an argon atmosphere and stirred at 60° C. for 18 hours.


After the completion of the reaction, the reaction solution was filtered through celite, the solid component was washed with ethyl acetate, and then, the filtrate was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=100:0 to 80:20 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 1.03 g of the title compound (yield: 91%) as a colorless oil.



1H-NMR spectrum (400 MHz, CDCl3) δ: 7.49-7.43 (m, 2H), 7.38-7.27 (m, 6H), 7.24-7.18 (m, 2H), 5.19 (d, J=12.4 Hz, 1H), 5.11 (d, J=12.4 Hz, 1H), 4.92 (s, 1H), 3.65-3.46 (m, 2H), 1.27 (t, J=7.0 Hz, 3H).


Reference Example 77
(R)-2-Ethoxy-2-phenylacetic acid



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To a solution of 1.03 g (3.81 mmol) of (R)-benzyl 2-ethoxy-2-phenylacetate synthesized in the similar manner as in Reference Example 76 in 20 ml of methanol, 0.11 of palladium/carbon (ASCA2 (trade name), manufactured by N.E. Chemcat Corp., containing 54% water) was added in an argon atmosphere and then, after replacement with a hydrogen atmosphere under reduced pressure, stirred at room temperature for 2 hours.


After the completion of the reaction, the reaction solution was filtered through celite, the solid component was washed with methanol, and then, the filtrate was concentrated under reduced pressure to obtain 0.63 g of the title compound (yield: 92%) as a pale yellow oil.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.80 (br s, 1H), 7.44-7.28 (m, 5H), 4.84 (s, 1H), 3.60-3.50 (m, 1H), 3.47-3.20 (m, 1H), 1.15 (t, J=7.0 Hz, 3H).


Reference Example 78
Methyl 2-{[(benzyloxy)carbonyl](2-cyanoethyl)amino}-2-methylpropanoate



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To a solution of 5.00 g (29.4 mmol) of methyl 2-[(2-cyanoethyl)amino]-2-methylpropanoate [synthesized according to the method described in J. Med. Chem., 1968, 11 (3), 616-618] in 23 ml of toluene, 15.5 ml (90.7 mol) of DIPEA and 32.0 ml of a solution of 30 to 35% benzyl chloroformate in toluene [purchased from Tokyo Chemical Industry Co., Ltd.)] were added in this order with stirring at room temperature in an argon atmosphere and stirred for 1.5 hours with the temperature unchanged. Subsequently, the resultant was stirred at 50° C. for 1.5 hours and then allowed to cool to room temperature, and 4.80 ml (44.1 mmol) of N,N-dimethylethane-1,2-diamine was added at room temperature and stirred for 2.5 hours with the temperature unchanged.


After the completion of the reaction, the reaction solution was poured to 2 N hydrochloric acid and stirred. An aqueous layer and an organic layer were separated, the organic layer was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in this order, dried over anhydrous magnesium sulfate, and filtered, and then, the filtrate was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=84:16 to 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 8.32 g of the title compound (yield: 93%) as a colorless oil.


Mass spectrum (CI, m/z): 305 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 7.43-7.28 (m, 5H), 5.07 (s, 2H), 3.64 (t, J=6.7 Hz, 2H), 3.50 (br s, 3H), 2.76 (t, J=6.7 Hz, 2H), 1.45 (s, 6H).


Reference Example 79
Benzyl 4-cyano-3-hydroxy-2,2-dimethyl-2,5-dihydro-1H-pyrrole-1-carboxylate



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52 ml (52 mmol) of a 1 mol/L solution of potassium tert-butoxide in THF was heated to 60° C., and a solution of 12.1 g (39.7 mmol) of methyl 2-{[(benzyloxy)carbonyl](2-cyanoethyl)amino}-2-methylpropanoate synthesized in the similar manner as in Reference Example 78 in 30 ml of dehydrated THF was added dropwise with stirring under argon stream and stirred for 1 hour while heated to reflux.


After the completion of the reaction, 90 ml of water was added to the reaction solution allowed to cool to room temperature and adjusted to pH <2 by further adding 2 N hydrochloric acid. Extraction was performed from the mixed solution with 100 ml of ethyl acetate twice, and all of the organic layers were combined and washed with 100 ml of water and 100 ml of a saturated aqueous solution of sodium chloride in this order. After drying over magnesium sulfate, filtration and concentration under reduced pressure were performed, and half the amount of the solvent was distilled off. 12 g of active carbon was added to the obtained solution, stirred at room temperature for 30 minutes, filtered, and concentrated under reduced pressure. The obtained concentration residue was diluted with 10 ml of diisopropyl ether, and 50 ml of n-hexane was added thereto and stirred at room temperature for 30 minutes after the deposited solid was disrupted. The solid component was collected by filtration and dried under reduced pressure at 50° C. to obtain 8.27 g of the title compound (yield: 76%) as a pale yellow solid.


Mass spectrum (DUIS, m/z): 273 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.32 (br s, 1H), 7.46-7.25 (m, 5H), 5.18-5.02 (m, 2H), 4.24-4.02 (m, 2H), 1.51-1.35 (m, 6H).


Reference Example 80
Benzyl 3-amino-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate



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To a solution of 200 mg (0.734 mmol) of benzyl 4-cyano-3-hydroxy-2,2-dimethyl-2,5-dihydro-1H-pyrrole-1-carboxylate synthesized in the similar manner as in Reference Example 79 in 5 ml of ethanol, 0.336 ml (5.87 mmol) of acetic acid was added with stirring at room temperature under argon stream and stirred at room temperature for 5 minutes. Subsequently, 0.178 ml (3.66 mmol) of hydrazine monohydrate was added thereto dropwise with stirring at room temperature and stirred for 12 hours under heating to reflux.


After the completion of the reaction, 15 ml of water was added to the reaction solution allowed to cool to room temperature, and then adjusted to pH 8 by adding an aqueous sodium bicarbonate solution. Extraction was performed from the mixed solution with ethyl acetate three times, and all of the organic layers were washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=50:50 to 0:100 (V/V)→1,2-dichloroethane:methanol=80:20 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 141 mg of the title compound (yield: 67%) as a pale yellow foam.


Mass spectrum (CI, m/z): 287 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 11.20 (br s, 1H), 7.45-7.28 (m, 5H), 5.18-5.05 (m, 2H), 5.05-4.77 (m, 2H), 4.28-4.14 (m, 2H), 1.58-1.46 (m, 6H).


Reference Example 81
5-Benzyl 2-ethyl 3-amino-6,6-dimethylpyrrolo[3,4-c]pyrazole-2,5(4H,6H)-dicarboxylate



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To a solution of 400 mg (1.40 mmol) of benzyl 3-amino-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate synthesized in the similar manner as in Reference Example 80 in 4 ml of dehydrated THF, 0.594 ml (3.49 mmol) of DIPEA was added with stirring at room temperature under argon stream and stirred at room temperature for 3 minutes. Subsequently, 0.133 ml (1.40 mmol) of ethyl chloroformate was added thereto dropwise with stirring at 0° C. and stirred at 0° C. for 30 minutes.


After the completion of the reaction, water was added to the reaction solution, followed by extraction from the mixed solution with ethyl acetate twice. All of the organic layers were washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=71:29 to 30:70 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to respectively obtain 200 mg of the title compound (yield: 40%) as a white foam and 190 mg of an isomer of the title compound (5-benzyl 1-ethyl 3-amino-6,6-dimethylpyrrolo[3,4-c]pyrazole-1,5(4H,6H)-dicarboxylate) (yield: 38%) as a white foam.


Title compound (5-benzyl 2-ethyl 3-amino-6,6-dimethylpyrrolo[3,4-c]pyrazole-2,5(4H,6H)-dicarboxylate)


Mass spectrum (CI, m/z): 359 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 7.45-7.29 (m, 5H), 6.63-6.49 (m, 2H), 5.19-5.04 (m, 2H), 4.41-4.30 (m, 2H), 4.28-4.15 (m, 2H), 1.62-1.49 (m, 6H), 1.36-1.28 (m, 3H).


Isomer of the title compound (5-benzyl 1-ethyl 3-amino-6,6-dimethylpyrrolo[3,4-c]pyrazole-1,5(4H,6H)-dicarboxylate)


Mass spectrum (CI, m/z): 359 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 7.45-7.29 (m, 5H), 5.78-5.65 (m, 2H), 5.19-5.05 (m, 2H), 4.36-4.17 (m, 4H), 1.79-1.66 (m, 6H), 1.33-1.25 (m, 3H).


Reference Example 82
5-Benzyl 2-ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]pyrrolo[3,4-c]pyrazole-2,5(4H,6H)-dicarboxylate



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To a solution of 885 mg (5.14 mmol) of 1-(trimethylsilyl)cyclobutanecarboxylic acid synthesized in the similar manner as in Reference Example 1 in 20 ml of dehydrated dichloromethane, 0.530 ml (6.17 mmol) of oxalyl chloride and 0.020 mL (0.26 mmol) of DMF were added in this order at 0° C. in an argon atmosphere and stirred for 1 hour with the temperature unchanged.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure.


To a solution of 2.25 ml (12.9 mmol) of DIPEA and 920 mg (2.57 mmol) of 5-benzyl 2-ethyl 3-amino-6,6-dimethylpyrrolo[3,4-c]pyrazole-2,5(4H,6H)-dicarboxylate synthesized in the similar manner as in Reference Example 81 in 10 ml of dehydrated dichloromethane, a solution of the obtained concentration residue in 10 ml of dehydrated dichloromethane was added dropwise at 0° C. in an argon atmosphere and then stirred at room temperature for 24 hours.


After the completion of the reaction, a saturated aqueous solution of sodium bicarbonate was added to the reaction solution, followed by extraction from the solution with dichloromethane twice. All of the organic layers were combined, washed with a 5% aqueous potassium bisulfate solution and a saturated aqueous solution of sodium chloride in this order, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=100:0 to 70:30 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 991 mg of the title compound (yield: 75%) as a pale yellow foam.


Mass spectrum (DUIS, m/z): 513 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 9.78-9.70 (m, 1H), 7.45-7.29 (m, 5H), 5.20-5.08 (m, 2H), 4.63-4.50 (m, 2H), 4.47-4.37 (m, 2H), 2.58-2.41 (m, 2H), 2.31-2.18 (m, 2H), 1.95-1.80 (m, 2H), 1.67-1.51 (m, 6H), 1.39-1.29 (m, 3H), 0.12-0.06 (m, 9H).


Reference Example 83
Ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate



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To a solution of 150 mg (0.293 mmol) of 5-benzyl 2-ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]pyrrolo[3,4-c]pyrazole-2,5(4H,6H)-dicarboxylate synthesized in the similar manner as in Reference Example 82 in 4 ml of 2-propanol, 75 mg of 10% palladium/carbon [manufactured by N.E. Chemcat Corp., PE type, containing 50% water] and 1 ml of acetic acid were added in this order at room temperature. After replacement with a hydrogen atmosphere, the resultant was stirred at room temperature for 1 hour.


After the completion of the reaction, the reaction solution was diluted with ethyl acetate and filtered by adding celite. An aqueous sodium bicarbonate solution was added to the filtrate, stirred, and neutralized. This was subjected to extraction with ethyl acetate twice. All of the organic layers were combined, washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (elution solvent: 1,2-dichloroethane:methanol=100:0 to 86:14 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 101 mg of the title compound (yield: 91%) as a white foam.


Mass spectrum (DUIS, m/z): 379 [M+1]+.



1H-NMR spectrum (400 MHz, CDCl3) δ: 9.86 (s, 1H), 4.52 (q, J=7.1 Hz, 2H), 4.22 (s, 2H), 2.65-2.52 (m, 2H), 2.38-2.26 (m, 2H), 2.03-1.88 (m, 2H), 1.50-1.43 (m, 9H), 0.15 (s, 9H).


Reference Example 84
Ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate



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To a solution of 57.1 g (119 mmol) of 5-tert-butyl 2-ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]pyrrolo[3,4-c]pyrazole-2,5(4H,6H)-dicarboxylate synthesized in the similar manner as in Reference Example 2 in 500 ml of dichloromethane, 28.0 ml (242 mmol) of 2,6-dimethylpyridine and 43.0 ml (238 mmol) of trimethylsilyl trifluoromethanesulfonate were added dropwise in this order at 0° C. in a nitrogen atmosphere and reacted with stirring at 0° C. for 2 hours.


After the completion of the reaction, the reaction solution was poured to 1000 ml of a saturated aqueous solution of sodium bicarbonate, then stirred at room temperature, and subsequently separated into an aqueous layer and an organic layer. The aqueous layer was subjected to extraction with 500 ml of ethyl acetate twice, and then, all of the obtained organic layers were washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The operation of adding toluene to the obtained concentration residue and concentrating the resultant under reduced pressure was performed three times, then the obtained brown oil was refrigerated overnight, and subsequently, 50 ml of diethyl ether and 100 ml of n-hexane were added and stirred at room temperature for 0.5 hours. The deposited solid was collected by filtration, washed with n-hexane, and then dried under reduced pressure to obtain 17.0 g of the title compound (yield: 38%) as a white solid.


Mass spectrum (DUIS, m/z): 379 [M+1]+.



1H-NMR spectrum (400 MHz, CDCl3) δ: 9.86 (s, 1H), 4.52 (q, J=7.1 Hz, 2H), 4.23 (s, 2H), 2.64-2.52 (m, 2H), 2.38-2.27 (m, 2H), 2.03-1.89 (m, 2H), 1.53-1.42 (m, 9H), 0.14 (s, 9H).


Reference Example 85
(R)-Benzyl 2-cyclopropoxy-2-phenylacetate



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To a solution of 7.50 ml (7.50 mmol) of a 1 M solution of diethylzinc in n-hexane in 4 ml of dehydrated dichloromethane, a solution of 0.750 ml (9.31 mmol) of diiodomethane in 1 ml of dehydrated dichloromethane was added dropwise with stirring at 0° C. in an argon atmosphere and stirred at the same temperature as above for 30 minutes. Subsequently, a solution of 500 mg (1.86 mmol) of (R)-benzyl 2-phenyl-2-(vinyloxy)acetate [synthesized according to the method described in J. Am. Chem. Soc., 2006, 128, 2587-2593] in 1 ml of dehydrated dichloromethane was added dropwise with stirring at 0° C. and stirred at room temperature for 6 hours.


After the completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction with dichloromethane. The obtained organic layer was washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel chromatography (elution solvent: n-hexane:ethyl acetate=100:0 to 80:20 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 416 mg of the title compound (yield: 79%) as a colorless oil.



1H-NMR spectrum (400 MHz, CDCl3) δ: 7.47-7.41 (m, 2H), 7.38-7.28 (m, 6H), 7.25-7.20 (m, 2H), 5.20 (d, J=12.5 Hz, 1H), 5.12 (d, J=12.5 Hz, 1H), 5.01 (s, 1H), 3.43 (tt, J=3.0, 6.1 Hz, 1H), 0.76-0.65 (m, 2H), 0.53-0.43 (m, 2H).


Reference Example 86
(R)-2-Cyclopropoxy-2-phenylacetic acid



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To a solution of 416 mg (1.47 mmol) of (R)-benzyl 2-cyclopropoxy-2-phenylacetate synthesized in the similar manner as in Reference Example 85 in 2 ml of methanol/2 ml of water, 93 mg (2.2 mmol) of lithium hydroxide monohydrate was added at room temperature and then reacted with stirring at room temperature for 2 hours.


After the completion of the reaction, diethyl ether was added to the reaction solution and then the aqueous layer and the organic layer were separated. The aqueous layer was adjusted to pH 2 by adding 2 N hydrochloric acid, followed by extraction with ethyl acetate three times. All of the obtained organic layers were washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 274 mg of the title compound (yield: 97%) as a colorless oil.


Mass spectrum (DUIS, m/z): 191 [M−1]−.



1H-NMR spectrum (400 MHz, CDCl3) δ: 7.48-7.32 (m, 5H), 4.99 (s, 1H), 3.43 (tt, J=2.9, 6.0 Hz, 1H), 0.76-0.64 (m, 2H), 0.61-0.43 (m, 2H).


Reference Example 87
(R)-2-Isopropoxy-2-phenylacetic acid



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To a suspension of 1.46 g (6.03 mmol) of (R)-benzyl 2-hydroxy-2-phenylacetate in 14.0 ml (140 mmol) of 2-iodopropane, 2.79 g (12.0 mmol) of silver(I) oxide was added at room temperature in an argon atmosphere and then reacted with stirring for 14.5 hours under heating to reflux.


After the completion of the reaction, the reaction solution was allowed to cool to room temperature and then filtered using a celite filter. The filtration cake was washed with ethyl acetate, and then, all of the filtrates were concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=95:5 to 90:10 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 675 mg of a concentration residue.


To a solution of the obtained concentration residue in 10 ml of methanol/2.0 ml of water, 176 mg (4.19 mmol) of lithium hydroxide monohydrate was added at room temperature in an argon atmosphere and then reacted with stirring at room temperature for 4 hours.


After the completion of the reaction, water and diethyl ether were added to the reaction solution, stirred, and then the aqueous layer and the organic layer were separated. The aqueous layer was adjusted to pH 2 by adding 2 N hydrochloric acid, followed by extraction with ethyl acetate three times. All of the obtained organic layers were washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=85:15 to 70:30 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 467 mg of a concentration residue. The obtained concentration residue was subjected to preparative HPLC (column: X-Bridge (trade name) ODS, elution solvent: 1 vol % formic acid/acetonitrile:1 vol % aqueous formic acid solution=20:80 to 70:30 (V/V)), a fraction containing the compound of interest was concentrated under reduced pressure, and acetonitrile was distilled off. The obtained concentration residue was subjected to extraction with ethyl acetate three times, and subsequently, all of the organic layers were washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and dried under reduced pressure to obtain 346 mg of the title compound (yield: 30% [2 steps]) as a white solid.


Mass spectrum (CI, m/z): 195 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.74 (br s, 1H), 7.43-7.27 (m, 5H), 4.95 (s, 1H), 3.62 (spt, J=6.1 Hz, 1H), 1.15 (d, J=6.1 Hz, 3H), 1.09 (d, J=6.1 Hz, 3H).


Reference Example 88
(R)-Ethyl 2-phenyl-2-(trifluoromethoxy)acetate



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To a solution of 25.0 g (139 mmol) of (R)-ethyl 2-hydroxy-2-phenylacetate in 10 ml of deuterated chloroform, 3.75 g (4.75 mmol) of 40% 1-trifluoromethyl-3,3-dimethyl-1,2-benziodoxole [Togni Reagent II (trade name), diatomaceous earth mixture, purchased from Tokyo Chemical Industry Co., Ltd.] and 0.900 g (1.44 mmol) of bis(trifluoromethylsulfonyl)imide zinc(II) were added with stirring at room temperature in an argon atmosphere and stirred at room temperature for 88 hours.


After the completion of the reaction, a saturated aqueous solution of sodium bicarbonate was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel chromatography (elution solvent: n-hexane:ethyl acetate=100:0 to 60:40 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 421 mg of the title compound (containing impurities) as a yellow oil.


Mass spectrum (CI, m/z): 249 [M+1]+.



1H-NMR spectrum (400 MHz, CDCl3) δ: 7.53-7.36 (m, 5H), 5.52 (s, 1H), 4.32-4.16 (m, 2H), 1.25 (t, J=7.1 Hz, 3H).


Reference Example 89
(R)-2-Phenyl-2-(trifluoromethoxy)acetic acid



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To a solution of 421 mg of (R)-ethyl 2-phenyl-2-(trifluoromethoxy)acetate (containing impurities) synthesized in the similar manner as in Reference Example 88 in 3 ml of methanol/3 ml of water, 93 mg (2.2 mmol) of lithium hydroxide monohydrate was added at room temperature and then reacted with stirring at room temperature for 4 hours.


After the completion of the reaction, diethyl ether was added to the reaction solution and then the aqueous layer and the organic layer were separated. The aqueous layer was adjusted to pH 2 by adding 2 N hydrochloric acid, followed by extraction with ethyl acetate three times. All of the obtained organic layers were washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 390 mg of the title compound (containing impurities) as a pale yellow oil.


Mass spectrum (DUIS, m/z): 219 [M−1]−.



1H-NMR spectrum (400 MHz, CDCl3) δ: 7.52-7.37 (m, 5H), 5.57 (s, 1H).


Reference Example 90
(R)-Benzyl 2-phenyl-2-propoxyacetate



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To a suspension of 1.58 g (6.52 mmol) of (R)-benzyl 2-hydroxy-2-phenylacetate in 14.5 ml (149 mmol) of 1-iodopropane, 3.03 g (13.1 mmol) of silver(I) oxide was added at room temperature in an argon atmosphere and then reacted with stirring at 80° C. for 14 hours.


After the completion of the reaction, the reaction solution was allowed to cool to room temperature and then filtered using a celite filter. The filtration cake was washed with ethyl acetate, and then, all of the filtrates were concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=97:3 to 90:10 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 1.23 g of the title compound (yield: 66%) as a colorless oil.


Mass spectrum (CI, m/z): 285 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 7.43-7.27 (m, 8H), 7.26-7.20 (m, 2H), 5.13 (s, 2H), 5.06 (s, 1H), 3.46 (td, J=6.6, 9.0 Hz, 1H), 3.40-3.28 (m, 1H), 1.60-1.49 (m, 2H), 0.85 (t, J=7.4 Hz, 3H).


Reference Example 91
(R)-2-Phenyl-2-propoxyacetic acid



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To a solution of 1.23 g (4.33 mmol) of (R)-benzyl 2-phenyl-2-propoxyacetate synthesized in the similar manner as in Reference Example 90 in 15 ml of ethanol, 274 mg of 10% palladium/carbon [PE type (trade name), manufactured by N.E. Chemcat Corp., containing 54% water] was added at room temperature in an argon atmosphere and then, after replacement with a hydrogen atmosphere under reduced pressure, reacted with stirring at room temperature for 1.5 hours.


After the completion of the reaction, the inside of the reaction container was replaced with an argon atmosphere under reduced pressure. The reaction solution was filtered using a celite filter, the removed solid was washed with ethanol, and then, the filtrate was concentrated under reduced pressure and dried under reduced pressure to obtain 892 mg of the title compound (containing impurities) as a colorless oil.


Mass spectrum (CI, m/z): 195 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 12.78 (br s, 1H), 7.42-7.29 (m, 5H), 4.83 (s, 1H), 3.47 (td, J=6.6, 9.0 Hz, 1H), 3.40-3.25 (m, 1H), 1.61-1.49 (m, 2H), 0.87 (t, J=7.4 Hz, 3H).


Reference Example 92
Methyl 2-(4-fluorophenyl)-2-methoxyacetate



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To a solution of 800 mg (4.70 mmol) of 4-fluoromandelic acid in 20 ml of dehydrated DMF, 450 mg (10.3 mmol) of 55% sodium hydride was dividedly added with stirring at 0° C. in an argon atmosphere and stirred at the same temperature as above for 1 hour. Subsequently, 0.732 ml (11.8 mmol) of iodomethane was added dropwise at 0° C. and then stirred at room temperature for 2 hours. 0.732 ml (11.8 mmol) of iodomethane was further added dropwise at 0° C. and then stirred at room temperature for 2 hours.


After the completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel chromatography (elution solvent: n-hexane:ethyl acetate=100:0 to 70:30 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 247 mg of the title compound (yield: 27%) as a colorless oil.


Mass spectrum (CI, m/z): 199 [M+1]+.



1H-NMR spectrum (400 MHz, CDCl3) δ: 7.46-7.38 (m, 2H), 7.11-7.02 (m, 2H), 4.76 (s, 1H), 3.73 (s, 3H), 3.40 (s, 3H).


Reference Example 93
2-(4-Fluorophenyl)-2-methoxyacetic acid



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To a solution of 247 mg (1.25 mmol) of methyl 2-(4-fluorophenyl)-2-methoxyacetate synthesized in the similar manner as in Reference Example 92 in 5 ml of THF, 2.0 ml (2.0 mmol) of a 1 N aqueous sodium hydroxide solution was added with stirring at room temperature and stirred at the same temperature as above for 16 hours.


After the completion of the reaction, 1 N hydrochloric acid was added to the reaction solution to adjust the pH to 2, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate, and filtered, and the filtrate was concentrated under reduced pressure and dried under reduced pressure to obtain 260 mg of the title compound (containing impurities) as a brown oil.


Mass spectrum (CI, m/z): 185 [M+1]+.



1H-NMR spectrum (400 MHz, CDCl3) δ: 7.49-7.36 (m, 2H), 7.13-7.03 (m, 2H), 4.77 (s, 1H), 3.43 (s, 3H).


Reference Example 94
Ethyl 2-(3-fluorophenyl)-2-hydroxyacetate



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To a suspension of 1.00 g (7.15 mmol) of 3-fluorophenylboronic acid in 30 ml of dehydrated toluene, 2.20 g (10.8 mmol) of a solution of 50% ethyl oxoacetate in toluene [purchased from Apollo scientific limited] and 107 mg (0.359 mmol) of 2-(di-tert-butylphosphino)biphenyl were added with stirring at room temperature in an argon atmosphere, followed by replacement with a nitrogen atmosphere under reduced pressure. Subsequently, 92.0 mg (0.100 mmol) of tris(dibenzylideneacetone)dipalladium(0) was added with stirring at room temperature and reacted at 80° C. for 9 hours.


The reaction solution was filtered using a celite filter, and water was added to the filtrate, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel chromatography (elution solvent: n-hexane:ethyl acetate=100:0 to 60:40 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 263 mg of the title compound (yield: 19%) as a pale yellow oil.


Mass spectrum (CI, m/z): 199 [M+1]+.



1H-NMR spectrum (400 MHz, CDCl3) δ: 7.38-7.29 (m, 1H), 7.25-7.20 (m, 1H), 7.19-7.13 (m, 1H), 7.06-6.98 (m, 1H), 5.15 (d, J=5.4 Hz, 1H), 4.34-4.14 (m, 2H), 3.50 (d, J=5.4 Hz, 1H), 1.25 (t, J=7.2 Hz, 3H).


Reference Example 95
Ethyl 2-(3-fluorophenyl)-2-methoxyacetate



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To a solution of 263 mg (1.33 mmol) of ethyl 2-(3-fluorophenyl)-2-hydroxyacetate synthesized in the similar manner as in Reference Example 94 in 8.0 ml (130 mmol) of iodomethane, 615 mg (2.65 mmol) of silver oxide was added at room temperature in an argon atmosphere and reacted with stirring at the same temperature as above for 3 hours.


After the completion of the reaction, the resultant was filtered using a celite filter, and the filtrate was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=100:0 to 60:40 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 155 mg of the title compound (yield: 55%) as a colorless oil.


Mass spectrum (CI, m/z): 213 [M+1]+.



1H-NMR spectrum (400 MHz, CDCl3) δ: 7.37-7.29 (m, 1H), 7.25-7.15 (m, 2H), 7.07-7.00 (m, 1H), 4.75 (s, 1H), 4.28-4.12 (m, 2H), 3.43 (s, 3H), 1.23 (t, J=7.1 Hz, 3H).


Reference Example 96
2-(3-Fluorophenyl)-2-methoxyacetic acid



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To a solution of 155 mg (0.730 mmol) of ethyl 2-(3-fluorophenyl)-2-methoxyacetate synthesized in the similar manner as in Reference Example 95 in 5 ml of THF, 1.0 ml (1.0 mmol) of a 1 N aqueous sodium hydroxide solution was added with stirring at room temperature and stirred at the same temperature as above for 20 hours.


After the completion of the reaction, 1 N hydrochloric acid was added to the reaction solution to adjust the pH to 2, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate, and filtered, and the filtrate was concentrated under reduced pressure to obtain 144 mg of the title compound (containing impurities) as a colorless oil.


Mass spectrum (CI, m/z): 185 [M+1]+.



1H-NMR spectrum (400 MHz, CDCl3) δ: 7.41-7.32 (m, 1H), 7.25-7.20 (m, 1H), 7.19-7.13 (m, 1H), 7.10-7.03 (m, 1H), 4.79 (s, 1H), 3.46 (s, 3H).


Reference Example 97
(R)-Methyl 2-(2-fluorophenyl)-2-methoxyacetate



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To a solution of 1.00 g (5.88 mmol) of (R)-2-(2-fluorophenyl)-2-hydroxyacetic acid [purchased from Combi-Blocks Inc.] in 20 ml of dehydrated DMF, 310 mg (7.10 mmol) of 55% sodium hydride was dividedly added with stirring at 0° C. in an argon atmosphere and stirred at the same temperature as above for 1 hour. Subsequently, 0.842 ml (13.5 mmol) of iodomethane was added dropwise at 0° C. and then stirred at room temperature for 4 hours.


After the completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel chromatography (elution solvent: n-hexane:ethyl acetate=100:0 to 70:30 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 858 mg of the title compound (yield: 74%) as a colorless oil.


Mass spectrum (CI, m/z): 199 [M+1]+.



1H-NMR spectrum (400 MHz, CDCl3) δ: 7.50-7.42 (m, 1H), 7.38-7.30 (m, 1H), 7.21-7.14 (m, 1H), 7.13-7.05 (m, 1H), 5.14 (s, 1H), 3.43 (s, 3H).


Reference Example 98
(R)-2-(2-Fluorophenyl)-2-methoxyacetic acid



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To a solution of 858 mg (4.33 mmol) of (R)-methyl 2-(2-fluorophenyl)-2-methoxyacetate synthesized in the similar manner as in Reference Example 97 in 10 ml of THF, 5.2 ml (5.2 mmol) of a 1 N aqueous sodium hydroxide solution was added with stirring at room temperature and stirred at 50° C. for 3 hours.


After the completion of the reaction, the resultant was allowed to cool to room temperature, and then, 1 N hydrochloric acid was added to the reaction solution to adjust the pH to 2, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate, and filtered, and the filtrate was concentrated under reduced pressure to obtain 390 mg of the title compound (yield: 49%) as a brown oil.


Mass spectrum (CI, m/z): 185 [M+1]+.



1H-NMR spectrum (400 MHz, CDCl3) δ: 7.46-7.32 (m, 2H), 7.22-7.05 (m, 2H), 5.11 (s, 1H), 3.43 (s, 3H).


Reference Example 99
Ethyl 2-hydroxy-2-(thiophen-2-yl)acetate



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To a suspension of 1.00 g (7.82 mmol) of thiophene-2-boronic acid in 30 ml of dehydrated toluene, 2.40 g (11.8 mmol) of a solution of 50% ethyl oxoacetate in toluene [purchased from Apollo scientific limited] and 117 mg (0.392 mmol) of 2-(di-tert-butylphosphino)biphenyl were added with stirring at room temperature in an argon atmosphere, followed by replacement with a nitrogen atmosphere under reduced pressure. Subsequently, 101 mg (0.110 mmol) of tris(dibenzylideneacetone)dipalladium(0) was added with stirring at room temperature and reacted at 80° C. for 9 hours.


The reaction solution was filtered using a celite filter, and water was added to the filtrate, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel chromatography (elution solvent: n-hexane:ethyl acetate=100:0 to 60:40 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 86 mg of the title compound (yield: 6%) as a yellow oil.



1H-NMR spectrum (400 MHz, CDCl3) δ: 7.29 (dd, J=1.2, 5.1 Hz, 1H), 7.13-7.09 (m, 1H), 7.00 (dd, J=3.6, 5.1 Hz, 1H), 5.43-5.37 (m, 1H), 4.37-4.22 (m, 2H), 3.48 (d, J=6.4 Hz, 1H), 1.30 (t, J=7.2 Hz, 3H).


Reference Example 100
Ethyl 2-methoxy-2-(thiophen-2-yl)acetate



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To a solution of 86 mg (0.46 mmol) of ethyl 2-hydroxy-2-(thiophen-2-yl)acetate synthesized in the similar manner as in Reference Example 99 in 4.0 ml (64 mmol) of iodomethane, 214 mg (0.923 mmol) of silver oxide was added at room temperature in an argon atmosphere and reacted with stirring at the same temperature as above for 3 hours.


After the completion of the reaction, the resultant was filtered using a celite filter, and the filtrate was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=100:0 to 60:40 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 68.5 mg of the title compound (yield: 74%) as a colorless oil.



1H-NMR spectrum (400 MHz, CDCl3) δ: 7.33 (dd, J=1.2, 5.1 Hz, 1H), 7.16-7.10 (m, 1H), 7.00 (dd, J=3.5, 5.1 Hz, 1H), 5.02 (s, 1H), 4.33-4.17 (m, 2H), 3.44 (s, 3H), 1.28 (t, J=7.2 Hz, 3H).


Reference Example 101
2-Methoxy-2-(thiophen-2-yl)acetic acid



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To a solution of 68 mg (0.34 mmol) of ethyl 2-methoxy-2-(thiophen-2-yl)acetate synthesized in the similar manner as in Reference Example 100 in 3 ml of THF, 0.5 ml (0.5 mmol) of a 1 N aqueous sodium hydroxide solution was added with stirring at room temperature and stirred at the same temperature as above for 16 hours.


After the completion of the reaction, 1 N hydrochloric acid was added to the reaction solution to adjust the pH to 2, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate, and filtered, and the filtrate was concentrated under reduced pressure and dried under reduced pressure to obtain 60 mg of the title compound (containing impurities) as a pale yellow oil.


Mass spectrum (DUIS, m/z): 171 [M−1]−.



1H-NMR spectrum (400 MHz, CDCl3) δ: 7.36 (dd, J=1.2, 5.1 Hz, 1H), 7.19-7.14 (m, 1H), 7.02 (dd, J=3.5, 5.1 Hz, 1H), 5.07 (s, 1H), 3.48 (s, 3H).


Reference Example 102
Mixture of 2-ethyl 5-(trichloromethyl) 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]pyrrolo[3,4-c]pyrazole-2,5(4H,6H)-dicarboxylate, and ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarbox amido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate



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To a solution of 8.03 g (21.2 mmol) of ethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 84 in 100 ml of dehydrated dichloromethane, 12.9 ml (74.1 mmol) of DIPEA was added at room temperature in an argon atmosphere. Subsequently, a solution of 4.40 g (14.8 mmol) of bis(trichloromethyl)carbonate in 10 ml of dehydrated dichloromethane was added dropwise at −78° C. and then stirred for 1.5 hours with the temperature unchanged.


After the completion of the reaction, a saturated aqueous solution of sodium bicarbonate and dichloromethane were added to the reaction solution and then stirred for 1 hour while the temperature was raised to room temperature for a while. The reaction solution was separated into an aqueous layer and an organic layer, and then, the aqueous layer was subjected to extraction with ethyl acetate twice. All of the organic layers were washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=85:15→75:25 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure. n-Hexane was added to the obtained concentration residue, stirred at room temperature for 10 minutes, and then left standing for 15 minutes in a freezer. The deposited solid was filtered off, and the filtrate obtained by washing the removed solid with n-hexane was concentrated under reduced pressure and dried under reduced pressure to obtain a mixture of 2.90 g of 2-ethyl 5-(trichloromethyl) 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]pyrrolo[3,4-c]pyrazole-2,5(4H,6H)-dicarboxylate (yield: 25%) and 1.75 g of ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarbox amido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate (yield: 19%) as a white foam.


Mass spectrum (ESI, m/z): 539 [M+1]+, 441 [M+1]+.



1H-NMR spectrum (400 MHz, CDCl3) δ: 9.99-9.84 (m, total 1H), 4.97 (s, 0.85H), 4.84-4.79 (m, total 1.15H), 4.59-4.51 (m, total 2H), 2.64-2.53 (m, total 2H), 2.39-2.28 (m, total 2H), 2.03-1.92 (m, total 2H), 1.82-1.75 (m, total 6H), 1.51-1.44 (m, total 3H), 0.19-0.13 (m, total 9H).


Reference Example 103
{1-[Amino(phenyl)methyl]cyclobutyl}methanol



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To a solution of 2.07 g (23.2 mmol) of ethyl carbamate in 20 ml of toluene, 2.36 ml (23.2 mmol) of benzaldehyde and 235 mg (1.23 mmol) of p-toluenesulfonic acid monohydrate were added in this order at room temperature in an argon atmosphere and then stirred at room temperature for 5 minutes. Subsequently, 1.80 ml (23.2 mmol) of cyclobutanecarbaldehyde was added at room temperature and then stirred at 60° C. for 4 hours.


After the completion of the reaction, the reaction solution was poured to a saturated aqueous solution of sodium bicarbonate and then stirred at room temperature. After separation into an aqueous layer and an organic layer, the aqueous layer was subjected to extraction with toluene once. All of the obtained organic layers were washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=90:10 to 60:40 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 2.20 g of a concentration residue.


To a solution of the obtained concentration residue in 10 ml of ethanol, 199 mg (5.26 mmol) of sodium borohydride was dividedly added at 0° C. in an argon atmosphere and then stirred at 0° C. for 0.5 hours and further at room temperature for 2.5 hours. Subsequently, 990 mg (17.7 mmol) of potassium hydroxide and 5.0 ml of water were added to the reaction solution at room temperature and then stirred for 2.5 hours under heating to reflux.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure, and ethanol was distilled off. 2 N hydrochloric acid was added to the concentration residue and then washed with diethyl ether. After separation into an aqueous layer and an organic layer, the obtained aqueous layer was adjusted to pH >10 by adding a 2 N aqueous sodium hydroxide solution, followed by extraction with dichloromethane three times. All of the obtained organic layers were washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was dissolved in 1,2-dichloroethane, then n-hexane was added, and the deposited solid was collected by filtration, washed with n-hexane, and then dried under reduced pressure to obtain 859 mg of the title compound (yield: 19% [2 steps]) as a white solid.


Mass spectrum (CI, m/z): 192 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 7.36-7.25 (m, 4H), 7.24-7.16 (m, 1H), 3.97 (s, 1H), 3.41 (d, J=10.7 Hz, 1H), 3.25 (d, J=10.7 Hz, 1H), 2.06-1.92 (m, 2H), 1.79-1.63 (m, 2H), 1.61-1.50 (m, 1H), 1.47-1.37 (m, 1H).


Reference Example 104
(R)—N-[2-(1-Hydroxycyclopropyl)-1-phenylethyl]-2,2,2-trifluoroacetamide



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To a solution of 1.01 g (3.67 mmol) of (R)-methyl 3-phenyl-3-(2,2,2-trifluoroacetamido)propanoate synthesized in the similar manner as in Reference Example 22 in 10 ml of dehydrated THF, 0.22 ml (0.75 mmol) of tetraisopropyl orthotitanate was added at 0° C. in an argon atmosphere, and then, 11.0 ml (11.0 mmol) of 1 M ethyl magnesium bromide/THF solution was added dropwise at 0° C. over 1 hour and then stirred for 3 hours with the temperature unchanged and subsequently for 1.5 hours after the temperature was raised to room temperature.


After the completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution and stirred, and then, insoluble matter was filtered off using a celite filter. The solid collected by filtration was washed with ethyl acetate, and then, the filtrate was separated into an aqueous layer and an organic layer. The aqueous layer was subjected to extraction with ethyl acetate once, and then, all of the organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=95:5 to 75:25 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 489 mg of the title compound (yield: 49%) as a pale yellow solid.


Mass spectrum (CI, m/z): 274 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 9.67 (br s, 1H), 7.37-7.30 (m, 4H), 7.30-7.21 (m, 1H), 5.33-5.05 (m, 2H), 2.01 (dd, J=5.2, 14.2 Hz, 1H), 1.93 (dd, J=9.2, 14.2 Hz, 1H), 0.57-0.46 (m, 2H), 0.45-0.37 (m, 1H), 0.11-0.04 (m, 1H).


Reference Example 105
(R)-1-(2-Amino-2-phenylethyl)cyclopropanol



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To a solution of 412 mg (1.51 mmol) of (R)—N-[2-(1-hydroxycyclopropyl)-1-phenylethyl]-2,2,2-trifluoroacetamide synthesized in the similar manner as in Reference Example 104 in 7 ml of ethanol, 174 mg (4.60 mmol) of sodium borohydride was added at room temperature in an argon atmosphere and then stirred at room temperature for 14.5 hours.


After the completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution at 0° C. and then stirred at room temperature. Insoluble matter was dissolved by adding water, followed by extraction with dichloromethane twice. All of the organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=75:25 to 60:40 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 259 mg of the title compound (containing impurities) as a pale yellow solid.


Mass spectrum (CI, m/z): 178 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 7.38-7.24 (m, 4H), 7.21-7.14 (m, 1H), 4.15 (dd, J=4.0, 9.4 Hz, 1H), 1.82 (ddd, J=1.3, 9.4, 13.9 Hz, 1H), 1.51-1.44 (m, 1H), 0.58-0.51 (m, 1H), 0.49-0.42 (m, 1H), 0.41-0.34 (m, 1H), 0.21-0.14 (m, 1H).


Reference Example 106
(R)—N-(3-Ethyl-3-hydroxy-1-phenylpentyl)-2,2,2-trifluoroacetamide



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To a solution of 700 mg (2.54 mmol) of (R)-methyl 3-phenyl-3-(2,2,2-trifluoroacetamido)propanoate synthesized in the similar manner as in Reference Example 22 in 10 ml of dehydrated THF, 7.63 ml (7.63 mmol) of 1 M ethyl magnesium bromide-THF solution was added dropwise at 0° C. in an argon atmosphere and then stirred at room temperature for 6 hours.


After the completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction with ethyl acetate. All of the obtained organic layers were washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=100:0 to 90:10 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 714 mg of the title compound (containing impurities) as a colorless oil.


Mass spectrum (CI, m/z): 304 [M+1]+.


Reference Example 107
(R)-1-Amino-3-ethyl-1-phenylpentan-3-ol



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To a solution of 714 mg of (R)—N-(3-ethyl-3-hydroxy-1-phenylpentyl)-2,2,2-trifluoroacetamide (containing impurities) synthesized in Reference Example 106 in 1 ml of water/5 ml of methanol, 651 mg (4.71 mmol) of potassium carbonate was added at room temperature in an argon atmosphere and then stirred for 20 hours with the temperature unchanged.


After the completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction with ethyl acetate. All of the obtained organic layers were washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=75:25 to 60:40 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 120 mg of the title compound (yield: 23% [2 steps]) as a colorless oil.


Mass spectrum (CI, m/z): 208 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 7.38-7.25 (m, 4H), 7.22-7.15 (m, 1H), 4.01 (dd, J=2.6, 10.9 Hz, 1H), 1.66-1.41 (m, 4H), 1.38-1.25 (m, 2H), 0.86-0.71 (m, 6H)


Reference Example 108
(E)-Methyl 3-(4-fluorophenyl)acrylate



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To a solution of 2.0 g (16 mmol) of 4-fluorobenzaldehyde in 20 ml of dehydrated THF, 6.47 g (19.4 mmol) of methyl 2-(triphenylphosphoranylidene)acetate was added at room temperature in an argon atmosphere and then stirred for 20 hours with the temperature unchanged.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure. 20 ml of TBME was added to the obtained concentration residue and filtered, and the filtrate was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=100:0 to 90:10(v/v)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 2.74 g of the title compound (yield: 94%) as a white solid.


Mass spectrum (CI, m/z): 181 [M+1]+.



1H-NMR spectrum (400 MHz, CDCl3) δ: 7.66 (d, J=16.0 Hz, 1H), 7.55-7.47 (m, 2H), 7.13-7.03 (m, 2H), 6.41-6.33 (m, 1H), 3.81 (s, 3H).


Reference Example 109
(R)-Methyl 3-{benzyl [(S)-1-phenylethyl]amino}-3-(4-fluorophenyl)propanoate



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To a solution of 2.79 ml (13.3 mmol) of (S)—N-benzyl-1-phenylethanamine in 30 ml of dehydrated THF, 7.80 ml (12.5 mmol) of a 1.6 M solution of n-butyllithium in n-hexane was added dropwise at −78° C. in an argon atmosphere and then stirred for 30 minutes with the temperature unchanged. Subsequently, a solution of 1.5 g (8.3 mmol) of (E)-methyl 3-(4-fluorophenyl)acrylate synthesized in the similar manner as in Reference Example 108 in 5 ml of THF was added at −78° C. and then stirred for 1 hour with the temperature unchanged.


After the completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=100:0 to 95:5 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 1.53 g of the title compound (yield: 47%) as a pale yellow oil.


Mass spectrum (CI, m/z): 392 [M+1]+.



1H-NMR spectrum (400 MHz, CDCl3) δ: 7.43-7.16 (m, 12H), 7.08-6.96 (m, 2H), 4.42 (dd, J=5.4, 9.7 Hz, 1H), 3.97 (q, J=6.9 Hz, 1H), 3.72 (d, J=14.7 Hz, 1H), 3.65 (d, J=14.7 Hz, 1H), 3.47 (s, 3H), 2.65 (dd, J=5.4, 14.9 Hz, 1H), 2.52 (dd, J=9.7, 14.9 Hz, 1H), 1.27-1.21 (m, 3H).


Reference Example 110
(R)-4-{Benzyl[(S)-1-phenylethyl]amino}-4-(4-fluorophenyl)-2-methylbutan-2-ol



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To a solution of 1.35 g (3.45 mmol) of (R)-methyl 3-{benzyl [(S)-1-phenylethyl]amino}-3-(4-fluorophenyl)propanoate synthesized in the similar manner as in Reference Example 109 in 20 ml of dehydrated THF, 10.4 ml (10.4 mmol) of 1 M methyl magnesium bromide-THF solution was added dropwise at 0° C. under argon stream and then stirred at room temperature for 20 hours.


After the completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=95:5 to 85:15 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 850 mg of the title compound (yield: 63%) as a colorless oil.


Mass spectrum (ESI, m/z): 392 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 7.48-7.09 (m, 14H), 4.21 (s, 1H), 4.09-3.98 (m, 1H), 3.92-3.85 (m, 1H), 3.74 (d, J=15.1 Hz, 1H), 3.63 (d, J=15.1 Hz, 1H), 2.10 (dd, J=9.2, 13.9 Hz, 1H), 2.02-1.93 (m, 1H), 0.93 (d, J=6.8 Hz, 3H), 0.82 (s, 3H), 0.69 (s, 3H).


Reference Example 111
(R)-4-Amino-4-(4-fluorophenyl)-2-methylbutan-2-ol



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To a solution of 850 mg (2.17 mmol) of (R)-4-{benzyl [(S)-1-phenylethyl]amino}-4-(4-fluorophenyl)-2-methylbutan-2-ol synthesized in the similar manner as in Reference Example 110 in 10 ml of methanol, 425 mg of 20% palladium hydroxide/carbon (containing 50% water) was added at room temperature under argon stream and after replacement with a hydrogen atmosphere, stirred at room temperature for 7 hours.


After the completion of the reaction, the reaction solution was diluted with ethyl acetate and filtered through celite. The filtrate was concentrated under reduced pressure, the obtained concentration residue was subjected to silica gel column chromatography (DIOL, elution solvent: n-hexane:ethyl acetate=75:25 to 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 248 mg of the title compound (containing impurities) as a colorless oil.


Mass spectrum (CI, m/z): 198 [M+1]+.


Reference Example 112
(E)-Methyl 3-(3-fluorophenyl)acrylate



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To a solution of 1.27 ml (12.1 mmol) of 3-fluorobenzaldehyde in ml of dehydrated THF, 5.25 g (15.7 mmol) of methyl 2-(triphenylphosphoranylidene)acetate was added at room temperature under argon stream and then stirred for 16 hours with the temperature unchanged.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure. 20 ml of TBME was added to the obtained concentration residue, insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=100:0 to 90:10 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 1.75 g of the title compound (yield: 80%) as a colorless oil.


Mass spectrum (CI, m/z): 181 [M+1]+.



1H-NMR spectrum (400 MHz, CDCl3) δ: 7.65 (d, J=16.1 Hz, 1H), 7.40-7.33 (m, 1H), 7.32-7.27 (m, 1H), 7.25-7.19 (m, 1H), 7.12-7.05 (m, 1H), 6.44 (d, J=16.1 Hz, 1H), 3.82 (s, 3H).


Reference Example 113
(R)-Methyl 3-{benzyl[(S)-1-phenylethyl] amino}-3-(3-fluorophenyl)propanoate



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To a solution of 3.25 ml (15.5 mmol) of (S)—N-benzyl-1-phenylethanamine in 30 ml of dehydrated THF, 9.11 ml (14.6 mmol) of a 1.6 M solution of n-butyllithium in n-hexane was added dropwise at −78° C. in an argon atmosphere and then stirred for 1 hour with the temperature unchanged. Subsequently, a solution of 1.75 g (9.71 mmol) of (E)-methyl 3-(3-fluorophenyl)acrylate synthesized in the similar manner as in Reference Example 112 in 5 ml of THF was added at −78° C. and then stirred for 1 hour with the temperature unchanged.


After the completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=100:0 to 95:5 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 2.22 g of the title compound (yield: 58%) as a pale yellow oil.


Mass spectrum (CI, m/z): 392 [M+1]+.



1H-NMR spectrum (400 MHz, CDCl3) δ: 7.45-7.09 (m, 13H), 7.00-6.91 (m, 1H), 4.44 (dd, J=5.4, 9.4 Hz, 1H), 3.98 (q, J=6.9 Hz, 1H), 3.73 (d, J=14.6 Hz, 1H), 3.66 (d, J=14.6 Hz, 1H), 3.49 (s, 3H), 2.63 (dd, J=5.4, 15.2 Hz, 1H), 2.54 (dd, J=9.4, 15.2 Hz, 1H), 1.25 (d, J=6.9 Hz, 3H).


Reference Example 114
(R)-4-{Benzyl[(S)-1-phenylethyl]amino}-4-(3-fluorophenyl)-2-methylbutan-2-ol



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To a solution of 2.22 g (5.67 mmol) of (R)-methyl 3-{benzyl [(S)-1-phenylethyl]amino}-3-(3-fluorophenyl)propanoate synthesized in the similar manner as in Reference Example 113 in 20 ml of dehydrated THF, 17.0 ml (17.0 mmol) of 1 M methyl magnesium bromide-THF solution was added dropwise at 0° C. in an argon atmosphere and then stirred at room temperature for 17 hours.


After the completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=95:5 to 85:15 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 1.95 g of the title compound (yield: 88%) as a colorless oil.


Mass spectrum (CI, m/z): 392 [M+1]+.



1H-NMR spectrum (400 MHz, CDCl3) δ: 7.42-7.22 (m, 11H), 7.20-7.15 (m, 1H), 7.13-7.07 (m, 1H), 7.06-6.99 (m, 1H), 5.45 (s, 1H), 4.32-4.20 (m, 2H), 4.17-4.05 (m, 1H), 3.61 (d, J=13.2 Hz, 1H), 2.39 (dd, J=10.6, 14.7 Hz, 1H), 1.40 (dd, J=3.4, 14.7 Hz, 1H), 1.12 (s, 3H), 1.03 (d, J=7.0 Hz, 3H), 0.62 (s, 3H).


Reference Example 115
(R)-4-Amino-4-(3-fluorophenyl)-2-methylbutan-2-ol



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To a solution of 1.1 g (2.8 mmol) of (R)-4-{benzyl [(S)-1-phenylethyl] amino}-4-(3-fluorophenyl)-2-methylbutan-2-ol synthesized in the similar manner as in Reference Example 114 in 10 ml of methanol, 200 mg of 20% palladium hydroxide/carbon (containing 50% water) was added at room temperature under argon stream and after replacement with a hydrogen atmosphere, stirred at room temperature for 6 hours. Subsequently, after replacement with an argon atmosphere, 0.354 g (5.61 mmol) of ammonium formate was added at room temperature and stirred at 60° C. for 2 hours.


After the completion of the reaction, the reaction solution was diluted with ethyl acetate and then filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL, elution solvent: n-hexane:ethyl acetate=75:25 to 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 276 mg of the title compound (yield: 50%) as a colorless oil.


Mass spectrum (CI, m/z): 198 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 7.37-7.28 (m, 1H), 7.25-7.14 (m, 2H), 7.03-6.95 (m, 1H), 4.08 (dd, J=3.0, 10.5 Hz, 1H), 1.63 (dd, J=10.5, 13.9 Hz, 1H), 1.52 (dd, J=3.0, 13.9 Hz, 1H), 1.22 (s, 3H), 1.09 (s, 3H).


Reference Example 116
(R)-Ethyl 5-{[1-(3-fluorophenyl)-3-hydroxy-3-methylbutyl]carbamoyl}-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate



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To a solution of 70 mg (0.35 mmol) of (R)-4-amino-4-(3-fluorophenyl)-2-methylbutan-2-ol synthesized in the similar manner as in Reference Example 115 in 5 ml of 1,4-dioxane, 0.31 ml (1.8 mol) of DIPEA and 172 mg (0.390 mmol) of ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarbox amido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 3 were added in this order with stirring at room temperature under argon stream and stirred at 90° C. for 2 hours.


After the completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution allowed to cool to room temperature, followed by extraction from the mixed solution with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=70:30 to 27:73 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 149 mg of the title compound (yield: 70%) as a white foam.


Mass spectrum (CI, m/z): 602 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 9.78 (s, 1H), 7.36-7.26 (m, 1H), 7.19-7.12 (m, 2H), 7.01-6.93 (m, 1H), 6.71 (d, J=6.2 Hz, 1H), 4.96-4.88 (m, 1H), 4.67-4.60 (m, 2H), 4.54 (d, J=13.6 Hz, 1H), 4.41 (q, J=7.1 Hz, 2H), 2.59-2.42 (m, 2H), 2.29-2.21 (m, 2H), 2.02-1.84 (m, 3H), 1.66 (dd, J=3.2, 14.2 Hz, 1H), 1.59 (s, 3H), 1.54 (s, 3H), 1.33 (t, J=7.1 Hz, 3H), 1.14 (s, 3H), 1.13 (s, 3H), 0.11 (s, 9H).


Reference Example 117
(E)-Methyl 3-(2-fluorophenyl)acrylate



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To a solution of 1.26 ml (12.1 mmol) of 2-fluorobenzaldehyde in ml of dehydrated THF, 5.25 g (15.7 mmol) of methyl 2-(triphenylphosphoranylidene)acetate was added at room temperature under argon stream and then stirred for 17 hours with the temperature unchanged.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure. 20 ml of TBME was added to the obtained concentration residue, insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=100:0 to 90:10 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 1.58 g of the title compound (yield: 73%) as a colorless oil.


Mass spectrum (CI, m/z): 181 [M+1]+.



1H-NMR spectrum (400 MHz, CDCl3) δ: 7.83 (d, J=16.3 Hz, 1H), 7.57-7.50 (m, 1H), 7.40-7.33 (m, 1H), 7.20-7.07 (m, 2H), 6.55 (d, J=16.3 Hz, 1H), 3.82 (s, 3H).


Reference Example 118
(R)-Methyl 3-{benzyl [(S)-1-phenylethyl]amino}-3-(2-fluorophenyl)propanoate



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To a solution of 2.94 ml (14.1 mmol) of (S)—N-benzyl-1-phenylethanamine in 30 ml of dehydrated THF, 8.22 ml (13.2 mmol) of a 1.6 M solution of n-butyllithium in n-hexane was added dropwise at −78° C. under argon stream and then stirred for 1 hour with the temperature unchanged. Subsequently, a solution of 1.58 g (8.77 mmol) of (E)-methyl 3-(2-fluorophenyl)acrylate synthesized in the similar manner as in Reference Example 117 in 5 ml of THF was added dropwise at −78° C. and then stirred for 1 hour with the temperature unchanged.


After the completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=100:0 to 95:5 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 1.27 g of the title compound (yield: 37%) as a pale yellow oil.


Mass spectrum (CI, m/z): 392 [M+1]+.



1H-NMR spectrum (400 MHz, CDCl3) δ: 7.45-7.03 (m, 14H), 4.75 (dd, J=6.8, 8.9 Hz, 1H), 4.05 (q, J=6.9 Hz, 1H), 3.81 (d, J=14.6 Hz, 1H), 3.65 (d, J=14.6 Hz, 1H), 3.44 (s, 3H), 2.79 (dd, J=6.8, 14.9 Hz, 1H), 2.65 (dd, J=8.9, 14.9 Hz, 1H), 1.20 (d, J=6.9 Hz, 3H).


Reference Example 119
(R)-4-{Benzyl[(S)-1-phenylethyl]amino}-4-(2-fluorophenyl)-2-methylbutan-2-ol



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To a solution of 1.27 g (3.24 mmol) of (R)-methyl 3-{benzyl[(S)-1-phenylethyl]amino}-3-(2-fluorophenyl)propanoate synthesized in the similar manner as in Reference Example 118 in 15 ml of dehydrated THF, 9.73 ml (9.73 mmol) of 1 M methyl magnesium bromide-THF solution was added dropwise at 0° C. under argon stream and then stirred at room temperature for 17 hours.


After the completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=95:5 to 85:15 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 1.10 g of the title compound (yield: 87%) as a pale yellow oil.


Mass spectrum (CI, m/z): 392 [M+1]+.



1H-NMR spectrum (400 MHz, CDCl3) δ: 7.51-7.08 (m, 14H), 5.58 (s, 1H), 4.72 (dd, J=3.1, 11.3 Hz, 1H), 4.31 (d, J=12.9 Hz, 1H), 4.16-4.05 (m, 1H), 3.55 (d, J=12.9 Hz, 1H), 2.47 (dd, J=11.3, 14.6 Hz, 1H), 1.32 (dd, J=3.1, 14.6 Hz, 1H), 1.11 (s, 3H), 1.06 (d, J=7.0 Hz, 3H), 0.53 (s, 3H).


Reference Example 120
(R)-4-Amino-4-(2-fluorophenyl)-2-methylbutan-2-ol



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To a solution of 1.1 g (2.8 mmol) of (R)-4-{benzyl [(S)-1-phenylethyl]amino}-4-(2-fluorophenyl)-2-methylbutan-2-ol synthesized in the similar manner as in Reference Example 119 in 10 ml of methanol, 200 mg of 20% palladium hydroxide/carbon (containing 50% water) was added at room temperature under argon stream and after replacement with a hydrogen atmosphere, stirred at room temperature for 6 hours. Subsequently, after replacement with an argon atmosphere, 354 mg (5.61 mmol) of ammonium formate was added at room temperature and stirred at 60° C. for 2 hours.


After the completion of the reaction, the reaction solution was diluted with ethyl acetate and then filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL, elution solvent: n-hexane:ethyl acetate=75:25 to 50:50 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 265 mg of the title compound (yield: 48%) as a colorless oil.


Mass spectrum (CI, m/z): 198 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 7.61-7.55 (m, 1H), 7.28-7.21 (m, 1H), 7.20-7.14 (m, 1H), 7.13-7.06 (m, 1H), 4.39 (dd, J=2.7, 10.4 Hz, 1H), 1.64 (dd, J=10.4, 13.8 Hz, 1H), 1.52 (dd, J=2.7, 13.8 Hz, 1H), 1.22 (s, 3H), 1.09 (s, 3H).


Reference Example 121
(R)-Ethyl 5-{[1-(2-fluorophenyl)-3-hydroxy-3-methylbutyl]carbamoyl}-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate



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To a solution of 70 mg (0.35 mmol) of (R)-4-amino-4-(2-fluorophenyl)-2-methylbutan-2-ol synthesized in the similar manner as in Reference Example 120 in 5 ml of 1,4-dioxane, 0.309 ml (1.77 mol) of DIPEA and 235 mg (0.533 mmol) of ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarbox amido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 3 were added in this order with stirring at room temperature under argon stream and stirred at 90° C. for 2 hours.


After the completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution allowed to cool to room temperature, followed by extraction from the mixed solution with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=65:35 to 29:71 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 150 mg of the title compound (yield: 70%) as a white solid.


Mass spectrum (CI, m/z): 602 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 9.79 (s, 1H), 7.54-7.46 (m, 1H), 7.27-7.07 (m, 3H), 6.70 (d, J=5.8 Hz, 1H), 5.24-5.16 (m, 1H), 4.71-4.54 (m, 3H), 4.42 (q, J=7.2 Hz, 2H), 2.58-2.44 (m, 2H), 2.32-2.22 (m, 2H), 2.02-1.87 (m, 3H), 1.67-1.57 (m, 4H), 1.53 (s, 3H), 1.34 (t, J=7.2 Hz, 3H), 1.19-1.14 (m, 6H), 0.13 (s, 9H).


Reference Example 122
(R)-Methyl 3-[(tert-butoxycarbonyl)amino]-4-methylpentanoate



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To a solution of 600 mg (2.59 mmol) of (R)-3-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid in 6 ml of dichloromethane, 63 mg (0.52 mmol) of 4-dimethylaminopyridine and 0.53 ml (13 mmol) of methanol were added in this order with stirring at room temperature under argon stream.


Subsequently, 746 mg (3.89 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride was added in one portion with stirring at 0° C. and stirred at room temperature for 2 hours.


After the completion of the reaction, water was added to the reaction solution, followed by extraction from the mixed solution with ethyl acetate twice. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=100:0 to 80:20 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 630 mg of the title compound (yield: 99%) as a colorless oil.


Mass spectrum (CI, m/z): 246 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 6.72 & 6.37 (br d, J=9.2 Hz, total 1H), 3.71-3.61 (m, 1H), 3.60-3.52 (m, 3H), 2.44 (dd, J=4.6, 15.0 Hz, 1H), 2.30 (dd, J=9.4, 15.0 Hz, 1H), 1.71-1.58 (m, 1H), 1.36 (s, 9H), 0.86-0.73 (m, 6H).


Reference Example 123
(R)-tert-Butyl (5-hydroxy-2,5-dimethylhexan-3-yl)carbamate



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To a solution of 630 mg (2.57 mmol) of (R)-methyl 3-[(tert-butoxycarbonyl)amino]-4-methylpentanoate synthesized in the similar manner as in Reference Example 122 in 6 ml of dehydrated THF, 7.7 ml (7.7 mol) of 1 M methyl magnesium bromide-THF solution was added dropwise with stirring at 0° C. under argon stream and stirred at room temperature for 4 hours.


After the completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction from the mixed solution with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=91:9 to 70:30 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 133 mg of the title compound (yield: 21%) as a white solid.


Mass spectrum (CI, m/z): 246 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 6.53 & 6.14 (br d, J=8.9 Hz, total 1H), 4.09 (s, 1H), 3.47-3.39 (m, 1H), 1.63-1.50 (m, 1H), 1.42-1.33 (m, 11H), 1.06 (s, 3H), 1.05 (s, 3H), 0.80-0.74 (m, 6H).


Reference Example 124
(R)-4-Amino-2,5-dimethylhexan-2-ol hydrochloride



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To a solution of 133 mg (0.542 mmol) of (R)-tert-butyl (5-hydroxy-2,5-dimethylhexan-3-yl)carbamate synthesized in the similar manner as in Reference Example 123 in 2 ml of 1,4-dioxane, 0.678 ml (2.71 mol) of 4 N hydrogen chloride/1,4-dioxane was added in one portion with stirring at room temperature under argon stream and stirred at room temperature for 3 hours. Subsequently, 0.678 ml (2.71 mol) of 4 N hydrogen chloride/1,4-dioxane was added in one portion with stirring at room temperature and stirred at room temperature for 15 hours.


After the completion of the reaction, the reaction solution was concentrated. 5 ml of n-hexane was added thereto and stirred at room temperature for 2 hours. The deposited solid was collected by filtration, washed with n-hexane, and dried under reduced pressure to obtain 58 mg of the title compound (yield: 59%) as a white solid.


Mass spectrum (CI, m/z): 146 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 8.25-4.63 (m, 3H), 3.16-3.04 (m, 1H), 1.96-1.82 (m, 1H), 1.58 (dd, J=2.0, 15.0 Hz, 1H), 1.49 (dd, J=9.8, 15.0 Hz, 1H), 1.21 (s, 3H), 1.17 (s, 3H), 0.91 (d, J=6.8 Hz, 3H), 0.89 (d, J=6.8 Hz, 3H).


Reference Example 125
(R)-Ethyl 5-[(5-hydroxy-2,5-dimethylhexan-3-yl)carbamoyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate



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To a solution of 260 mg (0.590 mmol) of ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 3 in 4 ml of 1,4-dioxane, 0.342 ml (1.96 mol) of DIPEA and 57 mg (0.31 mmol) of (R)-4-amino-2,5-dimethylhexan-2-ol hydrochloride synthesized in the similar manner as in Reference Example 124 were added in this order with stirring at room temperature under argon stream and stirred at 90° C. for 1.5 hours.


After the completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution allowed to cool to room temperature, followed by extraction from the mixed solution with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=70:30 to 30:70 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 99 mg of the title compound (yield: 57%) as a white foam.


Mass spectrum (CI, m/z): 550 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 9.78 (s, 1H), 5.83 (d, J=7.7 Hz, 1H), 4.55 (d, J=13.6 Hz, 1H), 4.47 (d, J=13.6 Hz, 1H), 4.42 (q, J=7.1 Hz, 2H), 4.30 (s, 1H), 3.73-3.62 (m, 1H), 2.58-2.43 (m, 2H), 2.31-2.21 (m, 2H), 1.96-1.82 (m, 2H), 1.75-1.57 (m, 8H), 1.50-1.42 (m, 1H), 1.34 (t, J=7.1 Hz, 3H), 1.10 (s, 3H), 1.08 (s, 3H), 0.89-0.78 (m, 6H), 0.15-0.08 (m, 9H).


Reference Example 126
Ethyl [1-(4-fluorophenyl)-2,2-dimethyl-3-oxopropyl] carbamate



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To a solution of 2.63 g (29.5 mmol) of ethyl carbamate in 25 ml of toluene, 3.1 ml (29 mmol) of 4-fluorobenzaldehyde and 0.281 g (1.48 mmol) of p-toluenesulfonic acid monohydrate were added in this order with stirring at room temperature under argon stream and stirred at room temperature for 5 minutes. Subsequently, 2.68 ml (29.5 mmol) of isobutylaldehyde was added thereto dropwise with stirring at room temperature and stirred at 60° C. for 3 hours.


After the completion of the reaction, the reaction solution was poured to a saturated aqueous solution of sodium bicarbonate and subsequently stirred at room temperature for 5 minutes. An organic layer and an aqueous layer were separated, and then, the separated aqueous layer was subjected to extraction with toluene once. All of the obtained organic layers were washed with a saturated aqueous solution of sodium chloride, then dehydrated over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=90:10 to 69:31 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 3.85 g of the title compound (yield: 49%) as a colorless oil. Mass spectrum (CI, m/z): 268 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 9.59 (s, 1H), 7.95 (d, J=10.1 Hz, 1H), 7.43-7.33 (m, 2H), 7.21-7.12 (m, 2H), 5.04 (d, J=10.1 Hz, 1H), 4.01-3.93 (m, 2H), 1.15 (t, J=7.1 Hz, 3H), 0.94 (s, 3H), 0.87 (s, 3H).


Reference Example 127
3-Amino-3-(4-fluorophenyl)-2,2-dimethylpropan-1-ol



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To a solution of 3.84 g (14.4 mmol) of ethyl [1-(4-fluorophenyl)-2,2-dimethyl-3-oxopropyl]carbamate synthesized in the similar manner as in Reference Example 126 in 20 ml of ethanol, 0.326 g (8.62 mmol) of sodium borohydride was dividedly added with stirring at 0° C. under argon stream and stirred at room temperature for 1 hour. Subsequently, 1.61 g (28.7 mmol) of potassium hydroxide and water (10 ml) were added with stirring at room temperature and then stirred for 2 hours under heating to reflux.


After the completion of the reaction, the reaction solution allowed to cool was concentrated under reduced pressure, and ethanol was distilled off. The concentration residue was adjusted to pH 2 by adding 2 N hydrochloric acid and washed with diethyl ether. The aqueous layer was rendered basic (pH 9) by adding 1 N aqueous sodium hydroxide solution, followed by extraction with dichloromethane three times. All of the obtained organic layers were washed with a saturated aqueous solution of sodium chloride, then dehydrated over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and dried under reduced pressure to obtain 1.93 g of the title compound (yield: 68%) as a white solid.


Mass spectrum (CI, m/z): 198 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 7.38-7.29 (m, 2H), 7.15-7.03 (m, 2H), 3.81 (s, 1H), 3.25 (d, J=10.5 Hz, 1H), 3.13 (d, J=10.5 Hz, 1H), 0.74 (s, 3H), 0.65 (s, 3H).


Reference Example 128
Ethyl [1-(3-fluorophenyl)-2,2-dimethyl-3-oxopropyl]carbamate



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To a solution of 2.63 g (29.5 mmol) of ethyl carbamate in 25 ml of toluene, 3.10 ml (29.5 mmol) of 3-fluorobenzaldehyde and 288 mg (1.51 mmol) of p-toluenesulfonic acid monohydrate were added in this order at room temperature in an argon atmosphere and then stirred at room temperature for 5 minutes. Subsequently, 2.70 ml (29.7 mmol) of isobutylaldehyde was added at room temperature and then stirred for 3 hours under heating to reflux after a Dean-Stark apparatus was loaded. Subsequently, 2.70 ml (29.7 mmol) of isobutylaldehyde was added and then further stirred for 3 hours under heating to reflux.


After the completion of the reaction, the reaction solution was poured to a saturated aqueous solution of sodium bicarbonate and then stirred at room temperature. After separation into an aqueous layer and an organic layer, the aqueous layer was subjected to extraction with toluene once. All of the obtained organic layers were washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=90:10 to 60:40 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 4.61 g of the title compound (yield: 59%) as a pale yellow oil.


Mass spectrum (CI, m/z): 268 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 9.59 (s, 1H), 7.95 (br d, J=10.2 Hz, 1H), 7.36 (dt, J=6.2, 7.9 Hz, 1H), 7.27-7.06 (m, 3H), 5.07 (d, J=10.2 Hz, 1H), 4.06-3.89 (m, 2H), 1.18-1.12 (m, 3H), 0.94 (s, 3H), 0.88 (s, 3H).


Reference Example 129
3-Amino-3-(3-fluorophenyl)-2,2-dimethylpropan-1-ol



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To a solution of 4.75 g (17.8 mmol) of ethyl [1-(3-fluorophenyl)-2,2-dimethyl-3-oxopropyl]carbamate synthesized in the similar manner as in Reference Example 128 in 12 ml of ethanol, 352 mg (9.30 mmol) of sodium borohydride was dividedly added with stirring at 0° C. in an argon atmosphere and then stirred at room temperature for 4 hours.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure, and 75 ml of dichloromethane was added to the residue. This solution was poured to 50 ml of a saturated aqueous solution of ammonium chloride, stirred at room temperature until foaming settled, and then the aqueous layer and the organic layer were separated. The aqueous layer was subjected to extraction with 25 ml of dichloromethane, all of the organic layers were dried over anhydrous magnesium sulfate and filtered, and then, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=78:22 to 57:43 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure.


12 ml of ethanol and 2.45 g (37.1 mmol) of 85% potassium hydroxide were added to the obtained residue (3.91 g) and heated to reflux for 4 hours.


After standing to cool, the resultant was concentrated under reduced pressure, and 50 ml of water and 50 ml of dichloromethane were added thereto and stirred at room temperature. After separation into an aqueous layer and an organic layer, the aqueous layer was subjected to extraction with 50 ml of dichloromethane twice. All of the organic layers were dried over anhydrous sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure to obtain 2.58 g of the title compound (yield: 74%) as a pale yellow viscous liquid.


Mass spectrum (CI, m/z): 198 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 7.36-7.25 (m, 1H), 7.19-7.08 (m, 2H), 7.06-6.97 (m, 1H), 5.00 (br s, 1H), 3.81 (s, 1H), 3.25 (d, J=10.5 Hz, 1H), 3.14 (d, J=10.5 Hz, 1H), 1.99 (br s, 2H), 0.77 (s, 3H), 0.66 (s, 3H).


Reference Example 130
3-Amino-3-(2-fluorophenyl)-2,2-dimethylpropan-1-ol



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To a solution of 2.62 g (29.4 mmol) of ethyl carbamate in 25 ml of toluene, 3.05 ml (29.2 mmol) of 2-fluorobenzaldehyde and 286 mg (1.51 mmol) of p-toluenesulfonic acid monohydrate were added in this order at room temperature in an argon atmosphere and then reacted at room temperature for 5 minutes. Subsequently, 2.70 ml (29.7 mmol) of isobutylaldehyde was added at 60° C. and then reacted at the same temperature as above for 5.5 hours.


After the completion of the reaction, the reaction solution was poured to a saturated aqueous solution of sodium bicarbonate and stirred at room temperature for 5 minutes. After separation into an aqueous layer and an organic layer, the aqueous layer was subjected to extraction with toluene once. All of the obtained organic layers were washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=90:10 to 60:40 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain a concentration residue.


To a solution of 6.23 g of the obtained residue in 15 ml of ethanol, 478 mg (12.6 mmol) of sodium borohydride was dividedly added with stirring at 0° C. in an argon atmosphere and then stirred at room temperature for 4 hours.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure, and 75 ml of dichloromethane was added to the residue. This solution was poured to 50 ml of a saturated aqueous solution of ammonium chloride, stirred at room temperature until foaming settled, and then the aqueous layer and the organic layer were separated. The aqueous layer was subjected to extraction with 25 ml of dichloromethane, all of the organic layers were dehydrated over anhydrous magnesium sulfate and filtered, and then, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: n-hexane:ethyl acetate=77:23 to 56:44 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure.


15 ml of ethanol and 3.08 g (46.7 mmol) of 85% potassium hydroxide were added to 5.03 g of the obtained residue and heated to reflux for 5 hours.


After standing to cool, the resultant was concentrated under reduced pressure, 50 ml of water and 100 ml of dichloromethane were added, stirred at room temperature, and then the aqueous layer and the organic layer were separated. The aqueous layer was subjected to extraction with 50 ml of dichloromethane twice. Diethyl ether was added until the turbidity of all of the obtained organic layers was eliminated, then dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure to obtain 3.60 g of the title compound (yield: 63%) as a pale yellow viscous liquid.


Mass spectrum (CI, m/z): 198 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 7.55-7.49 (m, 1H), 7.30-7.21 (m, 1H), 7.20-7.13 (m, 1H), 7.12-7.03 (m, 1H), 5.03 (br s, 1H), 4.15 (s, 1H), 3.35 (d, J=10.5 Hz, 1H), 3.21 (d, J=10.5 Hz, 1H), 2.01 (br s, 2H), 0.73 (s, 3H), 0.71-0.66 (m, 3H).


Reference Example 131
Ethyl (2,2,4-trimethyl-1-oxopentan-3-yl)carbamate



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To a solution of 2.06 g (23.1 mmol) of ethyl carbamate in 20 ml of toluene, 6.00 ml (66.1 mmol) of isobutylaldehyde and 224 mg (1.18 mmol) of p-toluenesulfonic acid monohydrate were added in this order at room temperature in an argon atmosphere and then stirred at room temperature for 5 minutes and at 60° C. for 4 hours.


After the completion of the reaction, the reaction solution was poured to a saturated aqueous solution of sodium bicarbonate and then stirred at room temperature. After separation into an aqueous layer and an organic layer, the aqueous layer was subjected to extraction with toluene once. All of the obtained organic layers were washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=90:10 to 60:40 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 1.55 g of the title compound (yield: 31%) as a pale yellow oil.


Mass spectrum (CI, m/z): 216 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 9.55 (s, 1H), 7.11 (br d, J=10.4 Hz, 1H), 4.01 (q, J=7.1 Hz, 2H), 3.67 (dd, J=6.2, 10.4 Hz, 1H), 1.80-1.66 (m, 1H), 1.17 (t, J=7.1 Hz, 3H), 0.98 (s, 3H), 0.90 (s, 3H), 0.80 (d, J=6.8 Hz, 3H), 0.75 (d, J=6.8 Hz, 3H).


Reference Example 132
3-Amino-2,2,4-trimethylpentan-1-ol



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To a solution of 1.55 g (7.20 mmol) of ethyl (2,2,4-trimethyl-1-oxopentan-3-yl)carbamate synthesized in the similar manner as in Reference Example 131 in 10 ml of ethanol, 176 mg (4.66 mmol) of sodium borohydride was dividedly added at 0° C. in an argon atmosphere and then stirred at 0° C. for 1 hour and further at room temperature for 13.5 hours. Subsequently, 853 mg (15.2 mmol) of potassium hydroxide and 5.0 ml of water were added to the reaction solution at room temperature and then stirred for 3 hours under heating to reflux.


After the completion of the reaction, the reaction solution was concentrated under reduced pressure, and ethanol was distilled off. 2 N hydrochloric acid was added to the concentration residue and then washed with diethyl ether. After separation into an aqueous layer and an organic layer, the obtained the aqueous layer was adjusted to pH >10 by adding a 1 N aqueous sodium hydroxide solution, followed by extraction with dichloromethane three times. All of the obtained organic layers were washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent: 1,2-dichloroethane:n-hexane=30:70 to 100:0→1,2-dichloroethane:methanol=95:5 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 577 mg of the title compound (yield: 55%) as a colorless oil.


Mass spectrum (CI, m/z): 146 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 3.23 (d, J=10.4 Hz, 1H), 3.15 (d, J=10.4 Hz, 1H), 2.36 (d, J=1.8 Hz, 1H), 1.87 (dspt, J=1.8, 6.8 Hz, 1H), 0.88 (d, J=6.8 Hz, 3H), 0.81-0.76 (m, 9H).


Reference Example 133
(R)-Benzyl 2-butoxy-2-phenylacetate



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To a suspension of 2.34 g (9.66 mmol) of (R)-benzyl 2-hydroxy-2-phenylacetate in 25.0 ml (219 mmol) of 1-iodobutane, 4.55 g (19.6 mmol) of silver(I) oxide was added at room temperature in an argon atmosphere and then reacted at 80° C. for 10.5 hours with stirring.


After the completion of the reaction, the reaction solution was allowed to cool to room temperature and then filtered using a celite filter. The filtration cake was washed with ethyl acetate, and then, all of the filtrates were concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=97:3 to 93:7 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure and dried under reduced pressure to obtain 1.65 g of the title compound (yield: 57%) as a colorless oil.


Mass spectrum (CI, m/z): 299 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 7.45-7.17 (m, 10H), 5.18-5.09 (m, 2H), 5.05 (s, 1H), 3.50 (td, J=6.4, 9.2 Hz, 1H), 3.40 (td, J=6.4, 9.2 Hz, 1H), 1.58-1.46 (m, 2H), 1.38-1.26 (m, 2H), 0.85 (t, J=7.4 Hz, 3H).


Reference Example 134
tert-Butyl (3-hydroxy-2,2-dimethyl-1-phenylpropyl)carbamate



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To a solution of 1.00 g (5.58 mmol) of 3-amino-2,2-dimethyl-3-phenylpropan-1-ol [synthesized according to the method described in Synthetic Communications, 1994, 24 (7), 899-906] in 5 ml of dichloromethane, 2.34 ml (16.8 mmol) of triethylamine and 2.56 ml (11.1 mmol) of di-tert-butyl dicarbonate were added in this order at room temperature under argon stream and stirred at room temperature for 2 hours.


After the completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction from the mixed solution with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=91:9 to 70:30 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 1.45 g of the title compound (yield: 93%) as a white solid.


Mass spectrum (CI, m/z): 280 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 7.37-7.18 (m, 6H), 4.97-4.75 (m, 1H), 4.62-4.32 (m, 1H), 3.22-3.08 (m, 1H), 3.05-2.90 (m, 1H), 1.40-1.29 (m, 9H), 0.83-0.73 (m, 6H).


Reference Example 135
tert-Butyl (3-methoxy-2,2-dimethyl-1-phenylpropyl)carbamate



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To a solution of 600 mg (2.15 mmol) of tert-butyl (3-hydroxy-2,2-dimethyl-1-phenylpropyl)carbamate synthesized in the similar manner as in Reference Example 134 in 6 ml of dichloromethane, 370 mg (6.59 mmol) of potassium hydroxide was added in one portion with stirring at 0° C. under argon stream and stirred at 0° C. for 15 minutes. Subsequently, 0.407 ml (4.29 mmol) of dimethylsulfuric acid was added dropwise at 0° C. and stirred at room temperature for 8 hours.


After the completion of the reaction, water was added to the reaction solution, followed by extraction from the mixed solution with dichloromethane. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=100:0 to 87:13 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 114 mg of the title compound (yield: 18%) as a colorless oil.


Mass spectrum (CI, m/z): 294 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 7.35-7.16 & 6.95-6.82 (m, total 6H), 4.67-4.37 (m, 1H), 3.28-3.19 (m, 3H), 3.08-2.91 (m, 1H), 2.88-2.76 (m, 1H), 1.43-1.13 (m, 9H), 0.90-0.82 (m, 3H), 0.81-0.70 (m, 3H).


Reference Example 136
3-Methoxy-2,2-dimethyl-1-phenylpropan-1-amine



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To a solution of 114 mg (0.389 mmol) of tert-butyl (3-methoxy-2,2-dimethyl-1-phenylpropyl)carbamate synthesized in the similar manner as in Reference Example 135 in 2 ml of 1,4-dioxane, 0.486 ml (1.94 mmol) of 4 N hydrogen chloride/1,4-dioxane was added in one portion with stirring at room temperature under argon stream and stirred at room temperature for 20 hours.


After the completion of the reaction, the reaction solution was concentrated. The residue was dissolved by adding water and then adjusted to pH 8 by adding a saturated aqueous solution of sodium bicarbonate, followed by extraction with ethyl acetate twice. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 71 mg of the title compound (yield: 95%) as a colorless oil.


Mass spectrum (CI, m/z): 194 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 7.34-7.16 (m, 5H), 3.78 (s, 1H), 3.23 (s, 3H), 3.13 (d, J=8.8 Hz, 1H), 2.92 (d, J=8.8 Hz, 1H), 1.82 (br s, 2H), 0.83 (s, 3H), 0.70 (s, 3H).


Reference Example 137
Ethyl 5-[(3-methoxy-2,2-dimethyl-1-phenylpropyl)carbamoyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate



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To a solution of 70 mg (0.36 mmol) of 3-methoxy-2,2-dimethyl-1-phenylpropan-1-amine synthesized in the similar manner as in Reference Example 136 in 5 ml of 1,4-dioxane, 0.315 ml (1.81 mol) of DIPEA and 176 mg (0.399 mmol) of ethyl 5-(chlorocarbonyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarbox amido]-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate synthesized in the similar manner as in Reference Example 3 were added in this order with stirring at room temperature under argon stream and stirred at 90° C. for 2 hours.


After the completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution allowed to cool to room temperature, followed by extraction from the mixed solution with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was subjected to silica gel column chromatography (elution solvent: n-hexane:ethyl acetate=61:39 to 40:60 (V/V)), and a fraction containing the compound of interest was concentrated under reduced pressure to obtain 131 mg of the title compound (yield: 61%) as a white foam.


Mass spectrum (CI, m/z): 598 [M+1]+.



1H-NMR spectrum (400 MHz, DMSO-d6) δ: 9.75 (s, 1H), 7.38-7.20 (m, 5H), 6.78 (d, J=8.3 Hz, 1H), 4.64-4.50 (m, 3H), 4.42 (q, J=7.1 Hz, 2H), 3.40 (s, 3H), 3.15 (d, J=9.2 Hz, 1H), 2.93 (d, J=9.2 Hz, 1H), 2.57-2.45 (m, 2H), 2.32-2.23 (m, 2H), 1.97-1.82 (m, 2H), 1.61 (s, 3H), 1.52 (s, 3H), 1.35 (t, J=7.0 Hz, 3H), 1.13 (s, 3H), 0.68 (s, 3H), 0.13 (s, 9H).


Test Example 1

CDK7 Enzyme Inhibition Test


The preparation of a buffer solution was performed by mixing a N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid buffer solution (HEPES buffer solution) (pH 7.4), dithiothreitol (DTT), Triton X-100, and magnesium chloride (MgCl2). A 500 μM [γ-33P]ATP solution was used by diluting a 10 mM ATP solution and a commercially available [γ-33P]ATP solution (manufactured by PerkinElmer, Inc., Code No. NEG-302H) with the buffer solution. A CDK7 solution was used by diluting commercially available CDK7 (manufactured by Carna Biosciences, Inc., Catalog No. 04-108) with the buffer solution. A substrate solution was used by diluting myelin basic protein (MBP) with the buffer solution. As for the preparation of a reaction solution, the buffer solution, the 500 μM [γ-33P]ATP solution, the CDK7 solution, and the substrate solution were mixed at 4° C. to obtain a reaction solution.


CDK7 enzyme reaction was performed by adding 5 μL of a test compound solution prepared with 10% dimethyl sulfoxide (DMSO)/90% injectable distilled water, and 45 μL of the reaction solution to a 1.5 mL microtube at 4° C. and reacting in the microtube at 30° C. for 20 minutes in a water bath incubator. After the reaction, a 10% aqueous trichloroacetic acid (TCA) solution was added to each microtube while cooled to 4° C., and mixed to terminate the reaction. The resultant was left standing at 4° C. for 10 minutes and then centrifuged in a centrifuge, and the supernatant was discarded. Next, a 2% aqueous TCA solution was added, mixed, and then centrifuged in a centrifuge, and the supernatant was discarded. This washing operation was performed twice. After the washing, precipitates were dissolved in a 1 N aqueous sodium hydroxide (NaOH) solution, and the energy quantity (radioactivity) of the reaction product was measured with a liquid scintillation counter.


The calculation of the inhibitory activity of the test compound against CDK7 was performed as a test compound concentration inhibiting 50% of the amount of 33P bound to MBP (IC50 value) by using EXSUS (version 8.0.0 or version 8.0.1, manufactured by CAC Exicare Corp.).


The calculation of a Ki value was performed according to the following calculation expression. S means the concentration of ATP contained in the reaction solution, and Km means a Michaelis-Menten constant.

Ki=IC50/(1+S/Km)


In this test, the compounds of the present invention exhibited excellent CDK7 inhibitory activity, and, for example, the Ki values of compound Nos. II-114, II-116, III-114, III-170, III-226, III-298, III-353, III-592, III-1059, III-1140, IV-2, IV-114, IV-117, IV-119, IV-123, IV-139, IV-171, IV-227, IV-283, IV-291, IV-299, IV-362, IV-378, IV-403 (sodium salt), IV-438, IV-442, IV-446, IV-450, IV-455, IV-475, IV-495, IV-510, IV-519, IV-527, IV-534, IV-542, IV-632, IV-633, IV-634, IV-673, IV-743, IV-786, IV-787, IV-815, IV-822, IV-862, IV-911, IV-920, IV-939, IV-959, IV-1067, IV-1175, IV-1176, IV-1178, IV-1180, IV-1188, IV-1196, IV-1204, IV-1208, IV-1215, IV-1241, IV-1255, IV-1258, IV-1274, IV-1330, IV-1348, IV-1372, IV-1383, IV-1404, IV-1427, IV-1546, and IV-1547 were 50 nM or lower.


Test Example 2

CDK2 Enzyme Inhibition Test


The preparation of a buffer solution was performed by mixing a HEPES buffer solution (pH 7.4), DTT, Triton X-100, and MgCl2. A 500 μM [γ-33P]ATP solution was used by diluting a 10 mM ATP solution and a commercially available [γ-33P]ATP solution (manufactured by PerkinElmer, Inc., Code No. NEG-302H) with the buffer solution. A CDK2 solution was used by diluting commercially available CDK2 (manufactured by Invitrogen Corp., Catalog No. PV3267) with the buffer solution. A substrate solution was used by diluting MBP with the buffer solution. As for the preparation of a reaction solution, the buffer solution, the 500 μM [γ-33P]ATP solution, the CDK2 solution, and the substrate solution were mixed at 4° C. to obtain a reaction solution.


CDK2 enzyme reaction was performed by adding 5 μL of a test compound solution prepared with 10% DMSO/90% injectable distilled water, and 45 μL of the reaction solution in a 1.5 mL microtube at 4° C. and reacting in the microtube at 30° C. for 20 minutes in a water bath incubator. After the reaction, a 10% aqueous TCA solution was added to each microtube while cooled to 4° C., and mixed to terminate the reaction. The resultant was left standing at 4° C. for 10 minutes and then centrifuged in a centrifuge, and the supernatant was discarded. Next, a 2% aqueous TCA solution was added, mixed thereto, and then centrifuged in a centrifuge, and the supernatant was discarded. This washing operation was performed twice. After the washing, precipitates were dissolved in a 1 N aqueous NaOH solution, and the radioactivity was measured with a liquid scintillation counter.


The calculation of the inhibitory activity of the test compound against CDK2 was performed as a test compound concentration inhibiting 50% of the amount of 33P bound to MBP (IC50 value) by using EXSUS (version 8.0.0 or version 8.0.1, manufactured by CAC Exicare Corp.).


The calculation of a Ki value was performed according to the following calculation expression. S means the concentration of ATP contained in the reaction solution, and Km means a Michaelis-Menten constant.

Ki=IC50/(1+S/Km)


In this test, the Ki values of CDK2 inhibitory activity of the compounds of the present invention, for example, compound Nos. II-114, II-116, III-114, III-298, III-353, IV-2, IV-114, IV-115, IV-117, IV-119, IV-123, IV-171, IV-227, IV-283, IV-291, IV-299, IV-403 (sodium salt), IV-438, IV-442, IV-450, IV-455, IV-475, IV-495, IV-534, IV-632, IV-718, IV-743, IV-822, IV-883, IV-890, IV-911, IV-939, IV-946, IV-1184, IV-1196, IV-1204, and IV-1258 were 1000 nM or higher; thus they had high selectivity for CDK7 inhibitory activity with respect to CDK2 inhibitory activity.


Test Example 3

PAK4 Enzyme Inhibition Test


The preparation of a buffer solution was performed by mixing a trishydroxyaminomethane buffer solution (Tris buffer solution) (pH 7.5), DTT, Triton X-100, MgCl2, ethylene glycol bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid (EGTA), (3-glycerol phosphate, and sodium orthovanadate(V). A 40 μM [γ-33P]ATP solution was used by diluting a 10 mM ATP solution and a commercially available [γ-33P]ATP solution (manufactured by PerkinElmer, Inc., Code No. NEG-302H) with the buffer solution. A PAK4 solution was used by diluting commercially available PAK4 (manufactured by Invitrogen Corp., Catalog No. PV4212) with the buffer solution. A substrate solution was used by diluting MBP with the buffer solution. As for the preparation of a reaction solution, the buffer solution, the 40 μM [γ-33P]ATP solution, the PAK4 solution, and the substrate solution were mixed at 4° C. to obtain a reaction solution.


PAK4 enzyme reaction was performed by adding 5 μL of a test compound solution prepared with 10% DMSO/90% injectable distilled water, and 45 μL of the reaction solution in a 1.5 mL microtube at 4° C. and reacting in the microtube at 30° C. for 20 minutes in a water bath incubator. After the reaction, a 10% aqueous TCA solution was added to each microtube while cooled to 4° C., and mixed to terminate the reaction. The resultant was left standing at 4° C. for 10 minutes and then centrifuged in a centrifuge, and the supernatant was discarded. Next, a 2% aqueous TCA solution was added, mixed, and then centrifuged in a centrifuge, and the supernatant was discarded. This washing operation was performed twice. After the washing, precipitates were dissolved in a 1 N aqueous NaOH solution, and the radioactivity was measured with a liquid scintillation counter.


The calculation of the inhibitory activity of the test compound against PAK4 was performed as a test compound concentration inhibiting 50% of the amount of 33P bound to MBP (IC50 value) by using EXSUS (version 8.0.0 or version 8.0.1, manufactured by CAC Exicare Corp.).


The calculation of a Ki value was performed according to the following calculation expression. S means the concentration of ATP contained in the reaction solution, and Km means a Michaelis-Menten constant.

Ki=IC50/(1+S/Km)


In this test, the Ki values of PAK4 inhibitory activity of the compounds of the present invention, for example, compound Nos. II-114, II-116, III-114, III-298, III-353, IV-2, IV-114, IV-115, IV-117, IV-119, IV-123, IV-171, IV-227, IV-283, IV-291, IV-299, IV-403 (sodium salt), IV-438, IV-442, IV-450, IV-455, IV-475, IV-495, IV-534, IV-632, IV-673, IV-718, IV-743, IV-822, IV-883, IV-911, IV-918, IV-946, IV-1184, IV-1204, IV-1208, IV-1258, IV-1383, IV-1404, and IV-1546 were 500 nM or higher; thus they had high selectivity for CDK7 inhibitory activity with respect to PAK4 inhibitory activity.


Test Example 4

Human Large Intestine Cancer (HCT-116) Cell Growth Inhibition Test


The measurement of a human large intestine cancer cell growth inhibitory effect was carried out by modifying the method of Simak et al. (Cancer Research, 69, 6208 (2009)).


A human large intestine cancer cell line (HCT-116) (manufactured by DS Pharma Biomedical Co., Ltd., Cat. No. EC91091005) was cultured in McCoy's 5a (manufactured by GIBCO/Thermo Fisher Scientific, Inc., REF. 16600-082) medium containing 10% FBS (manufactured by GIBCO/Thermo Fisher Scientific, Inc., REF. 10082-147) and 1% penicillin/streptomycin/amphotericin B (manufactured by GIBCO/Thermo Fisher Scientific, Inc., REF. 15240-096) and inoculated at 1.0×103 cells/well in a 96-well plate (manufactured by Corning Inc., REF. 353072). After overnight culture in a carbon dioxide incubator, it was replaced with a fresh McCoy's 5a medium containing 10% FBS on the next day, and a test compound dissolved in DMSO (manufactured by Wako Pure Chemical Industries, Ltd., Code No. 043-07216) (final DMSO concentration: 0.1%) was added and left standing in a carbon dioxide incubator. After culturing for 3 days, the absorbance of each well was measured by using In Vitro Toxicology Assay Kit Sulforhodamine B based (manufactured by Sigma-Aldrich Co. LLC., Pcode 1001910706).


The rate of inhibition of cell growth at each concentration was calculated from the test compound concentration and the absorbance of sulforhodamine B, and the concentration of the test compound necessary for inhibiting 50% of cell growth (IC50 value) was calculated by using EXSUS (version 8.0.0 or version 8.0.1, manufactured by CAC Exicare Corp.).


In this test, the compounds of the present invention exhibited excellent HCT-116 cell growth inhibitory activity, and, for example, the IC50 values of compound Nos. II-114, II-116, III-114, III-170, III-226, III-298, III-353, III-592, III-1059, III-1140, IV-2, IV-114, IV-117, IV-119, IV-123, IV-131, IV-139, IV-171, IV-227, IV-235, IV-283, IV-291, IV-299, IV-354, IV-362, IV-378, IV-438, IV-442, IV-446, IV-450, IV-475, IV-495, IV-510, IV-519, IV-527, IV-534, IV-558, IV-562, IV-632, IV-633, IV-634, IV-672, IV-673, IV-718, IV-743, IV-759, IV-786, IV-787, IV-815, IV-822, IV-861, IV-862, IV-883, IV-890, IV-911, IV-918, IV-939, IV-946, IV-959, IV-1067, IV-1175, IV-1176, IV-1178, IV-1180, IV-1184, IV-1188, IV-1196, IV-1204, IV-1208, IV-1211, IV-1215, IV-1224, IV-1241, IV-1255, IV-1258, IV-1266, IV-1268, IV-1274, IV-1330, IV-1348, IV-1383, IV-1404, IV-1427, and IV-1546 were 500 nM or lower.


Test Example 5

Human Breast Cancer (MCF-7) Cell Growth Inhibition Test


The measurement of a human breast cancer cell growth inhibitory effect was carried out by modifying the method of Simak et al. (Cancer Research, 69, 6208 (2009)).


A human breast cancer cell line (MCF-7) manufactured by DS Pharma Biomedical Co., Ltd., Cat. No. EC86012803, was cultured in MEM (manufactured by GIBCO/Thermo Fisher Scientific, Inc., REF. 11095-080) medium containing 10% FBS (manufactured by GIBCO/Thermo Fisher Scientific, Inc., REF. 10082-147), nonessential amino acids (manufactured by GIBCO/Thermo Fisher Scientific, Inc., REF. 11140-050), and 1% penicillin/streptomycin/amphotericin B (manufactured by GIBCO/Thermo Fisher Scientific, Inc., REF. 15240-096) and inoculated at 3.0×103 cells/well to a 96-well plate (manufactured by Corning Inc., REF. 353072). After overnight culture in a carbon dioxide incubator, it was replaced with a fresh MEM medium containing 10% FBS, nonessential amino acids, and 1% penicillin/streptomycin/amphotericin B on the next day, and a test compound dissolved in DMSO (manufactured by Wako Pure Chemical Industries, Ltd., Code No. 043-07216) (final DMSO concentration: 0.1%) was added and left standing in a carbon dioxide incubator. After culture for 3 days, the absorbance of each well was measured by using In Vitro Toxicology Assay Kit Sulforhodamine B based (manufactured by Sigma-Aldrich Co. LLC., Pcode 1001910706).


The rate of inhibition of cell growth at each concentration was calculated from the test compound concentration and the absorbance of sulforhodamine B, and the concentration of the test compound necessary for inhibiting 50% of cell growth (IC50 value) was calculated by using EXSUS (version 8.0.0 or version 8.0.1, manufactured by CAC Exicare Corp.).


In this test, the compounds of the present invention exhibited excellent MCF-7 cell growth inhibitory activity, and, for example, the IC50 values of compound Nos. IV-114, IV-117, IV-123, IV-171, IV-227, IV-291, IV-438, IV-455, IV-475, and IV-495 were 500 nM or lower.


Test Example 6

Human Peripheral Blood Mononuclear Cell (PBMC) CD3/CD28-Induced IL-2 Production Inhibition Test


PBMC was separated and collected by using Ficoll-Paque (17-1440-02 manufactured by GE Healthcare Japan Corp.) from blood collected from healthy human adult in the presence of heparin. RPMI1640 medium (manufactured by GIBCO/Thermo Fisher Scientific, Inc., REF. 11875) containing 10% FBS (manufactured by GIBCO/Thermo Fisher Scientific, Inc. REF. 10082) and containing a test compound dissolved in DMSO and 2 μg/mL anti-hCD28 (manufactured by R&D Systems, Inc., Cat. No. MAB342) was added at 100 μL/well to T cell Activation Plate Anti-Human CD3 96-well plate (manufactured by Corning Inc., REF. 354725), and subsequently, a PBMC suspension adjusted such that the number of cells was 2×106 cells/mL was added at 100 μL/well (final DMSO concentration: 0.1%). A RPMI1640 medium containing 10% FBS and containing 0.1% DMSO and 2 μg/mL anti-hCD28 was similarly added to wells not supplemented with the test compound. After incubation for 2 days in a carbon dioxide incubator, the culture supernatant was collected. The collected culture supernatant was stored at −20° C. until IL-2 content measurement.


In the measurement of IL-2 content in the culture supernatant, a sandwich ELISA kit Quantikine Human IL-2 (manufactured by R&D Systems, Inc., Cat. No. S2050) was used. The IL-2 content of each sample was calculated from the calibration curve of Standard IL-2 included in the kit. When the amount of IL-2 produced by CD3/CD28 stimulation in the case of the addition of only DMSO was defined as 100%, the rate of inhibition of IL-2 production at each concentration of the test compound was calculated. A test compound concentration inhibiting 50% of IL-2 production was calculated as an IC50 value (nM) from the concentration of the added test compound and the rate of inhibition of IL-2 production by the test compound by using EXSUS (version 8.0.0 or version 8.0.1, manufactured by CAC Exicare Corp.).


In this test, the compounds of the present invention exhibited excellent IL-2 production inhibitory activity, and, for example, the IC50 values of compound Nos. II-114, III-114, III-170, III-226, IV-114, IV-123, IV-139, IV-171, IV-227, IV-235, IV-283, IV-299, IV-354, IV-450, IV-510, IV-519, IV-527, IV-1175, IV-1178, IV-1180, IV-1188, and IV-1255 were 50 nM or lower.


Test Example 7

Human PBMC Various-Stimulant Cocktail-Induced IL-17 Production Inhibition Test


PBMC was separated and collected by using Ficoll-Paque (17-1440-02 manufactured by GE Healthcare Japan Corp.) from blood collected from healthy human adult in the presence of heparin. The collected PBMC was further cultured in a flask for a certain time, and then, non-adherent cells in the supernatant were collected and used as a T-cell suspension. RPMI1640 medium (manufactured by GIBCO/Thermo Fisher Scientific, Inc., REF. 11875), which is containing 10% FBS (manufactured by GIBCO/Thermo Fisher Scientific, Inc., REF. 10082), 1% penicillin/streptomycin/amphotericin B (manufactured by GIBCO/Thermo Fisher Scientific, Inc., REF. 15240-096), 1% nonessential amino acids (manufactured by GIBCO/Thermo Fisher Scientific, Inc., REF. 11140-050), and 1% pyruvic acid (manufactured by GIBCO/Thermo Fisher Scientific, Inc., REF. 11140) and containing a test compound dissolved in DMSO, 2 μg/mL (final concentration) CD28 antibody (manufactured by BioLegend, Inc., Cat. No. 302914), 10 μg/mL (final concentration) human IFN-γ antibody (manufactured by BD Biosciences, Cat. No. 554698), 10 μg/mL (final concentration) human IL-4 antibody (manufactured by BD Biosciences, Cat. No. 554481), 20 ng/mL (final concentration) human IL-6 (manufactured by BioLegend, Inc., Cat. No. 570802), 10 ng/mL (final concentration) human IL-23 (manufactured by BioLegend, Inc., Cat. No. 574102), 10 ng/mL (final concentration) human IL-1(3 (manufactured by PeproTech Inc., Cat. No. 200-01B), and 10 ng/mL (final concentration) human TGF-13 (manufactured by BioLegend, Inc., Cat. No. 580702), was added at 100 μL/well to T cell Activation Plate Anti-Human CD3 96-well plate (manufactured by Corning Inc., REF. 354725). Subsequently, 100 μL of a T-cell suspension adjusted to 2×105 cells/mL was added to each well (final DMSO concentration: 0.1%). Only DMSO was added to wells in the absence of the test compound. After incubation for 5 days in a carbon dioxide incubator, the culture supernatant was collected and stored at −20° C. until IL-17 content measurement.


In the IL-17 content measurement in the culture supernatant, a sandwich ELISA kit (Quantikine Human IL-17, manufactured by R&D Systems, Inc.) was used. The IL-17 content of each sample was calculated from the calibration curve of Standard IL-17 included in the kit. When the amount of IL-17 produced by the cocktail of various stimulants in the case of the addition of only DMSO was defined as 100%, the rate of inhibition of IL-17 production at each concentration of the test compound was calculated. The concentration of the test compound necessary for inhibiting 50% of IL-17 production (IC50 value) was calculated from the concentration of the added test compound and the rate of inhibition of IL-17 production by the test compound by using EXSUS (version 8.0.0 or version 8.0.1, manufactured by CAC Exicare Corp.).


In this test, the compounds of the present invention exhibited excellent IL-17 production inhibitory activity, and, for example, the IC50 values of compound Nos. IV-299, IV-354, IV-673, IV-718, IV-743, IV-911, IV-918, IV-939, IV-946, IV-1175, IV-1178, IV-1180, IV-1184, IV-1188, IV-1196, IV-1204, IV-1208, IV-1383, IV-1404, and IV-1546 were 50 nM or lower.


Test Example 8

Human Keratinocyte Growth Inhibition Assay


The measurement of a human keratinocyte growth inhibitory effect was carried out by modifying the method of Schafer et al. (British Journal of Pharmacology, 159, 842 (2011)).


Human keratinocytes (NHEK-Neo Pooled, manufactured by Lonza Group AG, Cat. No. 00192906) were cultured in KGM-Gold Bullet Kit (manufactured by Lonza Group AG, Cat. No. 00192060) and inoculated at 2.0×103 cells/well to a 96-well plate. After overnight culture in a carbon dioxide incubator, a test compound dissolved in DMSO (final DMSO concentration: 0.1%) was added and left standing in a carbon dioxide incubator. After culture for 2 days, the absorbance thereof was measured by using Cell Counting Kit-8 (343-07623 manufactured by Dojindo Laboratories)).


The rate of inhibition of cell growth at each concentration was calculated from the test compound concentration and the absorbance of Cell Counting Kit-8, and the concentration of the test compound necessary for inhibiting 50% of cell growth (IC50 value) was calculated by using EXSUS (version 8.0.0 or version 8.0.1, manufactured by CAC Exicare Corp.).


In this test, the compounds of the present invention exhibited excellent human keratinocyte growth inhibitory activity, and, for example, the IC50 values of compound Nos. III-170, III-226, III-1059, IV-123, IV-131, IV-139, IV-171, IV-227, IV-235, IV-299, IV-354, IV-378, IV-519, IV-527, IV-1175, IV-1178, IV-1180, and IV-1188 were 500 nM or lower.


Test Example 9

IL-6 Production Inhibition Test in Rat Adjuvant Arthritis Model


A single-dose drug efficacy test using rat adjuvant arthritis models was carried out by modifying the method of Magari. K et al. (J. Rheumatol. 30 (10), 2193 (2003)).


LEW rats (female, supplied by Charles River Laboratories Japan, Inc.) were used as laboratory animals. An adjuvant prepared from heat-killed bacteria of Mycobacterium butyricum (264010 manufactured by Difco Laboratories Ltd.) and liquid paraffin (manufactured by Wako Pure Chemical Industries, Ltd., Code No. 128-04375) was subcutaneously administered as a phlogogenic material to the right hind leg footpads of the rats under inhalation anesthesia with isoflurane (manufactured by Wako Pure Chemical Industries, Ltd., Code No. 099-06571) to prepare arthritis models. Approximately 2 weeks later, left paw edema was measured with a paw volume meter (model TK-101CMP manufactured by Unicorn Co., Ltd.), and grouping was performed such that the average volume of left paw edema was equal among groups. A test compound or only a solvent was administered, after a certain time, they were sacrificed by exsanguination from the abdomens under isoflurane anesthesia, and the left ankles were collected, chopped, and frozen by using liquid nitrogen. The collected left ankle portions were disrupted in CRYOPress (model CP-100WP manufactured by Microtec Co., Ltd.), then supplemented with a buffer solution, shaken overnight at 4° C., and then centrifuged to collected a supernatant. The preparation of the buffer solution was performed by mixing a Tris buffer solution (pH 7.4), sodium chloride (NaCl), phenyl methyl sulfonyl fluoride (PMSF), Triton X-100, EDTA-free complete tablets (manufactured by F. Hoffmann-La Roche, Ltd., REF. 11 873 580 001), and Otsuka distilled water (manufactured by Otsuka Pharmaceutical Co., Ltd., product No. 1323). IL-6 in the collected supernatant was measured by using a sandwich ELISA kit (manufactured by R&D Systems, Inc., Catalog No. S6050).


The IL-6 content of each sample was calculated from the calibration curve of Standard IL-6 included in the kit. When the amount of IL-6 produced in the solvent administration control group was defined as 100%, the rate of inhibition of IL-6 production (%) at each dose of the test compound was calculated.


In this test, the compounds of the present invention exhibited excellent IL-6 production inhibitory activity, and, for example, compound Nos. II-114, IV-2, IV-119, IV-171, and IV-235 exhibited 50% or more rate of inhibition by the administration of 10 mg/kg, and compound Nos. IV-123, IV-139, IV-227, IV-299, and IV-632 exhibited 50% or more rate of inhibition by the administration of 3 mg/kg.


Test Example 10

Paw Edema Suppression Test in Rat Adjuvant Arthritis Model


LEW rats (female, supplied by Charles River Laboratories Japan, Inc.) were used as laboratory animals. An adjuvant prepared from heat-killed bacteria of Mycobacterium butyricum (264010 manufactured by Difco Laboratories Ltd.) and liquid paraffin (manufactured by Wako Pure Chemical Industries, Ltd., Code No. 128-04375) was subcutaneously administered as a phlogogenic material to the right hind leg footpads of the rats under inhalation anesthesia with isoflurane (manufactured by Wako Pure Chemical Industries, Ltd., Code No. 099-06571) to prepare arthritis models. Also, liquid paraffin not containing the killed bacteria was administered by a similar method to obtain an untreated group. The administration of the test compound or only the solvent was performed by oral administration 28 times once a day from the adjuvant injection day (day 0) to day 27. The volumes of the adjuvant-administered right hind legs and the non-administered left hind legs were measured several times on days 7 to 28 after the adjuvant administration with a paw volume meter (model TK-101CMP manufactured by Unicorn Co., Ltd.), and the rate of edema was calculated according to the following expression.

Rate of edema (%)=[{(Footpad volume at the time of measurement)−(Footpad volume before the start of the test)}/(Footpad volume before the start of the test)]×100


The rate of suppression of edema in the solvent-administered control group was further calculated according to the following expression.

Rate of suppression of edema (%)=[1−{(Rate of edema of the test compound-administered group)−(Rate of edema of the untreated group)}/{Rate of edema of the control group)−(Rate of edema of the untreated group)}]×100


In this test, the compounds of the present invention exhibited excellent edema suppressive activity, and, for example, compound Nos. IV-114 and IV-171 exhibited 50% or more rate of suppression by the administration of 10 mg/kg.


Test Example 11

Tumor Growth Inhibition Test in Human Large Intestine Cancer Cell (HCT116)-Subcutaneously Transplanted Nude Mouse


A human large intestine cancer cell line (HCT-116) (manufactured by DS Pharma Biomedical Co., Ltd., Cat. No. EC91091005) was cultured in a McCoy's 5a medium containing 10% FBS (manufactured by GIBCO/Thermo Fisher Scientific, Inc., REF. 10082-147) and 1% penicillin/streptomycin/amphotericin B (manufactured by GIBCO/Thermo Fisher Scientific, Inc., REF.15240-096) and adjusted to 1.0×108 cells/mL with PBS (manufactured by GIBCO/Thermo Fisher Scientific, Inc., REF. 10010-031) or Hanks solution (HBSS(−)) (manufactured by GIBCO/Thermo Fisher Scientific, Inc., REF. 14025-076). The adjusted cell suspension was subcutaneously injected at 0.1 mL/mouse to the right abdomens of BALB/c-nu/nu mice (female, supplied by Charles River Laboratories Japan, Inc.). After rearing for a certain period, the long diameter (mm) and short diameter (mm) of tumor were measured with electronic calipers (manufactured by Mitsutoyo Corp., Cat. 500-712-10), and the tumor volume was calculated according to the following expression.

Tumor volume (mm3)=(Long diameter)×(Short diameter)×(Short diameter)×0.5


Individuals whose tumor volume was within the range of 50 to 200 mm3 were selected and grouped such that the tumor volume was almost equivalent, and then, a test compound or only a solvent was orally administered. When the first day of administration was defined as day 0, the oral administration was repeated once a day up to day 3, and the tumor size was measured on day 4. When increase in tumor volume from day 0 of the solvent-administered control group was defined as 100%, the rate of suppression of tumor volume (%) at each dose of the test compound was calculated.


In this test, the compounds of the present invention exhibited excellent tumor growth inhibitory activity, and, for example, compound Nos. III-170, IV-171, IV-299, and IV-632 exhibited 50% or more rate of inhibition by the administration of 100 mg/kg.


Test Example 12

Ear Thickening Suppression Test Using Mouse Imiquimod-Induced Psoriasis Model


An imiquimod-induced psoriasis model test was carried out by modifying the method of Leslie van der Fits et al. (J. Immunol. 182, 5836 (2009)). BALB/c mice were used (female, supplied by Charles River Laboratories Japan, Inc.) as laboratory animals. On the start day of the test, the thicknesses of the right auricles of the mice were measured with a thickness gauge (model SMD-565J manufactured by TECLOCK Corp.). A test compound solution or only a solvent was applied or orally administered, and after 60 minutes, 5 mg of imiquimod (Beselna Cream 5% manufactured by Mochida Pharmaceutical Co., Ltd.) was applied to the insides of the right auricles. The test compound solution or solvent administration and the imiquimod application were carried out for 4 days, and the thicknesses of the right auricles were measured again on day 5. When increase in the thicknesses of the right auricles of the solvent-administered group on day 5 was defined as 100%, the rate of inhibition of increase (%) at each dose of the test compound was calculated.


In this test, the compounds of the present invention exhibited excellent activity, and, for example, compound Nos. IV-114, IV-123, IV-227, V-1442, V-1446, V-1454, V-1462, V-1470, and V-1474 exhibited 50% or more rate of inhibition by the application of a 1% solution in methanol, and compound Nos. III-1059, IV-299, IV-354, IV-673, IV-676, IV-718, IV-743, IV-911, IV-918, IV-939, IV-946, IV-1175, IV-1178, IV-1180, IV-1184, IV-1188, IV-1196, IV-1200, IV-1204, IV-1208, IV-1383, IV-1404, and IV-1546 exhibited 50% or more rate of inhibition by the application of a 0.01% methanol solution.


Test Example 13

Metabolism Test Using Human Liver Microsome Fraction


To a reaction composition solution (50 μL of NADPH production system solution A (manufactured by Corning Inc., REF. 451220), 10 μL of NADPH production system solution B (manufactured by Corning Inc., REF. 451200), 40 μL of 250 mM UDP-glucuronic acid, 200 μL of UGT Reaction Mix solution B (manufactured by Corning Inc., REF. 451320), and 590 μL of distilled water) in which human liver microsome (manufactured by Sekisui XenoTech, LLC., Cat No. H610) corresponding to 2 mg of protein was suspended, 10 μL of a test compound (prodrug represented by formula (V) or (VI)) dissolved in DMSO (manufactured by Wako Pure Chemical Industries, Ltd., Code No. 043-07216) (final DMSO concentration: 1.0%) was added and incubated at 37° C. for 5 minutes.


The peak areas (measurement UV wavelength: 245 nm) of the test compound (prodrug represented by formula (V) or (VI)) and an alcohol form which was a produced pharmacologically active form were calculated by high-performance liquid chromatography (model LC-20A series manufactured by Shimadzu Corp.).


HPLC conditions: column: Phenomenex Kinetex C18 (manufactured by Phenomenex Inc., Part No. 00D-4462-AN), 2.1 mm×100 mm, 2.6 μm, column temperature: 40° C., eluent: solution A: 0.1% formic acid (manufactured by Wako Pure Chemical Industries, Ltd., Code No. 063-04192), solution B: acetonitrile (manufactured by Wako Pure Chemical Industries, Ltd., Code No. 019-08631)/methanol (manufactured by Wako Pure Chemical Industries, Ltd., Code No. 138-06473)/formic acid=500/500/1, gradient conditions: 0→3 min: 90% solution A, 3→11 min: 20% solution A→5%, 11→15 min: 5% solution A, analysis time: 20 min)


In this test, for example, for compound No. V-1442, only the peak of compound No. IV-114 which was a produced alcohol form was detected after incubation for 5 minutes.


In this test, the prodrug of the present invention was immediately converted to the pharmacologically active form.


From the results of Test Examples 1 to 13 described above, it is concluded that the compound of the present invention has excellent CDK7 inhibitory activity and high selectivity in itself or functions as a prodrug of a compound having excellent CDK7 inhibitory activity and high selectivity, and is useful as, for example, a therapeutic drug and/or a prophylactic drug for cancers or inflammatory diseases.


A novel substituted dihydropyrrolopyrazole compound having a particular structure represented by formula (I) of the present invention or a pharmacologically acceptable salt thereof has excellent CDK7 inhibitory activity in itself or is capable of functioning as a prodrug of a compound having excellent CDK7 inhibitory activity, and is useful as a drug (e.g., a therapeutic drug and/or a prophylactic drug for cancers or inflammatory diseases).

Claims
  • 1. A compound represented by formula (I) or a pharmacologically acceptable salt thereof:
  • 2. The compound or a pharmacologically acceptable salt thereof according to claim 1, wherein L1 is an optionally substituted linear or branched C1-6 alkylene group or an optionally substituted C3-6 cycloalkylene group.
  • 3. The compound or a pharmaceutically acceptable salt thereof according to claim 1, where the compound or a pharmaceutically acceptable thereof is a compound represented by formula (II) or a pharmacologically acceptable salt thereof:
  • 4. The compound or a pharmacologically acceptable salt thereof according to claim 3, wherein R1, R2, and R3 each independently represent an optionally substituted linear or branched C1-4 alkyl group.
  • 5. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound or a pharmaceutically acceptable thereof is a compound represented by formula (III) or a pharmacologically acceptable salt thereof:
  • 6. The compound or a pharmacologically acceptable salt thereof according to claim 5, wherein R1, R2, and R3 are each independently an optionally substituted linear or branched C1-4 alkyl group.
  • 7. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound or a pharmaceutically acceptable thereof is a compound represented by formula (IV) or a pharmacologically acceptable salt thereof:
  • 8. The compound or a pharmacologically acceptable salt thereof according to claim 7, wherein R1, R2, and R3 are each independently an optionally substituted linear or branched C1-4 alkyl group.
  • 9. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound or a pharmaceutically acceptable thereof is a compound represented by formula (V) or (VI) or a pharmacologically acceptable salt thereof:
  • 10. The compound or a pharmacologically acceptable salt thereof according to claim 9, wherein L1 is an optionally substituted linear or branched C1-6 alkylene group or an optionally substituted C3-6 cycloalkylene group, and R1, R2, and R3 are each independently an optionally substituted linear or branched C1-4 alkyl group.
  • 11. A compound selected from a compound group consisting of (S)—N-(2-hydroxy-1-phenylethyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide,(S)—N-(2-hydroxy-1-phenylethyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide,(S)—N-(2-hydroxy-1-phenylethyl)-6,6-dimethyl-3-[2-methyl-2-(trimethylsilyl)propaneamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,(S)-3-[1-(ethyldimethylsilyl)cyclobutanecarboxamido]-N-(2-hydroxy-1-phenylethyl)-6,6-dimethyl-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide,(S)-3-[2-(ethyldimethylsilyl)-2-methylpropaneamido]-N-(2-hydroxy-1-phenylethyl)-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide,(S)—N-(2-hydroxy-1-phenylethyl)-N,6,6-trimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide,(S)-2-[(2-methoxypropan-2-yl)oxy]-1-phenylethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxylate,(S)-2-hydroxy-1-phenylethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxylate,2-Methoxy-1-phenylethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxylate,N-[5-(4-hydroxy-3-phenylbutanoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide,N-[5-(3-hydroxy-3-phenylpropanoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide,(R)—N-(3-hydroxy-1-phenylpropyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide,(R)—N-(3-hydroxy-1-phenylpropyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide,(R)—N-(4-hydroxy-1-phenylbutyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide,(R)—N-(5-hydroxy-1-phenylpentyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide,(S)—N-(2-hydroxy-2-methyl-1-phenylpropyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide,(S)—N-(2-hydroxy-2-methyl-1-phenylpropyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide,N-(3-hydroxy-2,2-dimethyl-1-phenylpropyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide,(R)—N-(3-hydroxy-3-methyl-1-phenylbutyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide,(S)—N-(2-methoxy-1-phenylethyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide,(S)—N-[2-(difluoromethoxy)-1-phenylethyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide,(S)—N-(2-ethoxy-1-phenylethyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide,(R)—N-(3-methoxy-1-phenylpropyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide,Sodium (S)-2-{6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamide}-2-phenylacetate,(R)—N-(2-hydroxy-1-phenylethyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide,N-[1-(2-fluorophenyl)-2-hydroxyethyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide,(S)—N-[1-(3-fluorophenyl)-2-hydroxyethyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide,(S)—N-[1-(4-fluorophenyl)-2-hydroxyethyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide,N-[2-hydroxy-1-(pyridin-2-yl)ethyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide,N-[2-hydroxy-1-(pyridin-3-yl)ethyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide,N-[1-(benzo[d][1,3]dioxol-4-yl)-2-hydroxyethyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide,(S)—N-(1-cyclohexyl-2-hydroxyethyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide,(S)—N-(1-hydroxy-3-methylbutan-2-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide,(S)—N-(1-hydroxypropan-2-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide,N-(2-hydroxyethyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide,N-(2-hydroxy-2-phenylethyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide,N-(2-hydroxypropyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide,N-[(2S)-1-hydroxy-3-methyl-1-phenylbutan-2-yl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide,N-(4-hydroxy-1-phenyl-2-butyn-1-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide,(S)-2-{6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylethyl acetate,(S)-2-{6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylethyl propionate,(S)-2-{6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylethyl butanoate,(S)-2-{6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo [3,4-c]pyrazole-5-carboxamido}-2-phenylethyl pentanoate,(S)-2-{6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo [3,4-c]pyrazole-5-carboxamido}-2-phenylethyl octanoate,(S)-2-{6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylethyl dodecanoate,(S)-2-{6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylethyl palmitate,(S)-2-{6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylethyl isobutanoate,(S)-2-{6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylethyl pivalate,(S)-2-{6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo [3,4-c]pyrazole-5-carboxamido}-2-phenylethyl 3-methylbutanoate,(S)-2-{6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylethyl benzoate,(S)-2-{6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylethyl ethyl carbonate,Sodium (S)-4-(2-{6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo [3,4-c]pyrazole-5-carboxamido}-2-phenylethoxy)-4-oxobutanoate,(S)-(2-{6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylethoxy)methyl pivalate,(S)-2-acetoxy-1-phenylethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxylate,(S)-benzyl 2-{6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylacetate,(S)-methyl 2-{6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxamido}-2-phenylacetate,N-(2,2-difluoro-3-hydroxy-1-phenylpropyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide,N-(2-isopropoxy-1-phenylethyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide,6,6-Dimethyl-N-(2-phenoxy-1-phenylethyl)-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide,(S)—N-[1-(2-chlorophenyl)-2-hydroxyethyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide,(S)—N-[2-hydroxy-1-(o-tolyl)ethyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide,(S)—N-(1-hydroxy-3-phenylpropan-2-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide,N-(2-hydroxy-3-methylbutyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide,(R)—N-(1-hydroxy-3-phenylpropan-2-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide,(R)—N-(2-hydroxy-2-phenylethyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide,(S)—N-(2-hydroxy-2-phenylethyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide,2-Hydroxy-2-phenylethyl 6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxylate,(R)—N-[6,6-dimethyl-5-(2-phenoxypropanoyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide,(S)—N-[6,6-dimethyl-5-(2-phenoxypropanoyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide,N-[6,6-dimethyl-5-(2-phenoxyacetyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide,(R)—N-[6,6-dimethyl-5-(2-phenoxypropanoyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclopropanecarboxamide,N-{5-[3-(benzyloxy)-2-phenoxypropanoyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide,N-[5-(3-hydroxy-2-phenoxypropanoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide,N-{5-[2-(4-chlorophenoxy)propanoyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide,N-{5-[2-(2-chlorophenoxy)propanoyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide,N-{5-[2-(cyclohexyloxy)propanoyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide,N-{5-[2-(3-chlorophenoxy)propanoyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide,N-[5-(2-methoxypropanoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide,N-[5-(3-methoxy-2-phenoxypropanoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide,N-{6,6-dimethyl-5-[2-(pyridin-3-yloxy)propanoyl]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide,N-{5-[3-(dimethylamino)-2-phenoxypropanoyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide,N-[6,6-dimethyl-5-(2-phenoxy-2-phenylacetyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide,N-{5-[3-(3,3-difluoropyrrolidin-1-yl)-2-phenoxypropanoyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide,N-[5-(3-hydroxy-2-phenylpropanoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide,(S)—N-[5-(3-hydroxy-2-phenylpropanoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide,(R)—N-{5-[3-(benzyloxy)-2-phenylpropanoyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide,(R)—N-[5-(3-hydroxy-2-phenylpropanoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide,(R)—N-[5-(2-methoxy-2-phenylacetyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide,(S)—N-[5-(2-methoxy-2-phenylacetyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide,N-[5-(3-methoxy-2-phenylpropanoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide,N-[5-(4-methoxy-2-phenylbutanoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide,(S)—N-[5-(3-hydroxy-2-phenylpropanoyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclopropanecarboxamide,(R)—N-[5-(2-methoxy-2-phenylacetyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclopropanecarboxamide,(R)—N-{5-[2-(difluoromethoxy)-2-phenylacetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide,(R)—N-[5-(2-ethoxy-2-phenylacetyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide,(R)-1-(ethyldimethylsilyl)-N-[5-(2-methoxy-2-phenylacetyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]cyclobutanecarboxamide,(R)—N-[5-(2-cyclopropoxy-2-phenylacetyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide,(R)—N-[5-(2-isopropoxy-2-phenylacetyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide,(R)—N-{6,6-dimethyl-5-[2-phenyl-2-(trifluoromethoxy)acetyl]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide,(R)—N-[6,6-dimethyl-5-(2-phenyl-2-propoxyacetyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide,N-{5-[2-(4-fluorophenyl)-2-methoxyacetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide,N-{5-[2-(3-fluorophenyl)-2-methoxyacetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide,(R)—N-{5-[2-(2-fluorophenyl)-2-methoxyacetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide,N-{5-[2-methoxy-2-(thiophen-2-yl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide,(−)-N-{5-[2-methoxy-2-(thiophen-2-yl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide,(+)-N-{5-[2-methoxy-2-(thiophen-2-yl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide,N-{[1-(hydroxymethyl)cyclobutyl](phenyl)methyl}-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide,(R)—N-[2-(1-hydroxycyclopropyl)-1-phenylethyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide,(R)—N-(3-ethyl-3-hydroxy-1-phenylpentyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide,(R)—N-[1-(4-fluorophenyl)-3-hydroxy-3-methylbutyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide,(R)—N-[1-(3-fluorophenyl)-3-hydroxy-3-methylbutyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide,(R)—N-[1-(2-fluorophenyl)-3-hydroxy-3-methylbutyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide,(R)—N-(5-hydroxy-2,5-dimethylhexan-3-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide,N-[1-(4-fluorophenyl)-3-hydroxy2,2-dimethylpropyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide,N-[1-(3-fluorophenyl)-3-hydroxy-2,2-dimethylpropyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide,(−)-N-[1-(3-fluorophenyl)-3-hydroxy-2,2-dimethylpropyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide,(+)-N-[1-(3-fluorophenyl)-3-hydroxy-2,2-dimethylpropyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide,N-[1-(2-fluorophenyl)-3-hydroxy-2,2-dimethylpropyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide,N-(1-hydroxy-2,2,4-trimethylpentan-3-yl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide,(R)—N-(3-hydroxy-3-methyl-1-phenylbutyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide,N-(3-hydroxy-2,2-dimethyl-1-phenylpropyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide,(−)-N-(3-hydroxy-2,2-dimethyl-1-phenylpropyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide,(+)-N-(3-hydroxy-2,2-dimethyl-1-phenylpropyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide,(R)—N-[5-(2-butoxy-2-phenylacetyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide, andN-(3-methoxy-2,2-dimethyl-1-phenylpropyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide
  • 12. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound or a pharmaceutically acceptable thereof is (R)—N-[1-(4-fluorophenyl)-3-hydroxy-3-methylbutyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide or a pharmacologically acceptable salt thereof.
  • 13. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound or a pharmaceutically acceptable thereof is (−)-N-(3-hydroxy-2,2-dimethyl-1-phenylpropyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclopropane-1-carboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide or a pharmacologically acceptable salt thereof.
  • 14. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound or a pharmaceutically acceptable thereof is (R)—N-[5-(2-methoxy-2-phenylacetyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide or a pharmacologically acceptable salt thereof.
  • 15. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound or a pharmaceutically acceptable thereof is (R)—N-[6,6-dimethyl-5-(2-phenyl-2-propoxyacetyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide or a pharmacologically acceptable salt thereof.
  • 16. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound or a pharmaceutically acceptable thereof is (R)—N-{5-[2-(2-fluorophenyl)-2-methoxyacetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide or a pharmacologically acceptable salt thereof.
  • 17. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound or a pharmaceutically acceptable thereof is (R)—N-[5-(2-ethoxy-2-phenylacetyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide or a pharmacologically acceptable salt thereof.
  • 18. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound or a pharmaceutically acceptable thereof is (R)—N-[5-(2-cyclopropoxy-2-phenylacetyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide or a pharmacologically acceptable salt thereof.
  • 19. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound or a pharmaceutically acceptable thereof is (R)—N-[5-(2-isopropoxy-2-phenylacetyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclobutanecarboxamide or a pharmacologically acceptable salt thereof.
  • 20. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound or a pharmaceutically acceptable thereof is (+)-N-{5-[2-methoxy-2-(thiophen-2-yl)acetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide or a pharmacologically acceptable salt thereof.
  • 21. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound or a pharmaceutically acceptable thereof is (−)-N-[1-(3-fluorophenyl)-3-hydroxy-2,2-dimethylpropyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide or a pharmacologically acceptable salt thereof.
  • 22. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound or a pharmaceutically acceptable thereof is N-{5-[2-(3-fluorophenyl)-2-methoxyacetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide or a pharmacologically acceptable salt thereof.
  • 23. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound or a pharmaceutically acceptable thereof is N-[1-(4-fluorophenyl)-3-hydroxy-2,2-dimethylpropyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide or a pharmacologically acceptable salt thereof.
  • 24. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound or a pharmaceutically acceptable thereof is (R)—N-[1-(3-fluorophenyl)-3-hydroxy-3-methylbutyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide or a pharmacologically acceptable salt thereof.
  • 25. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound or a pharmaceutically acceptable thereof is (R)—N-{6,6-dimethyl-5-[2-phenyl-2-(trifluoromethoxy)acetyl]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide or a pharmacologically acceptable salt thereof.
  • 26. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound or a pharmaceutically acceptable thereof is (R)—N-[2-(1-hydroxycyclopropyl)-1-phenylethyl]-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide or a pharmacologically acceptable salt thereof.
  • 27. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound or a pharmaceutically acceptable thereof is (R)—N-(3-hydroxy-3-methyl-1-phenylbutyl)-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide or a pharmacologically acceptable salt thereof.
  • 28. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound or a pharmaceutically acceptable thereof is (R)—N-[5-(2-methoxy-2-phenylacetyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-1-(trimethylsilyl)cyclopropanecarboxamide or a pharmacologically acceptable salt thereof.
  • 29. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound or a pharmaceutically acceptable thereof is (R)—N-{5-[2-(difluoromethoxy)-2-phenylacetyl]-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-1-(trimethylsilyl)cyclobutanecarboxamide or a pharmacologically acceptable salt thereof.
  • 30. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound or a pharmaceutically acceptable thereof is (R)-1-(ethyldimethylsilyl)-N-[5-(2-methoxy-2-phenylacetyl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]cyclobutanecarboxamide or a pharmacologically acceptable salt thereof.
  • 31. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound or a pharmaceutically acceptable thereof is N-{[1-(hydroxymethyl)cyclobutyl](phenyl)methyl}-6,6-dimethyl-3-[1-(trimethylsilyl)cyclobutanecarboxamido]-4,6-dihydropyrrolo [3,4-c]pyrazole-5(1H)-carboxamide or a pharmacologically acceptable salt thereof.
  • 32. A pharmaceutical composition comprising the compound or a pharmacologically acceptable salt thereof according to claim 1.
  • 33. A pharmaceutical composition comprising the compound or a pharmacologically acceptable salt thereof according to claim 3.
  • 34. A pharmaceutical composition comprising the compound or a pharmacologically acceptable salt thereof according to claim 5.
  • 35. A pharmaceutical composition comprising the compound or a pharmacologically acceptable salt thereof according to claim 7.
  • 36. A pharmaceutical composition comprising the compound or a pharmacologically acceptable salt thereof according to claim 9.
  • 37. A pharmaceutical composition comprising the compound or a pharmacologically acceptable salt thereof according to claim 11.
  • 38. A method for treating a cancer, an inflammatory disease, atopic dermatitis, chronic obstructive pulmonary disease (COPD), an infection by HIV, an infection by EBV, an infection by HCV, idiopathic pulmonary fibrosis, cardiomegaly, or Alzheimer's disease; wherein the cancer is selected from a group consisting of urinary bladder cancer, breast cancer, large intestine cancer, kidney cancer, liver cancer, lung cancer, esophageal cancer, gallbladder cancer, ovary cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid gland cancer, head and neck cancer, prostate cancer, skin cancer, hematopoietic organ tumors of the lymph system, hematopoietic organ tumors of the myeloid system, mesenchymal tumors, tumors of the central or peripheral nervous system, melanoma, teratoma, osteosarcoma, and Kaposi's sarcoma, andthe inflammatory disease is selected from a group consisting of autoimmune hepatitis, autoimmune pancreatitis, aortitis syndrome, Goodpasture's syndrome, autoimmune hemolytic anemia, autoimmune neutropenia, rheumatoid arthritis, and psoriasis; comprising administering the compound or the pharmacologically acceptable salt thereof according to claim 1 to a subject in need thereof.
  • 39. A method for treating a CDK-7-mediated cancer or a CDK-7-mediated autoimmune disease, wherein the cancer or the autoimmune disease is treated by inhibiting CDK-7, comprising administering the compound or the pharmacologically acceptable salt thereof according to claim 1 to a subject in need thereof.
Priority Claims (1)
Number Date Country Kind
2014-223221 Oct 2014 JP national
PCT Information
Filing Document Filing Date Country Kind
PCT/JP2015/080727 10/30/2015 WO 00
Publishing Document Publishing Date Country Kind
WO2016/068287 5/6/2016 WO A
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Related Publications (1)
Number Date Country
20170313727 A1 Nov 2017 US