HK1080375B - Cathepsin cysteine protease inhibitors - Google Patents

Description

Cathepsin cysteine protease inhibitors

Background

Many conditions in humans and other mammals involve or are associated with abnormal bone resorption. Such conditions include, without limitation, osteoporosis, glucocorticoid-induced osteoporosis, paget's disease, abnormally increased bone turnover, periodontal disease, tooth loss, bone fractures, rheumatoid arthritis, osteoarthritis, periprosthetic osteolysis, incomplete osteogenesis, metastatic bone disease, malignant hypercalcemia, and multiple myeloma. One of the most common of these conditions is osteoporosis, which occurs most frequently in postmenopausal women. Osteoporosis is a systemic skeletal disease characterized by low bone mass and a deterioration in the microstructure of the bone tissue, with consequent increase in bone fragility and susceptibility to fracture. Osteoporotic fractures are a major cause of morbidity and mortality in the elderly population. As many as 50% of women and one third of men experience osteoporotic fractures. A large part of the elderly population already has low bone density and a high risk of fracture. Prevention and treatment of osteoporosis and other conditions associated with bone resorption is highly desirable. Since osteoporosis and other conditions associated with bone loss are generally chronic conditions, it is believed that proper treatment generally requires long-term treatment.

Osteoporosis is characterized by a gradual loss of the bone structural system and mineralization leading to a decrease in bone strength and an increase in fracture rate. Bone is constantly altered by the balance between osteoblasts, which form new bone, and osteoclasts, which destroy or dissolve bone. In some disease conditions and with age, the balance between bone formation and resorption is broken; bone is removed at a faster rate. This long-term imbalance of resorption and formation leads to weakening of the bone structure and increased risk of fracture.

Bone resorption is mainly performed by osteoclasts, which are multinucleated giant cells. Osteoclasts resorb bone by initially coming into contact with bone tissue forming cells and then forming an extracellular compartment or cavity line. The cavity system is maintained by a proton-ATP pump at low pH. The environment in the luminal system is acidified so that the bone begins to demineralize, and then the bone proteins or collagen are degraded by proteases such as cysteine proteases. See Delaisse, J.M. et al, 1980, Biochem J192: 365-; delaisse, j, et al, 1984, Biochem biophysis Res Commun: 441- > 447; delaisse, J.M. et al, 1987, Bone8: 305-313, which are all incorporated herein by reference in their entirety. Collagen constitutes 95% of the organ matrix of bone. Thus, proteases involved in collagen degradation are essential components of bone turnover and, therefore, of the development and progression of osteoporosis.

Cathepsins belong to the papain superfamily of cysteine proteases. These proteases play a role in the normal physiological and pathological degradation of connective tissue. Cathepsins play an important role in intracellular protein degradation and turnover as well as remodeling. To date, a number of cathepsins have been identified and a number of sources of cathepsins sequenced. These cathepsins are found naturally in many tissues. For example, cathepsin B, F, H, L, K, S, W, and Z have been cloned. Cathepsin K (which is also known by the abbreviation cat K) is also known as cathepsin O and cathepsin O2. See published PCT application WO 96/13523, Khepri Pharmaceuticals, Inc., 1996, 5/9, which is incorporated herein by reference in its entirety. Cathepsin L is implicated in normal lysosomal proteolysis as well as in some disease states, including, without limitation, metastasis of melanoma. In Alzheimer's disease and certain autoimmune diseases, including but not limited to juvenile onset diabetes, multiple sclerosis, pemphigus vulgaris, Graves ' disease, myasthenia gravis, systemic lupus erythematosus, rheumatoid arthritis and Hashimoto's thyroiditis; allergic conditions, including but not limited to asthma; and allogeneic immune (immunbe) responses, including, without limitation, involving cathepsin S in organ transplant or tissue transplant rejection. Increased levels of cathepsin B and redistribution of the enzyme are found in tumors, suggesting that the enzyme plays a role in tumor pathogenesis and metastasis. In addition, aberrant cathepsin B activity is implicated in conditions such as rheumatoid arthritis, osteoarthritis, pneumocystis carinii, acute pancreatitis, inflammatory airway disease, and bone and joint disorders.

Cysteine protease inhibitors such as E-64 (trans-epoxysuccinyl-L-leucylamide- (4-guanidino) butane) are known to be effective in inhibiting bone resorption. See Delaisse, J.M. et al, 1987, Bone8: 305-313, which are incorporated herein by reference in their entirety. Recently, cathepsin K has been cloned and found to be specifically expressed in osteoclasts. See Tezuka, K. et al, 1994, J Biol Chem269: 1106-1109; shi, G.P. et al, 1995, FEBS Lett357：129-134；Bromme，D.and Okamoto，K.，1995，Biol Chem HoppeSeyler376: 379-; bromme, D. et al, 1996, J Biol Chem271: 2126-2132; drake, F.H. et al, 1996, J Biol Chem271: 12511, 12516, which are all incorporated herein by reference in their entirety. Concurrent with this cloning, the dense osteogenesis imperfecta mapping, an autosomal recessive disorder characterized by a osteoporotic phenotype with reduced bone resorption, presents a mutation in the cathepsin K gene. To date, it is known that all mutations identified in the cathepsin K gene can lead to inactive proteins. See Gelb, b.d. et al, 1996, Science273: 1236-1238; johnson, M.R. et al, 1996, genomeRes6: 1050- & 1055, which are all incorporated herein by reference in their entirety. Therefore, cathepsin K is apparently involved in osteoclast-mediated bone resorption.

Cathepsin K is synthesized as a 37 kDa pro-zymogen, which localizes in the lysosomal compartment, presumably at low pHIn which it is automatically activated to the mature 27 kDa enzyme. See McQueney, M.S. et al, 1997, J Biol Chem272: 13955-; Littlewood-Evans, a. et al, 1997, Bone 20: 81-86, which are all incorporated herein by reference in their entirety. Cathepsin K is most closely related to cathepsin S, which has 56% sequence homology at the amino acid level. Cathepsin K vs S₂P₂The substrate specificity is similar to that of cathepsin S, with preference for positively charged residues such as arginine, and hydrophobic residues such as phenylalanine or leucine at positions P1 and P2, respectively. See Bromme, D. et al, 1996, J Biol Chem271: 2126-2132; bossard, M.J. et al, 1996, JBiol Chem271: 12517, 12524, which are all incorporated herein by reference in their entirety. Cathepsin K is active over a wide pH range, with significant activity between pH 4-8, and therefore, the osteoclast's absorption cavity line, in which pH is about 4-5, has good catalytic activity.

Human collagen type I, the major collagen in bone, is a good substrate for cathepsin K. See Kafinah, W., et al, 1998, Biochem J 331: 727-732, which are incorporated herein by reference in their entirety. In vitro experiments with antisense oligonucleotides to cathepsin K have shown a reduction in bone resorption in vitro, which may be due to a reduced translation of cathepsin K mRNA. See Inui, T, et al, 1997, J Biol Chem272: 8109-. The crystal structure of cathepsin K has been resolved. See McGrath, M.E., et al, 1997, Nat Struct Biol4: 105-109; zhao, b, et al 1997, Nat Struct Bio4: 109-11, which are all incorporated herein by reference in their entirety. Selective peptide-based cathepsin K inhibitors have also been developed. See Bromme, D., et al, 1996, Biochem J315: 85-89 parts; thompson, S.K., et al, 1997, Proc Natl Acad Sci U S A94: 14249 and 14254, which are all incorporated herein by reference in their entirety. Therefore, cathepsin K inhibitors may reduce bone resorption. The inhibitor can be used for treating bone related diseasesDisorders of absorption, such as osteoporosis.

Summary of The Invention

The present invention relates to compounds that are capable of treating and/or preventing cathepsin dependent conditions or diseases in a mammal in need thereof. The compounds of formula I, as well as pharmaceutically acceptable salts, stereoisomers and N-oxide derivatives thereof, represent one embodiment of the present invention:

Detailed Description

The present invention relates to compounds of the following formula and pharmaceutically acceptable salts, stereoisomers and N-oxide derivatives thereof:

wherein R is¹Is hydrogen, C_1-6Alkyl or C_2-6Alkenyl, wherein the alkyl and alkenyl are optionally substituted with 1 to 6 halogens, C_3-6Cycloalkyl, -SR⁹、-SR¹²、-SOR⁹、-SOR¹²、-SO₂R⁹、-SO₂R¹²、-SO₂CH(R¹²)(R¹¹)、-OR¹²、-OR⁹、-N(R¹²)₂Aryl, heteroaryl or heterocyclyl, wherein said aryl, heteroaryl and heterocyclyl are optionally substituted with one or two substituents independently selected from C_1-6Alkyl, halogen, hydroxyalkyl, hydroxy, alkoxy or keto;

R²is hydrogen, C_1-6Alkyl or C_2-6Alkenyl, wherein the alkyl and alkenyl are optionallyBy 1 to 6 halogens, C_3-6Cycloalkyl, -SR⁹、-SR¹²、-SOR⁹、-SOR¹²、-SO₂R⁹、-SO₂R¹²、-SO₂CH(R¹²)(R¹¹)、-OR¹²、-OR⁹、-N(R¹²)₂Aryl, heteroaryl or heterocyclyl, wherein said aryl, heteroaryl and heterocyclyl are optionally substituted with one or two substituents independently selected from C_1-6Alkyl, halogen, hydroxyalkyl, hydroxy, alkoxy or keto;

or R¹And R²May form a C group together with the carbon atom to which it is attached_3-8A cycloalkyl or heterocyclyl ring, wherein said ring system is optionally substituted with one or two substituents independently selected from C_1-6Alkyl, hydroxyalkyl, haloalkyl, or halogen;

R³is hydrogen, C_1-6Alkyl or C_2-6Alkenyl, wherein the alkyl and alkenyl are optionally substituted by C _3-6Cycloalkyl or 1 to 6 halogen;

R⁴is hydrogen, C_1-6Alkyl or C_2-6Alkenyl, wherein the alkyl and alkenyl are optionally substituted by C_3-6Cycloalkyl or 1 to 6 halogen;

or R³And R⁴May form a C group together with the carbon atom to which it is attached_3-8Cycloalkyl ring, C_5-8A cycloalkenyl ring, or a 5-to 7-membered heterocyclyl, wherein said cycloalkyl, cycloalkenyl and heterocyclyl are optionally substituted with one or two independently selected from C_1-6Alkyl, halogen, hydroxyalkyl, hydroxy, alkoxy or keto;

R⁵selected from hydrogen or C substituted by 1-6 halogens_1-6An alkyl group;

R⁶is aryl, heteroaryl, C_1-6Haloalkyl, arylalkyl or heteroarylalkyl, wherein said aryl, heteroaryl, arylalkyl and heteroarylalkylOptionally substituted with one, two, or three independently selected from halogen, C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-6Cycloalkyl, haloalkoxy, -SR⁹、-SR¹²、-SOR⁹、-SOR¹²、-SO₂R⁹、-SO₂R¹²、-SO₂CH(R¹²)(R¹¹)、-OR¹²、-N(R¹0)(R¹¹) Cyano, or optionally by-SO₂R¹²Substituted aryl substituted with a substituent;

each D is independently C_1-3Alkyl radical, C_2-3Alkenyl radical, C_2-3Alkynyl, aryl, heteroaryl, C_3-6Cycloalkyl or heterocyclyl, wherein each of said aryl, heteroaryl, cycloalkyl and heteroalkyl, which may be monocyclic or bicyclic, may be optionally substituted on carbon or heteroatom with one to five substituents independently selected from C _1-6Alkyl, haloalkyl, halogen, keto, alkoxy, -SR⁹、-SR¹²、-OR⁹、-OR¹²、N(R¹²)₂、-SO₂R⁹or-SO₂R¹⁰Substituted with the substituent(s);

R⁷is hydrogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy, halogen, nitro, cyano, aryl, heteroaryl, C_3-8Cycloalkyl, heterocyclyl, -C (O) OR¹⁰、-C(O)OSi[CH(CH₃)₂]₃、-OR⁹、-OR¹⁰、-C(O)R¹⁰、-R¹⁰C(O)R⁹、-C(O)R⁹、-C(O)N(R^a)(R^b)、-C(O)N(R¹²)(R¹²)、-C(O)N(R¹⁰)(R¹¹)、-C(R¹⁰)(R¹¹)OH、-SR¹²、-SR⁹、-R¹⁰SR⁹、-R⁹、-C(R⁹)₃、-C(R¹⁰)(R¹¹)N(R⁹)₂、-NR¹⁰C(O)NR¹⁰S(O)₂R⁹、-SO₂R¹²、-SO(R¹²)、-SO₂R⁹、-SO_mN(R^c)(R^d)、-SO_mCH(R¹⁰)(R¹¹)、-SO₂N(R¹⁰)C(O)(R¹²)、-SO₂(R¹⁰)C(O)N(R¹²)₂、-OSO₂R¹⁰、-N(R¹⁰)(R¹¹)、-N(R¹⁰)C(O)N(R¹⁰)(R⁹)、-N(R¹⁰)C(O)R⁹、-N(R¹⁰)C(O)R¹⁰、-N(R¹⁰)C(O)OR¹⁰、-N(R¹⁰)SO₂(R¹⁰)、-C(R¹⁰)(R¹¹)NR¹⁰C(R¹⁰)(R¹¹)R⁹、-C(R¹⁰)(R¹¹)N(R¹⁰)R⁹、-C(R¹⁰)(R¹¹)N(R¹⁰)(R¹¹)、-C(R¹⁰)(R¹¹)SC(R¹⁰)(R¹¹)(R⁹)、R¹⁰S-、-C(R^a)(R^b)NR^aC(R^a)(R^b)(R⁹)、-C(R^a)(R^b)N(R^a)(R^b)、-C(R^a)(R^b)C(R^a)(R^b)N(R^a)(R^b)、-C(O)C(R^a)(R^b)N(R^a)(R^b)、-C(R^a)(R^b)N(R^a)C(O)R⁹、-C(O)C(R^a)(R^b)S(R^a)、C(R^a)(R^b)C(O)N(R^a)(R^b)、-B(OH)₂、-OCH₂O-or 4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl; wherein said group is optionally substituted on carbon or heteroatom by 1 to 5 substituents independently selected from C_1-6Alkyl, halogen, keto, cyano, haloalkyl, hydroxyalkyl, -OR⁹、-NO₂、-NH₂、-NHS(O)₂R⁸、-R⁹SO₂R¹²、-SO₂R¹²、-SO(R¹²)、-SR¹²、-SR⁹、-SO_mN(R^c)(R^d)、-SO_mN(R¹⁰)C(O)(R¹²)、-C(R¹⁰)(R¹¹)N(R¹⁰)(R¹¹)、-C(R¹⁰)(R¹¹)OH、-COOH、-C(R^a)(R^b)C(O)N(R^a)(R^b)、-C(O)(R^a)(R^b)、-N(R¹⁰)C(R¹⁰)(R¹¹)(R⁹)、-N(R¹⁰)CO(R⁹)、-NH(CH₂)₂OH、-NHC(O)OR¹⁰、-Si(CH₃)₃Heterocyclyl, aryl, or heteroaryl;

R⁸is hydrogen or C_1-6An alkyl group;

or R⁴And R⁸May form together with any atom attached to or between them a 4-to 10-membered heterocyclyl ring system, wherein said ring system, which may be mono-or bicyclic, is optionally substituted by one or two groups independently selected from C_1-6Alkyl, halogen, hydroxyalkyl, hydroxy, keto, -OR¹⁰、-SR¹⁰or-N (R)¹⁰)₂Substituted with the substituent(s);

R⁹selected from hydrogen, aryl (C)_1-4) Alkyl, heteroaryl (C)_1-4) Alkyl radical, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl (C)_1-4) Alkyl, and heterocyclic group (C)_1-4) Alkyl, wherein the group may optionally be substituted with one, two, or three independently selected from halogen, alkoxy, or-SO ₂R¹²Substituted with the substituent(s);

R¹⁰is hydrogen or C_1-6An alkyl group;

R¹¹is hydrogen or C_1-6An alkyl group;

R¹²is hydrogen or is optionally substituted by one, two, or three groups independently selected from halogen, alkoxy, -cyano, -NR¹⁰or-SR¹⁰C substituted by a substituent of (3)_1-6An alkyl group;

R^ais hydrogen, C_1-6Alkyl, (C)_1-6Alkyl) aryl, (C)_1-6Alkyl) hydroxy, -O (C)_1-6Alkyl), hydroxy,Halogen, aryl, heteroaryl, C_3-8Cycloalkyl, heterocyclyl, wherein said alkyl, aryl, heteroaryl, C_3-8The cycloalkyl and heterocyclyl groups may optionally be mono-, di-, or tri-independently selected from C on carbon or heteroatom_1-6Alkyl or halogen;

R^bis hydrogen, C_1-6Alkyl, (C)_1-6Alkyl) aryl, (C)_1-6Alkyl) hydroxy, alkoxy, hydroxy, halogen, aryl, heteroaryl, C_3-8Cycloalkyl, heterocyclyl, wherein said alkyl, aryl, heteroaryl, C_3-8The cycloalkyl and heterocyclyl groups may optionally be mono-, di-, or tri-independently selected from C on carbon or heteroatom_1-6Alkyl or halogen;

or R^aAnd R^bMay form a C together with the carbon atoms to which they are attached or between them_3-8Cycloalkyl ring or C_3-8A heterocyclyl ring wherein said 3-8 membered ring system may optionally be substituted with one or two substituents independently selected from C _1-6Alkyl and halogen;

R^cis hydrogen OR is optionally substituted by one, two, OR three independently selected from halogen OR-OR⁹C substituted by a substituent of (3)_1-6An alkyl group;

R^dis hydrogen OR is optionally substituted by one, two, OR three independently selected from halogen OR-OR⁹C substituted by a substituent of (3)_1-6An alkyl group;

or R^cAnd R^dMay form a C together with or between the nitrogen atoms to which they are attached_3-8A heterocyclyl ring, which may optionally be substituted by one or two substituents independently selected from C_1-6Alkyl, halogen, hydroxyalkyl, hydroxy, alkoxy or keto;

n is independently selected from an integer from 0 to 3;

each m is independently selected from an integer from 0 to 2.

The present invention preferably relates to compounds of the following structural formula and pharmaceutically acceptable salts, stereoisomers and N-oxide derivatives thereof:

wherein R is¹Is hydrogen, C_1-6Alkyl or C_2-6Alkenyl, wherein the alkyl and alkenyl are optionally substituted with 1 to 6 halogens, C_3-6Cycloalkyl, -SR⁹、-SR¹²、-SOR⁹、-SOR¹²、-SO₂R⁹、-SO₂R¹²、-SO₂CH(R¹²)(R¹¹)、-OR¹²、-OR⁹、-N(R¹²)₂Aryl, heteroaryl or heterocyclyl, wherein said aryl, heteroaryl and heterocyclyl are optionally substituted with one or two substituents independently selected from C_1-6Alkyl, halogen, hydroxyalkyl, hydroxy, alkoxy or keto;

R²is hydrogen, C_1-6Alkyl or C _2-6Alkenyl, wherein the alkyl and alkenyl are optionally substituted with 1 to 6 halogens, C_3-6Cycloalkyl, -SR⁹、-SR¹²、-SOR⁹、-SOR¹²、-SO₂R⁹、-SO₂R¹²、-SO₂CH(R¹²)(R¹¹)、-OR¹²、-OR⁹、-N(R¹²)₂Aryl, heteroaryl or heterocyclyl, wherein said aryl, heteroaryl and heterocyclyl are optionally substituted with one or two substituents independently selected from C_1-6Alkyl, halogen, hydroxyalkyl, hydroxy, alkoxy or keto;

or R¹And R²May form a C group together with the carbon atom to which it is attached_3-8A cycloalkyl or heterocyclyl ring, wherein said ring system is optionally substituted with one or two substituents independently selected from C_1-6Alkyl, hydroxyalkylHaloalkyl, or halogen;

R³is hydrogen, C_1-6Alkyl or C_2-6Alkenyl, wherein the alkyl and alkenyl are optionally substituted by C_3-6Cycloalkyl or 1 to 6 halogen;

R⁴is hydrogen, C_1-6Alkyl or C_2-6Alkenyl, wherein the alkyl and alkenyl are optionally substituted by C_3-6Cycloalkyl or 1 to 6 halogen;

or R³And R⁴May form a C group together with the carbon atom to which it is attached_3-8Cycloalkyl ring, C_5-8A cycloalkenyl ring, or a 5-to 7-membered heterocyclyl, wherein said cycloalkyl, cycloalkenyl and heterocyclyl are optionally substituted with one or two independently selected from C_1-6Alkyl, halogen, hydroxyalkyl, hydroxy, alkoxy or keto;

R⁵Selected from hydrogen or C substituted by 1-6 halogens_1-6An alkyl group;

R⁶is aryl, heteroaryl, C_1-6Haloalkyl, arylalkyl or heteroarylalkyl, wherein said aryl, heteroaryl, arylalkyl and heteroarylalkyl are optionally substituted with one, two or three independently selected from halogen, C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-6Cycloalkyl, haloalkoxy, -SR⁹、-SR¹²、-SOR⁹、-SOR¹²、-SO₂R⁹、-SO₂R¹²、-SO₂CH(R¹²)(R¹¹)、-OR¹²、-N(R¹⁰)(R¹¹) Cyano, or optionally by-SO₂R¹²Substituted with a substituent of the substituted aryl;

each D is independently C_1-3Alkyl radical, C_2-3Alkenyl radical, C_2-3Alkynyl, aryl, heteroaryl, C_3-8Cycloalkyl or heterocyclyl, wherein each of said aryl, heteroaryl, cycloalkyl and heterocyclyl, which may be monocyclic or bicyclic, is optionally at carbonIs substituted by 1 to 5 substituents independently selected from C_1-6Alkyl, haloalkyl, halogen, keto, alkoxy, -SR⁹、-SR¹²、-OR⁹、-OR¹²、N(R¹²)₂、-SO₂R⁹or-SO₂R¹⁰Substituted with the substituent(s);

R⁷is hydrogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy, halogen, nitro, cyano, aryl, heteroaryl, C_3-8Cycloalkyl, heterocyclyl, -C (O) OR¹⁰、-C(O)OSi[CH(CH₃)₂]₃、-OR⁹、-OR¹⁰、-C(O)R¹⁰、-R¹⁰C(O)R⁹、-C(O)R⁹、-C(O)N(R^a)(R^b)、-C(O)N(R¹²)(R¹²)、-C(O)N(R¹⁰)(R¹¹)、-C(R¹⁰)(R¹¹)OH、-SR¹²、-SR⁹、-R¹⁰SR⁹、-R⁹、-C(R⁹)₃、-C(R¹⁰)(R¹¹)N(R⁹)₂、-NR¹⁰C(O)NR¹⁰S(O)₂R⁹、-SO₂R¹²、-SO(R¹²)、-SO₂R⁹、-SO_mN(R^c)(R^d)、-SO_mCH(R¹⁰)(R¹¹)、-SO₂N(R¹⁰)C(O)(R¹²)、-SO₂(R¹⁰)C(O)N(R¹²)₂、-OSO₂R¹⁰、-N(R¹⁰)(R¹¹)、-N(R¹⁰)C(O)N(R¹⁰)(R⁹)、-N(R¹⁰)C(O)R⁹、-N(R¹⁰)C(O)R¹⁰、-N(R¹⁰)C(O)OR¹⁰、-N(R¹⁰)SO₂(R¹⁰)、-C(R¹⁰)(R¹¹)NR¹⁰C(R¹⁰)(R¹¹)R⁹、-C(R¹⁰(R¹¹)N(R¹⁰)R⁹、-C(R¹⁰)(R¹¹)N(R¹⁰)(R¹¹)、-C(R¹⁰)(R¹¹)SC(R¹⁰)(R¹¹)(R⁹)、R¹⁰S-、-C(R^a)(R^b)NR^aC(R^a)(R^b)(R⁹)、-C(R^a)(R^b)N(R^a)(R^b)、-C(R^a)(R^b)C(R^a)(R^b)N(R^a)(R^b)、-C(O)C(R^a)(R^b)N(R^a)(R^b)、-C(R^a)(R^b)N(R^a)C(O)R⁹、-C(O)C(R^a)(R^b)S(R^a)、C(R^a)(R^b)C(O)N(R^a)(R^b)、-B(OH)₂、-OCH₂O-or 4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl; wherein said group is optionally substituted on carbon or heteroatom by 1 to 5 substituents independently selected from C_1-6Alkyl, halogen, keto, cyano, haloalkyl, hydroxyalkyl, -OR ⁹、-NO₂、-NH₂、-NHS(O)₂R⁸、-R⁹SO₂R¹²、-SO₂R¹²、-SO(R¹²)、-SR¹²、-SR⁹、-SO_mN(R^c)(R^d)、-SO_mN(R¹⁰)C(O)(R¹²)、-C(R¹⁰)(R¹¹)N(R¹⁰)(R¹¹)、-C(R¹⁰)(R¹¹)OH、-COOH、-C(R^a)(R^b)C(O)N(R^a)(R^b)、-C(O)(R^a)(R^b)、-N(R¹⁰)C(R¹⁰)(R¹¹)(R⁹)、-N(R¹⁰)CO(R⁹)、-NH(CH₂)₂OH、-NHC(O)OR¹⁰、-Si(CH₃)₃Heterocyclyl, aryl, or heteroaryl;

R⁸is hydrogen or C_1-6An alkyl group;

or R⁴And R⁸Or may form together with any atom attached to or between them a 4-to 10-membered heterocyclyl ring system, wherein the ring system, which may be monocyclic or bicyclic, is optionally substituted by one or two substituents independently selected fromC_1-6Alkyl, halogen, hydroxyalkyl, hydroxy, keto, -OR¹⁰、-SR¹⁰or-N (R)¹⁰)₂Substituted with the substituent(s);

R⁹selected from hydrogen, aryl (C)_1-4) Alkyl, heteroaryl (C)_1-4) Alkyl radical, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl (C)_1-4) Alkyl, and heterocyclic group (C)_1-4) Alkyl, wherein the group may optionally be substituted with one, two, or three independently selected from halogen, alkoxy, or-SO₂R¹²Substituted with the substituent(s);

R¹⁰is hydrogen or C_1-6An alkyl group;

R¹¹is hydrogen or C_1-6An alkyl group;

R¹²is hydrogen or is optionally substituted by one, two, or three groups independently selected from halogen, alkoxy, -cyano, -NR¹⁰or-SR¹⁰C substituted by a substituent of (3)_1-6An alkyl group;

R^ais hydrogen, C_1-6Alkyl, (C)_1-6Alkyl) aryl, (C)_1-6Alkyl) hydroxy, -O (C)_1-6Alkyl), hydroxy, halogen, aryl, heteroaryl, C_3-8Cycloalkyl, heterocyclyl, wherein said alkyl, aryl, heteroaryl, C_3-8The cycloalkyl and heterocyclyl groups may optionally be mono-, di-, or tri-independently selected from C on carbon or heteroatom _1-6Alkyl or halogen;

R^bis hydrogen, C_1-6Alkyl, (C)_1-6Alkyl) aryl, (C)_1-6Alkyl) hydroxy, alkoxy, hydroxy, halogen, aryl, heteroaryl, C_3-8Cycloalkyl, heterocyclyl, wherein said alkyl, aryl, heteroaryl, C_3-8The cycloalkyl and heterocyclyl groups may optionally be mono-, di-, or tri-independently selected from C on carbon or heteroatom_1-6Alkyl or halogen;

or R^aAnd R^bMay form a C together with the carbon atoms to which they are attached or between them_3-8Cycloalkyl ring or C_3-8A heterocyclyl ring wherein said 3-8 membered ring system may optionally be substituted with one or two substituents independently selected from C_1-6Alkyl and halogen;

R^cis hydrogen OR is optionally substituted by one, two, OR three independently selected from halogen OR-OR⁹C substituted by a substituent of (3)_1-6An alkyl group;

R^dis hydrogen OR is optionally substituted by one, two, OR three independently selected from halogen OR-OR⁹C substituted by a substituent of (3)_1-6An alkyl group;

or R^cAnd R^dMay form together with the nitrogen atom to which it is attached or the nitrogen atom in between, an optionally substituted C_1-6C substituted by substituents of alkyl, halogen, hydroxyalkyl, hydroxy, alkoxy or keto groups _3-8A heterocyclyl ring;

n is independently selected from an integer from 1 to 3;

each m is independently selected from an integer from 0 to 2.

In one embodiment of the invention, R¹And R²Each is hydrogen. In another embodiment of the invention, R when on the same carbon atom¹And R²May form together with the carbon atom to which they are attached a 3-8 membered cycloalkyl ring system, wherein said ring system is optionally substituted by C_1-6Alkyl, hydroxyalkyl and halogen. Examples of ring systems that may be formed include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. A preferred embodiment is the formation of cyclopropyl.

In another embodiment of the invention, R¹And R²Together with the carbon atom to which they are attached form a 3-8 membered heterocyclyl ring system, wherein said ring system is optionally substituted with C_1-6Alkyl, hydroxyalkyl or haloalkylAnd (4) substituting. Examples of ring systems that may be formed include piperidinyl, pyrrolidinyl, or tetrahydropyranyl.

In one embodiment of the invention, R³And R⁴Each independently is C_1-4Alkyl or H. In another embodiment of the invention, R³Is isobutyl or n-propyl, and R⁴Is H, R³More preferably n-propyl.

In another embodiment, R ³Is C_1-6Alkyl, wherein the alkyl is substituted by C_3-6Cycloalkyl or halogen. R³Preferably 2-fluoro-2-methylpropyl, 2-trifluoromethylpropyl, 3-fluoro-2- (2-fluoromethyl) propyl, 2-difluoroethyl, 2-difluoropropyl, 3, 3, 3-trifluoropropyl, or 2, 2-dichloroethyl, and R⁴Is hydrogen. R³More preferably 2-fluoro-2-methylpropyl.

In another embodiment of the invention, R³And R⁴Together with the carbon atom to which they are attached form C_3-8Cycloalkyl ring, C_5-8A cycloalkenyl ring, or a 5-to 7-membered heterocyclyl, wherein said cycloalkyl, cycloalkenyl and heterocyclyl are optionally substituted with C_1-6Alkyl, halogen, hydroxyalkyl, hydroxy, alkoxy or keto. Examples of ring systems that may be formed include, without limitation, the following rings wherein the heterocyclic ring is optionally substituted with one or more substituents as defined above: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. In one class of embodiments, a cyclohexyl group is formed.

In one embodiment of the invention, R⁵Is C substituted by 1-6 halogen_1-6Alkyl, and R⁶Is C substituted by 1-6 halogen_1-6An alkyl group. In another embodiment of the invention, R⁵Is hydrogen, and R⁶Is C substituted by 1-6 halogen _1-6An alkyl group. In another embodiment, R⁵Is hydrogen, and R⁶Is C substituted by 1-6 fluorine_1-6An alkyl group. In another embodiment, R⁵Is hydrogen, and R⁶Is C substituted by 3 fluorine_1-3An alkyl group. In another embodiment, R⁵Is hydrogen, and R⁶Is trifluoromethyl or 3, 3, 3, 2, 2-pentafluoroethyl, R⁶More preferably trifluoromethyl.

In another embodiment of the invention, R⁵Is hydrogen, and R⁶Is aryl or heteroaryl, wherein said aryl and heteroaryl groups may optionally be substituted by halogen or-SO₂R¹²And (4) substituting.

In another embodiment of the invention, R¹And R²And the carbon atoms to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, more preferably cyclopropyl; r³Is n-propyl, isobutyl, 2-fluoro-2-methylpropyl, 2-trifluoromethylpropyl, 3-fluoro-2- (2-fluoromethyl) propyl, 2-difluoroethyl, 2-difluoropropyl, 3, 3, 3-trifluoropropyl, or 2, 2-dichloroethyl; r⁴And R⁵Is hydrogen; and R is⁶Is C substituted by 1-6 halogen_1-6An alkyl group; r⁶Preferably C substituted by 3 fluorines_1-3An alkyl group; more preferably, R⁶Is trifluoromethyl or 3, 3, 3, 2, 2-pentafluoroethyl, most preferably trifluoromethyl. In this embodiment, a particularly preferred embodiment is where n is 1. Another particularly preferred embodiment is where n is 2. Yet another particularly preferred embodiment, wherein n is 3. n is preferably 1, in which case D is heteroaryl optionally substituted by halogen or phenyl, wherein the phenyl is hydroxyalkyl, -COR ¹⁰(wherein R is¹⁰Is C_1-6Alkyl) or-SO₂R¹²Substituted, or D is optionally halogen, -CONR^aR^b(wherein R is^aIs hydrogen or C_1-6Alkyl, and R^bIs hydrogen, C_1-6Alkyl, cycloalkyl or C_1-6Alkoxy, or R^aAnd R^bAnd the nitrogen atom to which they are attached, wherein said heterocyclic group is optionally substituted with alkyl, hydroxyalkyl, or haloalkyl), -SO₂R¹²(wherein R is¹²Is C_1-6Alkyl), -COOR¹⁰Alkynyl optionally substituted by hydroxy OR cycloalkyl, alkenyl substituted by hydroxy, alkyl optionally substituted by hydroxy, -OR⁹(wherein R is⁹Is aryl), -OR¹⁰、-CR¹⁰R¹¹SC₁₀R¹¹R⁹(wherein R is⁹Is aryl), -CH₂S (aryl), cyano, -COR⁹Or phenyl substituted with heteroaryl.

Preferably, n is 2 and each D is a phenyl group, with the second phenyl group attached to the first phenyl ring (attached to the ring with R)⁵And R⁶And further wherein each phenyl group is optionally substituted by one or two independently selected from C) and_1-6alkyl, halogen, hydroxy, alkoxy, haloalkyl, haloalkoxy or-SO₂R¹²(wherein R is¹²Is C_1-6Alkyl) and a second phenyl group is further substituted by R⁷And (4) substituting. More preferably, each D is phenyl, wherein a second phenyl is attached at the 4-position of the first phenyl ring, and a second phenyl is optionally positioned as R at the 4-position of the phenyl ring ⁷Substituted and said R⁷is-SO₂R¹²(wherein R is¹²Is C optionally substituted by hydroxy or halogen_1-6Alkyl), -SO₂NR^CR^d(wherein R is^cAnd R^dIndependently is hydrogen or C_1-6Alkyl, or R^cAnd R^dTogether with the nitrogen atom to which they are attached form a heterocyclyl ring), -SR¹²(wherein R is¹²Is C_1-6Alkyl), -SOR¹²(wherein R is¹²Is C_1-6Alkyl), -NHCOR¹⁰(wherein R is¹⁰Is C_1-6Alkyl), -NR-¹⁰R¹¹(wherein R is¹⁰And R¹¹Is C_1-6Alkyl), -SO₂NHCOR¹⁰Heteroaryl, halogen, -COOR¹⁰(wherein R is¹⁰Is hydrogen or C_1-6Alkyl), -OR-⁹(wherein R is⁹Is hydrogen OR aryl), -OR¹⁰(wherein R is¹⁰Is C_1-6Alkyl), is-SO₂R¹²(wherein R is¹²Is C_1-6Alkyl) substituted aryl, cyano, haloalkyl, -C (R)¹⁰)(R¹¹) OH, optionally substituted by-OR¹⁰And C substituted by halogen_1-6Alkyl radical, COR⁹(wherein R is⁹Is aryl), -COR¹⁰or-NHSO₂R¹⁰(wherein R is¹⁰Is C_1-6Alkyl) and furthermore a second phenyl ring is optionally selected from C_1-6Alkyl, -CHO, -COOR¹⁰、-COR¹⁰、-NHCOR¹⁰Halogen, haloalkyl, -OR¹⁰(wherein R is¹⁰Is hydrogen or C_1-6Alkyl, wherein the alkyl is optionally substituted by halogen), -SO₂NH₂、-NHCOR¹⁰(wherein R is¹⁰Is C_1-6Alkyl), or-SO₂R¹²(wherein R is¹²Is C_1-6Alkyl) is substituted with a second substituent. More preferably, the second phenyl group is substituted by R in the 4-position⁷Is substituted in which R⁷Is wherein R is¹²Is C_1-6Alkyl (preferably methyl) -SOR ¹²、-SO₂R¹²Or wherein R is^cAnd R^dIndependently is hydrogen or alkyl or R^cAnd R^d-SO together forming a heterocyclic group, and m is an integer from 0 to 2_mNR^CR^d。R⁷Preferably methylsulfonyl, N-methylaminosulfonyl, aminosulfonyl, or morpholin-4-ylsulfonyl.

Preferably, n is 2, in which case the first D (connected to the carrier R)⁵And R⁶D) on carbon of (A) is phenyl and the second D is optionally substituted by cycloalkyl, heteroaryl, C_1-6A heterocyclyl (preferably morpholin-4-yl, piperazin-1-yl, or piperidin-4-yl) substituted with alkyl or hydroxyalkyl, more preferably with cyclopropyl, methyl, ethyl, or hydroxyethyl, and said heterocyclyl ring is attached at the 4-position of the phenyl ring.

Preferably, n is 2, in which case the first D (connected to the carrier R)⁵And R⁶D) on the carbon of (A) is phenyl,and the second D is substituted with one or two groups independently selected from hydroxyalkyl, -SO₂R¹²(wherein R is¹²Is C_1-6Alkyl group), C_1-6Alkyl, halogen, haloalkyl, amino, OR-OR¹⁰Heteroaryl substituted with the substituent(s) of (a).

n is preferably 3, wherein the first and second D are phenyl and the third D is heterocyclyl and they may be optionally substituted as defined above. The first and second D are more preferably phenyl, wherein the second phenyl is attached to the 4-position of the first phenyl and the heterocyclyl is substituted with R ⁷Substituted morpholin-4-yl, pyrrolidin-1-yl, piperidin-4-yl or piperazin-1-yl. R⁷Preferably hydrogen, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, COOR¹⁰or-SO₂R¹²(wherein R is¹²Is C_1-6Alkyl groups).

In another embodiment of the invention, R¹And R²And the carbon atoms to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, more preferably cyclopropyl; r³And R⁴Together with the carbon atom to which they are attached form C_3-8Cycloalkyl ring, C_5-8A cycloalkenyl ring, or a 5-to 7-membered heterocyclyl, wherein said cycloalkyl, cycloalkenyl and heterocyclyl may optionally be substituted by C_1-6Alkyl, halogen, hydroxyalkyl, hydroxy, alkoxy or keto. Examples of ring systems that may be formed include, without limitation, the following rings wherein the heterocyclic ring may be optionally substituted with one or more of the above substituents: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuran-4-yl, piperidin-4-yl. R³And R⁴Preferably together with the carbon atom to which they are attached to form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl group. A more preferred embodiment is R³And R⁴Together with the carbon atom to which they are attached form cyclohexyl. In this embodiment, a particularly preferred embodiment is where R is ⁵Is hydrogen; and R is⁶Is C substituted by 1-6 halogen_1-6An alkyl group; r⁶Preferably C substituted by 3 fluorines_1-3An alkyl group; more preferably, R⁶Is trifluoromethyl or 3, 3, 3, 2, 2-pentafluoroethyl, most preferably trifluoromethyl. In this embodiment, a particularly preferred embodiment is where n is 1. Another particularly preferred embodiment is where n is 2. Yet another particularly preferred embodiment is where n is 3. n is preferably 1, in which case D is heteroaryl optionally substituted by halogen or phenyl, wherein the phenyl is hydroxyalkyl, -COR¹⁰(wherein R is¹⁰Is C_1-6Alkyl) or-SO₂R¹²Substituted, or D is optionally substituted by halogen, -CONR^aR^b(wherein R is^aIs hydrogen or C_1-6Alkyl, and R^bIs hydrogen, C_1-6Alkyl, cycloalkyl or C_1-6Alkoxy, or R^aAnd R^bTogether with the nitrogen atom to which they are attached form a heterocyclyl group, wherein the heterocyclyl group is optionally substituted by alkyl or haloalkyl), -SO₂R¹²(wherein R is¹²Is C_1-6Alkyl), -COOR¹⁰Alkynyl substituted by hydroxy, alkenyl substituted by hydroxy, alkyl optionally substituted by hydroxy, -OR¹⁰、-CR¹⁰R¹¹SC¹⁰R¹¹R⁹(wherein R is⁹Is aryl), -CH₂S (aryl), -COR⁹Or phenyl substituted with heteroaryl.

Preferably, n is 2 and each D is a phenyl group, wherein a second phenyl group is attached to the first phenyl ring (attached to the ring with R) ⁵And R⁶Phenyl on carbon) and further wherein each phenyl group is optionally substituted by one or two independently selected from C_1-6Alkyl, halogen, hydroxy, alkoxy, haloalkyl, haloalkoxy, and a second phenyl group is further substituted with R⁷And (4) substituting. More preferably, each D is phenyl, wherein a second phenyl is attached at the 4-position of the first phenyl ring, and a second phenyl is optionally positioned as R at the 4-position of the phenyl ring⁷Is substituted, and R⁷is-SO₂R¹²(wherein R is¹²Is C optionally substituted by halogen_1-6Alkyl), -SO₂NR^CR^d(wherein R is^cAnd R^dIndependently is hydrogen or C_1-6Alkyl, or R^cAnd R^dTogether with the nitrogen atom to which they are attached form a heterocyclyl ring), -SR¹²(wherein R is¹²Is C_1-6Alkyl), -NHCOR⁹(wherein R is⁹Is C_1-6Alkyl), -NR-¹⁰R¹¹(wherein R is¹⁰And R¹¹Is C_1-6Alkyl), heteroaryl, halogen, -COOR¹⁰(wherein R is¹⁰Is hydrogen or C_1-6Alkyl), -OR-⁹(wherein R is⁹Is hydrogen or aryl), by SO₂R¹²(wherein R is¹²Is C_1-6Alkyl) substituted aryl, cyano, haloalkyl, -CHO, -C (R)¹⁰)(R¹¹) OH, optionally substituted by-OR¹⁰And halogen substituted C_1-6Alkyl, -COR¹⁰or-NHSO₂R¹⁰(wherein R is¹⁰Is C_1-6Alkyl) and the second phenyl ring is optionally further substituted with a group selected from halogen, haloalkyl, -OR¹⁰(wherein R is¹⁰Is hydrogen or C _1-6Alkyl, wherein the alkyl may be optionally substituted with halogen) or-SO₂R¹²(wherein R is¹²Is C_1-6Alkyl) is substituted with a second substituent. More preferably, the second phenyl group is substituted by R in the 4-position⁷Is substituted in which R⁷is-SO₂R¹²Wherein R is¹²Is C_1-6Alkyl (preferably methyl) or wherein R^cAnd R^dIndependently is hydrogen or alkyl or R^cAnd R^dTogether form a heterocyclic group, and m is-SO of an integer from 0 to 2_mNR^CR^d。R⁷Preferably methylsulfonyl, N-methylaminosulfonyl, aminosulfonyl, or morpholine-4-sulfonyl.

n is preferably 2, in which case the first D (connected to the carrier R)⁵And R⁶D) on carbon of (A) is phenyl and the second D is cycloalkyl, C_1-6Alkyl or hydroxyalkyl, more preferably by cyclopropylMethyl, ethyl, or hydroxyethyl substituted heterocyclyl (preferably piperazin-1-yl or piperidin-4-yl) and the heterocyclyl ring is attached at the 4-position of the phenyl ring.

Preferably, n is 2, in which case the first D (connected to the carrier R)⁵And R⁶D) on carbon of (A) is phenyl and the second D is substituted with one or two groups independently selected from hydroxyalkyl, -SO₂R¹²(wherein R is¹²Is C_1-6Alkyl group), C_1-6Alkyl, halogen, OR-OR¹⁰Heteroaryl substituted with the substituent(s) of (a).

n is preferably 3, wherein the first and second D are phenyl and the third D is heterocyclyl and they may be optionally substituted as defined above. The first and second D are more preferably phenyl, wherein the second phenyl is attached to the 4-position of the first phenyl and said heterocyclyl is substituted with R⁷Substituted morpholin-4-yl, pyrrolidin-1-yl, piperidin-4-yl or piperazin-1-yl. R⁷Preferably hydrogen, alkyl, hydroxyalkyl, haloalkyl or cycloalkyl.

In another embodiment of the invention, R⁵Is hydrogen, and R⁶Is optionally substituted by one, two, or three independently selected from halogen, C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-6Cycloalkyl, haloalkoxy, -SR⁹、-SR¹²、-SOR⁹、-SOR¹²、-SO₂R⁹、-SO₂R¹²、-SO₂CH(R¹²)(R¹¹)、-OR¹²、-N(R¹⁰)(R¹¹) Cyano, or optionally by-SO₂R¹²Substituted aryl group substituted with a substituent of substituted aryl group. Phenyl is more preferably substituted by C_1-6Alkyl, halogen, haloalkyl, or haloalkoxy. In this embodiment, a preferred embodiment is where R is¹And R²Each is hydrogen. In this embodiment, another preferred embodiment is that wherein R is¹And R²And is connected theretoTogether form a 3-8 membered cycloalkyl or heterocyclyl ring system, wherein said ring system is optionally substituted with C _1-6Alkyl, hydroxyalkyl and halogen. Preferred ring systems that may be formed include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, more preferably cyclopropyl. In these preferred and more preferred embodiments, the more preferred embodiment is that wherein R is³Is C_1-4Alkyl, and R⁴Is H. Preferably, R³Is n-propyl or isobutyl, and R⁴Is H. In these preferred and more preferred embodiments, another more preferred embodiment is that wherein R is³Is 2-fluoro-2-methylpropyl, 2-trifluoromethylpropyl, 3-fluoro-2- (2-fluoromethyl) propyl, 2-difluoroethyl, 2-difluoropropyl, 3, 3, 3-trifluoropropyl, or 2, 2-dichloroethyl; and R is⁴Is hydrogen. In these preferred and most preferred embodiments, another more preferred embodiment is that wherein R is³And R⁴May form C together with the carbon atom to which it is attached_3-8Cycloalkyl ring, C_5-8A cycloalkenyl ring, or a 5-to 7-membered heterocyclyl, wherein said cycloalkyl, cycloalkenyl and heterocyclyl are optionally substituted with C_1-6Alkyl, halogen, hydroxyalkyl, hydroxy, alkoxy or keto. Examples of ring systems that may be formed include, without limitation, the following rings wherein the heterocyclic ring may be optionally substituted with one or more of the above substituents: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. One preferred embodiment is the formation of cyclohexyl.

In this embodiment, a particularly preferred embodiment is where n is 1. Another particularly preferred embodiment is where n is 2. Yet another particularly preferred embodiment, wherein n is 3. n is preferably 1, in which case D is heteroaryl, optionally substituted by halogen or phenyl, said phenyl being substituted by hydroxyalkyl, -COR¹⁰(wherein R is¹⁰Is C_1-6Alkyl) or-SO₂R¹²Substituted, or D is phenyl, optionally substituted by halogen, -CONR^aR^b(wherein R is^aIs hydrogen or C_1-6Alkyl, and R^bIs hydrogen, C_1-6Alkyl, cycloalkyl or C_1-6Alkoxy, or R^aAnd R^bTogether with the nitrogen atom to which they are attached form a heterocyclyl group, wherein the heterocyclyl group is optionally substituted by alkyl or haloalkyl), -SO₂R¹²(wherein R is¹²Is C_1-6Alkyl), -COOR¹⁰Alkynyl substituted by hydroxy, alkenyl substituted by hydroxy, alkyl optionally substituted by hydroxy, -OR¹⁰、-CR¹⁰R¹¹SC¹⁰R¹¹R⁹(wherein R is⁹Is aryl), -CH₂S (aryl), -COR⁹Or heteroaryl.

Preferably, n is 2 and each D is a phenyl group, wherein a second phenyl group is attached to the first phenyl ring (attached to the ring with R)⁵And R⁶Phenyl on carbon) and further wherein each phenyl group is optionally substituted by one or two independently selected from C_1-6Alkyl, halogen, hydroxy, alkoxy, haloalkyl, haloalkoxy, and a second phenyl group is further substituted with R ⁷And (4) substituting. More preferably, each D is phenyl, wherein a second phenyl is attached at the 4-position of the first phenyl ring, and a second phenyl is optionally positioned as R at the 4-position of the phenyl ring⁷Is substituted, and R⁷is-SO₂R¹²(wherein R is¹²Is C optionally substituted by halogen_1-6Alkyl), -SO₂NR^CR^d(wherein R is^cAnd R^dIndependently is hydrogen or C_1-6Alkyl, or R^cAnd R^dTogether with the nitrogen atom to which they are attached form a heterocyclyl ring), -SR¹²(wherein R is¹²Is C_1-6Alkyl), -NHCOR⁹(wherein R is⁹Is C_1-6Alkyl), -NR-¹⁰R¹¹(wherein R is¹⁰And R¹¹Is C_1-6Alkyl), heteroaryl, halogen, -COOR¹⁰(wherein R is¹⁰Is hydrogen or C_1-6Alkyl), -OR-⁹(wherein R is⁹Is hydrogen or aryl), by SO₂R¹²(wherein R is¹²Is C_1-6Alkyl) substituted aryl, cyano, alkyl halideRadical, -CHO, -C (R)¹⁰)(R¹¹) OH, optionally substituted by-OR¹⁰And halogen substituted C_1-6Alkyl, -COR¹⁰or-NHSO₂R¹⁰(wherein R is¹⁰Is C_1-6Alkyl) and the second phenyl ring is optionally further substituted with a group selected from halogen, haloalkyl, -OR¹⁰(wherein R is¹⁰Is hydrogen or C_1-6Alkyl, wherein the alkyl may be optionally substituted with halogen) or-SO₂R¹²(wherein R is¹²Is C_1-6Alkyl) is substituted with a second substituent. More preferably, the second phenyl group is substituted by R in the 4-position⁷Is substituted in which R⁷Is wherein R is¹²Is C_1-6-SO of an alkyl group (preferably methyl) ₂R¹²Or wherein R is^cAnd R^dIndependently is hydrogen or alkyl or R^cAnd R^d-SO together forming a heterocyclic group and m is an integer from 0 to 2_mNR^CR^d。R⁷Preferably methylsulfonyl, N-methylaminosulfonyl, aminosulfonyl, or morpholin-4-ylsulfonyl.

Preferably, n is 2, in which case the first D (attached to the carrier R)⁵And R⁶D) on carbon of (A) is phenyl and the second D is cycloalkyl, C_1-6Alkyl or hydroxyalkyl, more preferably heterocyclyl (preferably piperazin-1-yl or piperidin-4-yl) substituted with cyclopropyl, methyl, ethyl, or hydroxyethyl, and said heterocyclyl ring is attached at the 4-position of the phenyl ring.

Preferably, n is 2, in which case the first D (connected to the carrier R)⁵And R⁶D) on carbon of (A) is phenyl and the second D is substituted with one or two groups independently selected from hydroxyalkyl, -SO₂R¹²(wherein R is¹²Is C_1-6Alkyl group), C_1-6Alkyl, halogen, OR-OR¹⁰Heteroaryl substituted with the substituent(s) of (a).

n is preferably 3, wherein the first and second D are phenyl and the third D is heterocyclyl and they may be optionally substituted as defined above. The first and second D are more preferably phenyl, wherein the second phenyl is attached to the 4-position of the first phenyl and said heterocyclyl is substituted with R ⁷Substituted morpholin-4-yl, pyrrolidin-1-yl, piperidin-4-yl or piperazin-1-yl. R⁷Preferably hydrogen, alkyl, hydroxyalkyl, haloalkyl or cycloalkyl.

In one embodiment of the invention, R⁵Is hydrogen, and R⁶Is optionally substituted by C_1-6Alkyl, halogen, haloalkyl, or haloalkoxy substituted heteroaryl. Preferably, R⁶Is optionally substituted by C_1-4Alkyl or halogen substituted thiazolyl, pyridyl, tetrazolyl, thienyl, or furyl. In this embodiment, a preferred embodiment is where R is¹And R²Each is hydrogen. In this embodiment, another preferred embodiment is that wherein R is¹And R²Together with the carbon atom to which they are attached form a 3-8 membered cycloalkyl or heterocyclyl ring system, wherein said ring system is optionally substituted by C_1-6Alkyl, hydroxyalkyl and halogen. Preferred ring systems that may be formed include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, more preferably cyclopropyl. In these preferred and more preferred embodiments, the more preferred embodiment is that wherein R is³Is C_1-4Alkyl, and R⁴Is H. Preferably, R³Is n-propyl or isobutyl, and R⁴Is H. In these preferred and more preferred embodiments, another more preferred embodiment is that wherein R is ³Is 2-fluoro-2-methylpropyl, 2-trifluoromethylpropyl, 3-fluoro-2- (2-fluoromethyl) propyl, 2, 2-difluoroethyl, 2, 2-difluoropropyl, 3, 3, 3-trifluoropropyl, or 2, 2-dichloroethyl; and R is⁴Is hydrogen. In these preferred and more preferred embodiments, another more preferred embodiment is that wherein R is³And R⁴May form C together with the carbon atom to which it is attached_3-8Cycloalkyl ring, C_5-8A cycloalkenyl ring, or a 5-to 7-membered heterocyclyl, wherein said cycloalkyl, cycloalkenyl and heterocyclyl may optionally be substituted with C_1-6Alkyl, halogen, hydroxyalkyl, hydroxy, alkoxy or keto. Examples of ring systems that may be formed include, without limitation, the following rings wherein the heterocyclic ring may be optionally substituted with one or more of the above substituents: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. One preferred embodiment is the formation of cyclohexyl.

In this embodiment, a particularly preferred embodiment is where n is 1. Another particularly preferred embodiment is where n is 2. Yet another particularly preferred embodiment, wherein n is 3. n is preferably 1, in which case D is heteroaryl optionally substituted by halogen or phenyl, said phenyl being substituted by hydroxyalkyl, -COR ¹⁰(wherein R is¹⁰Is C_1-6Alkyl) or-SO₂R¹²Substituted, or D is optionally halogen, -CONR^aR^b(wherein R is^aIs hydrogen or C_{1- 6}Alkyl, and R^bIs hydrogen, C_1-6Alkyl, cycloalkyl or C_1-6Alkoxy, or R^aAnd R^bAnd the nitrogen atom to which they are attached, form a heterocyclic group, wherein the heterocyclic group is optionally substituted with alkyl or haloalkyl), -SO₂R¹²(wherein R is¹²Is C_1-6Alkyl), -COOR¹⁰Alkynyl substituted by hydroxy, alkenyl substituted by hydroxy, alkyl optionally substituted by hydroxy, -OR¹⁰、-CR¹⁰R¹¹SC¹⁰R¹¹R⁹(wherein R is⁹Is aryl), -CH₂S (aryl), -COR⁹Or phenyl substituted with heteroaryl.

Preferably, n is 2 and each D is a phenyl group, wherein a second phenyl group is attached to the first phenyl ring (attached to the ring with R)⁵And R⁶Phenyl on carbon) and further wherein each phenyl group is optionally substituted by one or two independently selected from C_1-6Alkyl, halogen, hydroxy, alkoxy, haloalkyl, haloalkoxy, and a second phenyl group is further substituted with R⁷And (4) substituting. More preferably, each D is phenyl, wherein the second phenyl is attached to the firstR at the 4-position of the phenyl ring and a second phenyl group optionally located at the 4-position of the phenyl ring⁷Is substituted, and R⁷is-SO₂R¹²(wherein R is ¹²Is C substituted by halogen_1-6Alkyl), -SO₂NR^CR^d(wherein R is^cAnd R^dIndependently is hydrogen or C_1-6Alkyl, or R^cAnd R^dTogether with the nitrogen atom to which they are attached form a heterocyclyl ring), -SR¹²(wherein R is¹²Is C_1-6Alkyl), -NHCOR⁹(wherein R is⁹Is C_1-6Alkyl), -NR-¹⁰R¹¹(wherein R is¹⁰And R¹¹Is C_1-6Alkyl), heteroaryl, halogen, -COOR¹⁰(wherein R is¹⁰Is hydrogen or C_1-6Alkyl), -OR-⁹(wherein R is⁹Is hydrogen or aryl), by SO₂R¹²Substituted aryl (wherein R is¹²Is C_1-6Alkyl), cyano, haloalkyl, -CHO, -C (R)¹⁰)(R¹¹) OH, optionally substituted by-OR¹¹And halogen substituted C_1-6Alkyl, -COR¹⁰or-NHSO₂R¹⁰(wherein R is¹⁰Is C_1-6Alkyl) and the second phenyl ring is optionally further substituted with a group selected from halogen, haloalkyl, -OR¹⁰(wherein R is¹⁰Is hydrogen or C_1-6Alkyl, wherein the alkyl is optionally substituted with halogen) or-SO₂R¹²(wherein R is¹²Is C_1-6Alkyl) is substituted with a second substituent. More preferably, the second phenyl group is substituted by R in the 4-position⁷Is substituted in which R⁷Is wherein R is¹²Is C_1-6-SO of an alkyl group, preferably a methyl group₂R¹²Or wherein R is^cAnd R^dIndependently is hydrogen or alkyl or R^cAnd R^d-SO together forming a heterocyclic group, and m is an integer from 0 to 2_mNR^CR^d。R⁷Preferably methylsulfonyl, N-methylaminosulfonyl, aminosulfonyl, or morpholin-4-ylsulfonyl.

Preferably, n is 2, in which case the secondOne D (connected to the carrier with R)⁵And R⁶D) on carbon of (A) is phenyl and the second D is cycloalkyl, C_1-6Alkyl or hydroxyalkyl, more preferably heterocyclyl (preferably piperazin-1-yl or piperidin-4-yl) substituted with cyclopropyl, methyl, ethyl, or hydroxyethyl, and said heterocyclyl ring is attached at the 4-position of the phenyl ring.

Preferably, n is 2, in which case the first D (connected to the carrier R)⁵And R⁶D) on carbon of (A) is phenyl and the second D is substituted with one or two groups independently selected from hydroxyalkyl, -SO₂R¹²(wherein R is¹²Is C_1-6Alkyl group), C_1-6Alkyl, halogen, OR-OR¹⁰Substituted heteroaryl.

n is preferably 3, wherein the first and second D are phenyl and the third D is heterocyclyl, and they may be optionally substituted as defined above. The first and second D are more preferably phenyl, wherein the second phenyl is attached to the 4-position of the first phenyl and said heterocyclyl is substituted with R⁷Substituted morpholin-4-yl, pyrrolidin-1-yl, piperidin-4-yl or piperazin-1-yl. R⁷Preferably hydrogen, alkyl, hydroxyalkyl, haloalkyl or cycloalkyl.

In one embodiment of the invention, R⁴And R⁸May form together with any atom attached thereto or therebetween a 4-to 10-membered heterocyclyl ring system, wherein said ring system, which may be mono-or bicyclic, is optionally substituted by C_1-6Alkyl, halogen, hydroxyalkyl, hydroxy, keto, -OR¹⁰、-SR¹⁰or-N (R)¹⁰)₂And (4) substitution. In another embodiment of the invention, R⁴And R⁸Are defined as they may form, together with the nitrogen atom to which they are attached, a monocyclic or bicyclic heterocyclic radical having 5 to 7 ring members in each ring and optionally containing, in addition to nitrogen, 1 or two heteroatoms selected from N, O and S, which heterocyclic radical may optionally be substituted by one or more heteroatoms selected from C_1-6Alkyl, halogen, hydroxyalkyl, hydroxyKeto group, -OR¹⁰、-SR¹⁰or-N (R)¹⁰)₂Substituted with the substituent(s). In another example, R⁴And R⁸Are defined as they may form together with the nitrogen atom to which they are attached a 5 or 6 membered heterocyclic ring system. Examples of heterocyclic rings that may be formed thereby include, without limitation, five or six membered rings containing at least one nitrogen, optionally substituted with one or more of the substituents described above. A preferred embodiment is the formation of optionally substituted pyrrolidinyl.

In one embodiment of the invention, R ^aAnd R^bAre defined as they may form, together with the carbon or nitrogen to which they are attached, a monocyclic or bicyclic carbocyclic ring having 5 to 7 ring members in each ring. In addition to nitrogen, the heterocyclic ring may optionally contain 1 or 2 additional heteroatoms selected from N, O and S. The carbocycle and heterocycle may optionally be substituted with one or more substituents selected from C_1-6Alkyl and halogen.

Unless otherwise indicated, all combinations including specific and preferred groups are meant to be included when referring to the preferred embodiments described above.

Another embodiment of the present invention includes a process for preparing a compound of the present invention, comprising:

(i) reacting a compound of formula (a) with a compound of formula (b):

wherein R is¹-R⁶And D is as defined above, n¹Is an integer from 1 to 3, and X is halogen,

wherein R is⁷Is as defined above, n²Is an integer from 0 to 2, provided that n¹And n²Taken together are an integer from 1 to 3, and Y is boronic acid or 4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl; or

(ii) Reacting a compound of formula (c) with a compound of formula (d) or a salt thereof:

wherein R is³-R⁷N, and D are as defined above, and Z is hydroxy, halogen, or succinimidyl ester

Wherein R is¹And R²Is as defined above;

(iii) optionally to R¹-R⁷And any of the D groups are modified;

(iv) (iv) optionally treating the compound of formula (I) prepared in steps (I) to (iii) above with an acid to obtain the corresponding acid addition salt;

(v) (iv) optionally treating the compound of formula (I) prepared in steps (I) to (iii) above with a base to give the corresponding free base; and

(vi) optionally separating the mixture of stereoisomers of the compound of formula (I) prepared in steps (I), (ii), (iii), (iv) or (v) above to give a single stereoisomer.

The present invention includes methods of treating conditions involving abnormal bone resorption. Such conditions include, without limitation, osteoporosis, glucocorticoid-induced osteoporosis, paget's disease, abnormally increased bone turnover, periodontal disease, tooth loss, bone fractures, rheumatoid arthritis, osteoarthritis, periprosthetic osteolysis, incomplete osteogenesis, metastatic bone disease, malignant hypercalcemia, and multiple myeloma. A preferred embodiment includes a method for treating osteoporosis and metastatic bone disease. A more preferred embodiment includes a method of treating osteoporosis.

Representative compounds of the invention are disclosed in tables I-IV below:

shown in Table 1 below is the formula¹、R²、R⁴、R⁵And R⁸A compound of formula (I) which is hydrogen:

in (1)C，C) Stereochemistry of	R	R	-(D)n-R
				RS，S	2-methylpropyl radical	CF	Phenyl radical
RS，S	2-methylpropyl radical	CF	4' - (4-tert-Butoxycarbonylpiperazin-1-yl) -biphenyl-4-yl
				RS，S	2-methylpropyl radical	CF	4' - (piperazin-1-yl) -biphenyl-4-yl
RS，S	2-methylpropyl radical	CF	4' - [ (4- (2-hydroxyethyl) piperazin-1-yl) -biphenyl-4-yl
				RS，S	2-methylpropyl radical	CF	4' - [ (4- (2-hydroxy-2-methylpropyl) piperazin-1-yl) -biphenyl-4-yl
RS，R	2-methylpropyl radical	CF	4-bromophenyl radical
				RS，R	2-methylpropyl radical	CF	4' -methylsulfonylbiphenyl-4-yl
RS，R	2-methylpropyl radical	CF	4' -morpholin-4-ylsulfonylbiphenyl-4-yl

RS，R	2-methylpropyl radical	CF	4' -N-methylaminosulfonylbiphenyl-4-yl
				R，S	2-methylpropyl radical	CF	4-pyridin-4-ylphenyl
RS，S	2-methylpropyl radical	CF	4-N, N-dimethylaminocarbonylphenyl
				R，S	2-methylpropyl radical	CF	4- (pyridin-4-yl-1-N-oxide) phenyl
RS，S	2-methylpropyl radical	CF	4- [6- (1-hydroxy-1-methylethyl) pyridin-3-yl-1-N-oxide]Phenyl radical
				RS，S	2-methylpropyl radical	CF	4- (6-methylsulfonylpyridin-3-yl) -phenyl
RS，S	2-methylpropyl radical	CF	4' - (methylsulfinyl) biphenyl-4-yl
				RS，S	2-methylpropyl radical	CF	4-morpholin-4-ylphenyl
RS，S	2-methylpropyl radical	CF	4-piperazin-1-ylphenyl
				RS，S	2-methylpropyl radical	2, 4, 6-trifluorophenyl	4-bromophenyl radical
RS，S	2-methylpropyl radical	CF	4-Cyclopropylaminocarbonylphenyl
				RS，S	2-methylpropyl radical	CF	4' -methylthiobiphenyl-4-yl
RS，S	2-methylpropyl radical	CF	4- (2-methylquinolin-7-yl) phenyl
				RS，S	2-methylpropyl radical	CF	4- (1H-indol-5-yl) phenyl
RS，S	2-methylpropyl radical	CF	4-carboxyphenyl radical
				RS，S	2-methylpropyl radical	CF	3-Acetylaminobiphenyl-4-yl
RS，S	2-methylpropyl radical	CF	4-piperidin-4-ylphenyl
				RS，S	2-methylpropyl radical	CF	4- (4-pyridin-2-ylpiperazin-1-yl) phenyl
RS，S	2-methylpropyl radical	2, 4, 6-trifluorophenyl	4-pyridin-4-ylphenyl
				RS，S	2-methylpropyl radical	CF	4- [2- (4-methylpiperazin-1-yl) -1, 3-thiazol-4-yl]-phenyl radical

RS，S	2-methylpropyl radical	CF	4- (4-ethylpiperazin-1-yl) phenyl
				RS，S	2-methylpropyl radical	CF	4' - (4- (2-fluoroethyl) piperazin-1-yl) -biphenyl-4-yl
RS，S	2-methylpropyl radical	CF	4- (4-methylpiperazin-1-yl-carbonyl) phenyl
				RS，S	2-methylpropyl radical	CF	4' -dimethylaminobiphenyl-4-yl
RS，S	2-methylpropyl radical	CF	4- (piperazin-1-ylcarbonyl) phenyl
				RS，S	2-methylpropyl radical	CF	4- [4- (2-hydroxyethyl) piperazin-1-yl-carbonyl]Phenyl radical
R，S	2-methylpropyl radical	CF	4- [4- (2-fluoroethyl) piperazin-1-yl-carbonyl]Phenyl radical
				RS，S	2-methylpropyl radical	CF	4- [4- (2-hydroxy-2-methylpropyl) -piperazin-1-ylcarbonyl]Phenyl radical
R，S	2-methylpropyl radical	CF	4-cyanomethylaminocarbonylaminophenyl
				RS，RS	Cyclopropyl methyl group	CF	4-bromophenyl radical
RS，RS	Cyclopropyl methyl group	CF	4-pyridin-4-ylphenyl
				S，S	2-methylpropyl radical	CF	4-morpholin-4-ylcarbonylphenyl
RS，S	2-methylpropyl radical	CF	4' - (pyridin-4-yl) biphenyl-4-yl
				S，S	2-methylpropyl radical	CF	4- (2-methylpyridin-5-yl) phenyl
RS，S	2-methylpropyl radical	CF	5-Phenylthiophen-2-yl
				RS，S	2-methylpropyl radical	CF	4-quinolin-8-ylphenyl
RS，S	2-methylpropyl radical	CF	Biphenyl-4-yl
				S，S	2-methylpropyl radical	CF	4-pyridin-2-ylphenyl
S，S	2-methylpropyl radical	CF	4- [3- (3-trifluoromethylphenyl) -oxadiazol-5-yl]-phenyl radical
				RS，S	2-methylpropyl radical	CF	4' - (aminosulfonyl) biphenyl-4-yl
S，S	2-methylpropyl radical	CF	4' - (N-methyl-N-methoxyaminocarbonyl) -phenyl
				RS，S	2-methylpropyl radical	CF	4- (3-hydroxy-3-methylbut-1-ynyl) -phenyl
S，S	2-methylpropyl radical	CF	4- (trans-3-hydroxy-3-methylbutane-1-)

			Alkenyl) phenyl
				R，S	2-methylpropyl radical	CF	4- (3-hydroxy-3-methylbutyl) phenyl
S，S	2-methylpropyl radical	CFCF	4-bromophenyl radical
				S，S	2-methylpropyl radical	CFCF	4-pyridin-4-ylphenyl
S，S	2-methylpropyl radical	CF	4- (2-methyl-1, 3-thiazol-4-yl) phenyl
				RS，S	2-methylpropyl radical	CF	4- (3-tert-butyl-1, 2, 4-triazin-5-yl) -phenyl
S，S	2-methylpropyl radical	CF	4' -Fluorobiphenyl-4-yl
				S，S	2-methylpropyl radical	CF	4-methoxycarbonylphenyl
S，S	2-methylpropyl radical	CF	4- (E-2-quinolin-2-ylvinyl) phenyl
				RS，S	2-methylpropyl radical	CF	3' -Methylsulfonylbiphenyl-4-yl
RS，S	2-methylpropyl radical	CF	4' -Carboxybiphenyl-4-yl
				S，S	2-methylpropyl radical	CFCF	4' -methylthiobiphenyl-4-yl
R，S	2-methylpropyl radical	CF	1, 3-Thiazol-2-Yl
				S，S	2-methylpropyl radical	CF	4' -Methoxybiphenyl-4-yl
RS，S	2-methylpropyl radical	CF	4' - (N-methyl-N-methoxyamino) -biphenyl-4-yl
				S，S	2-methylpropyl radical	CF	4-methoxyphenyl radical
S，S	2-methylpropyl radical	CFCF	4' -methylsulfonylbiphenyl-4-yl
				RS，S	2-methylpropyl radical	CF	4- [2- (3-Methylsulfonylphenyl) -1, 3-thiazol-4-yl]Phenyl radical
S，S	2-methylpropyl radical	CF	4- [2- (1H-pyrazol-4-yl) -1, 3-thiazol-4-ylphenyl
				S，S	2-methylpropyl radical	CF	4- (4-methylsulfonyl-benzylthio-methyl) phenyl
S，S	2-methylpropyl radical	CF	4- (3-methyl- [1, 2, 4 ]]Oxadiazol-5-yl) -phenyl
				S，S	2-methylpropyl radical	CF	4- (3-chloropyridin-6-yl) -phenyl
S，S	2-methylpropyl radical	CF	3 '-aminosulfonyl-4' -bromobiphenyl-

			4-radical
				S，S	2-methylpropyl radical	CF	3 '-methylsulfonyl-4' -bromobiphenyl-4-yl
S，S	2-methylpropyl radical	CF	4-phenoxyphenyl
				S，S	2-methylpropyl radical	CF	4- [3- (5-Bromopyridin-3-yl) - [1, 2, 4 ]]Oxadiazol-5-yl]-phenyl radical
S，S	2-methylpropyl radical	CF	4- (Phenylthiomethyl) -phenyl
				S，S	2-methylpropyl radical	CF	4- (benzoyl) phenyl
S，S	2-methylpropyl radical	CF	4' -Bromobiphenyl-4-yl
				RS，S	2-methylpropyl radical	CF	4' - [ 4-methylsulfonylpiperazin-1-yl]-biphenyl-4-yl
S，S	2-methylpropyl radical	CF	4- (4-Chloropyridin-3-yl) -phenyl
				S，S	2-methylpropyl radical	CF	4 '-acetylamino-2' -methylbiphenyl-4-yl
S，S	2-methylpropyl radical	CF	4' -Trifluoromethanesulfonylbiphenyl-4-yl
				S，S	2-methylpropyl radical	CF	4- (4-fluorobenzoylaminomethyl) -phenyl
S，S	2-methylpropyl radical	CF	4- (thien-2-ylcarbonyl) -phenyl
				S，S	2-methylpropyl radical	CF	4-methylsulfonylphenyl
S，S	2-methylpropyl radical	CF	4- (1, 3-Thiazol-2-ylcarbonyl) -phenyl
				S，S	2-methylpropyl radical	CF	4- (6-methoxypyridin-3-yl) -phenyl
S，S	2-methylpropyl radical	CF	4- (6-methoxypyridin-2-yl) -phenyl
				S，S	2-methylpropyl radical	CF	4-ethylsulfonylbiphenyl-4-yl
S，S	2-methylpropyl radical	CF	4- (3- (2-chloro-6-fluorophenyl) -5-methyl-isoxazol-4-ylcarbonyl-aminomethyl) phenyl
				S，S	2-methylpropyl radical	CF	4- (cis-2- (4-methylsulfonylphenyl) -vinyl) -phenyl

S，S	2-methylpropyl radical	CF	4- (9-chloro-3-methyl-4-oxo-isoxazolo [4, 3-c)]-quinolin-5 (H) ylmethyl) phenyl
				S，S	2-methylpropyl radical	CF	4 '-methoxy-3' -methylsulfonyl-biphenyl-4-yl
RS，S	2-methylpropyl radical	CF	3-bromophenyl radical
				S，S	2-methylpropyl radical	CF	4' - (4-methylsulfonylphenyl) biphenyl-4-yl
S，S	2-methylpropyl radical	CF	4' - (4-isopropylsulfonylphenyl) biphenyl-4-yl
				S，S	2-methylpropyl radical	CF	4 '-methylsulfonyl-2' - (4-chloro-phenyl) -biphenyl-4-yl
S，S	2-methyl radicalPropyl radical	CF	4 '-methylsulfonyl-2' -methoxy-biphenyl-4-yl
				S，S	2-methylpropyl radical	CF	4- (4-bromo-1, 3-thiazol-2-yl) -phenyl
S，S	2-methylpropyl radical	CF	2 '-chloro-4' -methylsulfonyl-biphenyl-4-yl
				S，S	1-methyl-cyclopropyl-methyl	CF	4-bromophenyl radical
S，S	1-methyl-cyclopropyl-methyl	CF	4' -methylsulfonylbiphenyl-4-yl
				RS，S	2-methylpropyl radical	CF	2-bromothien-5-yl
S，S	2-methylpropyl radical	CF	4-thiophen-3-ylphenyl
				S，S	2-methylpropyl radical	CF	4-pyridin-2-ylphenyl
S，S	2-methylpropyl radical	CF	4- (4-methylpyridin-2-yl) phenyl
				S，S	2-methylpropyl radical	CF	2' -Fluorobiphenyl-4-yl
S，S	2-methylpropyl radical	CF	4- (3, 5-dimethylisoxazol-4-yl) phenyl
				S，S	2-methylpropyl radical	CF	4' -Hydroxymethylbiphenyl-4-yl
S，S	2-methylpropyl radical	CF	4' -Cyanobiphenyl-4-yl

S，S	2-methylpropyl radical	CF	3 ', 4' -Difluorobiphenyl-4-yl
				S，S	2-methylpropyl radical	CF	2' -methoxycarbonylbiphenyl-4-yl
S，S	2-methylpropyl radical	CF	3' -methoxycarbonylbiphenyl-4-yl
				S，S	2-methylpropyl radical	CF	3 ', 4' -Dimethoxybiphenyl-4-yl
S，S	2-methylpropyl radical	CF	2' -trifluoromethyl biphenyl-4-yl
				S，S	2-methylpropyl radical	CF	3 ', 4' -Dichlorobiphenyl-4-yl
S，S	2-methylpropyl radical	CF	3' -Formylbiphenyl-4-yl
				S，S	2-methylpropyl radical	CF	4- (2-oxo-2, 3-dihydrobenzothiazol-6-yl) -phenyl
S，S	2-methylpropyl radical	CF	4- (5-bromopyridin-3-yl) phenyl
				S，S	2-methylpropyl radical	CF	4' -trifluoromethoxy-biphenyl-4-yl
S，S	2-methylpropyl radical	CF	4- (1H-indol-4-yl) phenyl
				S，S	2-methylpropyl radical	CF	4- (pyrimidin-5-yl) phenyl
S，S	2-methylpropyl radical	CF	4- (quinolin-3-yl) phenyl
				S，S	2-methylpropyl radical	CF	4- (1, 3-thiazol-2-yl) phenyl
S，S	2-methylpropyl radical	CF	4' -Methoxycarbonylbiphenyl-4-yl
				S，S	2-methylpropyl radical	CF	4- (pyrimidin-2-yl) phenyl
S，S	2-methylpropyl radical	CF	4- (3-methylpyridin-2-yl) phenyl
				S，S	2-methylpropyl radical	CF	4- (furan-3-yl) phenyl
S，S	2-methylpropyl radical	CF	4- (pyridin-3-yl) phenyl
				S，S	2-methylpropyl radical	CF	4' - (morpholin-4-ylsulfonyl) biphenyl-4-yl
S，S	2-methylpropyl radical	CF	4- (trans-2-methylsulfonylphenyl-vinyl) -phenyl
				S，S	2-methylpropyl radical	CF	Biphenyl-4-yl
R，S	2-methylpropyl radical	CF	4' -methylsulfonylbiphenyl-4-yl
				S，S	2-methylpropyl radical	CF	4-bromobiphenyl-4-yl
S，S	2-methylpropyl radical	CF	4-pyridin-4-ylphenyl
				S，S	2-methylpropyl radical	CF	4' - (pyridin-4-yl) biphenyl-4-yl
S，S	2-methylpropyl radical	CF	4' -methylthiobiphenyl-4-yl
				S，S	2-methylpropyl radical	CF	4' -methylsulfonylbiphenyl-4-yl

S，S	2-methylpropyl radical	CF	4- (3-hydroxy-3-methylbutenyl) phenyl
				S，S	2-methylpropyl radical	CF	4- (3-hydroxy-3-methylbutyl) phenyl
S，S	2-methylpropyl radical	CF	4' -Aminosulfonylbiphenyl-4-yl
				RS，S	2-methylpropyl radical	CF	4' -piperazin-1-ylbiphenyl-4-yl
R，S	2-methylpropyl radical	CF	4-cyanomethylaminocarbonylaminophenyl
				RS，S	2-methylpropyl radical	CF	4- (4- (2-fluoroethyl) piperazin-1-yl-carbonyl) phenyl
RS，S	2-methylpropyl radical	CF	4- (4-methylpiperazin-1-ylcarbonyl) -phenyl
				S，S	2-methylpropyl radical	CF	4- (pyridin-3-yl-N-oxide) phenyl
RS，S	2-methylpropyl radical	CF	4' - (piperazin-1-yl) biphenyl-4-yl
				S，S	2-methylpropyl radical	Thien-2-yl	4-bromophenyl radical
R，S	2-methylpropyl radical	4-trifluoromethoxy-phenyl	4-bromophenyl radical
				S，S	2-methylpropyl radical	4-trifluoromethoxy-phenyl	4' -methylsulfonylbiphenyl-4-yl
S，S	2-methylpropyl radical	Thien-2-yl	4' -methylsulfonylbiphenyl-4-yl
				S，S	2-methylpropyl radical	Thien-2-yl	4' - (tert-butoxycarbonylpiperazin-1-yl) biphenyl-4-yl
S，S	2-methylpropyl radical	Thien-2-yl	4' -piperazin-1-ylbiphenyl-4-yl
				S，S	2-methylpropyl radical	4-fluoro-phenyl	4' -methylsulfonylbiphenyl-4-yl
S，S	2-methylpropyl radical	Furan-2-yl	4' -bromophenyl radical
				S，S	2-methylpropyl radical	Furan-2-yl	4' -methylsulfonylbiphenyl-4-yl
RS，S	N-propyl radical	CF	4-bromophenyl radical
				RS，S	N-propyl radical	CF	4' -methylsulfonylbiphenyl-4-yl
R，S	2-methylpropyl radical	4-CF-phenyl radical	4-bromophenyl radical
				S，S	2-methylpropyl radical	4-CF-phenyl radical	4' -methylsulfonylbiphenyl-4-yl

S，S	N-propyl radical	CF	4' -methylsulfonylbiphenyl-4-yl
				RS，S	N-propyl radical	CF	4' - (4-Cyclopropylpiperazin-1-yl) -biphenyl-4-yl
R，S	2-methylpropyl radical	4-chloro-phenyl	4-bromophenyl radical
				S，S	2-methylpropyl radical	4-chloro-phenyl	4' -methylsulfonylbiphenyl-4-yl
S，S	2-methylpropyl radical	3-methyl-thiophen-2-yl	4-bromophenyl radical
				S，S	2-methylpropyl radical	Thien-3-yl	4-bromophenyl radical
RS，RS	2-methylpropyl radical	2, 4-difluoro-phenyl	4-bromophenyl radical
				S，S	2-methylpropyl radical	2, 4-difluoro-phenyl	4' -methylsulfonylbiphenyl-4-yl
S，S	2-methylpropyl radical	Thien-3-yl	4' -methylsulfonylbiphenyl-4-yl
				S，S	2-methylpropyl radical	3-methyl-thiophen-2-yl	4' -methylsulfonylbiphenyl-4-yl
S，S	2-methylpropyl radical	3-methyl-thiophen-2-yl	4' - (4-Cyclopropylpiperazin-1-yl) -biphenyl-4-yl
				S，S	2-methylpropyl radical	Thien-3-yl	4' - (4-Cyclopropylpiperazin-1-yl) -biphenyl-4-yl
RS，S	3, 3, 3-trifluoropropyl radical	CF	4-bromophenyl radical
				S，S	3, 3, 3-trifluoropropyl radical	CF	4' -methylsulfonylbiphenyl-4-yl
S，S	2-methylpropyl radical	Furan-3-yl	4' -methylsulfonylbiphenyl-4-yl
				S，S	2-methylpropyl radical	4-bromo-thiophen-2-yl	4-bromophenyl radical
S，S	2-methylpropyl radical	4- (4-methyl-sulfonyl-phenyl) -thiophen-2-yl	4' -methylsulfonylbiphenyl-4-yl
				S，S	2-methylpropyl radical	Thien-3-yl	4' -Aminosulfonylbiphenyl-4-yl

S，S	N-propyl radical	CF	4' -methylsulfonylbiphenyl-4-yl
				RS，S	N-propyl radical	Pyridin-4-yl	4-bromophenyl radical
RS，S	N-propyl radical	Thiazol-2-yl	4-bromophenyl radical
				S，S	2-methylpropyl radical	Thiazol-2-yl	4-bromophenyl radical
S，S	2-methylpropyl radical	Thiazol-2-yl	4' -methylsulfonylbiphenyl-4-yl
				RS，S	2-methylpropyl radical	1H-tetrazol-5-yl	4-bromophenyl radical
S，S	2-fluoro-2-methylpropyl	CF	4' -methylsulfonylbiphenyl-4-yl
				S，S	2S-Trifluoromethylpropyl radical	CF	4' -methylsulfonylbiphenyl-4-yl
S，S	2S-Trifluoromethylpropyl radical	CF	4' -methylthiobiphenyl-4-yl
				S，S	2-methylpropyl radical	CFCF	4- (6-methylpyridin-3-yl) phenyl
S，S	2-methylpropyl radical	CF	4' - (1-hydroxyethyl) biphenyl-4-yl
				S，S	2-methylpropyl radical	CF	4' - (2, 2, 2-trifluoro-1-hydroxyethyl) biphenyl-4-yl
S，S	2R-Trifluoromethylpropyl radical	CF	4' - (methylsulfonyl) biphenyl-4-yl
				S，S	2-methylpropyl radical	CFCF	4- (1, 3-thiazol-2-yl) phenyl
S，S	2-methylpropyl radical	CF	4- (5-methyl-1, 3-thiazol-2-yl) phenyl
				S，S	2-methylpropyl radical	CF	4- (4-methyl-1, 3-thiazol-2-yl) phenyl
S，S	2-methylpropyl radical	CF	4- (4, 5-dimethyl-1, 3-thiazole-2-)Radical) phenyl
				S，S	2-methylpropyl radical	CFCF	4- (2-hydroxy-2-methylpropylsulfonyl) biphenyl-4-yl

In which R is set forth in Table II below¹And R²And the carbon atom to which they are attached together form a cyclopropyl group, R⁴、R⁵And R⁸A compound of formula (I) which is hydrogen:

in (1)C，C) Stereochemistry of	R	R	-(D)n-R
				RS，S	2-methylpropyl radical	CF	4-bromophenyl radical
S，S	2-methylpropyl radical	CF	4' -methylsulfonylbiphenyl-4-yl
				S，S	2-methylpropyl radical	3-methyl-thiophen-2-yl	4-bromophenyl radical
S，S	2-methylpropyl radical	3-methyl-thiophen-2-yl	4' -methylsulfonylbiphenyl-4-yl
				S，S	N-propyl radical	CF	4' -methylsulfonylbiphenyl-4-yl
S，S	N-propyl radical	CF	4-bromophenyl radical
				S，S	2-methylpropyl radical	Thien-3-yl	4-bromophenyl radical
S，S	2-methylpropyl radical	Thien-3-yl	4' -methylsulfonylbiphenyl-4-yl
				S，S	N-propyl radical	CF	4' -Aminosulfonylbiphenyl-4-yl
S，S	2-methylpropyl radical	Thien-3-yl	4' -Aminosulfonylbiphenyl-4-yl
				S，S	N-propyl radical	CF	4 '-methoxy-3' -methylsulfonylbiphenyl-4-yl
S，S	N-propyl radical	CF	4- (2-methylpyridin-4-yl) phenyl
				S，S	3, 3, 3-trifluoropropyl radical	CF	4' -methylsulfonylbiphenyl-4-yl
S，S	N-propyl radical	CF	4- (1H-pyrazol-3-yl) phenyl
				S，S	N-propyl radical	CF	4' - (1-hydroxy-1-methylethyl) -biphenyl-4-yl
S，S	N-propyl radical	CF	4- (5-methylpyridin-2-yl) phenyl
				S，S	N-propyl radical	CF	4' -acetylbiphenyl-4-yl
S，S	N-propyl radical	CF	2 ', 4' -Difluorobiphenyl-4-yl
				S，S	N-propyl radical	CF	3 ', 4' -Difluorobiphenyl-4-yl
S，S	N-propyl radical	CF	3 '-chloro-4' -fluorobiphenyl-4-yl

S，S	N-propyl radical	CF	4' -Methylsulfonylamino-biphenyl-4-yl
				S，S	N-propyl radical	CF	4' -chlorobiphenyl-4-yl
S，S	N-propyl radical	CF	4 '-chloro-3' -methylbiphenyl-4-yl
				S，S	N-propyl radical	CF	4 '-chloro-2' -methylbiphenyl-4-yl
S，S	N-propyl radical	CF	4' -indol-5-ylphenyl
				S，S	N-propyl radical	CF	3' -Methylsulfonylamino-biphenyl-4-yl
S，S	N-propyl radical	CF	4' -Fluorobiphenyl-4-yl
				S，S	N-propyl radical	CF	4 '-fluoro-3' -methylbiphenyl-4-yl
S，S	N-propyl radical	CF	3 '-fluoro-4' -methylbiphenyl-4-yl
				S，S	N-propyl radical	CF	4' -trifluoromethoxybiphenyl-4-radical
S，S	N-propyl radical	CF	4' -Methylbiphenyl-4-yl
				S，S	N-propyl radical	CF	4' -Cyanobiphenyl-4-yl
S，S	N-propyl radical	CF	4' -Methoxybiphenyl-4-yl
				S，S	N-propyl radical	CF	4- (3, 4-methylenedioxyphenyl) phenyl
S，S	N-propyl radical	CF	4' -Methoxycarbonylbiphenyl-4-yl
				S，S	2-methylpropyl radical	Thiazol-2-yl	4-bromophenyl radical
S，S	N-propyl radical	CF	4' -trifluoromethyl biphenyl-4-yl
				S，S	N-propyl radical	CF	2' -trifluoromethyl biphenyl-4-yl
RS，S	2-methylpropyl radical	Thiazol-2-yl	2 ', 4' -Difluorobiphenyl-4-yl
				RS，S	2-methylpropyl radical	Thiazol-2-yl	4' -methylsulfonylbiphenyl-4-yl
S，S	2-methylpropyl radical	4-bromo-thiophen-2-yl	4-bromophenyl radical
				S，S	2-methylpropyl radical	CF	4-methylphenyl radical
S，S	2-methylpropyl radical	CF	4- (1H-pyrazol-3-yl) phenyl
				S，S	2-methylpropyl radical	CF	4- (2-methyl-1, 3-oxazol-4-yl) phenyl
S，S	2-methylpropyl radical	CF	4- (2-methylpyridine-4-1) phenyl
				S，S	2-methylpropyl radical	CF	4- (4-methylpyridin-3-yl) phenyl

S，S	2-methylpropyl radical	CF	3' -acetylbiphenyl-4-yl
				S，S	2-methylpropyl radical	CF	5- [4- (1-hydroxy-1-methylethyl) -phenyl]Pyridin-2-yl
S，S	2-methylpropyl radical	CF	4 '-methoxy-3' -methylsulfonyl-biphenyl-4-yl
				S，S	2-methylpropyl radical	CF	3 '-aminosulfonyl-4' -methoxy-biphenyl-4-yl
S，S	2-methylpropyl radical	CF	4- (6-methoxypyridin-3-yl) phenyl
				S，S	2-methylpropyl radical	CFCF	4- (5-methylpyridin-2-yl) phenyl
S，S	2-methylpropyl radical	CF	4- (5-methylsulfonylpyridin-2-yl) phenyl
				S，S	2-methylpropyl radical	CF	4- (5-methylpyridin-2-yl) phenyl
S，S	2-fluoro-2-methylpropyl	CF	4' -methylsulfonylbiphenyl-4-yl
				S，S	2-fluoro-2-methylpropyl	CF	2 '-methyl-4' -methylsulfonyl-biphenyl-4-yl
S，S	2-methylpropyl radical	CF	5- (quinolin-6-yl) pyridin-2-yl
				S，S	2-methylpropyl radical	CHF	4' -methylsulfonylbiphenyl-4-yl
S，S	2-methylpropyl radical	CFCF	4' -acetylbiphenyl-4-yl
				S，S	2-methylpropyl radical	CF	6-chloropyridin-3-yl
S，S	2-methylpropyl radical	CF	5- (4-acetylphenyl) pyridin-2-yl
				S，S	2-methylpropyl radical	CF	6- (4-acetylphenyl) pyridin-3-yl
S，S	2-methylpropyl radical	CF	5- (3-acetylphenyl) pyridin-2-yl
				S，S	2-methylpropyl radical	CF	5- [4- (1-hydroxyethyl) phenyl]-pyridin-2-yl
S，S	2-methylpropyl radical	CF	4- [2- (1H-pyrazol-4-yl) -1, 3-thiazol-4-yl]Phenyl radical
				S，S	2-methylpropyl radical	CF	4- (2-methyl-1, 3-thiazol-4-yl) -phenyl
S，S	2-methylpropyl radical	CF	4- (2-methylpyridin-4-yl) phenyl
				S，S	2-methylpropyl radical	CF	4- (2-methylpyridin-3-yl) phenyl

S，S	2-fluoro-2-methylpropyl	CF	3' -acetylbiphenyl-4-yl
				S，S	2-fluoro-2-methylpropyl	CF	4- (1H-pyrazol-3-yl) phenyl
S，S	2-methylpropyl radical	CF	5- (4-Methylsulfonylphenyl) -pyridin-2-yl
				S，S	2-methylpropyl radical	CF	4' - (1-hydroxy-1-methylethyl) -biphenyl-4-yl
S，S	2S-Trifluoromethylpropyl radical	CF	4' -methylsulfonylbiphenyl-4-yl
				S，S	2S-Trifluoromethylpropyl radical	CF	4' -methylthiobiphenyl-4-yl
S，S	2-methylpropyl radical	CFCF	4- (6-methylpyridin-3-yl) phenyl
				S，S	2-methylpropyl radical	CF	4- (6-methylpyridin-3-yl) phenyl
S，S	2-methylpropyl radical	CFCF	4- (1-hydroxy-1-methylethyl) -biphenyl-4-yl
				S，S	2-methylpropyl radical	CFCF	4' -methylsulfonylbiphenyl-4-yl
S，S	2-methylpropyl radical	CFCF	4- (6-methoxypyridin-2-yl) phenyl
				S，S	2R-Trifluoromethylpropyl radical	CF	4' -methylsulfonylbiphenyl-4-yl
S，S	2-methyl radicalPropyl radical	CF	4- (1, 3-thiazol-2-yl) phenyl
				S，S	2-methylpropyl radical	CF	4- (5-methyl-1, 3-thiazol-2-yl) -phenyl
S，S	2-methylpropyl radical	CF	4- (4-methyl-1, 3-thiazol-2-yl) -phenyl
				S，S	2-fluoro-2-methylpropyl	CF	4' -ethylsulfonylbiphenyl-4-yl
S，S	2-fluoro-2-methylpropyl	CF	4-pyridin-3-ylphenyl
				S，S	2-fluoro-2-methylpropyl	CF	4 '-methoxy-3' -methylsulfonyl-biphenyl-4-yl

S，S	2-methylpropyl radical	CF	4' - (2-hydroxy-2-methyl-propylsulfonyl) biphenyl-4-yl
				S，S	2-methylpropyl radical	CF	2 '-methyl-4' -methylsulfonyl-biphenyl-4-yl
S，S	2-methylpropyl radical	CF	4' -ethylsulfonylbiphenyl-4-yl
				S，S	2-fluoro-2-methylpropyl	CF	4' -Aminosulfonylbiphenyl-4-yl

This is set forth in Table III belowIn R³And R⁴Together with the carbon atom to which they are attached form cyclohexyl, R¹、R⁵And R⁸A compound of formula I which is hydrogen:

in (1)C) Stereochemistry of	R	R	-(D)n-R
				RS	H	CF	Phenyl radical
RS	H	CF	4-bromophenyl radical
				RS	H	CF	4' -piperazin-1-yl) biphenyl-4-yl

In which R is given in Table IV below¹、R⁴、R⁵And R⁸A compound of formula I which is hydrogen:

in (1)C，C，C) Stereochemistry of	R	R	R	-(D)n-R
					S，S，S	Methyl radical	2-methyl-propyl	CF	4' -methylsulfonylbiphenyl-4-yl
S，S，S	2-methylthioethyl group	2-methyl-propyl	CF	4' -methylsulfonylbiphenyl-4-yl
					S，S，S	2-methylsulfonylethyl	2-methyl-propyl	CF	4' -methylsulfonylbiphenyl-4-yl

Particular embodiments of the present invention include, without limitation:

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl ]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- (2, 2, 2-trifluoro-1-phenylethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- [2, 2, 2-trifluoro-1- (4-fluoro-3-methylphenyl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1R) -2, 2, 2-trifluoro-1- (4-pyridin-3-ylphenyl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (4-pyridin-3-ylphenyl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1R) -2, 2, 2-trifluoro-benzene-1- (4-pyridin-4-ylphenyl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (4-pyridin-4-ylphenyl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1R) -2, 2, 2-trifluoro-1- (4- { [4- (2-fluoroethyl) piperazin-1-yl]Carbonyl } phenyl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- [2, 2, 2-trifluoro-1- (4- { [4- (2-fluoroethyl) piperazin-1-yl group]Carbonyl } phenyl) ethyl]-L-leucinamide;

N²- [1- (1, 1' -Biphenyl-4-yl) -2, 2, 2-trifluoroethyl group]-N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- {2, 2, 2-trifluoro-1- [4- (3-hydroxy-3-methylbut-1-ynyl) phenyl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (3-hydroxy-3-methylbutyl) phenyl ]Ethyl } -L-leucinamide;

N²- [ (1S) -1- (4-bromophenyl) -2, 2, 3, 3, 3-pentafluoropropyl radical]-N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 3, 3, 3-pentafluoro-1- (4-pyridin-4-ylphenyl) propyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (4 '-fluoro-1, 1' -biphenyl-4-yl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- ((1S) -2, 2, 2-trifluoro-1- {4- [ (1E) -3-hydroxy-3-methylbut-1-enyl)]Phenyl } ethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 3, 3, 3-Pentafluoro-1- [4 '- (methylthio) -1, 1' -biphenyl-4-Base of]Propyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 3, 3, 3-Pentafluoro-1- [4 '- (methylsulfonyl) -1, 1' -Biphenyl-4-yl]Propyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (1-oxidopyridin-3-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (morpholin-4-ylcarbonyl) phenyl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (4- { [ methoxy (methyl) amino group]Carbonyl } phenyl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (4-thiophen-3-ylphenyl) ethyl ]-L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (4-methylpyridin-2-yl) phenyl]Ethyl } L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (5-methylpyridin-2-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (2 '-fluoro-1, 1' -biphenyl-4-yl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -1- [4- (3, 5-Dimethylisoxazol-4-yl) phenyl]-2, 2, 2-trifluoroethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (hydroxymethyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N²- [ (1S) -1- (4 '-cyano-1, 1' -biphenyl-4-yl) -2, 2, 2-trifluoroethyl radical]-N¹- (cyano radicals)Methyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -1- (3 ', 4 ' -difluoro-1, 1 ' -biphenyl-4-yl) -2, 2, 2-trifluoroethyl radical]-L-leucinamide;

4' - {1- [1- (cyanomethyl-carbamoyl) -3-methyl-butylamino ] -2, 2, 2-trifluoroethyl } biphenyl-2-carboxylic acid methyl ester;

4' - {1- [1- (cyanomethyl-carbamoyl) -3-methyl-butylamino ] -2, 2, 2-trifluoroethyl } biphenyl-3-carboxylic acid methyl ester;

N¹- (cyanomethyl) -N²- [ (1S) -1- (3 ', 4 ' -dimethoxy-1, 1 ' -biphenyl-4-yl) -2, 2, 2-trifluoroethyl radical ]-L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [2 '- (trifluoromethyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -1- (3 ', 4 ' -dichloro-1, 1 ' -biphenyl-4-yl) -2, 2, 2-trifluoroethyl radical]-L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (3 '-formyl-1, 1' -biphenyl-4-yl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (2-oxo-2, 3-dihydro-1, 3-benzothiazol-6-yl) phenyl]Ethyl } -L-leucinamide;

N²- { (1S) -1- [4- (5-Bromopyridin-3-yl) phenyl]-2, 2, 2-trifluoroethyl } -N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (trifluoromethoxy) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (1H-indole-)4-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (4-pyrimidin-5-ylphenyl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (4-quinolin-3-ylphenyl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (1, 3-thiazol-2-yl) phenyl ]Ethyl } -L-leucinamide;

4' - {1- [1- (cyanomethyl-carbamoyl) -3-methyl-butylamino ] -2, 2, 2-trifluoroethyl } biphenyl-4-carboxylic acid methyl ester;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (4-pyrimidin-2-ylphenyl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (3-methylpyridin-2-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (3-furyl) phenyl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- ((1S) -2, 2, 2-trifluoro-1- {4- [3- (trifluoromethyl) pyridin-2-yl]Phenyl } ethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- ((1S) -2, 2, 2-trifluoro-1- {4- [4- (trifluoromethyl) pyridin-2-yl]Phenyl } ethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- ((1S) -2, 2, 2-trifluoro-1- {4- [5- (trifluoromethyl) pyridin-2-yl]Phenyl } ethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (3 '-methoxy-1, 1' -biphenyl-4-yl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (3 '-methoxy-1, 1' -biphenyl-4-yl) ethyl]-L-leucinamide;

N²- { (1S) -1- [4 ' - (acetylamino) -3 ' -fluoro-1, 1 ' -biphenyl-4-yl ]-2, 2, 2-trifluoroethyl } -N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (3-methylthiophen-2-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (3 '-fluoro-1, 1' -biphenyl-4-yl) ethyl]-L-leucinamide;

N²- { (1S) -1- [4- (5-acetylthiophen-2-yl) phenyl]-2, 2, 2-trifluoroethyl } -N¹- (cyanomethyl) -L-leucinamide;

N²- [ (1S) -1- (3 '-acetyl-1, 1' -biphenyl-4-yl) -2, 2, 2-trifluoroethyl radical]-N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [3 '- (trifluoromethyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (5 ' -fluoro-2 ' -methoxy-1, 1 ' -biphenyl-4-yl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -1- (3 ', 5 ' -difluoro-1, 1 ' -biphenyl-4-yl) -2, 2, 2-trifluoroethyl radical]-L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (2 ', 3', 5 '-trifluoro-1, 1' -biphenyl-4-yl) ethyl]-L-leucinamide;

3- (4' - {1- [1- (cyanomethyl-carbamoyl) -3-methyl-butylamino ] -2, 2, 2-trifluoro-ethyl } -biphenyl-3-yl) -acrylic acid;

N²- { (1S) -1- [4- (9-anthracenyl) phenyl]-2, 2, 2-trifluoroethyl } -N¹- (cyanomethyl) -L-leucinamide;

N²- [ (1S) -1- (4 '-benzoyl-1, 1' -biphenyl-4-yl) -2, 2, 2-trifluoroethyl radical]-N¹- (cyanomethyl) -L-leucinamide;

N²- [ (1S) -1- (3 ' -acetyl-4 ' -hydroxy-1, 1 ' -biphenyl-4-yl) -2, 2, 2-trifluoroethyl radical]-N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -1- [2 '- (cyanomethyl) -1, 1' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- {2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- {2, 2, 2-trifluoro-1- [4 '- (methylsulfinyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- [2, 2, 2-trifluoro-1- (4-morpholin-4-ylphenyl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- { (1R) -2, 2, 2-trifluoro-1- [4- (6-methylpyridin-3-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (6-methylpyridin-3-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- [2, 2, 2-trifluoro-1- (5-phenylthiophen-2-yl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- [2, 2, 2-trifluoro-1- (4-quinolin-8-ylphenyl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (4-pyridin-2-ylphenyl) ethyl]-L-leucinamide;

N²- {1- [4 '- (aminosulfonyl) -1, 1' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -N¹- (cyanomethyl) -L-leucinamide;

N²- { (1S) -1- [4 '- (aminosulfonyl) -1, 1' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylthio) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N²- [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl radical]-N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1R) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (morpholin-4-ylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (isopropylsulfonyl) -1, 1' -biphenyl-4-yl ]Ethyl } -L-leucinamide;

N²- { (1S) -1- [4 '- (aminosulfonyl) -1, 1' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -N¹- (cyanomethyl) -L-leucinamide;

N²- ((1S) -1- { 4' - [ (acetylamino) sulfonyl group]-1, 1' -biphenyl-4-yl } -2, 2, 2-trifluoroethyl) -N¹- (cyanoformazan)Yl) -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [2 ' -methyl-4 ' - (methylsulfonyl) -1, 1 ' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N²- [1- (5-bromothien-2-yl) -2, 2, 2-trifluoroethyl group]-N¹- (cyanomethyl) -L-leucinamide;

N²- [1- (4-bromophenyl) -2, 2, 2-trifluoroethyl group]-N¹- (cyanomethyl) -L-leucinamide;

4- (4' - {1- [1- (cyanomethyl-carbamoyl) -3-methyl-butylamino ] -2, 2, 2-trifluoroethyl) -biphenyl-4-yl) -piperazine-1-carboxylic acid tert-butyl ester;

N¹- (cyanomethyl) -N²- [2, 2, 2-trifluoro-1- (4 '-piperazin-1-yl-1, 1' -biphenyl-4-yl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- (2, 2, 2-trifluoro-1- { 4' - [4- (2-hydroxyethyl) piperazin-1-yl]-1, 1' -biphenyl-4-yl } ethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- (2, 2, 2-trifluoro-1- { 4' - [4- (2-hydroxy-2-methylpropyl) piperazin-1-yl]-1, 1' -biphenyl-4-yl } ethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- (1- {4- [ (dimethylamino) carbonyl group]Phenyl } -2, 2, 2-trifluoroethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- [2, 2, 2-trifluoro-1- (4 '-piperazin-1-yl-1, 1' -biphenyl-4-yl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- (1- {4- [ (cyclopropylamino) carbonyl]Phenyl } -2, 2, 2-trifluoroethyl) -L-leucinamide;

4- {1- [1- (cyanomethyl-carbamoyl) -3-methyl-butylamino ] -2, 2, 2-trifluoroethyl } -benzoic acid;

N¹- (cyanomethyl) -N²- (2, 2, 2-trifluoro-1- { 4' - [4- (2-fluoroethyl) piperazin-1-yl]-1, 1' -biphenyl-4-yl } ethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- (2, 2, 2-trifluoro-1- {4- [ (4-methylpiperazin-1-yl) carbonyl]Phenyl } ethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- [2, 2, 2-trifluoro-1- (4- { [4- (2-hydroxy-2-methylpropyl) piperazin-1-yl group]Carbonyl } phenyl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (2-methyl-1, 3-thiazol-4-yl) phenyl]Ethyl } -L-leucinamide;

N²- {1- [4- (3-tert-butyl-1, 2, 4-triazin-5-yl) phenyl]-2, 2, 2-trifluoroethyl } -N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- [2, 2, 2-trifluoro-1- (4- {2- [3- (methylsulfonyl) phenyl group ]-1, 3-thiazol-4-yl } phenyl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- ((1S) -2, 2, 2-trifluoro-1- {4- [2- (1H-pyrazol-4-yl) -1, 3-thiazol-4-yl)]Phenyl } ethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- (2, 2, 2-trifluoro-1- {4 '- {4- (methylsulfonyl) piperazin-1-yl } -1, 1' -biphenyl-4-yl } ethyl) -L-leucinamide;

N²- [1- (3-bromophenyl) -2, 2, 2-trifluoroethyl group]-N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- {2, 2, 2-trifluoro-1- [4 '- (methylthio) -1, 1' -biphenyl-3-yl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- [2, 2, 2-trifluoro-1-, (3-pyridin-4-ylphenyl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- [2, 2, 2-trifluoro-1- (4 '-piperazin-1-yl-1, 1' -biphenyl-3-yl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- {2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-3-yl]Ethyl } -L-leucinamide;

n- (cyanomethyl) -1- [ (2, 2, 2-trifluoro-1-phenylethyl) amino ] cyclohexanecarboxamide;

1- { [1- (4-bromophenyl) -2, 2, 2-trifluoroethyl ] amino } -N- (cyanomethyl) cyclohexanecarboxamide;

1- { [2, 2, 2-trifluoro-1- (4 '-piperazin-1-yl-1, 1' -biphenyl-4-yl) ethyl ] amino } cyclohexanecarboxamide;

N¹- (cyanomethyl) -N²- [2, 2, 2-trifluoro-1- (4-piperidin-4-ylphenyl) ethyl group]-L-leucinamide;

N¹- (cyanomethyl) -N²- {2, 2, 2-trifluoro-1- [4- (4-pyridin-2-ylpiperazin-1-yl) phenyl]Ethyl } -L-leucinamide;

N²- [1- (4-bromophenyl) -2, 2, 2-trifluoroethyl group]-N¹- (cyanomethyl) -3-cyclopropylalaninamide;

N¹- (cyanomethyl) -3-cyclopropyl-N²- [2, 2, 2-trifluoro-1- (4-pyridin-4-ylphenyl) ethyl](ii) an alaninamide;

N¹- (cyanomethyl) -N²- [2, 2, 2-trifluoro-1- (4 '-pyridin-4-yl-1, 1' -biphenyl-4-yl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1R) -2, 2, 2-trifluoro-1- (1, 3-thiazol-2-yl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 2-trifluoro-benzene-1- (4 '-methoxy-1, 1' -biphenyl-4-yl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (4-methoxyphenyl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (4 '-pyridin-4-yl-1, 1' -biphenyl-4-yl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (4-phenoxyphenyl) ethyl]-L-leucinamide;

N²- [ (1S) -1- (4 '-bromo-1, 1' -biphenyl-4-yl) -2, 2, 2-trifluoroethyl radical ]-N¹- (cyanomethyl) -L-leucinamide;

N²- { (1S) -1- [4- (4-Chloropyridin-3-yl) phenyl]-2, 2, 2-trifluoroethyl } -N¹- (cyanomethyl) -L-leucinamide;

N²- { (1S) -1- [4 ' - (acetylamino) -2 ' -methyl-1, 1 ' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -N¹- (cyanomethyl) -L-leucinamide;

N²- [ (1S) -1- (1, 1' -biphenyl-4-yl) -2, 2, 2-trifluoroethyl radical]-N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (6-methoxypyridin-3-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (6-methoxypyridin-2-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 "- (methylsulfonyl) -1, 1': 4 ', 1' -terphenyl-4-yl]Ethyl } -L-leucinamide;

N²- [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl radical]-N¹- (cyanomethyl) -3- (1-methylcyclopropyl) -L-alaninamide;

N¹- (cyanomethyl) -3- (1-methylcyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-alaninamide;

N¹- (cyanomethyl) -3- (1-methylcyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylthio) -1, 1' -biphenyl-4-yl ]Ethyl } -L-alaninamide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (4 '-methyl-1, 1' -biphenyl-4-yl) ethyl]-L-leucinamide;

N²- [ (1S) -1- (4 '-acetyl-1, 1' -biphenyl-4-yl) -2, 2, 2-trifluoroethyl radical]-N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (hydroxymethyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N²- [1- (4-bromophenyl) -2, 2, 2-trifluoroethyl group]-N¹- (cyanomethyl) -D-leucinamide;

N¹- (cyanomethyl) -N²- {2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -D-leucinamide;

N¹- (cyanomethyl) -N²- {2-2, 2-trifluoro-1- [4 '- (morpholin-4-ylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -D-leucinamide;

N¹- (cyanomethyl) -N²- (2, 2, 2-trifluoro-1- { 4' - [ (methylamino) sulfonyl group]-1, 1' -biphenyl-4-yl } ethyl) -D-leucinamide;

N¹- (cyanomethyl) -N²- { (1R) -2, 2, 2-trifluoro-1- [4- (1-oxidopyridin-4-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- {2, 2, 2-trifluoro-1- [4- (1-oxidopyridin-4-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- (2, 2, 2-trifluoro-1- {4- [6- (1-hydroxy-1-methylethyl) -1-oxidopyridin-3-yl) ]Phenyl } ethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- (2, 2, 2-trifluoro-1- {4- [6- (methylsulfonyl) pyridin-3-yl]Phenyl } ethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- (2, 2, 2-trifluoro-1- {4- [2- (4-methylpiperazin-1-yl) -1, 3-thiazol-4-yl)]Phenyl } ethyl) -L-leucinamide;

N²- [1- (4-bromophenyl) -2, 2, 2-trifluoroethyl group]-N¹- (1-cyanocyclopropyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- [2, 2, 2-trifluoro-1- (4-piperazin-1-ylphenyl) ethyl]-L-leucinamide;

N²- {1- [3 '- (acetylamino) -1, 1' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- {2, 2, 2-trifluoro-1- [4- (4-propylpiperazin-1-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- {2, 2, 2-trifluoro-1- [4- (piperazin-1-ylcarbonyl) phenyl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- [2, 2, 2-trifluoro-1- (4- { [4- (2-hydroxyethyl) piperazin-1-yl group]Carbonyl } phenyl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (4- {3- [3- (trifluoromethyl) phenyl]-1, 2, 4-oxadiazol-5-yl } phenyl) ethyl]-L-leucinamide;

4- {1- [1- (cyanomethyl-carbamoyl) -3-methyl-butylamino ] -2, 2, 2-trifluoroethyl } -benzoic acid methyl ester;

N¹- (cyanomethyl) -N²- ((1S) -2, 2, 2-trifluoro-1- {4- [ (E) -2-quinolin-2-ylvinyl)]Phenyl } ethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (3-methyl-1, 2, 4-oxadiazol-5-yl) phenyl]Ethyl } -L-leucinamide;

N²- ((1S) -1- {4- [3- (5-bromopyridin-3-yl) -1, 2, 4-oxadiazol-5-yl)]Phenyl } -2, 2, 2-trifluoroethyl) -N¹- (cyanomethyl) -L-leucinamide;

N²- [ (1S) -1- (4-benzoylphenyl) -2, 2, 2-trifluoroethyl radical]-N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (thien-2-ylcarbonyl) phenyl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (1, 3-thiazol-2-ylcarbonyl) phenyl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (4- { (Z) -2- [4- (methylsulfonyl) phenyl]Vinyl } phenyl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (4- { (E) -2- [4- (methylsulfonyl) phenyl]Vinyl } phenyl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (4-isobutyrylphenyl) ethyl]-L-leucinamide;

N²- { (1S) -1- [4- (4-bromo-1, 3-thiazol-2-yl) phenyl ]-2, 2, 2-trifluoroethyl } -N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -1- (4-cyanophenyl) -2, 2, 2-trifluoroethyl radical]-L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -1- (4-ethynylphenyl) -2, 2, 2-trifluoroethyl radical]-L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (2 '-fluoro-1, 1' -biphenyl-4-yl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (1, 3-thiazol-2-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- {2, 2, 2-trifluoro-1- [4 '- (methylthio) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- {2, 2, 2-trifluoro-1- [4- (2-methylquinolin-7-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- {2, 2, 2-trifluoro-1- [4- (1H-indol-5-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- {1- [4 '- (dimethylamino) -1, 1' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -1- (4- { [ (cyanomethyl) amino]Carbonyl } phenyl) -2, 2, 2-trifluoroethyl]-L-leucinamide;

N¹- (cyanomethyl) N²- [ (1R) -1- (4- { [ (cyanomethyl) amino]Carbonyl } phenyl) -2, 2, 2-trifluoroethyl ]-L-leucinamide;

N¹- (cyanomethyl) -N²- {2, 2, 2-trifluoro-1- [3 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

4' - {1- [1- (cyanomethyl-carbamoyl) -3-methyl-butylamino ] -2, 2, 2-trifluoroethyl } -biphenyl-4-carboxylic acid;

4' - {1- [1- (cyanomethyl-carbamoyl) -3-methyl-butylamino ] -2, 2, 2-trifluoroethyl } -biphenyl-4-carboxylic acid methoxy-methyl-amide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- ({ [4- (methylsulfonyl) benzyl)]Thio } methyl) phenyl]Ethyl } -L-leucinamide;

N²- { (1S) -1- [4- (5-Chloropyridin-2-yl) phenyl]-2, 2, 2-trifluoroethyl } -N¹- (cyanomethyl) -L-leucinamide;

N²- { (1S) -1- [3 ' - (aminosulfonyl) -4 ' -bromo-1, 1 ' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -N¹- (cyanomethyl) -L-leucinamide;

N²- { (1S) -1- [4 ' -bromo-3 ' - (methylsulfonyl) -1, 1 ' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- ((1S) -2, 2, 2-trifluoro-1- {4- [ 5-methyl-6- (methylsulfonyl) pyridin-3-yl)]Phenyl } ethyl) -L-leucinamide;

N²- [ (1S) -1- (4- { 5-chloro-3- [4- (methylsulfonyl) phenyl]Pyridin-2-yl } phenyl) -2, 2, 2-trifluoroethyl ]-N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- ((1S) -2, 2, 2-trifluoro-1- {4- [ (phenylthio) methyl group]Phenyl } ethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- ((1S) -2, 2, 2-trifluoro-1- { 4' - [ (trifluoromethyl) sulfonyl group]-1, 1' -biphenyl-4-yl } ethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 2-trifluoro-1 (4- { [ (4-fluorobenzoyl) amino]Methyl } phenyl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (methylsulfonyl) phenyl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -1- [4 '- (ethylsulfonyl) -1, 1' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -L-leucinamide;

N²- ((1S) -1- {4- [ ({ [3- (2-chloro-6-fluorophenyl) -5-methylisoxazol-4-yl)]Carbonyl } amino) methyl]Phenyl } -2, 2, 2-trifluoroethyl) -N¹- (cyanomethyl) -L-leucinamide;

N²- ((1S) -1- {4- [ (9-chloro-3-methyl-4-oxoisoxazolo [4, 3-c)]Quinolin-5 (4H) -yl) methylphenyl]-2, 2, 2-trifluoroethyl } -N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 ' -methoxy-3 ' - (methylsulfonyl) -1, 1 ' -biphenyl-4-yl ]Ethyl } -L-leucinamide;

N²- { (1S) -1- [4 "-chloro-4 '- (methylsulfonyl) -1, 1': 2 ', 1' -terphenyl-4-yl]-2, 2, 2-trifluoroethyl } -N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [2 ' -methoxy-4 ' - (methylsulfonyl) -1, 1 ' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N²- { (1S) -1- [2 ' -chloro-4 ' - (methylsulfonyl) -1, 1 ' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- ((1S) -2, 2, 2-trifluoro-1- { 4' - [ (2-hydroxyethyl) thio)]-1, 1' -biphenyl-4-yl } ethyl) -L-a leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [3 ' -fluoro-4 ' - (methylsulfonyl) -1, 1 ' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- ((1S) -2, 2, 2-trifluoro-1- { 4' - [ (2-hydroxyethyl) sulfonyl]-1, 1' -biphenyl-4-yl } ethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [3 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [ 4' - ({2- [ methoxy (methyl) amino)]-2-oxoethyl } sulfonyl) -1, 1' -biphenyl-4-yl ]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- ((1S) -2, 2, 2-trifluoro-1- { 4' - [ (2-hydroxy-2-methylpropyl) sulfonyl)]-1, 1' -biphenyl-4-yl } ethyl) -L-leucinamide;

N²- { (1S) -1- [4 '- (aminosulfonyl) -1, 1' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -N¹- (1-cyanocyclopropyl) -L-leucinamide;

N²- [ (4-bromophenyl) (2, 4, 6-trifluorophenyl) methyl]-N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- [ (4-pyridin-4-ylphenyl) (2, 4, 6-trifluorophenyl) methyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- [ [4- (4-fluorobenzyl) phenyl group](phenyl) methyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- { phenyl [4- (pyridin-3-ylmethyl) phenyl]Methyl } -L-leucinamide;

N²- { (4-bromophenyl) [4- (methylsulfonyl) phenyl]Methyl } -N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- { [4- (methylsulfonyl) phenyl][4 '- (methylthio) -1, 1' -biphenyl-4-yl]Methyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- { [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl][4- (methylsulfonyl) phenyl group]Methyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- [2, 2, 2-trichloro-1- (4-glycolylphenyl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N ²- [ 2-fluoro-1- (fluoromethyl) -1-phenylethyl group]-L-leucinamide;

N¹- (cyanomethyl) -N²- {2, 2, 2-trifluoro-1- [4- (pyrrolidin-1-ylacetyl) phenyl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- {2, 2, 2-trifluoro-1- [4- (piperazin-1-ylcarbonyl) phenyl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- (2, 2, 2-trifluoro-1- {4- [2- (4-methylpiperazin-1-yl) -1, 3-thiazol-4-yl)]Phenyl } ethyl) -L-leucinamide;

N¹- (1-cyanocyclopropyl) -3- (1-methylcyclopropyl) -N²- (2, 2, 2-trifluoro-1- {4- [1- (2-hydroxyethyl) propyl group]Phenyl } ethyl) -L-alaninamide;

N²- [ [4- (4-tert-butylpiperazin-1-yl) phenyl group](pentafluorophenyl) methyl group]-N¹- (cyanomethyl) -L-leucinamide;

1- {4- [4- (4-methylpiperazin-1-yl) phenyl ] ethyl } piperidine-2-carboxamide;

N²- [ [4- (4-tert-butylpiperazin-1-yl) phenyl group](pyridin-2-yl) methyl]-N¹- (cyanomethyl) -L-leucinamide;

N²- [ [4- (4-tert-butylpiperazin-1-yl) phenyl group][5- (trifluoromethyl) pyridin-2-yl]Methyl radical]-N¹- (cyanomethyl) -L-leucinamide;

(4S) -N- (cyanomethyl) -4-methyl-1- [ (1S) -1- (4-piperazin-1-ylphenyl) ethyl ] -L-prolinamide;

(4S) -N- (cyanomethyl) -4-methyl-1- [ (1R) -1- (4-piperazin-1-ylphenyl) ethyl ] -L-prolinamide;

N- (cyanomethyl) -1- [ (1S) -1- (4-piperazin-1-ylphenyl) ethyl ] -L-prolinamide;

n- (cyanomethyl) -1- [ (1R) -1- (4-piperazin-1-ylphenyl) ethyl ] -L-prolinamide;

n- (cyanomethyl) -4, 4-difluoro-1- [ (1S) -1- (4-piperazin-1-ylphenyl) ethyl ] -L-prolinamide;

N¹- (1-cyanocyclopropyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (4-methylphenyl) ethyl]-L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (1H-pyrazol-3-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (2-methyl-1, 3-oxazol-4-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (4-pyrazin-2-ylphenyl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (2-methylpyridin-4-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (4-methylpyridin-3-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²-{(1S)-2，2，2-trifluoro-1- [4- (1H-pyrazol-4-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (4-pyridin-4-ylphenyl) ethyl]-L-leucinamide;

N²- [ (1S) -1- (3 '-acetyl-1, 1' -biphenyl-4-yl) -2, 2, 2-trifluoroethyl radical]-N¹- (1-cyanocyclopropyl) -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (3 ' -fluoro-4 ' -methyl-1, 1 ' -biphenyl-4-yl) ethyl]-L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- ((1S) -2, 2, 2-trifluoro-1- {5- [4- (1-hydroxy-1-methylethyl) phenyl]Pyridin-2-yl } ethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 3, 3, 3-Pentafluoro-1- [4 '- (1-hydroxy-1-methylethyl) -1, 1' -biphenyl-4-yl]Propyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- [ (1S) -2, 2, 3, 3, 3-pentafluoro-1- (4 '-methyl-1, 1' -biphenyl-4-yl) propyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 3, 3, 3-Pentafluoro-1- [4- (6-methoxypyridin-3-yl) phenyl]Propyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 3, 3, 3-pentafluoro-1- (2 '-fluoro-1, 1' -biphenyl-4-yl) propyl]-L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 ' -methoxy-3 ' - (methylsulfonyl) -1, 1 ' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N²- { (1S) -1- [3 ' - (aminosulfonyl) -4 ' -methoxy-1, 1 ' -biphenyl-4-yl ]-2, 2, 2-trifluoroethyl } -N¹- (1-cyanocyclopropyl) -L-A leucine amide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (6-methoxypyridin-3-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 3, 3, 3-Pentafluoro-1- [4- (5-methylpyridin-2-yl) phenyl]Propyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- ((1S) -2, 2, 2-trifluoro-1- {4- [5- (methylsulfonyl) pyridin-2-yl)]Phenyl } ethyl) -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (5-methylpyridin-2-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [2 ' -methyl-4 ' - (methylsulfonyl) -1, 1 ' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [5- (1H-pyrazol-3-yl) pyridin-2-yl]Ethyl } -L-leucinamide;

N¹- [ (1-cyanocyclopropyl) -N ²- [ (1S) -2, 2, 2-trifluoro-1- (5-quinolin-5-ylpyridin-2-yl) ethyl]-L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (5-quinolin-6-ylpyridin-2-yl) ethyl]-L-leucinamide;

N¹- (1-cyanocyclopropane)Radical) -N²- { (1S) -2, 2-difluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N²- [ (1S) -1- (4 '-acetyl-1, 1' -biphenyl-4-yl) -2, 2, 3, 3, 3-pentafluoropropyl radical]-N¹- (1-cyanocyclopropyl) -L-leucinamide;

N²- [ (1S) -1- (1, 1' -biphenyl-4-yl) -2, 2, 2-trifluoroethyl radical]-N¹- (1-cyanocyclopropyl) -L-leucinamide;

N²- { (1S) -1- [4 '- (aminosulfonyl) -1, 1' -biphenyl-4-yl]-2, 2, 3, 3, 3-pentafluoropropyl } -N¹- (1-cyanocyclopropyl) -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -1- [4- (1-ethoxyvinyl) phenyl]-2, 2, 2-trifluoroethyl } -L-leucinamide;

N²- [ (1S) -1- (4-acetylphenyl) -2, 2, 2-trifluoroethyl radical]-N¹- (1-cyanocyclopropyl) -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (4-isopropylphenyl) ethyl]-L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- [ (1S) -2, 2, 2-trifluoro-1-phenylethyl]-L-leucinamide;

N¹- (1-cyanocyclopropyl) -N ²- { (1S) -2, 2, 2-trifluoro-1- [4- (1-hydroxy-1-methylethyl) phenyl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (1-methylcyclopropyl) phenyl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (2 ', 4', 6 '-trimethyl-1, 1' -biphenyl-4-yl) ethyl]-L-leucinamide;

N²-[(1S) -1- (6-Chloropyridin-3-yl) -2, 2, 2-trifluoroethyl]-N¹- (1-cyanocyclopropyl) -L-leucinamide;

N²- { (1S) -1- [5- (4-acetylphenyl) pyridin-2-yl]-2, 2, 2-trifluoroethyl } -N¹- (1-cyanocyclopropyl) -L-leucinamide;

N²- { (1S) -1- [6- (4-acetylphenyl) pyridin-3-yl]-2, 2, 2-trifluoroethyl } -N¹- (1-cyanocyclopropyl) -L-leucinamide;

N²- [ (1S) -1- [5- (3-acetylphenyl) pyridin-2-yl]-2, 2, 2-trifluoroethyl]-N¹- (1-cyanocyclopropyl) -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- ((1S) -2, 2, 2-trifluoro-1- {5- [4- (1-hydroxyethyl) phenyl]Pyridin-2-yl } ethyl) -L-leucinamide;

N²- [ (1S) -1- (1, 1' -biphenyl-4-yl) -2, 2, 3, 3, 3-pentafluoropropyl radical]-N¹- (cyanomethyl) -L-leucinamide;

N²- [ (1S) -1- (4 '-acetyl-1, 1' -biphenyl-4-yl) -2, 2, 3, 3, 3-pentafluoropropyl radical ]-N¹- (cyanomethyl) -L-leucinamide;

N²- [ (1S) -1- (1, 1' -biphenyl-4-yl) -2, 2, 3, 3, 3-pentafluoropropyl radical]-N¹- (1-cyanocyclopropyl) -L-leucinamide;

N²- (1-benzyl-2, 2, 2-trifluoroethyl) -N¹- (1-cyanocyclopropyl) -L-leucinamide;

N²- [ (1S) -1- (4-tert-butylphenyl) -2, 2, 2-trifluoroethyl radical]-N¹- (1-cyanocyclopropyl) -L-leucinamide;

N²- [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl radical]-N¹- (cyanomethyl) -4-methyl-L-leucinamide;

N²- [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl radical]-N¹- (1-cyanocyclopropyl) -4-methyl-L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- ((1S) -2, 2, 2-trifluoro-1- {4- [2- (1H-pyrazol-4-yl) -1, 3-thiazol-4-yl)]Phenyl } ethyl) -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (2-methyl-1, 3-thiazol-4-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (2-methylpyridin-4-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (2-methylpyridin-3-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (6-methylpyridin-2-yl) phenyl]Ethyl } -L-leucinamide;

N²- [ (1S) -1- (3 '-acetyl-1, 1' -biphenyl-4-yl) -2, 2, 2-trifluoroethyl radical]-N¹- (1-cyanocyclopropyl) -4-fluoro-L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4- (1H-pyrazol-3-yl) phenyl]Ethyl } -L-leucinamide;

N¹- [ (1S) -1-cyanoethyl]-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- [ (1S) -1-cyano-3- (methylthio) propyl]-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- [ (1S) -1-cyano-3- (methylsulfonyl) propyl]-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl-L-leucinamide；

N²- [ (1S) -1- (4-bromophenyl) -2, 2, 3, 3, 3-pentafluoropropyl radical]-N¹- (1-cyanocyclopropyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 3, 3, 3-Pentafluoro-1- [4- (6-methoxypyridin-2-yl) phenyl]Propyl } -L-leucinamide;

N²- [ (1S) -1- (5-Bromopyridin-2-yl) -2, 2, 2-trifluoroethyl radical]-N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- ((1S) -2, 2, 2-trifluoro-1- {5- [4- (methylsulfonyl) phenyl]Pyridin-2-yl } ethyl) -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N ²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (1-hydroxy-1-methylethyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (6 '-methyl-3, 3' -bipyridin-6-yl) ethyl]-L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (6-methoxypyridin-2-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (6-oxo-1, 6-dihydropyridin-2-yl) phenyl]Ethyl } -L-leucinamide;

(4S)-N¹- (cyanomethyl) -5, 5, 5-trifluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

(4S)-N¹- (1-cyanocyclopropyl) -5, 5, 5-trifluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

(4S)-N¹- (cyanomethyl) -5, 5, 5-trifluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylthio) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

(4S)-N¹- (1-cyanocyclopropyl) -5, 5, 5-trifluoro-N²{ (1S) -2, 2, 2-trifluoro-1- [4 '- (methylthio) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

(4S)-N²- [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl radical]-N¹- (cyanomethyl) -5, 5, 5-trifluoro-L-leucinamide;

(4S)-N²- [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl radical]-N¹- (1-cyanocyclopropyl) -5, 5, 5-trifluoro-L-leucinamide;

N²- { (1S) -1- [4- (6-Aminopyridin-3-yl) phenyl]-2, 2, 2-trifluoroethyl } -N¹- (cyanomethyl) -L-leucinamide;

N²- [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl radical]-N¹- (1-cyanocyclopropyl) -4-fluoro-L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 3, 3, 3-Pentafluoro-1- [4- (6-methylpyridin-3-yl) phenyl]Propyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 3, 3, 3-Pentafluoro-1- [4- (6-methylpyridin-3-yl) phenyl]Propyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (6-methylpyridin-3-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (1-hydroxyethyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (2, 2, 2-trifluoro-1-hydroxyethyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 3, 3, 3-Pentafluoro-1- [4 '- (methylthio) -1, 1' -Biphenyl-4-yl]Propyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 3, 3, 3-Pentafluoro-1- [4 '- (1-hydroxy-1-methylethyl) -1, 1' -biphenyl-4-yl ]Propyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 3, 3, 3-Pentafluoro-1- [4 '- (methylsulfonyl) -1, 1' -Biphenyl-4-yl]Propyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 3, 3, 3-Pentafluoro-1- [4- (6-methoxypyridin-2-yl) phenyl]Propyl } -L-leucinamide;

(4R)-N¹- (cyanomethyl) -5, 5, 5-trifluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

(4R)-N¹- (1-cyanocyclopropyl) -5, 5, 5-trifluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 3, 3, 3-pentafluoro-1- (4 '-methyl-1, 1' -biphenyl-4-yl) propyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 3, 3, 3-Pentafluoro-1- [4- (1, 3-thiazol-2-yl) phenyl]Propyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- [ (1S) -1- (4-ethynylphenyl) -2, 2, 3, 3, 3-pentafluoropropyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -1- [4- (cyclopropylethynyl) phenyl]-2, 2, 2-trifluoroethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -1- [4- (cyclopropylethynyl) phenyl ]-2, 2, 2-trifluoroethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (5-methyl-1, 3-thiazol-2-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (1, 3-thiazol-2-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (5-methyl-1, 3-thiazol-2-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -1- [4- (cyclopropylethynyl) phenyl]-2, 2, 3, 3, 3-pentafluoropropyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (4-methyl-1, 3-thiazol-2-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (4-methyl-1, 3-thiazol-2-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -1- [4- (4, 5-dimethyl-1, 3-thiazol-2-yl) phenyl]-2, 2, 2-trifluoroethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -1- [4 '- (ethylsulfonyl) -1, 1' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -4-fluoro-L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- [ (1S) -2, 2, 2-trifluoro-1- (4-pyridin-3-ylphenyl) ethyl ]-L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '-methoxy-3' - (methylsulfonyl) S) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N²- [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl radical]-N¹- (cyanomethyl) -L-alaninamide;

N²- { (1S) -1- [4 '- (aminosulfonyl) -1, 1' -biphenyl-4-yl]-2, 2, 3, 3, 3-pentafluoropropyl } -N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- ((1S) -2, 2, 3, 3, 3-Pentafluoro-1- { 4' - [ (2-hydroxy-2-methylpropyl) sulfonyl)]-1, 1' -biphenyl-4-yl } propyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-alaninamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 3, 3, 3-Pentafluoro-1- [4 '- (isopropylsulfonyl) -1, 1' -biphenyl-4-yl]Propyl } -L-leucinamide;

N¹- (1-cyano-1-methylethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- ((1S) -2, 2, 2-trifluoro-1- { 4' - [ (2-hydroxy-2-methylpropyl) sulfonyl)]-1, 1' -biphenyl-4-yl } ethyl) -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N ²- { (1S) -2, 2, 2-trifluoro-1- [2 ' -methyl-4 ' - (methylsulfonyl) -1, 1 ' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -1- [4 '- (ethylsulfonyl) -1, 1' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -L-leucinamide;

N²- { (1S) -1- [4 '- (aminosulfonyl) -1, 1' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -N¹-(1-cyanocyclopropyl) -4-fluoro-L-leucinamide;

N¹- (cyanomethyl) -N²- { (S) - [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl][4- (trifluoromethoxy) phenyl group]Methyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- { (S) - [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl](thiophen-2-yl) methyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- [ (S) - [4 '-piperazin-4-ium-1-yl-1, 1' -biphenyl-4-yl](Thien-2-yl) methyl]-L-leucinamide mesylate;

N¹- (cyanomethyl) -N²- { (S) - (4-fluorophenyl) [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Methyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- { (S) - [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl][4- (trifluoromethyl) phenyl group]Methyl } -L-leucinamide;

N²- { (S) - (4-chlorophenyl) [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Methyl } -N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-norvalinamide;

N²- [ (S) - (4-bromophenyl) (thiophen-2-yl) methyl]-N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- [ (S) - [4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl](Thien-2-yl) methyl]-L-leucinamide;

N²- { (R) - (4-bromophenyl) [4- (trifluoromethoxy) phenyl]Methyl } -N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- { (S) - [4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl][4- (trifluoromethoxy) phenyl group]Methyl } -L-leucinamide;

N²- [ (S) - (4-bromophenyl) (2-furyl) methyl]-N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- { (S) -2-Furanyl [4 '- (methylsulfonyl) -1, 1' -Biphenyl-4-yl]Methyl } -L-leucinamide;

N²- [1- (4-bromophenyl) -2, 2, 2-trifluoroethyl group]-N¹- (cyanomethyl) -L-norvalinamide;

N²- { (R) - (4-bromophenyl) [4- (trifluoromethyl) phenyl]Methyl } -N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- {1- [4 '- (4-cyclopropylpiperazin-1-yl) -1, 1' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -L-norvalinamide;

N²- [ (R) - (4-bromophenyl) (4-chlorophenyl) methyl]-N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- {2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-norvalinamide;

N²- [ (S) - (4-bromophenyl) (3-methylthiophen-2-yl) methyl]-N¹- (cyanomethyl) -L-leucinamide;

N²- [ (S) - (4-bromophenyl) (thiophen-3-yl) methyl]-N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- { (S) - (2, 4-difluorophenyl) [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Methyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- [ (S) - [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl](Thien-3-yl)Methyl radical]-L-leucinamide;

N¹- (cyanomethyl) -N²- [ (S) - [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl](3-methylthiophen-2-yl) methyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- [ (S) - [4 '- (4-cyclopropylpiperazin-1-yl) -1, 1' -biphenyl-4-yl](3-methylthiophen-2-yl) methyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- [ (S) - [4 '- (4-cyclopropylpiperazin-1-yl) -1, 1' -biphenyl-4-yl](Thien-3-yl) methyl]-L-leucinamide;

N²- [1- (4-bromophenyl) -2, 2, 2-trifluoroethyl group]-N¹- (cyanomethyl) -5, 5, 5-trifluoro-L-norvalinamide;

N¹- (cyanomethyl) -5, 5, 5-trifluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-norvalinamide;

N²- [ (S) - (4-bromophenyl) (3-methylthiophen-2-yl) methyl]-N¹- (1-cyanocyclopropyl) -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- [ (S) - [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl](3-methylthiophen-2-yl) methyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- { (S) -3-furyl [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Methyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-norvalinamide;

N²- [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl radical]-N¹- (cyanocyclopropyl) -L-norvalinamide

N²- [ (S) - (4-bromophenyl) (4-bromothi-e)Phen-2-yl) methyl]-N¹- (cyanomethyl) -L-leucinamide;

N²- [ (S) - (4-bromophenyl) (thiophen-3-yl) methyl]-N' - (1-cyanocyclopropyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- ((S) - [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl)]{4- [4- (methylsulfonyl) phenyl]Thien-2-yl } methyl) -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- [ (S) - [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl ](Thien-3-yl) methyl]-L-leucinamide;

N²- { (1S) -1- [4 '- (aminosulfonyl) -1, 1' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -N¹- (1-cyanocyclopropyl) -L-norvalinamide;

N²- [ (S) - (4-bromophenyl) (4-bromothien-2-yl) methyl]-N¹- (1-cyanocyclopropyl) -L-leucinamide;

N²- [ (S) - [4 '- (aminosulfonyl) -1, 1' -biphenyl-4-yl](Thien-3-yl) methyl]-N¹- (1-cyanocyclopropyl) -L-leucinamide;

N²- [ (S) - [4 '- (aminosulfonyl) -1, 1' -biphenyl-4-yl](Thien-3-yl) methyl]-N¹- (cyanomethyl) -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 ' -methoxy-3 ' - (methylsulfonyl) -1, 1 ' -biphenyl-4-yl]Ethyl } -L-norvalinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (2-methylpyridin-4-yl) phenyl]Ethyl } -L-norvalinamide;

N¹- (1-cyanocyclopropyl) -5, 5, 5-trifluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-norvalinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (1H-pyrazol-3-yl) phenyl]Ethyl } -L-norvalinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (1-hydroxy-1-methylethyl) -1, 1' -biphenyl-4-yl ]Ethyl } -L-norvalinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (5-methylpyridin-2-yl) phenyl]Ethyl } -L-norvalinamide;

2- { [ (4-bromo-phenyl) -pyridin-4-yl-methyl ] -amino } -pentanoic acid cyanomethyl-amide;

2- { [ (4-bromo-phenyl) -thiazol-2-yl-methyl ] -amino } -pentanoic acid cyanomethyl-amide;

(2S) -2- [ (S) -1- (4' -acetylbiphenyl-4-yl) -2, 2, 2-trifluoroethylamino ] -pentanoic acid (1-cyanocyclopropyl) -amide;

(2S) -2- [ (S) -1- (2 ', 4' -difluorobiphenyl-4-yl) -2, 2, 2-trifluoroethylamino ] -pentanoic acid (1-cyanocyclopropyl) -amide;

(2S) -2- [ (S) -1- (3 ', 4' -difluorobiphenyl-4-yl) -2, 2, 2-trifluoroethylamino ] -pentanoic acid (1-cyanocyclopropyl) -amide;

(2S) -2- [ (S) -I- (3 '-chloro-4' -fluorobiphenyl-4-yl) -2, 2, 2-trifluoroethylamino ] -pentanoic acid (1-cyano-cyclopropyl) -amide;

(2S) -2- [ (S) -2, 2, 2-trifluoro-1- (4' -methanesulfonylamino-biphenyl-4-yl) -ethylamino ] -pentanoic acid (1-cyano-cyclopropyl) -amide;

(2S) -2- { (S) - [ (4-bromo-phenyl) -thiazol-2-ylmethyl ] -amino } -4-methylpentanoic acid cyanomethyl-amide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 '-chloro-1, 1' -biphenyl-4-yl ]Ethyl } -L-norvalinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 ' -chloro-3 ' -methyl-1, 1 ' -biphenyl-4-yl]Ethyl } -L-norvalinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 ' -chloro-2 ' -methyl-1, 1 ' -biphenyl-4-yl]Ethyl } -L-norvalinamide;

(2S) -2- { (S) -2, 2, 2-trifluoro-1- [4- (1H-indol-5-yl) -phenyl ] -ethylamino } -pentanoic acid (1-cyano-cyclopropyl) -amide;

(2S) -2- [ (S) -2, 2, 2-trifluoro-1- (3' -methanesulfonylamino-biphenyl-4-yl) -ethylamino ] -pentanoic acid (1-cyano-cyclopropyl) -amide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 '-fluoro-1, 1' -biphenyl-4-yl]Ethyl } -L-norvalinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 ' -fluoro-3 ' -methyl-1, 1 ' -biphenyl-4-yl]Ethyl } -L-norvalinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [3 ' -fluoro-4 ' -methyl-1, 1 ' -biphenyl-4-yl]Ethyl } -L-norvalinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 '-trifluoromethoxy-1, 1' -biphenyl-4-yl]Ethyl } -L-norvalinamide;

(2S) -2- [ (S) -2, 2, 2-trifluoro-1- (4' -methylbiphenyl-4-yl) -ethylamino ] -pentanoic acid (1-cyanocyclopropyl) -amide;

(2S) -2- [ (S) -1- (4' -cyanobiphenyl-4-yl) -2, 2, 2-trifluoroethylamino ] -pentanoic acid (1-cyanocyclopropyl) -amide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 '-methoxy-1, 1' -biphenyl-4-yl]Ethyl } -L-norvalinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (benzo [1, 3 ]]Dioxol-5-yl) phenyl]Ethyl } -L-norvalinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methoxycarbonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-norvalinamide;

(2S) -2- { (S) - [ (4-bromophenyl) -thiazol-2-yl-methyl ] -amino } -4-methylvaleric acid (1-cyanocyclopropyl) -amide;

(2S) -2- { (S) - [ (4' -methanesulfonyl-biphenyl-4-yl) -thiazol-2-yl-methyl ] -amino } -4-methyl-pentanoic acid cyanomethyl-amide;

(2S) -2- [ (S) -2, 2, 2-trifluoro-1- (4' -trifluoromethyl-biphenyl-4-yl) -ethylamino ] -pentanoic acid (1-cyano-cyclopropyl) -amide;

(2S) -2- [ (S) -2, 2, 2-trifluoro-1- (2' -trifluoromethyl-biphenyl-4-yl) -ethylamino ] -pentanoic acid (1-cyano-cyclopropyl) -amide;

(2S) -2- { (S) - [ (2 ', 4' -difluorobiphenyl-4-yl) -thiazol-2-yl-methyl ] -amino } -4-methylpentanoic acid (1-cyanocyclopropyl) -amide;

(2S) -2- { (S) - [ (4' -methanesulfonylbiphenyl-4-yl) -thiazol-2-yl-methyl ] -amino } -4-methylvaleric acid (1-cyanocyclopropyl) -amide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4- (1-oxo-2, 3-dihydro-1-benzothien-5-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -1- [4- (1, 1-dioxido-2, 3-dihydro-1-benzothien-5-yl) phenyl]-2, 2, 2-trifluoroethyl } -4-fluoro-L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -1- [4- (1, 1-dioxido-2, 3-dihydro-1, 2-benzisothiazol-5-yl) phenyl]-2, 2, 2-trifluoroethyl } -4-fluoro-L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfinyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -1- [4- (1, 1-dioxido-3-oxo-2, 3-dihydro-1, 2-benzisothiazol-5-yl) phenyl]-2, 2, 2-trifluoroethyl } -4-fluoro-L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [2 '- (1-hydroxy-1-methylethyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4, 4-difluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl ]Ethyl } -L-norvalinamide;

N¹- (cyanomethyl) -4, 4-difluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-norvalinamide;

N¹- (cyanomethyl) -4-fluoro-N²- { (1S) -2, 2, 2-trichloro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trichloro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4, 4-difluoro-N²- { (1S) -2, 2, 2-trichloro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-norvalinamide;

N¹- (cyanomethyl) -4, 4-difluoro-N²- { (1S) -2, 2, 2-trichloro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-norvalinamide;

(2S) -N- (cyanomethyl) -4, 4-difluoro-2- ({ (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl ] ethyl } amino) butanamide;

(2S) -N- (1-cyanocyclopropyl) -4, 4-difluoro-2- ({ (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl ] ethyl } amino) butanamide;

(2S) -N- (1-cyanocyclopropyl) -4, 4-difluoro-2- ({ (1S) -2, 2, 2-trichloro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl ] ethyl } amino) butanamide;

(2S) -N- (cyanomethyl) -4, 4-difluoro-2- ({ (1S) -2, 2, 2-trichloro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl ] ethyl } amino) butanamide;

(2S) -4, 4-dichloro-N- (cyanomethyl) -2- ({ (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl ] ethyl } amino) butanamide;

(2S) -4, 4-dichloro-N- (1-cyanocyclopropyl) -2- ({ (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl ] ethyl } amino) butanamide;

(2S) -4, 4-dichloro-N- (1-cyanocyclopropyl) -2- ({ (1S) -2, 2, 2-trichloro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl ] ethyl } amino) butanamide;

(2S) -4, 4-dichloro-N- (cyanocyclopropyl) -2- ({ (1S) -2, 2, 2-trichloro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl ] ethyl } amino) butanamide;

N²- [ (1S) -1- (1, 1' -biphenyl-4-yl) -2, 2, 2-trifluoroethyl radical]-N¹- (1-cyanocyclopropyl) -4-fluoro-L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [3 '- (1-hydroxyethyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- [ (1S) -2, 2, 2-trifluoro-1- (4 '-methyl-1, 1' -biphenyl-4-yl)) Ethyl radical]-L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- [ (1S) -2, 2, 2-trifluoro-1- [3 '- (1-hydroxy-1-methylethyl) -1, 1' -biphenyl-4-yl]Ethyl radical]-L-leucinamide;

N²- [ (1S) -1- (4 '-acetyl-1, 1' -biphenyl-4-yl) -2, 2, 2-trifluoroethyl radical]-N¹- (1-cyanocyclopropyl) -4-fluoro-L-leucinamide;

N²- [ (1S) -1- (4 '-acetyl-1, 1' -biphenyl-4-yl) -2, 2, 2-trifluoroethyl radical]-N¹- (1-cyanocyclopropyl) -4-fluoro-L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (1-hydroxyethyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [2 '- (1-hydroxyethyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (1-hydroxy-1-methylethyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [2 '- (1-hydroxy-1-methylethyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- {5- [4- (methylsulfonyl) phenyl]Pyridin-2-yl } ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N ²- ((1S) -2, 2, 2-trifluoro-1- {6- [4- (methylsulfonyl) phenyl]Pyridin-3-yl } ethyl) -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- [ (1S) -2, 2, 2-trifluoro-1- (4- {6- [ (methylsulfonyl) S) Amino group]Pyridin-3-yl } phenyl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -4-fluoro-N²- [ (1S) -2, 2, 2-trifluoro-1- (4- {6- [ (methylsulfonyl) amino group]Pyridin-3-yl } phenyl) ethyl]-L-leucinamide;

N¹- (1-cyanobutyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyano-2-cyclopropylethyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyano-2-pyridin-3-ylethyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyano-3-hydroxy-3-methylbutyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4- (1-oxo-1, 3-dihydro-2-benzofuran-5-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -1- [4- (3, 3-dimethyl-1-oxo-1, 3-dihydro-2-benzofuran-5-yl) phenyl]-2, 2, 2-trifluoroethyl } -4-fluoro-L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -1- [4- (3, 3-diethyl-1-oxo-1, 3-dihydro-2-benzofuran-5-yl) phenyl]-2, 2, 2-trifluoroethyl } -4-fluoro-L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4- (3-oxo-1, 3-dihydro-2-benzofuran-5-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -1- [4- (1, 1-dimethyl-3-oxo-1, 3-dihydro-2-benzofuran-5-yl) phenyl]-2, 2, 2-trifluoroethyl } -4-fluoro-L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -1- [4- (1, 1-diethyl-3-oxo-1, 3-dihydro-2-benzofuran-5-yl) phenyl]-2, 2, 2-trifluoroethyl } -4-fluoro-L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (3-oxo-1, 3-dihydro-2-benzofuran-5-yl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -1- [4 '- (1, 1-dimethyl-3-oxo-1, 3-dihydro-2-benzofuran-5-yl) -1, 1' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -4-fluoro-L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -1- [4 '- (1, 1-diethyl-3-oxo-1, 3-dihydro-2-benzofuran-5-yl) -1, 1' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -4-fluoro-L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (1-oxo-1, 3-dihydro-2-benzofuran-5-yl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -1- [4 '- (3, 3-dimethyl-1-oxo-1, 3-dihydro-2-benzofuran-5-yl) -1, 1' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -4-fluoro-L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -1- [4 '- (3, 3-diethyl-1-oxo-1, 3-dihydro-2-benzofuran-5-yl) -1, 1' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -4-fluoro-L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4- (5-oxo-2,5-dihydrofuran-3-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -1- [4- (2, 2-dimethyl-5-oxo-2, 5-dihydrofuran-3-yl) phenyl]-2, 2, 2-trifluoroethyl } -4-fluoro-L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -1- [4- (2, 2-diethyl-5-oxo-2, 5-dihydrofuran-3) phenyl-2, 2, 2-trifluoroethyl ]-4-fluoro-L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- {4- (2-oxo-2, 5-dihydrofuran-3-yl) phenyl } ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -1- [4- (5, 5-dimethyl-2-oxo-2, 5-dihydrofuran-3-yl) phenyl]-2, 2, 2-trifluoroethyl } -4-fluoro-L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -1- [4- (5, 5-diethyl-2-oxo-2, 5-dihydrofuran-3-yl) phenyl]-2, 2, 2-trifluoroethyl } -4-fluoro-L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4- (5-oxo-4-oxaspiro [2.4 ]]Hept-6-en-7-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4- (6-oxo-5-oxaspiro [3.4 ]]Oct-7-en-8-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4- (5-oxo-4-oxaspiro [2.4 ]]Hept-6-en-6-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4- (6-oxo-5-oxaspiro [3.4 ]]Oct-7-en-7-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- [ (1S) -2, 2, 2-trifluoro-1- (4-quinolin-6-ylphenyl) ethyl ]-L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfinyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N²- [ (1S) -1- (4 '-acetyl-1, 1' -biphenyl-4-yl) -2, 2, 2-trifluoroethyl radical]-N¹- (1-cyanocyclopropyl) -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (4-quinolin-6-ylphenyl) ethyl]-L-leucinamide;

N²- [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl radical]-N¹- (1-cyanocyclopropyl) -4, 4-difluoro-L-norvalinamide;

N¹- (1-cyanocyclopropyl) -4, 4-difluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylthio) -1, 1' -biphenyl-4-yl]Ethyl } -L-norvalinamide;

N¹- (1-cyanocyclopropyl) -4, 4-difluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-norvalinamide;

N¹- [ (1S) -1-cyano-3- (methylsulfonyl) propyl]-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- [ (1S) -2, 2, 2-trifluoro-1- (4-quinolin-6-ylphenyl) ethyl]-L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfinyl) -1, 1' -biphenyl-4-yl ]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²-{(1S)-2, 2, 2-trifluoro-1- [4 '- (1-hydroxyethyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N²- [ (1S) -1- (4 '-acetyl-1, 1' -biphenyl-4-yl) -2, 2, 2-trifluoroethyl radical]-N¹- (1 cyanocyclopropyl) -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (4-quinolin-6-ylphenyl) ethyl]-L-leucinamide;

N²- [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl radical]-N¹- (1-cyanocyclopropyl) -4, 4-difluoro-L-norvalinamide;

N¹- (1-cyanocyclopropyl) -4, 4-difluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylthio) -1, 1' -biphenyl-4-yl]Ethyl } -L-norvalinamide;

N¹- (1-cyanocyclopropyl) -4, 4-difluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-norvalinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- ((1S) -2, 2, 2-trifluoro-1- {4- [ 5-methyl-6- (methylsulfonyl) pyridin-3-yl)]Phenyl } ethyl) -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- ((1S) -2, 2, 2-trifluoro-1- {4- [6- (1-hydroxy-1-methylethyl) -5-methylpyridin-3-yl)]Phenyl } ethyl) -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- [ (1S) -2, 2, 2-trifluoro-1- (4 '-fluoro-1, 1' -biphenyl-4-yl) ethyl ]-L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [3 ' -methyl-4 ' - (methylsulfonyl) -1, 1 ' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4- (6-methylpyridin-3-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylthio) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (1-hydroxy-1-methylethyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4- (2-methylquinolin-7-yl) phenyl]Ethyl } -L-leucinamide;

N²- [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl radical]-N¹- (cyanomethyl) -4, 4-difluoro-L-norvalinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- ((1S) -2, 2, 2-trifluoro-1- { 4' - [ (1S) -1-hydroxyethyl]-1, 1' -biphenyl-4-yl } ethyl) -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- ((1S) -2, 2, 2-trifluoro-1- { 4' - [ (1R) -1-hydroxyethyl]-1, 1' -biphenyl-4-yl } ethyl) -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (trifluoroacetyl) -1, 1' -biphenyl-4-yl ]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [5- (2-naphthalenyl) pyridin-2-yl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -4, 4-difluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylthio) -1, 1' -biphenyl-4-yl]Ethyl } -L-norvalinamide;

N¹- (cyanomethyl) -4, 4-difluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl radical} -L-norvalinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4- (5-methyl-1, 3-thiazol-2-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -1- [4- (1, 1-dioxido-3-oxo-2, 3-dihydro-1, 2-benzisothiazol-5-yl) phenyl]-2, 2, 2-trifluoroethyl } -4-fluoro-L-leucinamide;

N²- [ (4-bromophenyl) (phenyl) methyl]-N¹- (1-cyanocyclopropyl) -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- [ (1S) -2, 2, 2-trifluoro-1- (4 '-methyl-1, 1' -biphenyl-4-yl) ethyl]-L-leucinamide;

N²- [ (1S) -1- (1, 1' -biphenyl-4-yl) -2, 2, 2-trifluoroethyl radical]-N¹- (1-cyanocyclopropyl) -4-fluoro-L-leucinamide;

N²- { (1S) -1- [4- (5-Chloropyridin-2-yl) phenyl]-2, 2, 2-trifluoroethyl } -N¹- (1-cyanocyclopropyl) -4-fluoro-L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- [ (1S) -2, 2, 2-trifluoro-1- (4-pyridin-4-ylphenyl) ethyl]-L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- ((1S) -2, 2, 2-trifluoro-1- { 4' - [ (methylsulfonyl) amino group]-1, 1' -biphenyl-4-yl } ethyl) -L-leucinamide;

N²- [ (S) -1- (4-bromophenyl) -2, 2-difluoroethyl]-N¹- (1-cyanocyclopropyl) -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2-difluoro-1- [4 '- (methylthio) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²-[(1S) -2, 2, 2-trifluoro-1- (4-pyrimidin-5-ylphenyl) ethyl]-L-leucinamide;

N²- [ (1S) -1- (4 '-acetyl-1, 1' -biphenyl-4-yl) -2, 2, 2-trifluoroethyl radical]-N¹- (1-cyanocyclopropyl) -4-fluoro-L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [3 '- (1-hydroxyethyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N²- [ (1S) -1- (4 '-acetyl-1, 1' -biphenyl-4-yl) -2, 2-difluoroethyl]-N¹- (1-cyanocyclopropyl) -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -1- [4- (3, 5-Dimethylisoxazol-4-yl) phenyl]-2, 2, 2-trifluoroethyl } -4-fluoro-L-leucinamide;

N¹- [ (1S) -1-cyano-3- (methylsulfonyl) propyl ]-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- [ (1S) -2, 2, 2-trifluoro-1- (4-quinolin-6-ylphenyl) ethyl]-L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfinyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (1-hydroxyethyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N²- [ (1S) -1- (4 '-acetyl-1, 1' -biphenyl-4-yl) -2, 2, 2-trifluoroethyl radical]-N¹- (1-cyanocyclopropyl) -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (4-quinolin-6-ylphenyl) ethyl]-L-leucinamide；

N²- [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl radical]-N¹- (1-cyanocyclopropyl) -4, 4-difluoro-L-norvalinamide;

N¹- (1-cyanocyclopropyl) -4, 4-difluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylthio) -1, 1' -biphenyl-4-yl]Ethyl } -L-norvalinamide;

N¹- (1-cyanocyclopropyl) -4, 4-difluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-norvalinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N ²- (1S) -2, 2, 2-trifluoro-1- {4- [ 5-methyl-6- (methylsulfonyl) pyridin-3-yl]Phenyl } ethyl) -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- ((1S) -2, 2, 2-trifluoro-1- {4- [6- (1-hydroxy-1-methylethyl) -5-methylpyridin-3-yl)]Phenyl } ethyl) -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- [ (1S) -2, 2, 2-trifluoro-1- (4 '-fluoro-1, 1' -biphenyl-4-yl) ethyl]-L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [3 ' -methyl-4 ' - (methylsulfonyl) -1, 1 ' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4- (6-methylpyridin-3-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylthio) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (1-hydroxy-1-methylethyl) -1, 1' -biphenyl-4-yl]Ethyl radical} -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4- (2-methylquinolin-7-yl) phenyl]Ethyl } -L-leucinamide;

N²- [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl radical ]-N¹- (cyanomethyl) -4, 4-difluoro-L-norvalinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- ((1S) -2, 2, 2-trifluoro-1- { 4' - [ (1S) -1-hydroxyethyl]-1, 1' -biphenyl-4-yl } ethyl) -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- ((1S) -2, 2, 2-trifluoro-1- { 4' - [ (1R) -1-hydroxyethyl]-1, 1' -biphenyl-4-yl } ethyl) -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (trifluoroacetyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [5- (2-naphthalenyl) pyridin-2-yl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -4, 4-difluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylthio) -1, 1' -biphenyl-4-yl]Ethyl } -L-norvalinamide;

N¹- (cyanomethyl) -4, 4-difluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-norvalinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4- (5-methyl-1, 3-thiazol-2-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -1- [4- (1, 1-dioxido-3-oxo-2, 3-dihydro-1, 2-benzisothiazol-5-yl) phenyl]-2, 2, 2-trifluoroethyl } -4-fluoro-L-leucinamide ；

N²- [ (4-bromophenyl) (phenyl) methyl]-N¹- (1-cyanocyclopropyl) -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- [ (1S) -2, 2, 2-trifluoro-1- (4 '-methyl-1, 1' -biphenyl-4-yl) ethyl]-L-leucinamide;

N²- [ (1S) -1- (1, 1' -biphenyl-4-yl) -2, 2, 2-trifluoroethyl radical]-N¹- (1-cyanocyclopropyl) -4-fluoro-L-leucinamide;

N²- { (1S) -1- [4- (5-Chloropyridin-2-yl) phenyl]-2, 2, 2-trifluoroethyl } -N¹- (1-cyanocyclopropyl) -4-fluoro-L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- [ (1S) -2, 2, 2-trifluoro-1- (4-pyridin-4-ylphenyl) ethyl]-L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- ((1S) -2, 2, 2-trifluoro-1- { 4' - [ (methylsulfonyl) amino group]-1, 1' -biphenyl-4-yl } ethyl) -L-leucinamide;

N²- [ (1S) -1- (4-bromophenyl) -2, 2-difluoroethyl]-N¹- (1-cyanocyclopropyl) -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2-difluoro-1- [4 '- (methylthio) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- [ (1S) -2, 2, 2-trifluoro-1- (4-pyrimidin-5-ylphenyl) ethyl]-L-leucinamide;

N²- [ (1S) -1- (4 '-acetyl-1, 1' -biphenyl-4-yl) -2, 2, 2-trifluoroethyl radical]-N¹- (1-cyanocyclopropyl) -4-fluoro-L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [3 '- (1-hydroxyethyl) -1, 1' -biphenyl-4-yl]Ethyl group }-L-leucinamide;

N²- [ (1S) -1- (4 '-acetyl-1, 1' -biphenyl-4-yl) -2, 2-difluoroethyl]-N¹- (1-cyanocyclopropyl) -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -1- [4- (3, 5-Dimethylisoxazol-4-yl) phenyl]-2, 2, 2-trifluoroethyl } -4-fluoro-L-leucinamide;

and pharmaceutically acceptable salts, stereoisomers and N-oxide derivatives thereof.

Also included within the scope of the present invention are pharmaceutical compositions comprised of a compound of formula I as described above and a pharmaceutically acceptable carrier. The invention also includes pharmaceutical compositions comprised of a pharmaceutically acceptable carrier and any one of the compounds specifically disclosed herein. These and other aspects of the invention will be apparent from the teachings provided herein.

Practicality of use

The compounds of the present invention are cathepsin inhibitors and are therefore useful for the treatment or prevention of cathepsin dependent diseases or conditions in mammals, preferably humans. In particular, the compounds of the present invention are cathepsin K inhibitors and are therefore useful for the treatment or prevention of cathepsin K dependent diseases in mammals, preferably humans.

"cathepsin dependent disease or disorder" refers to a pathological condition that is dependent on the activity of one or more cathepsins. "cathepsin K dependent diseases or conditions" refers to conditions which are dependent on the activity of cathepsin K. Conditions associated with cathepsin K activity include osteoporosis, glucocorticoid-induced osteoporosis, paget's disease, abnormally increased bone turnover, periodontal disease, tooth loss, bone fracture, rheumatoid arthritis, osteoarthritis, periprosthetic osteolysis, incomplete osteogenesis, metastatic bone disease, malignant hypercalcemia, and multiple myeloma. In treating such conditions with the presently claimed compounds, the amount of treatment required will vary with the particular disease, and can be readily determined by one skilled in the art. Although treatment and prevention are within the scope of the present invention, treatment of these conditions is a preferred application.

An embodiment of the invention is a method of inhibiting tissue protease activity in a mammal in need of such inhibition comprising administering to the mammal a therapeutically effective amount of any of the compounds or any pharmaceutical composition described above.

One class of embodiments of the method is wherein the cathepsin activity is cathepsin K activity.

Another embodiment of the present invention is a method of treating or preventing a cathepsin dependent disorder in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of any of the compounds or any pharmaceutical composition described above.

One class of embodiments of the method is wherein the cathepsin activity is cathepsin K activity.

Another embodiment of the present invention is a method of inhibiting bone loss in a mammal in need of such inhibition comprising administering to the mammal a therapeutically effective amount of any of the compounds or any pharmaceutical composition described above. Another embodiment of the present invention is a method of reducing bone loss in a mammal in need of such reduction, comprising administering to the mammal a therapeutically effective amount of any of the compounds or any pharmaceutical composition described above. Cathepsin K inhibitors are known in the literature for use in inhibiting bone resorption. See stroop, g.b., Lark, m.w., Veber, df, bhattacharya, a, Blake, s, Dare, l.c., Erhard, k.f., Hoffman, s.j., James, i.e., Marquis, r.w., Ru, y, Vasko-Moser, j.a., Smith, b.r., Tomaszek, t, and Gowen, m. effective and selective inhibition of human cathepsin K inhibits bone resorption in vivo tests in non-human primates j.bone miner.res, 16: 1739-1746; 2001; and peptide aldehyde inhibitors of Votta, b.j., Levy, m.a., Badger, a., Dodds, r.a., James, i.e., Thompson, s., boscard, m.j., Carr, t.a., Connor, j.r., Tomaszek, t.a., Szewczuk, l.a., Drake, f.h., Veber, d., and Gowen, m.cathepsin K inhibit bone resorption both in vivo and in vitro. 1396-; 1997.

Another embodiment of the present invention is a method of treating or preventing osteoporosis in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of any of the compounds described above or any of the pharmaceutical compositions described above. Cathepsin K inhibitors are known in the literature to be useful for the treatment or prevention of osteoporosis, see e.g. Saftig, p., Hunziker, e., Wehmeyer, o., Jones, s., Boyde, a., rommers kirch, w., Moritz, j.d., Schu, p., and von figura, k. cathepsin K deficient mice for osteoporosis caused by impaired osteoclastic bone resorption. 13453-13458; 1998.

another embodiment of the present invention is a method of treating or preventing a rheumatoid arthritis condition in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of any one of the compounds or any one of the pharmaceutical compositions described above. Progressive destruction of bone around joints is known in the literature to be the leading cause of joint dysfunction and disability in patients with Rheumatoid Arthritis (RA), see Goldring SR, "pathogenesis of bone erosion in rheumatoid arthritis". curr. opin. rheumatol.2002; 14: 406-10. Analysis of joint tissue from patients with RA has demonstrated that cathepsin K positive osteoclasts are the cell type that can mediate focal bone resorption with rheumatoid synovial lesions, see Hou, W-S, Li, W, keysizer, G, Weber, E, Levy, R, Klein, MJ, Gravallese, EM, Goldring, SR, brommee, D, "comparison of cathepsin K and S expression in rheumatoid and osteoarthritic synovium," Arthritis rhematosis 2002; 46: 663-74. In addition, generalized bone loss is a major cause of morbidity with severe RA. The frequency of hip and spine fractures is greatly increased in patients with chronic RA, see Gould a, Sambrook, P, Devlin J et al, "osteoclast activation is the primary mechanism responsible for secondary osteoporosis in rheumatoid arthritis". j.rheumatol.1998; 25: 1282-9. The use of cathepsin K inhibitors in the treatment or prevention of sub-articular (subarticular) bone resorption and generalized bone loss represents a rational approach to pharmacological intervention in the progression of rheumatoid arthritis.

Another embodiment of the present invention is a method of treating or preventing the progression of osteoarthritis in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of any of the compounds or any pharmaceutical composition described above. Osteoarthritis (OA) is known in the literature to be accompanied by well-defined changes in the joint, including erosion of the articular cartilage surface, ossification/osteophyte disease in the periarticular cartilage, and subchondral bone sclerosis, see Oettmeier R, abendoroth, K, "osteoarthritis and bone: bone type of hip osteoarthritis ", skelestal radio.1989; 18: 165-74. Recently, it has been suggested that subchondral bone sclerosis may contribute to the onset and progression of OA. The ability of the hardened subchondral bone to attenuate and distribute pressure through the joint in response to repeated impact loads is compromised, which makes its mechanical stress on the articular cartilage surface higher. This in turn accelerates cartilage wear and fibrosis, see Radin, EL and Rose RM, "the role subchondral bone plays in the initiation and progression of cartilage damage," clin. 213: 34-40. Inhibition of excessive sub-articular bone resorption by anti-resorptive agents such as cathepsin K inhibitors will inhibit the turnover of subchondral bone and thus may have a beneficial effect on OA progression. In addition to the above assumptions, cathepsin K protein expression has recently been determined in synovial fibroblasts, macrophage-like cells, and synovial and articular cartilage samples obtained from OA patients, see Hou, W-S, Li, W, Keyszer, G, Weber, E, Levy, R, Klein, MJ, Gravallese, EM, Goldring, SR, Brommee, D, "comparison of cathepsin K and S expression in rheumatoid and osteoarthritic synovial fluids", Arthritis Rheumatosis 2002; 46: 663-74; and Dodd, RA, Connor, JR, Drake, FH, Gowen, M, "expression of cathepsin K messenger RNA in giant cells and its precursors in synovial tissue of human osteoarthritis". Arthritis rhematomatic 1999; 42: 1588-93; and Konttinen, YT, Mandelin, J, Li, T-F, Salo, J, Lassus, J et al, "acidic cysteine endoprotease cathepsin K in hyaline cartilage of surface joints in osteoarthritis", Arthris Rheumatomerism 2002; 46: 953-60. Thus, these recent studies suggest a role for cathepsin K in the destruction of articular cartilage type II collagen with progression of osteoarthritis. As described herein, the use of cathepsin K inhibitors in the treatment and prevention of osteoarthritis involves two distinct mechanisms, one that inhibits osteoclast-driven subchondral bone turnover and one that directly inhibits collagen type II degeneration in synovium and cartilage in patients with OA.

Another embodiment of the present invention is a method of treating cancer in a mammal in need of such treatment comprising administering to the mammal a therapeutically effective amount of any of the compounds or any pharmaceutical composition described above. Cathepsin K is known in the literature to be expressed in human breast cancer, see Littlewood-Evans AJ, Bilbe G, Bowler WB, Farley D, Wlodarski B, Kokubo T, Inaoka T, Sloane J, Evans DB, Gallagher JA, "osteoclast-associated protease cathepsin K expressed in human breast cancer". cancer res 1997 Dec 1; 57(23): 5386-90.

For example, the present invention is the use of any of the compounds described above in the preparation of a medicament for the treatment and/or prevention of osteoporosis in a mammal in need thereof. Another illustration is the use of any of the compounds described above in the preparation of a medicament for the treatment and/or prevention of: bone loss, bone resorption, bone fracture, metastatic bone disease and/or disorders involving cathepsin function.

The compounds of the present invention may be administered to a mammal, preferably a human, alone or preferably together with a pharmaceutically acceptable carrier or diluent, optionally together with well-known adjuvants such as alum, in pharmaceutical compositions of standard pharmaceutical practice. The compounds may be administered orally or parenterally, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.

In the case of tablets for oral use, commonly used carriers include lactose and corn starch, and a lubricant such as magnesium stearate is usually added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. For oral use of the therapeutic compounds of the present invention, the selected compound may be administered, for example, in the form of a tablet or capsule or in the form of an aqueous solution or suspension. For oral administration in the form of tablets or capsules, the active pharmaceutical ingredient may be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral pharmaceutical composition can be combined with any orally non-toxic pharmaceutically acceptable carrier such as ethanol, glycerol, water, and the like. In addition, when necessary or desired, suitable binders, lubricants, disintegrating agents and coloring agents may also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants useful in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrants include, without limitation, starch, methylcellulose, agar, bentonite, xanthan gum, and the like. When aqueous suspensions are required for oral use, the active ingredient is combined with a lubricant and a suspending agent. If desired, certain sweetening and/or flavoring agents may be added. For intramuscular, intraperitoneal, subcutaneous and intravenous applications, sterile solutions of the active ingredients are usually prepared, and the pH of the solutions should be suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled to render the formulation isotonic.

The compounds of the invention may also be administered in the form of liposomal delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a number of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.

The compounds of the invention may also be delivered by the use of monoclonal antibodies as separate carriers to which the compound molecules are coupled. The compounds of the invention may also be coupled to soluble polymers as targetable drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamide-phenol, or polyethylene oxide-polylysine substituted with palmitoyl residues. In addition, the compounds of the present invention may also be coupled to a class of biodegradable polymers useful for obtaining controlled release of drugs, such as polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphiphilic block copolymers of hydrogels.

The compounds of the invention may also be used in combination with known substances for the treatment or prevention of osteoporosis, glucocorticoid-induced osteoporosis, paget's disease, abnormally increased bone turnover, periodontal disease, tooth loss, bone fractures, rheumatoid arthritis, osteoarthritis, periprosthetic osteolysis, incomplete osteogenesis, metastatic bone disease, hypercalcemia of malignancy, and multiple myeloma. Combinations of the disclosed compounds with agents useful for treating or preventing osteoporosis or other bone disorders are also within the scope of the invention. One skilled in the art would know which combinations of substances are useful based on the nature of the drugs and diseases involved. Such materials include the following: an organic diphosphonic acid compound; an estrogen receptor modulator; androgen receptor modulators; osteoclast proton atpase inhibitors; HMG-CoA reductase inhibitors; an integrin receptor antagonist; osteoblastic anabolic agents, such as PTH; and pharmaceutically acceptable salts and mixtures thereof. One preferred combination is a combination of a compound of the invention and an organic bisphosphonic acid compound. Another preferred combination is a combination of a compound of the invention and an estrogen receptor modulator. Another preferred combination is a combination of a compound of the invention and an androgen receptor modulator. Another preferred combination is a combination of a compound of the invention and an osteoblast anabolic agent.

"organic diphosphonic acid compounds" include, without limitation, compounds of the formula

Wherein n is an integer from 0 to 7, and wherein A and X are independently selected from H, OH, halogen, NH₂SH, phenyl, C₁-C₃₀Alkyl radical, C₃-C₃₀Branched or cyclic alkyl, bicyclic structure containing two or three N, C₁-C₃₀Substituted alkyl, C₁-C₁₀Alkyl substituted NH₂、C₃-C₁₀NH substituted by branched or cyclic alkyl groups₂、C₁-C₁₀Dialkyl substituted NH₂、C₁-C₁₀Alkoxy radical, C₁-C₁₀Alkyl-substituted mercapto, phenylthio, halophenylthio, C₁-C₁₀Alkyl substituted phenyl, pyridyl, furyl, pyrrolidinyl, imidazolyl, imidazopyridyl, and benzyl, wherein when n is 0, a and X cannot both be selected from H or OH; or A and X together with the carbon atom to which they are attached form a C₃-C₁₀And (4) a ring.

In the above formula, the alkyl group may be linear, branched or cyclic, and sufficient atoms provided may be selected for the formula. C₁-C₃₀The substituted alkyl group may include various substituents, non-limiting examples of which include those selected from phenyl, pyridyl, furyl, pyrrolidinyl, imidazolyl, NH₂、C₁-C₁₀Alkyl or dialkyl substituted NH₂OH, SH, and C₁-C₁₀A radical of an alkoxy group.

The above formulas also include complex carbocyclic, aromatic, and heteroatom structures for the A and/or X substituents, examples of which include, without limitation, naphthyl, quinolyl, isoquinolyl, adamantyl, and chlorophenylthio.

Pharmaceutically acceptable salts and derivatives of the bisphosphonic acid compounds may also be used herein. Non-limiting examples of salts include those selected from alkali metal salts, alkaline earth metal salts (alkaline metals), ammonium salts, and mono-, di-, tri-, or tetra-C₁-C₃₀-alkyl-substituted ammonium salts. Preferred salts are those selected from sodium, potassium, calcium, magnesium, and ammonium salts. More preferred is the sodium salt. Non-limiting examples of derivatives include those selected from esters, hydrates, and amides.

It should be noted that the terms "bisphosphonate" and "bisphosphonate" as used herein in reference to the therapeutic agents of the present invention are meant to also include bisphosphonic acid compounds, di-phosphonic acid compounds, bisphosphonic acids, and salts and derivatives of these. Unless otherwise specified, reference to the use of a diphosphonic acid compound or a diphosphonic acid compound is not intended to limit the scope of the invention. Since the mixing nomenclature is currently used by those of ordinary skill in the art, unless otherwise specified, reference to a particular weight or percentage of the bisphosphonate compounds of the present invention is based on the effective weight of the acid. For example, the phrase "about 5mg of a bone resorption inhibiting bisphosphonate selected from alendronate compounds, pharmaceutically acceptable salts thereof, and mixtures thereof, based on an effective weight of alendronate" means that the amount of the selected bisphosphonate is calculated on the basis of 5mg of alendronate.

Non-limiting examples of bisphosphonic acid compounds for use herein include the following:

alendronic acid, 4-amino-1-hydroxybutylidene-1, 1-diphosphonic acid.

Alendronate (also known as alendronate sodium or alendronate monosodium salt trihydrate), 4-amino-1-hydroxybutylidene-1, 1-diphosphonic acid monosodium trihydrate.

Published in US 4,922,007, Kieczykowski et al, 1990, 5 months and 1 day; 5,019,651, Kieczykowski et al, 1991, published 5 and 28 months; 5,510,517, Dauer et al, 1996 4/23; 5,648,491, Dauer et al, 1997, 7, 15, describe alendronate and alendronate, all of which are incorporated herein by reference in their entirety.

Cycloheptylaminomethylene-1, 1-diphosphonic acid, YM 175, Yamanouchi (incadronic acid, formerly known as cimadronate), described in US 4,970,335 issued by Isomura et al, 9, 13, 1990, the reference being incorporated herein in its entirety by reference.

1, 1-dichloromethylene-1, 1-diphosphonic acid (chlorophosphonic acid) and disodium salt (chlorophosphonate, Procter and Gamble) are described in Belgium Patent 672, 205(1966) and J.org.chem 32, 4111(1967), both of which are incorporated herein by reference in their entirety.

1-hydroxy-3- (1-pyrrolidinyl) -propylidene-1, 1-diphosphonic acid (EB-1053).

1-hydroxyethane-1, 1-diphosphonic acid (etidronic acid).

1-hydroxy-3- (N-methyl-N-pentylamino) propylidene-1, 1-diphosphonic acid, also known as BM-210955, Boehringer-Mannheim (ibandronic acid), is described in U.S. Pat. No. 4,927,814, 1990, month 5 and day 22, the reference being incorporated herein in its entirety by reference.

1-hydroxy-2-imidazo- (1, 2-a) pyridin-3-ylethylene (minodronic acid).

6-amino-1-hydroxyhexylidene-1, 1-diphosphonic acid (neridronic acid).

3- (dimethylamino) -1-hydroxypropylene-1, 1-diphosphonic acid (olpadronic acid).

3-amino-1-hydroxypropylene-1, 1-diphosphonic acid (pamidronic acid).

[2- (2-pyridyl) ethylene ] -1, 1-diphosphonic acid (piridronic acid) is described in U.S. Pat. No. 4,761,406, which reference is incorporated herein in its entirety by reference.

1-hydroxy-2- (3-pyridyl) -ethylene-1, 1-diphosphonic acid (risedronic acid).

(4-chlorophenyl) sulfanylmethane-1, 1-diphosphonic acid (tiludronic acid) is described in US 4,876,248, Breliere et al, 24.10.1989, which reference is incorporated herein in its entirety by reference.

1-hydroxy-2- (1H-imidazol-1-yl) ethylene-1, 1-diphosphonic acid (zoledronic acid).

Non-limiting examples of diphosphonic acid compounds include alendronic acid, cimadronate, clodronic acid, etidronic acid, ibandronic acid, incadronic acid, minodronic acid, neridronic acid, olpadronic acid, pamidronic acid, piridronic acid, risedronic acid, tiludronic acid, and zoledronic acid, and pharmaceutically acceptable salts and esters thereof. Particularly preferred bisphosphonic acid compounds are alendronate, especially the sodium, potassium, calcium, magnesium, or ammonium salts of alendronic acid. Examples of preferred bisphosphonic acid compounds are the sodium salts of alendronic acid, especially the hydrated sodium salts of alendronic acid. The salt may be hydrated by an entire mole of water or by an entire mole of water. Examples of more preferred bisphosphonic acid compounds are hydrated sodium salts of alendronic acid, especially monosodium alendronate trihydrate.

It is recognized that mixtures of two or more of such bisphosphonate actives may be used.

The exact dosage of the organic bisphosphonate will vary with the schedule of administration, the particular bisphosphonate selected, the age, size, sex and physical condition of the mammal or human, the nature and severity of the condition being treated, and other relevant medical and physical factors. Thus, the precise pharmaceutically effective amount cannot be predetermined and can be readily determined by the caregiver or clinician. Suitable amounts can be determined by routine animal model experimentation and human clinical studies. Generally, the amount of the bisphosphonate is selected to obtain a bone resorption inhibiting effect, i.e. a bone resorption inhibiting amount of the bisphosphonate is used. For humans, an orally effective dose of the bisphosphonate is generally from about 1.5 to about 6000 μ g/kg body weight, and preferably from about 10 to about 2000 μ g/kg body weight. For alendronate monosodium trihydrate, a typical human dose that can be administered is generally from 2 mg/day to about 40 mg/day, preferably from about 5 mg/day to about 40 mg/day. In U.S., the currently approved dose of alendronate monosodium trihydrate for the prevention of osteoporosis was 5 mg/day, the dose for the treatment of osteoporosis was 10 mg/day, and the dose for the treatment of paget's disease was 40 mg/day.

In alternative dosing regimens, the bisphosphonate may be administered at intervals other than daily, for example, once weekly, twice weekly, biweekly, and monthly. In a once weekly dosing schedule, alendronate monosodium trihydrate would be administered at a dose of 35 mg/week or 70 mg/week.

"Selective estrogen receptor modulators" refers to compounds that, regardless of mechanism, can interfere with or inhibit the binding of estrogen to the receptor. Examples of estrogen receptor modulators include, without limitation, estrogen, progestin, estradiol, droloxifene, raloxifene, lasofoxifene, TSE-424, tamoxifen, idoxifene, LY353381, LY117081, toremifene, fulvestrant, 4- [7- (2, 2-dimethyl-1-oxopropoxy-4-methyl-2- [4- [2- (1-piperidinyl) ethoxy ] phenyl ] -2H-1-benzopyran-3-yl) -phenyl-2, 2-dimethylpropionate, 4' -dihydroxybenzophenone-2, 4-dinitrophenyl-hydrazone, and SH 646.

An "estrogen receptor beta modulator" is a compound that can selectively agonize or antagonize estrogen receptor beta (ER β). Agonism of ER β increases transcription of tryptophan hydroxylase gene (TPH, a key enzyme in serotonin synthesis) by ER β -mediated events. Examples of estrogen receptor beta agonists are found in PCT patent applications WO 01/82923, published on 8/11/2001, and WO 02/41835, published on 20/5/2002, both of which are incorporated herein by reference in their entirety.

"androgen receptor modulators" refers to compounds that, regardless of mechanism, can interfere with or inhibit the binding of androgens to the receptor. Examples of androgen receptor modulators include finasteride and other 5 α -reductase inhibitors, nilutamide, flutamide, bicalutamide, liarozole, and abiraterone acetate.

"osteoclast proton atpase inhibitor" refers to an inhibitor of proton atpase, which is found on the apical membrane of osteoclasts and has been reported to play an important role in the bone resorption process. Such proton pumps represent an attractive target for the design of bone resorption inhibitors useful for the treatment and prevention of osteoporosis and related metabolic diseases. Farina et al, "selective inhibitors of osteoclast vacuolar proton atpase as novel bone resorption inhibitors," DDT, 4: 163-172(1999)), which is incorporated herein by reference in its entirety.

"HMG-CoA reductase inhibitor" refers to an inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase. Compounds having inhibitory activity against HMG-CoA reductase can be readily determined by assays well known in the art. For example, see the assays described or exemplified in U.S. Pat. No. 4,231,938, column 6 and pages 30-33 of WO 84/02131. As used herein, the terms "HMG-CoA reductase inhibitor" and "inhibitor of HMG-CoA reductase" have the same meaning.

Examples of HMG-CoA reductase inhibitors that may be used include, without limitation, lovastatin(s) ((R))See U.S. Pat. Nos. 4,231,938, 4,294,926 and 4,319,039), simvastatin: (See U.S. Pat. Nos. 4,444,784, 4,820,850 and 4,916,239), pravastatin (seeSee U.S. Pat. Nos. 4,346,227, 4,537,859, 4,410,629, 5,030,447 and 5,180,589), fluvastatin (F:)See US 5,354,772, 4,911,165, 4,929,437, 5,189,164, 5,118,853, 5,290,946 and 5,356,896), atorvastatin(s) (see (a) in the patent literature)See US 5,273,995, 4,681,893, 5,489,691 and 5,342,952) and cerivastatin (also known as rivastatins and rivastatins)See US 5,177,080). Yalpani, "Cholesterol lowering drugs", Chemistry&The structural formulae of these and further HMG-CoA reductase inhibitors which can be used in the process of the invention are described in Industry, pages 85-89 (2.5.1996) and in US 4,782,084 and 4,885,314. The term HMG-CoA reductase inhibitor as used herein includes all pharmaceutically acceptable lactone and open-acid forms of compounds having HMG-CoA reductase inhibitory activity (i.e., wherein the lactone ring is opened to form the free acid) as well as salt and ester forms, and thus the use of such salts, esters, open acid and lactone forms is also included within the scope of the present invention. Examples of lactone moieties and their corresponding open acid forms are shown in structures I and II below.

In the case that an open acid form of the HMG-CoA reductase inhibitor may be present, salts and esters may preferably be formed from the open acid, and all such forms are included within the meaning of the term "HMG-CoA reductase inhibitor" as used herein. The HMG-CoA reductase inhibitor is preferably selected from lovastatin and simvastatin, and most preferably is simvastatin. The term "pharmaceutically acceptable salts" as used herein in relation to HMG-CoA reductase inhibitors refers to non-toxic salts of the compounds used in the present invention which may be prepared by reaction of the free acid with a suitable organic or inorganic base, particularly those salts formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc and tetramethylammonium, and those salts formed from amines such as ammonia, ethylenediamine, N-methylglucamine, lysine, arginine, ornithine, choline, N '-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, 1-p-chlorobenzyl-2-pyrrolidin-1' -yl-methylbenzimidazole, diethylamine, piperazine, and tris (hydroxymethyl) aminomethane. Additional examples of salt forms of HMG-CoA reductase inhibitors include, without limitation, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium ethylenediaminetetraacetate, camphorsulfonate, carbonate, chloride, clavulanate, citrate, dihydrochloride, ethylenediaminetetraacetate, edisylate, etonate, ethanesulfonate, fumarate, glucoheptonate, gluconate, glutamate, glycollylalsenoate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, methanesulfonate, methylsulfate, mucate, naphthalenesulfonate, nitrate, oleate, salts of sodium, potassium, magnesium, potassium, magnesium, Oxalate, pamoate (pamaote), palmitate, pantothenate (panthothenate), phosphate/diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, tannate, tartrate, theachlorate, tosylate, triethyliodide, and valerate.

The ester derivatives of HMG-CoA reductase inhibitors may act as prodrugs which, when absorbed into the bloodstream of a warm-blooded animal, may be cleaved in a manner that releases the drug form and results in improved therapeutic efficacy of the drug.

As used above, "integrin receptor antagonists" are meant to selectively antagonize, inhibit or counteract the interaction of physiological ligands with α_v β₃Integrin binding compounds that selectively antagonize, inhibit or counteract the binding of physiological ligands to alpha_v β₅Integrin binding compounds which antagonize, inhibit or counteract the binding of physiological ligands to alpha_vβ₃Integrins and alpha_vβ₅Integrin-bound compounds, and compounds that antagonize, inhibit, or counteract the activity of specific integrins expressed on capillary endothelial cells. The term also relates to alpha_v β₆、α_v β₈、α₁β₁、α₂β₁、α₅β₁、α₆β₁And alpha₆β₄Antagonists of integrins. The term also relates to alpha_vβ₃、α_v β₅、α_v β₆、α_v β₈、α₁β₁、α₂β₁、α₅β₁、α₆β₁And alpha₆β₄Antagonists of any combination of integrins. Lode and colleagues in PNAS USA 96: 1591-1596(1999) a synergistic effect between the anti-angiogenic α v integrin antagonist and the tumor-specific antibody-cytokine (interleukin-2) fusion protein has been observed in eradication of spontaneous tumor metastases. The results indicate that this combination may be useful in the treatment of cancer and metastatic tumor growth. Alpha is alpha _v β₃Integrin receptor antagonists inhibit bone resorption by a new mechanism different from that of all currently available drugs. Integrins are heterodimeric transmembrane adhesion receptors that mediate cell-cell and cell-matrix interactions. The alpha and beta integrin subunits interact non-covalently and bind to fine particles in a divalent-cation dependent mannerAn extracellular matrix ligand. The most abundant integrin on osteoclasts is alpha_v β₃(＞10⁷Individual/osteoclast) that appears to play a rate-limiting role in cytoskeletal organization important for cell migration and polarization. The alpha is_v β₃The antagonistic effect is selected from the group consisting of inhibiting bone resorption, inhibiting restenosis, inhibiting macular degeneration, inhibiting arthritis, and inhibiting cancer and metastatic growth.

"osteoblast anabolic agent" refers to a substance that can build bone, such as PTH. Intermittent administration of parathyroid hormone (PTH) or its amino-terminal fragments and analogs has been shown to prevent, arrest, partially reverse bone loss and stimulate bone formation in animals and humans. For a discussion thereof, see d.w. dempster et al, "anabolism of bone by parathyroid hormone," Endocr Rev 14: 690-709(1993). Studies have demonstrated that parathyroid hormone has the clinical benefit of stimulating bone formation, thereby increasing bone mass and strength. RM New et al reported this result in New Eng J Med 3441434-1441 (2001).

Furthermore, a potent anti-calnuria effect of parathyroid hormone-related protein fragments or analogs such as PTHrP- (1-36) has been demonstrated [ see M.A. Syed et al, "stimulation of tubular calcium reabsorption in normal human volunteers by parathyroid hormone-related protein- (1-36): significance to the pathogenesis of humoral malignant tumor hypercalcemia, "JCEM 86: 1525-1531(2001) and also as an assimilator for the treatment of osteoporosis.

Which can be prepared in fixed doses, such combination products using the compounds of the invention in the dosage ranges described below and the other pharmaceutically active substances in their approved dosage ranges. When such a combined preparation is not suitable, the compound of the present invention may alternatively be used sequentially with known pharmaceutically acceptable substances.

The term "administering" and variations thereof (e.g., "administering" a compound) as used in reference to a compound of the invention refers to introducing the compound or a prodrug of the compound into the system of an animal in need of treatment. When a compound of the invention or a prodrug thereof is provided in combination with one or more other active substances (e.g., cytotoxic agents), "administration" and variations thereof are each understood to include the simultaneous and sequential introduction of the compound or prodrug thereof and the other substance. The present invention includes within its scope prodrugs of the compounds of the present invention. In general, such prodrugs will be functional derivatives of the compounds of the present invention which can be readily converted in vivo to the desired compounds. Thus, in the methods of the present invention, the term "administering" shall encompass the treatment of the various conditions described with a compound that is specifically disclosed or with a compound that may not be specifically disclosed but which, upon administration to a patient, is converted in vivo to the specified compound. Conventional methods for selecting and preparing suitable prodrug derivatives are described, for example, in "Design of produgs," h. Metabolites of these compounds include active species produced when the compounds of the present invention are introduced into a biological environment.

The term "composition" as used herein includes a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

The term "therapeutically effective amount" as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medical response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.

The term "treatment" or "management" of a disease as used herein includes: preventing a disease, i.e., a mammal that either develops or is predisposed to developing the disease but does not yet experience or exhibit symptoms of the disease does not develop clinical symptoms of the disease; inhibiting the disease, i.e., preventing or reducing the development of the disease or its clinical symptoms; or relieving the disease, i.e., causing regression of the disease or its clinical symptoms.

The term "bone resorption" as used herein refers to the process by which osteoclasts degrade bone.

The invention also includes pharmaceutical compositions for treating osteoporosis or other bone conditions comprising a therapeutically effective amount of a compound of the invention, with or without a pharmaceutically acceptable carrier or diluent. Suitable compositions of the invention include aqueous solutions comprising a compound of the invention and a pharmaceutically acceptable carrier, e.g., saline, e.g., at a pH level of 7.4. The solution may be introduced into the blood of a patient by a topical bolus injection.

When the compounds of the present invention are administered to human patients, the daily dosage will generally be determined by the prescribing physician and will generally vary with the age, weight, and response of the individual patient, as well as the severity of the patient's symptoms.

In one example of use, a suitable amount of the compound is administered to a mammal being treated for a cathepsin dependent condition. When used for the indicated conditions, the oral dosage of the invention is from about 0.01mg per kilogram of body weight per day (mg/kg/day) to about 100 mg/kg/day, preferably from 0.01 to 10 mg/kg/day, and most preferably from 0.1 to 5.0 mg/kg/day. For oral administration, the compositions are preferably provided in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The medicament generally comprises from about 0.01mg to about 500mg of active ingredient, preferably from about 1mg to about 100mg of active ingredient. During infusion at a constant rate, the most preferred intravenous dose is from about 0.1 to about 10 mg/kg/minute. The compounds of the invention may advantageously be administered in a single daily dose form, or the total daily dose may be administered in divided doses of two, three or four times daily. In addition, preferred compounds of the present invention may be administered in intranasal form by using suitable intranasal matrices, or they may be administered by transdermal routes using such transdermal patch forms as are well known to those of ordinary skill in the art. For administration in the form of a transdermal delivery system, the dose administered will, of course, be administered continuously rather than intermittently during the dosage regimen.

The compounds of the present invention may be used in combination with other agents useful in the treatment of cathepsin-mediated conditions. The components of such combinations may be administered separately or simultaneously at different time points during the course of therapy, in divided or single combination forms. The invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term "administering" is to be interpreted accordingly. It will be appreciated that the scope of combinations of the compounds of the present invention with other agents useful in the treatment of cathepsin mediated conditions includes in principle any combination with any pharmaceutical composition useful in the treatment of conditions involving oestrogen function.

Thus, it is within the scope of the present invention to use a combination of the claimed compounds of the present invention in combination with a second material selected from the group consisting of: an organic diphosphonic acid compound; an estrogen receptor modulator; androgen receptor modulators; osteoclast proton atpase inhibitors; HMG-CoA reductase inhibitors; an integrin receptor antagonist; osteoblastic anabolic agents, such as PTH; and pharmaceutically acceptable salts and mixtures thereof.

These and other aspects of the invention will be apparent from the teachings contained herein.

Definition of

The compounds of the invention may have asymmetric centers, chiral axes, and chiral planes (as described in e.l. eliel and s.h. wilen, Stereochemistry of carbon compounds, John Wiley & Sons, New York, 1994, pages 1119-1190) and may exist as racemates, racemic mixtures, and may exist as individual diastereomers, as well as all possible isomers including optical isomers and mixtures thereof, which are also within the scope of the invention. Furthermore, the compounds disclosed herein may exist in tautomeric forms, both tautomeric forms being included within the scope of the invention even if only one tautomeric structure is depicted. For example, any claims below to compound a should be understood to include tautomeric structure B, and mixtures thereof, and vice versa.

In any component when any variable (e.g. R)¹、R²、R^aEtc.) occur more than one time, their definitions at each occurrence are independent of each other. Combinations of substituents and variables are also permitted only if such combinations result in stable compounds. Lines drawn from substituents onto ring systems indicate that the indicated substituent may be attached to any one of the substitutable ring carbon atoms. If the ring system is polycyclic, it means that the bond can only be attached to any suitable carbon atom that is closest to the ring.

It will be appreciated that substituents and substitution patterns on the compounds of the invention may be selected by those skilled in the art to provide compounds which are chemically stable and which are readily synthesized from readily available starting materials by techniques well known in the art, as well as those methods described below. If a substituent is itself substituted with more than one group, it will be appreciated that these multiple groups may be on the same carbon or different carbons, so long as a stable structure is obtained. The phrase "optionally substituted with one or more substituents" should be read as the same as the phrase "optionally substituted with at least one substituent", and preferred embodiments in such cases will have from 0 to 3 substituents.

As used herein, unless otherwise specified, "alkyl" is intended to include both branched and straight chain saturated aliphatic hydrocarbons having from 1 to 10 carbon atoms. For example, in "C₁-C₁₀Alkyl radical "in, C₁-C₁₀Is defined as being included in a straight chain, branched chain orGroups having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbons in the cyclic arrangement. For example, "C₁-C₁₀Alkyl "specifically includes methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and the like.

Unless otherwise indicated, "alkoxy" or "alkoxy" represents an alkyl group as defined above, wherein the alkyl group is attached through an oxygen bridge.

Unless otherwise specified, the term "cycloalkyl" or "carbocyclic" refers to a cyclic alkane ring having a total of 3 to 8 carbon atoms or any number within this range (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl).

The term "alkenyl", if the number of carbon atoms is not specified, refers to a straight or branched chain nonaromatic hydrocarbon radical containing from 2 to 10 carbon atoms and at least 1 carbon-carbon double bond. Preferably 1 carbon-carbon double bond is present, and up to 4 non-aromatic carbon-carbon double bonds may be present. Thus, "C₂-C₆Alkenyl "refers to alkenyl groups having 2 to 6 carbon atoms. Alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl. In the above description relating to alkyl groups, the linear, branched or cyclic portion of the alkenyl group may contain a double bond and may be substituted if a substituted alkenyl group is indicated.

Unless otherwise specified, "cycloalkenyl" shall mean a cyclic ring of 3 to 10 carbon atoms containing at least one carbon-carbon double bond (i.e., cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, or cyclooctenyl).

Unless otherwise specified, the term "alkynyl" refers to a straight or branched chain hydrocarbon group containing 2 to 10 carbon atoms containing at least 1 carbon-carbon triple bond. Up to 3 carbon-carbon triple bonds may be present. Thus, "C₂-C₆Alkynyl "refers to alkynyl groups having 2 to 6 carbon atoms. Alkynyl includes ethynyl, propynyl and butynyl. In the above-described forms involving alkyl groups, the straight, branched or cyclic part of the hydrocarbon radicalMay contain triple bonds and may be substituted if a substituted hydrocarbyl group is indicated.

In some instances, substituents may be defined with a range of carbons including 0, such as (C)₀-C₆) Alkylene-aryl groups. If aryl is phenyl, this definition includes phenyl itself as well as-CH₂Ph、-CH₂CH₂Ph、CH(CH₃)CH₂CH(CH₃) Ph, and so on.

As used herein, "aryl" refers to any stable monocyclic or bicyclic carbocyclic ring having up to 12 atoms in each ring, wherein at least one ring is aromatic. Examples of such aryl groups include phenyl, naphthyl, tetrahydronaphthyl, 2, 3-indanyl, biphenyl, phenanthryl, anthryl or acenaphthenyl (acenaphthyl). In the case where the aryl substituent is bicyclic and one ring is not aromatic, it should be clear that the attachment is via the aromatic ring.

The term "heteroaryl" as used herein represents a stable monocyclic, bicyclic or tricyclic ring of up to 10 atoms in each ring, wherein at least one ring is aromatic and contains 1 to 4 heteroatoms selected from O, N and S. Heteroaryl groups within this definition include, without limitation: benzimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothienyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, indolinyl, indolyl, indolizinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthopyridyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothienyl, dihydrobenzoxazolyl, dihydroindolyl, dihydroquinolinyl, methylenedioxyphenyl, Benzothiazolyl, benzothienyl, quinolinyl, isoquinolinyl, oxazolyl, and tetrahydroquinoline. In the case where the heteroaryl substituent is bicyclic, and one ring is a non-aromatic ring or contains no heteroatoms, it will be appreciated that it is attached through an aromatic ring or through a heteroatom-containing ring, respectively. If the heteroaryl group contains a nitrogen atom, it should be understood that the definition also includes its corresponding N-oxide.

As one of skill in the art will appreciate, "halo" or "halogen" as used herein is meant to include chloro, fluoro, bromo, and iodo. The term "keto" refers to a carbonyl group (C ═ O). The term "alkoxy" as used herein refers to an alkyl moiety attached to the remainder of the molecule through an oxygen atom, wherein alkyl is as defined above. Examples of alkoxy groups include methoxy, ethoxy, and the like.

Unless otherwise specified, the term "haloalkyl" refers to an alkyl group as defined above substituted with 1 to 5, preferably 1 to 3, halogens. Representative examples include, without limitation, trifluoromethyl, dichloroethyl, and the like.

The term "haloalkoxy" represents a-OR group wherein R is alkyl as defined above substituted with 1 to 5, preferably 1 to 3, halogens. Representative examples include, without limitation, trifluoromethoxy, dichloroethoxy, and the like.

The term "arylalkyl" includes alkyl moieties wherein the alkyl is as described above, and includes aryl moieties wherein the aryl is as described above. Examples of arylalkyl groups include, without limitation, benzyl, fluorobenzyl, chlorobenzyl, phenylethyl, phenylpropyl, fluorophenylethyl, and chlorophenylethyl. Examples of alkylaryl groups include, without limitation, tolyl, ethylphenyl, and propylphenyl.

The term "heteroarylalkyl" as used herein refers to a system comprising a heteroaryl moiety and an alkyl-containing moiety, wherein the heteroaryl is as defined above. Examples of heteroarylalkyl include, without limitation, thienylmethyl, thienylethyl, thienylpropyl, pyridylmethyl, pyridylethyl, and imidazolylmethyl.

The term "cycloalkylalkyl" includes alkyl moieties wherein the alkyl is as described above, and also includes cycloalkyl moieties wherein the cycloalkyl is as described above. Examples of cycloalkylalkyl groups include, without limitation, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, and the like.

The term "hydroxyalkyl" refers to a straight chain monovalent hydrocarbon of 1 to 6 carbon atoms or a branched chain monovalent hydrocarbon of 3 to 6 carbon atoms substituted with one or two hydroxyl groups, provided that if two hydroxyl groups are present, they cannot both be present on the same carbon atom. Typical examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl and the like.

As used herein, unless otherwise specified, the term "heterocycle" or "heterocyclyl" is intended to include 1 to 4 substituents selected from O, N, S, SO, or SO ₂And 5-to 10-membered non-aromatic rings of heteroatoms of (a), and including bicyclic groups. Thus, "heterocyclyl" includes, without limitation, the following groups: piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, dihydropiperidinyl, tetrahydrothiophene, and the like. If the heterocycle contains nitrogen, it should be clear that this definition also includes its corresponding N-oxide.

The invention also includes N-oxide derivatives and protected derivatives of the compounds of formula I. For example, when the compound of formula I contains an oxidizable nitrogen atom, the nitrogen atom can be converted to the N-oxide by methods well known in the art. When the compounds of formula I further comprise groups such as hydroxyl, carboxyl, mercapto or any group comprising a nitrogen atom, these groups may be protected with suitable protecting groups. A comprehensive list of suitable protecting groups can be found in T.W.Greene, protective groups in Organic Synthesis, John Wiley & Sons, Inc.1981, the disclosure of which is incorporated herein by reference in its entirety. The protected derivatives of the compounds of formula I may be prepared by methods well known in the art.

When the term "alkyl" or "aryl" or any of its prefixes appears in the name of a substituent (e.g., aryl C_0-8Alkyl) which should be construed to include the definitions given above for "alkyl" and "aryl". Number of carbon atoms specified (e.g. C)_1-10) Independently, the number of carbon atoms in the alkyl or cycloalkyl portion or the alkyl portion of the larger substituent in which the alkyl group appears as a prefix.

Pharmaceutically acceptable salts of the compounds of the present invention include conventional salts of the compounds of the present invention which are non-toxic and formed with inorganic or organic acids. For example, non-toxic conventional salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid and the like, as well as salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethane disulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid and the like. Berg et al, "pharmaceutically acceptable salts", j.pharm.sci., 1977: 66: 1-19 the preparation of the above pharmaceutically acceptable salts and other typical pharmaceutically acceptable salts is described in more detail and is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the invention can be synthesized from the compounds of the invention which contain a basic or acidic moiety using conventional chemical methods. In general, salts of basic compounds are prepared by ion exchange chromatography or by reacting the free base with a stoichiometric or excess amount of the desired salt-forming inorganic or organic acid in a suitable solvent or various combinations of solvents. Similarly, salts of acidic compounds are formed by reaction with a suitable inorganic or organic base.

For the purposes of this specification, the following abbreviations have the indicated meanings:

AcOH ═ acetic acid

BF₃Boron trifluoride

Boc ═ tert-butoxycarbonyl

Boc₂Di-tert-butyl O-dicarbonate

BuLi ═ butyl lithium

CCl₄Carbon tetrachloride

CH₂Cl₂Methylene chloride ═

CH₃CN is acetonitrile

CHCl₃Chloroform ═

CS₂CO₃Cesium carbonate (MCH)

CuI ═ copper iodide

DAST ═ diethylaminosulfur trifluoride

DIPEA ═ diisopropylethylamine

DMA ═ N, N-dimethylacetamide

DMAP ═ 4- (dimethylamino) pyridine

DMF ═ N, N-dimethylformamide

DMSO ═ dimethyl sulfoxide

DPPA ═ diphenylphosphoryl azide

EDCI ═ 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride

Et₂Ethyl ether (O ═ ethyl ether)

Et₃N-triethylamine

EtOAc ═ ethyl acetate

EtOH ═ ethanol

HATU ═ 0- (7-azabenzotriazol-1-yl) -N, N' -tetramethyl

Phosphonium hexafluorophosphates

HOAC ═ acetic acid

K₂CO₃Arbutine potassium carbonate

KHMDS potassium hexamethyldisilazane

KOBu^tPotassium tert-butoxide

LDA ═ lithium diisopropylamide

LiOH lithium hydroxide

mCPBA ═ m-chloroperbenzoic acid

MeOH ═ methanol

MeSO₃H ═ methanesulfonic acid

MgSO₄Magnesium sulfate ═ magnesium sulfate

Ms is mesyl

MsCl ═ methanesulfonyl chloride

NaBH₄Sodium borohydride

NaH ═ sodium hydride

NaI ═ sodium iodide

NaCNBH₃Sodium cyanoborohydride

Na₂CO₃Sodium carbonate (sodium bicarbonate)

NaHCO₃Sodium bicarbonate

NaOH (sodium hydroxide)

Na₂SO₄Sodium ═ sulfate

NBS ═ N-bromosuccinimide

NH₃Ammonia (II) is

NH₄Cl ═ ammonium chloride

Pd/C-palladium on carbon

PdCl₂Palladium (II) dichloride

PdCl₂(dppf) ([ 1, 1' -bis (diphenylphosphino) ferrocene)]Palladium dichloride (II)

Pd₂(dba)₃Tris (dibenzylideneacetone) dipalladium (0)

PG ═ protective group

PPh₃Triphenylphosphine

(PhO)₃PMeI ═ methyltriphenoxy phosphonium iodide

PPTS ═ pyridinium p-toluenesulfonate

iPr₂Lithium diisopropylamide

PyBOP (p-butyl-p-hexafluorophosphate) benzotriazol-1-yloxytris (pyrrolidinone)

Radical) phosphorus

rt-room temperature

sat.aq. ═ saturated aqueous solution

TFA ═ trifluoroacetic acid

THF ═ tetrahydrofuran

TiCl₄Titanium chloride (IV)

tlc ═ thin layer chromatography

TMSCl ═ trimethylchlorosilane

Me is methyl

Et is ethyl

n-Pr ═ n-propyl

i-Pr ═ isopropyl

n-Bu ═ n-butyl

i-Bu ═ isobutyl

s-Bu ═ sec-butyl

t-Bu ═ tert-butyl

The novel compounds of the present invention can be prepared according to the following general procedure using suitable starting materials and are further illustrated by the following examples. However, the compounds listed in the examples are not to be considered as forming the only type of consideration for the present invention. The following examples illustrate the preparation of the compounds of the present invention in more detail. One skilled in the art will recognize that these compounds may be prepared using variations of the following preparative conditions and procedures. All temperatures are in degrees celsius unless otherwise noted.

Reaction scheme

The compounds of the present invention can be prepared according to reaction scheme 1 shown below. Thus, 2-amino esters can be added to haloalkyl ketones to form aminals, which can be in the presence of a dehydrating agent such as TiCl ₄、MgSO₄Or in the case of isopropyl trifluoroacetate, to the imine. Reduction of the imine with a reducing agent such as sodium cyanoborohydride or sodium borohydride yields the amine. Ester hydrolysis and amide formation with suitably substituted aminoacetonitriles gives the compounds of the invention. If the substituents on the D system are halogen, a palladium-catalyzed Suzuki coupling with the appropriate boronic acid gives the inventionAdditional compounds.

Reaction scheme 1

The compounds of the present invention can also be prepared according to reaction scheme 2 shown below.

Ketones or aldehydes may be condensed with amino alcohols to give cyclic aminals. Treatment with 3 equivalents of a grignard reagent or organolithium reagent provides the aminoalcohol which is suitably alkylated. By chromium systems, e.g. Jones oxidation or H₅IO₆/CrO₃By oxidation of alcohols, or by two-step oxidation (e.g. oxalyl chloride/DMSO/Et)₃N, then NaClO) to give the corresponding carboxylic acid. Peptide coupling and Suzuki reactions as described in scheme 1 will provide compounds of the invention.

Reaction scheme 2

The compounds of the present invention can also be prepared according to reaction scheme 3 shown below. Ketones or aldehydes may be condensed with amino alcohols to give cyclic aminals. It is treated with multiple equivalents of a grignard reagent or an organolithium reagent to provide the appropriate alkylated aminoalcohol. Such alcohols can be converted to the compounds of the present invention by the methods described in scheme 2.

Reaction scheme 3

The compounds of the present invention may also be prepared according to reaction scheme 4. Suitably substituted acetates can be enolated with a suitable base (including without limitation LDA, KHMDS, NaH or n-BuLi) and treated with paraformaldehyde to provide the diol. Such diols may be converted to difluorides using a fluorinating agent such as DAST. The ester is then hydrolyzed and then undergoes a Curtius rearrangement to give the amine. Such amines can displace the suitably substituted α -bromo ester to give the α -amino ester. It can be converted into the compounds of the present invention using the methods described in scheme 1.

Reaction scheme 4

The compounds of the present invention can also be prepared using reaction scheme 5 shown below. The hemiacetal may be condensed with an amino alcohol in which the alcohol moiety is protected with a suitable protecting group. The resulting imine is treated with a Grignard reagent or an organolithium reagent to provide the appropriate alkylated aminoalcohol. The alcohol protecting group can then be removed and the reaction can be carried out as described in scheme 2 or by first performing a Suzuk reaction followed by H₅IO₆/CrO₃The alcohol is oxidized and then peptide coupled to convert the alcohol to the compounds of the invention.

Reaction scheme 5

The compounds of the present invention can also be prepared according to reaction scheme 6 shown below. Peptide coupling of α -amino acids and α -amino amides as described in schemes 1, 2, or 5 followed by dehydration of the resulting primary amides (Voegel, J.J.; Benner, S.A. Helv. chem. acta1996, 79, 1863) gives the compounds of the invention.

Reaction scheme 6

The synthesis of some of the amino alcohols used at the beginning of reaction schemes 2, 3 and 5 is described in reaction schemes 7-11. For example, the synthesis of (2S) -2-amino-4-fluoro-4-methylpentan-1-ol, where R ═ Me, is described in reaction scheme 7 below. Starting with the appropriate di-protected aspartic acid, the carboxyl group can be reduced to the alcohol (i.e., forming a mixed anhydride, followed by NaBH) using standard literature procedures₄To effect reduction). The protected form of 2-amino-4-methylpentane-1, 4-diol (R ═ Me) is then produced by a suitable grignard or organolithiation reaction. Finally, the hydroxyl moieties are converted to the desired fluorine with a fluorinating agent such as DAST. This alcohol in protected or unprotected form can then be converted to the compounds of the present invention according to reaction schemes 1, 2, 3 and 5.

Reaction scheme 7

The 4-fluoroleucinol can also be synthesized according to reaction scheme 8. The 4, 5-dehydroleucine is converted to (4S) -4- (2-methylpropan-2-enyl) -1, 3-oxazolidin-2-one as described in the following reaction scheme. This intermediate is then treated with a fluorohydrogenant, such as HF-pyridine, to give (4S) -4- (2-fluoro-2-methylpropyl) -1, 3-oxazolidin-2-one. Followed by alkaline hydrolysis (i.e., Ba (OH) ₂Or NaOH) to give (2S) -2-amino-4-fluoro-4-methylpent-1-ol.

Reaction scheme 8

The synthesis of 4, 4-difluoro-L-norvaline where R ═ Me is described in reaction scheme 9 below. Starting with the appropriate doubly protected serine, using reagents such as (PhO)₃P⁺MeI^-To perform iodination. The resulting iodide may be zinc-coated with a Zn-Cu coupling and TMSCl. The resulting zincate can then be subjected to a palladium-catalyzed coupling reaction with alkanoyl chloride to yield a ketone. Finally, the ketone moiety can be converted to the desired difluoro derivative with a fluorinating agent such as DAST. This amino acid or amino alcohol, in protected or unprotected form, can then be converted to the compounds of the invention according to reaction schemes 1, 2, 3 and 5.

Reaction scheme 9

The amino alcohols used in the present invention may also be synthesized according to reaction scheme 10. With a reducing agent such as NaBH in a solvent such as EtOH or a mixed solvent system such as EtOH and THF in the presence or absence of an additive such as LiCl₄The protected amino acid is reduced. The amino protecting group is then removed by any suitable method depending on the nature of the protecting group.

Reaction scheme 10

The synthesis of (2S, 4S) -2-amino-5, 5, 5-trifluoro-4-methylpentan-1-ol for use in the present invention is illustrated in reaction scheme 11. N-benzoyl-5, 5, 5-trifluoroleucine (Ojiima, et al J. org. chem., 1989, 54, 4511-4522) can be hydrolyzed with a suitable aqueous acid such as 6M HCl under reflux conditions. The amino acid HCl salt intermediate is then converted to N-acetyl-5, 5, 5-trifluoroleucine and the amino chiral center is resolved by enzymatic methods (Synthetic Communications, 1996, 26, 1109-1115.). The isolated 5, 5, 5-trifluoro-L-leucine is then protected with a protecting group such as benzyl carbamate and the carboxylic acid group is esterified. The two diastereomers at the 4-position are then separated by flash column chromatography. One of the enantiomers, the (2S, 4S) -protected amino acid, is then converted to an amino alcohol as shown in the reaction scheme.

Reaction scheme 11

Wherein R is⁵Is hydrogen, and R⁶Compounds of the present invention that are aryl or heteroaryl groups can also be prepared using reaction scheme 12 shown below. Aryl or heteroaryl aldehydes are condensed with amino alcohols in which the alcohol moiety is protected by a suitable protecting group, and the resulting imines are then treated with a compound of the formula halogen- (D)_n-Li or halogen- (D)_nTreatment with a Grignard or organolithium reagent of MgX (wherein D is as defined in the summary of the invention) followed by removal of the oxygen protecting group gives the alkylated aminoalcohol. The alkylated aminoalcohol is then converted to the compound of the present invention using the method described in scheme 2, or by first reacting with the compound of formula R⁷-B(OH)₂By Suzuki reaction with a suitable oxidizing agent, e.g. H₅IO₆/CrO₃The alcohol is oxidized to give an acid, which is finally treated with aminoacetonitrile under peptide coupling conditions as described previously to convert the alkylated aminoalcohol into the compound of the invention.

Reaction scheme 12

The compounds of the present invention may also be prepared according to reaction scheme 13 shown below. The reaction of the N-protected amino acid derivative with oxetane tosylate in the presence of sodium iodide in a suitable organic solvent such as dimethylformamide gives the corresponding oxetane ester which on treatment with diborane gives the orthoester. Removal of the amino protecting group to give the amine, which is reacted with a compound of formula R under the reaction conditions described above ⁶CHO (wherein R⁶Is aryl or heteroaryl) or of the formula R⁶The hemiacetal of C (OH) (OR) (where R is an alkyl group) is condensed to give the imine. The imine is treated with a Grignard or organolithium reagent under the reaction conditions described above to give the N-alkylated derivative. The orthoester is removed to give the corresponding carboxylic acid, which is then converted to the compound of the invention by condensation with aminoacetonitrile under peptide coupling conditions, followed by the Suzuki reaction as described above.

Reaction scheme 13

The following examples are presented to illustrate the synthesis of selected compounds of the invention.

Example 1

N ¹ - (cyanomethyl) -N ² Synthesis of (2, 2, 2-trifluoro-1-phenylethyl) -L-leucinamide

To a solution of L-leucine methyl ester hydrochloride (975mg, 5.37mmol) in dichloromethane (30mL) was added 2, 2, 2-trifluoroacetophenone (0.75mL, 5.34mmol) and diisopropylethylamine (3.5mL, 20 mmol). To this was added dropwise TiCl in 0.45mL of dichloromethane₄(0.55mL, 5.0mmol) and the mixture was stirred overnight. Then adding additional TiCl thereto₄(0.4mL, 3.6mmol) and the mixture was stirred for 3 h. Adding NaCNBH thereto₃(1050mg, 16.7mmol) in MeOH (20mL) and the mixture stirred for 2 h. Pour into 1N NaOH and extract it with ethyl acetate (2 ×). The organic phase was washed with 1N NaOH and brine, then MgSO ₄Dried and evaporated. Purification by ISCO column chromatography (gradient elution from 30% to 90% ethyl acetate in hexanes) afforded N- (2, 2, 2-trifluoro-1-phenylethyl) -L-leucine methyl ester.

To a solution of N- (2, 2, 2-trifluoro-1-phenylethyl) -L-leucine methyl ester (150mg, 0.50mmol) in 2: 1 THF/MeOH at room temperature was added 1M LiOH. The mixture was stirred overnight and concentrated. The residue was partitioned between ethyl acetate and phosphate buffer pH 3.5. The organic phase was washed with brine, MgSO₄Drying and concentrating to obtain the N- (2, 2, 2-trifluoro-1-phenylethyl) -L-leucine.

A mixture of N- (2, 2, 2-trifluoro-1-phenylethyl) -L-leucine (149mg, 0.50mmol), aminoacetonitrile hydrochloride (102mg, 1.1mmol) and PyBOP (260mg, 0.50mmol) was dissolved in DMF (5 mL). Triethylamine (0.3mL, 2.1mmol) was added thereto and the mixture was stirred overnight, then poured into phosphate buffer pH 3 and extracted with 3: 1 diethyl ether/ethyl acetate. The organic phase was washed with saturated NaHCO₃The aqueous solution and brine were washed with MgSO₄Dried and evaporated. Purification by ISCO column chromatography (20% to 50% ethyl acetate/hexanes gradient) gave N as a 1: 1 diastereomer mixture ¹- (cyanomethyl) -N²- (2, 2, 2-trifluoro-1-phenylethyl) -L-leucinamide. MS (+ APCI): 313.9[ M +1 ]]。

Example 2

N ² - [1- (4-bromophenyl) -2, 2, 2-trifluoroethyl group]-N ¹ Synthesis of- (cyanomethyl) -L-leucinamide

Preparation of N by the method of example 1²- [1- (4-bromophenyl) -2, 2, 2-trifluoroethyl group]-N¹- (cyanomethyl) -L-leucinamide. MS (-ESI): 403.9, 405.9[ M-1 ]]^-

Example 3

N ¹ - (cyanomethyl) -N ² - [2, 2, 2-trifluoro-1- (4 '-piperazin-1-yl-1, 1' -biphenyl-4-yl) Ethyl radical]Synthesis of (E) -L-leucinamide

N in DME (3mL) under dry nitrogen²- [1- (4-bromophenyl) -2, 2, 2-trifluoroethyl group]-N¹- (cyanomethyl) -L-leucinamide (242mg, 0.60mmol) and 4- [4- (tert-butoxycarbonyl) -1-piperazinyl]To phenylboronic acid (220mg, 0.72mmol) was added 2M aqueous sodium carbonate (0.9mL, 1.8mmol) followed by the catalyst PdCl₂(dppf) (63mg, 0.077 mmol). The reaction was heated to 85 ℃ and heating continued for 18 hours. Water was added and the product was extracted with EtOAc and the organic layer was extracted with Na₂SO₄Drying and vacuum concentrating. The crude product was purified by chromatography using EtOAc in hexanes to give (4' {1- [ ((1S) -1- { [ (cyanomethyl) amino]Carbonyl } -3-methylbutyl) amino ]-2, 2, 2-trifluoroethyl } -1, 1' -biphenyl-4-yl) -1-piperazinecarboxylic acid tert-butyl ester.

(4' - {1- [ ((1S) -1- { [ (cyanomethyl) amino) in dry THF (1mL) under dry nitrogen over 15 minutes]Carbonyl } -3-methylbutyl) amino]-2, 2, 2-trifluoroethyl } -1, 1' -biphenyl-4-yl) -1-piperazinecarboxylic acid tert-butyl ester (275mg, 0.47mmol) to which MeSO was added dropwise₃H (125. mu.L, 1.9mmol), and the reaction was allowed to proceed for 18 hours. The reaction mixture was stirred in EtOAc and water + saturated NaHCO₃To adjust the pH to 7.5. The organic layer was washed with Na₂SO₄Drying and vacuum concentrating. The crude product was purified by column chromatography on silica gel using concentrated NH₄OH/MeOH/CH₂Cl₂(1/10/89) to give N in the form of a pale yellow foam¹- (cyanomethyl) -N²- [2, 2, 2-trifluoro-1- (4 '-piperazin-1-yl-1, 1' -biphenyl-4-yl) ethyl]-L-leucinamide. MS (+ ESI): 488.3[ M +1 ]]⁺。

Example 4

N ¹ - (cyanomethyl) -N ² - { [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl][4- (methylsulfonyl) phenyl]Methyl radical]Synthesis of (E) -L-leucinamide

Step 1: n- { (4-bromophenyl) [4- (methylsulfonyl) phenyl]methylene-L-leucine methyl ester

A solution of (4-bromophenyl) [4- (methylsulfonyl) phenyl ] methanone (202mg, 0.59mmol), L-leucine methyl ester hydrochloride (328mg, 2.0mmol), and camphorsulfonic acid (52mg, 0.22mmol) in toluene was refluxed for 18 hours using a Dean-Stark trap. The solvent was removed in vacuo and the resulting residue was purified by chromatography using EtOAc and hexane as eluents to give a 1: 1 mixture of the title compound and the starting (4-bromophenyl) [4- (methylsulfonyl) phenyl ] methanone.

Step 2: n- { (4-bromophenyl) [4- (methylsulfonyl) phenyl]Methyl } -L-leucine methyl ester

Over 2 days, N- { (4-bromophenyl) [4- (methylsulfonyl) phenyl ] from step 1 was added with a solid addition funnel]Methylene leucine methyl ester and (4-bromophenyl) [4- (methylsulfonyl) phenyl ]]A1: 1 mixture of methanones (185mg,. about.0.2 mmol) in acetic acid/methanol (1: 3, 4mL) was added portionwise sodium borohydride (. about.400 mg) every 30 minutes (the addition was stopped at night). The reaction mixture was partitioned between EtOAc and water and the organic layer was washed with Na₂SO₄Dried and evaporated. The resulting reaction mixture was purified by chromatography using EtOAc and hexane as eluent. Obtaining N- { (4-bromophenyl) [4- (methylsulfonyl) phenyl ] as a colorless gum]Methyl } -L-leucine methyl ester and (4-bromophenyl) [4- (methylsulfonyl) phenyl ] in the form of a white solid]Methanol.

And step 3: n- { (4-bromophenyl) [4- (methylsulfonyl) phenyl]methyl-L-leucine

To the N- { (4-bromophenyl) [4- (methylsulfonyl) phenyl ] obtained in step 2]To a solution of methyl } -L-leucine methyl ester (81mg, 0.17mmol) in THF (1mL) and MeOH (0.5mL) was added 1N LiOH (0.3mL, 0.3 mmol). The resulting reaction mixture was stirred at room temperature for 18 h, then partitioned between EtOAc and water +1N HCl (0.5 mL). The organic layer was washed with Na ₂SO₄Drying, filtration and concentration in vacuo afforded the title compound as a colorless gum.

And 4, step 4: n is a radical of ² - { (4-bromophenyl) [4- (methylsulfonyl) phenyl]Methyl } -N ¹ - (cyanomethyl) -L-leu Aminamides

To the cooled-to-10 deg.C N- { (4-bromophenyl) [4- (methylsulfonyl) phenyl ] obtained in step 3]To a solution of methyl } -L-leucine (76mg, 0.17mmol), HATU (146mg, 0.38mmol), aminoacetonitrile hydrochloride (52mg, 0.56mmol) in DMF (1.1mL) was added N, N-diisopropylethylamine (0.13mL, 0.75 mmol). The reaction was allowed to proceed at room temperature for 18h and partitioned between EtOAc and water. The organic layer was washed with Na₂SO₄Drying, filtering and vacuum concentrating. The crude product was purified by chromatography using EtOAc and hexanes as eluent to give the title compound as a colorless gum.

And 5: n is a radical of ¹ - (cyanomethyl) -N ² - { (4- (methylsulfonyl) phenyl } [4 '- (methylthio) -1, 1' -biphenyl -4-yl]methyl-L-leucinamide

N from step 4²- { (4-bromophenyl) [4- (methylsulfonyl) phenyl]Methyl } -N¹A heterogeneous mixture of (cyanomethyl) -L-leucinamide (72mg, 0.15mmol), 4- (methylthio) phenylboronic acid (37mg, 0.22mmol) in ethylene glycol dimethyl ether (1mL) and 2M aqueous sodium carbonate solution was degassed under vacuum and purged with nitrogen. To this mixture was added [1, 1' -bis (diphenylphosphino) ferrocene ] ]A complex of palladium (II) dichloride and dichloromethane (19mg, 0.023mmol) was then degassed and purged with nitrogen. The reaction mixture was heated at 85 ℃ for 16 hours with efficient stirring. The reaction mixture was washed with EtOAc and NH₄The OAC aqueous solution was partitioned between 25% w/v. The organic layer was washed with Na₂SO₄Drying, filtering and vacuum concentrating. The crude product was purified by chromatography using EtOAc and hexane as eluent to give a colorless gum formThe title compound of (1).

Step 6: n is a radical of ¹ - (cyanomethyl) -N ² - { [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl][4- (methylsulfonyl) Acyl) phenyl]methyl-L-leucinamide

To N¹- (cyanomethyl) -N²- { [4- (methylsulfonyl) phenyl][4 '- (methylthio) -1, 1' -biphenyl-4-yl]To a solution of methyl } -L-leucinamide (63mg, 0.12mmol), sodium tungstate dihydrate (2mg, 0.006mmol), tetrabutylammonium hydrogen sulfate (4mg, 0.01mmol) was added 30% w/v aqueous hydrogen peroxide (100L, 0.9mmol), and the resulting reaction mixture was stirred at room temperature for 10 minutes. The reaction mixture was washed with EtOAc and water +1M NaHSO₃(3: 1). The organic layer was washed with Na₂SO₄Drying, filtering and vacuum concentrating. The crude product was purified by chromatography using EtOAc and hexanes as eluent to give the title compound as a colorless gum.

MS(+ESI)：568.2[M+1]⁺。

Example 5

N ¹ - (cyanomethyl) -N ² - {2, 2, 2-trifluoro-1- [ 4' - (methylsulfonyl) -1, 1' -biphenyl-3-yl]Synthesis of ethyl } -L-leucinamide

Using the procedure described in example 8, N²- [1- (4-bromophenyl) -2, 2, 2-trifluoroethyl group]-N¹N for- (cyanomethyl) -L-leucinamide²- [1- (3-bromophenyl) group) -2, 2, 2-trifluoroethyl]-N¹- (cyanomethyl) -L-leucinamide to give the title compound as a colourless gum.

MS(+ESI)：482.2[M+1]⁺。

Example 6

N ¹ - (cyanomethyl) -N ² - [2, 2, 2-trifluoro-1- (3-pyridin-4-ylphenyl) ethyl] Synthesis of (E) -L-leucinamide

Using the procedure described in example 8, N²- [1- (4-bromophenyl) -2, 2, 2-trifluoroethyl group]-N¹N for- (cyanomethyl) -L-leucinamide²- [1- (3-bromophenyl) -2, 2, 2-trifluoroethyl group]-N¹- (cyanomethyl) -L-leucinamide to give the title compound as a colourless gum.

MS(+ESI)：405.1[M+1]⁺.

Example 7

N ¹ - (cyanomethyl) -N ² - [2, 2, 2-trifluoro-1- (4 '-piperazin-1-yl-1, 1' -biphenyl-3-yl) Ethyl radical]Synthesis of (E) -L-leucinamide

Using the procedure described in example 3, N²- [1- (4-bromobenzene)Yl) -2, 2, 2-trifluoroethyl]-N¹N for- (cyanomethyl) -L-leucinamide²- [1- (3-bromophenyl) -2, 2, 2-trifluoroethyl group]-N¹- (cyanomethyl) -L-leucinamide to give the title compound as a colourless gum.

MS(+ESI)：488.3[M+1]⁺。

Example 8

N ¹ (cyanomethyl) -N ² { (1S) -2, 2, 2-trifluoro-1- [ 4' - (methylsulfonyl) -1, 1' -biphenyl-4-yl]Synthesis of ethyl } -L-leucinamide

Step 1: (2S) -1- { [ tert-butyl (dimethyl) silyl]Preparation of oxy-4-methylpentane-2-amine Prepare for

To a solution of L-leucinol (6.0g) in dichloromethane (100mL) was added triethylamine (11mL), DMAP (0.1g) and tert-butyldimethylsilyl chloride (8.5g) at room temperature. The mixture was stirred at room temperature for 2 hours, and then water was added thereto. The organic layer was separated and the aqueous layer was further extracted with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate and the solvent removed in vacuo to give the title compound, which was used as such in the residue of the next reaction.

¹HNMR(CD₃COCD₃)δ3.48(m，2H)，3.32(m，1H)，2.76(m，1H)，1.78(m，1H)，1.22-1.02(m，2H)，0.88(m，15H)，0.06(s，6H).

Step 2: (2S) -1- { [ tert-butyl (dimethyl) silyl]Oxy } -4-methyl-N- [ (1E) -2, 2, 2- Trifluoroethylene radical]Preparation of pentane-2-amine

The (2S) -1- { [ tert-butyl (dimethyl) silyl group obtained in step 1]A solution of oxy } -4-methylpentane-2-amine (50g) and trifluoroacetaldehyde acetal-methanol (35mL) in toluene (300mL) was heated to reflux for 16 hours during which time water was collected in the Dean-Stark trap. The solvent was evaporated in vacuo and the residue was taken up in SiO using hexane and ethyl acetate (9: 1) as eluent ₂Purification as above gave the title compound.

¹H NMR(CD₃COCD₃)δ7.88(m，1H)，3.76-3.45(m，3H)，1.60-1.25(m，3H)，0.88(m，15H)，0.06(s，3H)，0.04(s，3H).

And step 3: (2S) -2- { [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl]Amino } -4-methylpentan-1-ol Preparation of

n-BuLi (2.5M in hexanes, 42mL) was added to a-70 ℃ solution of 1, 4-dibromobenzene (25.8g) in THF (400mL), and the mixture was stirred for 25 minutes. Then, (2S) -1- { [ tert-butyl (dimethyl) silyl group was added dropwise thereto]Oxy } -4-methyl-N- [ (1E) -2, 2, 2-trifluoroethylene]A solution of pentane-2-amine (31g) in THF (30mL) was added and the mixture was stirred for 1.5 hours. It was then poured slowly into a mixture of ethyl acetate (500mL), water (2L), ice (300g) and ammonium chloride (100g) with vigorous stirring. The organic layer was separated and the aqueous layer was further extracted with ethyl acetate (2X 500 mL). The combined organic layers were washed with brine, dried over magnesium sulfate and the solvent removed under vacuum to yield a residue which was used as such. The residue obtained above was dissolved in THF (250mL) and the solution was cooled to 0 ℃. A solution of 1M t-butylammonium fluoride (110mL) in THF was added dropwise thereto and the mixture was allowed to react for 4 hours. It was poured into ethyl acetate (300mL), water (2L) and ammonium chloride (100g) with vigorous stirring. The organic layer was separated and the aqueous layer was further extracted with ethyl acetate (2X 100 mL). Will be described The combined organic layers were washed with brine, dried over magnesium sulfate, and the solvent removed in vacuo to give a residue which was purified on SiO using a gradient of ethyl acetate and hexane (1: 5 to 1: 4) as eluent₂Purification was carried out to give the title compound.

¹H NMR(CD₃COCD₃)δ7.6(2H，d)，7.45(2H，d)，4.55(1H，m)，3.65-3.7(1H，m)，3.5-3.55(1H，m)，3.25-3.35(1H，m)，2.6-2.7(1H，m)，2.25-2.35(1H，m)，1.65-1.75(1H，m)，1.3-1.4(1H，m)，1.2-1.3(1H，m)，0.75-0.9(6H，dd).

And 4, step 4: (2S) -4-methyl-2- ({ (1S) -2, 2, 2-trifluoro-1- [4 '- (methylthio) -1, 1' -biphenyl-4-yl] Preparation of ethyl } amino) pentan-1-ol

A nitrogen stream was passed through the reaction mixture consisting of bromide from step 3 (27.7g), 4- (methylthio) phenylboronic acid (15.7g), 2M Na₂CO₃(100mL) and n-propanol (500mL) for 15 minutes. Pd (OAc) is then added thereto₂And PPh₃1: 3 (3.5g), the reaction was warmed to 70 ℃ and stirred under nitrogen for 8 hours. The mixture was cooled to room temperature, diluted with ethyl acetate (500mL) and poured onto water (2L) and ice (500 g). The ethyl acetate layer was separated and the aqueous layer was further extracted with ethyl acetate (200 mL). The combined ethyl acetate extracts were extracted with 0.5N NaOH (2X 200mL), NH₄The aqueous Cl solution, brine were washed, and dried over magnesium sulfate. Removing the solvent to leave a residue, using SiO ₂It was purified by chromatography, eluting with a gradient of ethyl acetate and hexane (1: 4 to 1: 3) and then acetone and toluene (1: 10). The residue was dissolved in hot hexane (200mL) and the solution was cooled to 0 ℃ with stirring. The resulting solid was filtered and dried to give the title compound.

¹H NMR(CD₃COCD₃)δ7.7(2H，d)，7.65(2H，d)，7.6(2H，d)，7.35(2H，d)，4.5-4.6(1H，m)，3.7(1H(OH)，m)，3.5-3.6(1H，m)，3.3-3.4(1H，m)，2.7(1H，m)，2.5(3H，s)，2.3-2.4(1H(NH)，m)，1.65-1.75(1H，m)，1.2-1.4(3H，m)，0.8-0.9(6H，dd).

And 5: (2S) -4-methyl-2- ({ (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4- Base of]Preparation of ethyl } amino) pentan-1-ol

To a 0 deg.C solution of sulfide from step 4 (19g) in toluene (400mL) was added Na₂WO₄·2H₂O (0.16g) and BU₄NHSO₄(0.81 g). Then, 30% hydrogen peroxide (12.2mL) was slowly added thereto and the mixture was stirred at room temperature for 4.5 hours. The mixture was slowly poured onto a mixture of ice, dilute aqueous sodium thiosulfate solution and ethyl acetate. The organic layer was separated and the aqueous layer was further extracted with ethyl acetate (2X 100 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, and the solvent was removed under vacuum to give a residue, which was washed with SiO₂This was purified using ethyl acetate and hexane (1: 1) as eluents to give the product.

¹H NMR(CD₃COCD₃)δ8.05(2H，d)，8.0(2H，d)，7.85(2H，d)，7.7(2H，d)，4.6-4.7(1H，m)，3.75(1H，m)，3.6(1H，m)，3.35-3.45(1H，m)，3.2(3H，s)，2.7-2.8(1H，m)，2.35-2.45(1H，m)，1.7-1.8(1H，m)，1.2-1.5(2H，m)，0.8-0.95(6H，dd).

Step 6: n- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl ]Ethyl } -L- Preparation of leucine

H is to be₅IO₆/CrO₃In CH (529mL, 0.44M)₃In CN; see comments below) was cooled to 0 ℃ and the alcohol from step 5 (20g) in CH was added dropwise thereto₃CN (230 mL). The mixture was stirred at 0-5 ℃ for 3.5 hours. In the intense fieldIt was poured over Na of pH 4 with stirring₂HPO₄(1.5L) and the mixture was extracted with diethyl ether (3X 250 mL). The combined ether extracts were washed with water and brine (1: 1) and diluted NaHSO₃The aqueous solution and brine were washed. The organic extract was dried over sodium sulfate, filtered and the solvent evaporated to dryness to give a residue which was divided into two batches for the following purification.

The crude acid obtained above (10g) was dissolved in isopropyl acetate (250mL) and extracted into cold 0.1N NaOH (3X 250 mL). The combined extracts were washed with diethyl ether (250mL) and slowly acidified to pH 4 with 6N HCl. The carboxylic acid was extracted with isopropyl acetate (2X 250mL), and the isopropyl acetate layer was dried and concentrated to give the substantially pure product, which was used in the next step.

Note that: oxidizing agent (H)₅IO₆/CrO₃) Was prepared as described in Tetrahedron Letters39(1998)5323-5326, but using HPLC grade CH ₃CN (containing 0.5% water); no water was added.

¹H NMR(CD₃COCD₃)δ8.05(2H，d)，7.95(2H，d)，7.8(2H，d)，7.65(2H，d)，4.45-4.55(1H，m)，3.55-3.6(1H，m)，3.2(3H，s)，2.8-3.0(broad m，NH/OH)1.95-2.05(1H，m)，1.55-1.6(2H，m)，0.9-1.0(6H，m).

And 7: n is a radical of ¹ (cyanomethyl) -N ² { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4- Base of]Preparation of ethyl } -L-leucinamide

To a solution of the acid from step 7 (9g) in DMF (200mL) was added benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (11.6g), aminoacetonitrile hydrochloride (3.94g), and the mixture was cooled to 0 ℃. Thereto was added dropwise triethylAmine (9.9mL), warm the mixture to room temperature and stir it for 16 h. It was poured onto ice and saturated aqueous sodium bicarbonate and extracted with diethyl ether (3X 100 mL). The combined extracts were washed with water, dried over magnesium sulfate and the solvent removed in vacuo. The residue is treated with SiO₂Was purified by chromatography, eluting with ethyl acetate and hexane (1: 1). The title compound was then stirred in ether for 16 h, filtered and dried (mp 140.5 ℃).

¹H NMR(CD₃COCD₃)δ8.0(2H，d)，7.95(2H，d)，7.8(2H，d)，7.65(2H，d)，4.35-4.45(1H，m)，4.1-4.2(2H，m)，3.45-3.55(1H，m)，3.15(3H，s)，2.65-2.7(1H，m)，1.85-1.95(1H，m)，1.4-1.6(2H，m)，0.85-0.95(6H，m).

Example 9

N ² { (1S) -1- [4 '- (aminosulfonyl) -1, 1' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -N ¹ Synthesis of (cyanomethyl) -L-leucinamide

Step 1: n is a radical of ² [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl) ]-N ¹ (cyanomethyl) -L-leucinamide Preparation of

H is to be₅IO₆/CrO₃In CH (1925mL, 0.44M)₃In CN; see comments made in step 6 of example 8) to 0 ℃ and (2S) -2- { [ (1S) -1- (4-bromo) from step 4 of example 8 was added dropwise theretoPhenyl) -2, 2, 2-trifluoroethyl]Amino } -4-methylpentan-1-ol (60g) in CH₃CN (1500 mL). The mixture was stirred at 0-5 ℃ for 3.5 hours. It was poured over Na of pH 4 with vigorous stirring₂HPO₄(2.5L) and the mixture was extracted with diethyl ether (3X 500 mL). The combined ether extracts were washed with water and brine (1: 1), diluted NaHSO₃The aqueous solution and brine were washed. The organic extract was dried over sodium sulfate, filtered, and concentrated in vacuo to give N- [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl group]L-leucine, which can be used as such in the following couplings with aminoacetonitrile.

To a solution of this acetic acid (46g) in DMF (1500mL) was added benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (71.5g), aminoacetonitrile hydrochloride (25.4g), and the mixture was cooled to 0 ℃. Triethylamine (60.8mL) was added dropwise thereto, and the mixture was warmed to room temperature and stirred for 16 hours. It was poured onto ice and a saturated aqueous solution of sodium hydrogencarbonate, and extracted with diethyl ether (3X 300 mL). The combined extracts were washed with brine, dried over magnesium sulfate and the solvent removed in vacuo. The residue is treated with SiO ₂Purification by chromatography with a gradient elution of ethyl acetate and hexane (1: 3 to 1: 2) gave the title compound in sufficient purity for the next step.

¹H NMR(CD₃COCD₃)δ7.95-8.05(bs，NH)，7.6(2H，d)，7.45(2H，d)，4.4(1H，m)，4.1-4.2(2H，m)，3.4-3.5(1H，m)，2.6-2.7(1H，m)，1.8-1.95(1H，m)，1.4-1.6(2H，m)，0.85-0.95(6H，m).

Step 2: n is a radical of ¹ - (cyanomethyl) -N ² { (1S) -2, 2, 2-trifluoro-1- [4- (4, 4, 5, 5-tetramethyl-1, 3, 2-di Oxaborazol-2-yl) phenyl]Preparation of ethyl } -L-leucinamide

A nitrogen stream was passed over N from step 1²[ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl)]-N¹(cyanomethyl) -L-leucinamide (28.5g), bis (pinacol) diboron (23g) and potassium acetate (24g) in DMF (700mL) was aerated for 15 minutes and then [1, 1' -bis (diphenylphosphino) -ferrocene ] added]Palladium (II) dichloride complex with dichloromethane (1: 1) (2.9 g). The mixture was warmed to 65 ℃ and stirred under nitrogen for 2.5 hours. The mixture was cooled to room temperature, diluted with ethyl acetate and hexane (1: 1, 300mL) and then poured onto water (2L) and ice (500 g). The organic layer was separated and the aqueous layer was extracted with ethyl acetate and hexane (1: 1, 3X 200 mL). The combined extracts were washed with brine and dried over magnesium sulfate. Removing the solvent to leave a residue, using SiO ₂This was purified by chromatography, eluting with ethyl acetate and hexane (1: 2) to give the borate salt.

¹H NMR(CD₃COCD₃) δ 7.95-8.05(bs, NH), 7.7-7.8(2H, d), 7.45-7.55(2H, d), 4.3-4.4(1H, m), 4.05-4.15(2H, m), 3.4-3.5(1H, m), 2.55-2.65(1H, m), 1.85-1.95(1H, m), 1.45-1.55(2H, m), 1.15-1.4(12H, m; some pinacols are also present as contaminants), 0.85-0.95(6H, m).

And step 3: n is a radical of ² { (1S) -1- [4 '- (aminosulfonyl) -1, 1' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl- N ¹ Preparation of (cyanomethyl) -L-leucinamide

A nitrogen stream was passed over the borate (4g) to give step 2, 4-bromobenzenesulfonamide (3.3g), 2MNa₂CO₃A mixture of (20mL) and n-propanol (100mL) was aerated for 15 minutes. Pd (OAc) is then added thereto₂And PPh₃1: 3 (0.25g), the reaction was warmed to 85 ℃ and stirred under nitrogen for 3 hours. The mixture was cooled to room temperature and extracted with ethyl acetate (1)100mL) and poured onto water (500mL) and ice (100 g). The ethyl acetate layer was separated and the aqueous layer was further extracted with ethyl acetate (100 mL). The combined ethyl acetate extracts were extracted with dilute NaHCO₃The aqueous solution and brine were washed, and dried over magnesium sulfate. Removing the solvent to leave a residue, using SiO ₂It was purified by chromatography eluting with a gradient of ethyl acetate, hexane and dichloromethane (2: 3: 0.1 to 1: 0.1). The product was then stirred in ether for 16 hours, filtered and dried to give the title compound.

¹H NMR(CD₃COCD₃)δ8-8.1(3H，m)，7.9(2H，d)，7.8(2H，d)，7.65(2H，d)，6.6-6.7(2H，m)，4.4(1H，m)，4.1-4.2(2H，m)，3.5(1H，m)，2.6-2.7(1H，m)，1.9(1H，m)，1.45-1.6(2H，m)，1.4-1.6(4H，m)，0.9-1.0(6H，m).

Example 10

N ¹ (1-cyanocyclopropyl) -N ² { (1S) -2, 2, 2-trifluoro-1- [ 4' - (methylsulfonyl) -1, 1' -biphenyl-4-yl]Synthesis of ethyl } -L-leucinamide

To N- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl obtained in example 8 was added at 0 deg.C]Triethylamine (0.9mL) was added to a mixture of ethyl } -L-leucine (0.83g), O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (0.78g), cyclopropylamine hydrochloride (0.466g) in DMF (18 mL). The mixture was kept at room temperature for 48 hours and then poured into dilute aqueous ammonium chloride and diethyl ether. The ether layer was separated and the aqueous layer was extracted with ether in one step.The combined ether extracts were washed with brine, dried over magnesium sulfate and the solvent removed in vacuo. The residue is treated with SiO₂Purification was performed using ethyl acetate and hexane (1: 1) as eluent followed by trituration with ether (swish) to give the title compound.

¹H NMR(CD₃COCD₃)δ8.15(1H，bs)，8.05(2H，d)，8.0(2H，d)，7.8(2H，d)，7.65(2H，d)，4.35-4.45(1H，m)，3.35-3.45(1H，m)，3.2(3H，s)，2.65-2.7(1H，m)，1.85-1.95(1H，m)，1.3-1.6(5H，m)，1.05-1.15(1H，m)，0.85-0.95(6H，m).

Example 11

N ¹ - (cyanomethyl) -N ² - [ (1S) -2, 2, 3, 3, 3-pentafluoro-1- (4-pyridin-4-ylphenyl) Propyl radical]Synthesis of (E) -L-leucinamide

Step 1: preparation of (4S) -4-isobutyl-2- (pentafluoroethyl) -1, 3-oxazolidine

Pentafluoropropionaldehyde formal-methanol (14.9g, 82.8mmol) and L-leucinol (9.7g, 82.8mmol) were dissolved in 100mL of benzene and heated at reflux overnight in a flask equipped with a Dean-Stark tube. The resulting solution was cooled and concentrated to give the title compound as an oil, which was used directly in the next step.

Step 2: (2S) -2- [ (1S) -1- (4-bromophenyl) -2, 2, 3, 3, 3-pentafluoropropyl]Amino } -4-methylpentane-1- Preparation of alcohols

To a solution of dibromobenzene (9.85g, 41.8mmol) at-78 deg.C in 100mL THF was added n-BuLi (16.5mL, 2.5M in hexane, 41.2mmol) to give a thick suspension. After stirring for 10 minutes, a solution of (4S) -4-isobutyl-2- (pentafluoroethyl) -1, 3-oxazolidine (3.3g, 13mmol) in 3mL THF was added to give a dark brown solution. The solution was warmed to room temperature, then poured into a saturated aqueous solution of ammonium chloride and extracted with diethyl ether. Purification by silica gel chromatography (gradient elution 10% to 40% ethyl acetate in hexanes) afforded the title compound as a single diastereomer.

And step 3: n is a radical of ² - [ (1S) -1- (4-bromophenyl) -2, 2, 3, 3, 3-pentafluoropropyl radical]-N ¹ - (cyanomethyl) -L-leu Preparation of aminoamides

An entire sample of (2S) -2- { [ (1S) -1- (4-bromophenyl) -2, 2, 3, 3, 3-pentafluoropropyl ] amino } -4-methylpentan-1-ol (1.6g, 4.0mmol) was converted to the title compound by the method of example 8, steps 6 and 7. Purification by silica gel chromatography (gradient elution from 15% to 80% ethyl acetate in hexanes) afforded the title compound as a solid.

¹H NMR(CD₃COCD₃，500MHz)δ7.8(1H，br)，7.55(2H，m)，7.40(2H，m)，4.4-4.5(1H，m)，3.95(2H，m)，3.33(1H，m)，2.75(1H，m)，1.82(1H，m)，1.5(1H，m)，1.38(1H，m)，0.88(6H，dd).

And 4, step 4: n is a radical of ¹ - (cyanomethyl) -N- [ (1S) -2, 2, 3, 3, 3-pentafluoro-1- (4-pyridin-4-ylphenyl) propane Base of]Preparation of (E) -L-leucinamide

To N²- [ (1S) -1- (4-bromophenyl) -2, 2, 3, 3, 3-pentafluoropropyl radical]-N¹- (cyanomethyl) -L-leucinamide (82mg, 0.18mmol), 4-pyridylboronic acid (30mg, 0.24mmol) and PdCl₂(dppf)(14mg，0.02mmol) in 2.5mL DMF was added 2MNa₂CO₃(0.25 mL). The mixture was heated to 95 ℃ and heating continued for 2.5 hours, after which it was cooled over Na₂CO₃Partition between aqueous solution and ether. The aqueous phase was washed with brine, MgSO₄And (5) drying. Purification by silica gel chromatography (65% to 95% ethyl acetate/hexanes gradient) gave the title compound.

¹H NMR(CD₃COCD₃，500MHz)δ8.66(2H，m)，7.85(1H，br)，7.81(2H，m)，7.70(2H，m)，7.62(2H，m)，4.5-4.6(1H，m)，3.95(2H，m)，3.4(1H，m)，2.81(1H，m)，1.88(1H，m)，1.55(1H，m)，1.42(1H，m)，0.92(6H，dd).

Example 12

N ¹ - (1-cyanocyclopropyl) -N ² - { (1S) -2, 2-difluoro-1- [ 4' - (methylsulfonyl) -1, 1' -biphenyl-4-yl]Synthesis of ethyl } -L-leucinamide

Step 1: (2S) -1- { [ tert-butyl (dimethyl) silyl]Preparation of oxy-4-methylpentane-2-amine Prepare for

The preparation was carried out as described in step 1 of example 8.

Step 2: (2S) -1- { [ tert-butyl (dimethyl) silyl]Oxy } -N- [ (1E) -2, 2-difluoroethylene Base of]Preparation of (E) -4-methylpentane-2-amine

A mixture of (2S) -1- { [ tert-butyl (dimethyl) silyl ] oxy } -4-methylpentane-2-amine (8.5g, 36.8mmol) and difluoroacetaldehyde-ethanol (5.0g, 39.7mmol) in benzene was refluxed in a Dean-stark trap overnight. The solvent was evaporated under vacuum. The residue was passed through a short silica column, eluting with hexane: EtOAc (10: 1) to give the title compound as a pale yellow oil.

¹H NMR(CD₃COCD₃)δ7.72(m，1H)，6.12(dt，1H)，3.70(dd，1H)，3.54(dd，1H)，3.36(m，1H)，1.48(m，2H)，1.32(m，1H)，0.95-0.78(m，15H)，0.06(s，3H)，0.02(s，3H).

And step 3: (2S) -2- { [1S) -1- (4-bromophenyl) -2, 2-difluoroethyl]Process for preparing amino } -4-methylpentan-1-ol Preparation of

n-BuLi (2.5M in hexanes, 1.43mL) was added to a-70 ℃ solution of 1, 4-dibromobenzene (884mg) in THF (8.5mL) and the mixture was stirred for 15 minutes. Then, (2S) -1- { [ tert-butyl (dimethyl) silyl group was added dropwise thereto ]Oxy } -4-methyl-N- [ (1E) -2, 2-difluoroethylene]A solution of pentane-2-amine (1.0g) in THF (8.5mL) was added and the mixture was stirred for 1.5 hours. The mixture was then slowly poured into an ice-cold saturated aqueous solution of ammonium chloride with vigorous stirring and extracted with 3 parts of ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate and the solvent removed in vacuo to give a residue which was washed with SiO₂Purification was carried out eluting with a gradient of hexane and ethyl acetate (90: 10 to 75: 25) to give (2S) -N- [ (1S) -1- (4-bromophenyl) -2, 2-difluoroethyl]-1- { [ tert-butyl (dimethyl) silyl]Oxy } -4-methylpentane-2-amine. Reacting (2S) -N- [ (1S) -1- (4-bromophenyl) -2, 2-difluoroethyl]-1- { [ tert-butyl (dimethyl) silyl]Oxy } -4-methylpentane-2-amine (200mg) dissolved in CH₃CN (4mL) and the solution was cooled to 0 ℃. HF-pyridine (40. mu.L) was added dropwise thereto and the mixture was reacted for 16 hours. The mixture was poured into a saturated solution of sodium bicarbonate, ethyl acetate was added thereto and the resulting mixture was shaken vigorously. The organic layer was separated and the aqueous phase was washed with ethyl acetate (2X 50)mL) was further extracted. The combined organic layers were washed with brine, dried over magnesium sulfate and the solvent removed in vacuo to give a residue which was washed with SiO ₂Purification was performed using a gradient of hexane and ethyl acetate (80: 20 to 60: 40) as eluent to give the title compound.

¹H NMR(CD₃COCD₃)δ7.6(2H，d)，7.45(2H，d)，6.0(1H，dt)，4.25(1H，m)，3.65(1H，t)，3.5-3.55(1H，m)，3.3-3.35(1H，m)，2.55-2.65(1H，m)，2.15-2.25(1H，m)，1.6-1.7(1H，m)，1.3-1.4(1H，m)，1.2-1.3(1H，m)，0.9(3H，d)，0.8(3H，d).

And 4, step 4: n- [ (1S) -1- (4-bromophenyl) -2, 2-difluoroethyl]Preparation of (E) -L-leucine

H is to be₅IO₆/CrO₃Suspension of (5.5mL, 0.40M in CH)₃In CN; see comments below) was cooled to 0 ℃ and the alcohol from step 3 (250mg) in CH was added dropwise thereto₃CN (3.7 mL). The mixture was stirred at 0-5 ℃ for 3.5 hours. Thereafter, 2.0mL of an oxidizing agent was added thereto. After 1.5 hours, the mixture was poured over Na with vigorous stirring₂HPO₄The mixture was extracted with ether (3X 20mL) in buffer (0.4g, 10 mL). The combined ether extracts were washed with water and brine (1: 1), diluted NaHSO₃The aqueous solution and brine were washed. The organic extracts were dried over magnesium sulfate, filtered and the solvent evaporated to dryness to give the title compound, which was used without further purification.

Note that: the oxidizing agent (H)₅IO₆/CrO₃) Prepared as described for Tetrahedron Letters39(1998)5323-₃CN (containing 0.5% water); no water was added.

¹H NMR(CD₃COCD₃)δ7.55(2H，d)，7.4(2H，d)，6.05(1H，dt)，3.95-4.05(1H，m)，3.45(1H，t)，2.7-3.0(bm，NH/OH)，1.85-1.95(1H，m)，1.5(2H，t)，0.95(3H，d)，0.9(3H，d).

And 5: n is a radical of ² - [ (1S) -1- (4-bromophenyl) -2, 2-difluoroethyl ]-N ¹ - (1-cyanocyclopropyl) -L-leucineamide Preparation of amides

To a solution of the acid from step 4 (258mg) in DMF (2mL) was added O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (337mg) and 1-aminocyclopropanecarbonitrile hydrochloride (175 mg). After stirring for 1 minute, diisopropylethylamine (0.45mL) was added dropwise thereto and the mixture was stirred for 16 hours. The resulting mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate (3X 15 mL). The combined extracts were washed with brine, dried over magnesium sulfate and the solvent removed in vacuo. The residue is treated with SiO₂Purification by chromatography eluting with hexane and ethyl acetate (80: 20 to 50: 50) gave the title compound.

¹H NMR(CD₃COCD₃)δ8.05(1H，m)，7.55(2H，d)，7.4(2H，d)，6.05(1H，dt)，3.95-4.05(1H，m)，3.25-3.3(1H，m)，2.4-2.45(1H，m)，1.8-1.9(1H，m)，1.4-1.55(2H，m)，0.95-1.1(2H，m)，0.95(6H，t).

Step 6: n is a radical of ¹ - (1-cyanocyclopropyl) -N ² - { [1S) -2, 2-difluoro-1- [4 '- (methylthio) -1, 1' -biphenyl- 4-radical]Preparation of ethyl } -L-leucinamide

A nitrogen stream was passed over the aryl bromide from step 5 (65mg), 4- (methylthio) phenylboronic acid (40mg), 2M Na₂CO₃(0.22mL) and DMF (1.0mL) were aerated for 5 minutes. Then theTo which PdCl was added₂dppf, the reaction was warmed to 80 ℃ and stirred under nitrogen for 4 hours. The mixture was cooled to room temperature, diluted with ethyl acetate (20mL) and poured into a saturated solution of sodium bicarbonate. The ethyl acetate layer was separated and further extracted with ethyl acetate (2X 15 mL). The combined ethyl acetate was washed with brine and dried over magnesium sulfate. Removing the solvent to leave a residue, using SiO ₂Chromatography which purified with a gradient of hexane and ethyl acetate (90: 10 to 50: 50) afforded the title compound.

¹H NMR(CD₃COCD₃)δ8.1(1H，m)，7.6-7.65(4H，m)，7.45(2H，d)，7.35(2H，d)，6.05(1H，dt)，3.9-4.0(1H，m)，3.2-3.3(1H，m)，2.5(3H，s)，2.35-2.4(1H，m)，1.8-1.9(1H，m)，1.3-1.5(4H，m)，0.85-1.0(8H，m).

And 7: n is a radical of ¹ - (1-cyanocyclopropyl) -N ² - { (1S) -2, 2-difluoro-1- [4 '- (methylsulfonyl) -1, 1' -bi-ethyl Phenyl-4-yl]Preparation of ethyl } -L-leucinamide

To a solution of the sulfide from step 6 (50mg) in toluene (1.0mL) and ethyl acetate (0.1mL) was added Na₂WO₄·2H₂O (1mg) and BU₄NHSO₄(2 mg). Then 30% hydrogen peroxide (30 μ L) was slowly added thereto and the mixture was stirred at room temperature for 1.5 hours. The mixture was poured into dilute aqueous sodium thiosulfate and ethyl acetate. The organic layer was separated and the aqueous layer was further extracted with ethyl acetate (2X 10 mL). The combined organic layers were washed with brine, dried over magnesium sulfate and the solvent removed in vacuo to give a residue which was washed with SiO₂Purification was performed using hexane and ethyl acetate (50: 50 to 0: 100) followed by dichloromethane and diethyl ether (90: 10) as eluents to give the title compound.

¹H NMR(CD₃COCD₃)δ8.15(1H，m)，8.0(2H，d)，7.95(2H，d)，7.75(2H，d)，7.55(2H，d)，6.1(1H，dt)，4.0-4.1(1H，m)，3.25-3.35(1H，m)，3.15(3H，s)，2.4-2.5(1H，m)，1.8-1.9(1H，m)，1.4-1.55(4H，m)，0.85-1.05(8H，m).

Example 13

N ² - [ (1S) -1- (6-Chloropyridin-3-yl) -2, 2, 2-trifluoroethyl radical]-N ¹ - (1-cyanocyclopropyl) Synthesis of (E) -L-leucinamide

Step 1: (2S) -2- { [ (1S) -1- (6-Chloropyridin-3-yl) -2, 2, 2-trifluoroethyl ]Amino } -4-methylpentane Preparation of (E) -1-alcohols

To a solution of 5-bromo-2-chloropyridine (2.5g, 13mmol) in diethyl ether (30mL) was added n-butyllithium (13mmol, 2.5M in hexane) at-78 ℃. The mixture was stirred at-78 ℃ for 1 h. To which was added (2S) -1- { [ tert-butyl (dimethyl) silyl group]Oxy } -4-methyl-N- [ (1E) -2, 2, 2-trifluoroethylene]Pentane-2-amine (3.64g, 11.7mmol, see example 8, step 2). The mixture was stirred at-78 ℃ for 2 h. Adding NH to the reaction mixture₄The aqueous solution was saturated with Cl and the mixture was extracted twice with EtOAc. The combined organic extracts were washed with brine, anhydrous MgSO₄It was dried and concentrated to an oil (5.3 g). The crude oil (2.0g) was then washed with (Bu)₄NF (6mL, 1M in THF). The mixture was stirred at room temperature for 1h, NH was added thereto₄The aqueous solution was saturated with Cl and the mixture was extracted twice with EtOAc. Combining the organic extractsThe extract was washed with brine and anhydrous MgSO₄Dried and concentrated to an oil. Chromatographic purification (20% EtOAc/hexanes) afforded the title compound.

Step 2: n- [ (1S) -1- (6-Chloropyridin-3-yl) -2, 2, 2-trifluoroethyl ]Preparation of (E) -L-leucine

By mixing H₅IO₆(68.4g, 0.3mol) and CrO₃(138mg, 1.2 mol%) in CH₃CN (684mL) to give a 0.44M solution₅IO₆/CrO₃The stock solution of (1). Down H at-5 deg.C (in ice and salt bath)₅IO₆/CrO₃(16mmol, 36mL, 0.44M in THF) was added dropwise to a solution of (2S) -2- { [ (1S) -1- (6-chloropyridin-3-yl) -2, 2, 2-trifluoroethyl]A solution of amino } -4-methylpentan-1-ol (1g) in 3mL THF. The internal temperature was monitored and the reaction temperature could not be made higher than 0 ℃. The reaction was monitored by TLC until complete (3-4 h). Mixing Na₂HPO₄(80mL) was added to the mixture, which was then extracted with EtOAc. The organic extract was washed with brine, NaHSO₃(120mL), washed with brine, and then anhydrous MgSO₄Dried and concentrated to an oil. The oil was redissolved in EtOAc and filtered through a short pad of silica gel, washed with EtOAc, and the filtrate was concentrated to give the title compound.

And step 3: n is a radical of ² - [ (1S) -1- (6-Aminopyridin-3-yl) -2, 2, 2-trifluoroethyl radical]-N ¹ - (-Cyanocyclopropan) Preparation of yl) -L-leucinamide

To a solution of the crude acid from step 2 (0.73g, 2.25mmol) in DMF (12mL) was added 1-aminocyclopropanecarbonitrile hydrochloride (0.4g, 3.37mmol.) and HATU (0.86g, 2.25 mmol). Diisopropylethylamine (1.96mL, 11.24mmol) was added thereto, and the mixture was stirred at room temperature for 20 hours. To this was added EtOAc and water. Stirring the mixture After stirring, the mixture was separated and the organic extracts were washed with water and brine, anhydrous MgSO₄Drying is carried out. The organic extracts were concentrated and then purified by chromatography (30-50% EtOAc/hexanes) to give the title compound.

MS(+ESI)：389.3[M+1]⁺。

¹H NMR(500MHz，CD₃COCD₃)：δ0.92(d，3H，J＝6.6Hz)，0.93(d，3H，J＝6.6Hz)，1.00(m，1H)，1.09(m，1H)，1.45(m，4H)，1.90(m，1H)，2.81(m，1H)，3.43(m，1H)，4.47(m，1H)，7.54(d，1H，J＝8.3Hz)，7.98(d，1H J＝6.2Hz)，8.1(s，1H)，8.5(s，1H).

Example 14

N ² - { (1S) -1- [6- (4-acetylphenyl) pyridin-3-yl]-2, 2, 2-trifluoroethyl } -N ¹ Synthesis of (1-cyanocyclopropyl) -L-leucinamide

Under nitrogen flow to N²- [ (1S) -1- (6-Chloropyridin-3-yl) -2, 2, 2-trifluoroethyl radical]-N¹To a solution of (1-cyanocyclopropyl) -L-leucinamide (100mg, 0.26mmol) in toluene (1.5mL) and n-propanol (0.4mL) was added 4- (acetyl) phenylboronic acid (55mg, 0.33mmol), Pd (PPh)₃)₄(15mg, 0.013mmol) and Na₂CO₃(2M, 0.5 mL). The mixture was degassed by bubbling a stream of nitrogen through the mixture quickly and heated to 150 ℃ in a Smith Creator microwave reactor (Personal Chemistry AB, Uppsala, Sweden) for 800 seconds. The mixture was cooled, diluted with EtOAc and washed with water. Chromatographic purification (50% EtOAc/hexanes)) To yield the title compound.

MS(+ESI)：473.2[M+1]⁺。

¹H NMR(500MHz，CD₃COCD₃)：δ0.93(d，3H，J＝6.6Hz)，0.94(d，3H，J＝6.6Hz)，1.07(m，1H)，1.40(m，2H)，1.49(m，1H)，1.55(m，1H)，1.92(m，1H)，2.66(s，3H)，2.83(m，2H)，3.45(m，1H)，4.50(m，1H)，8.15(m，5H)，8.30(d，2H，J＝8.5Hz)，8.79(s，1H).

Example 15

N ¹ - (1-cyanocyclopropyl) -4-fluoro-N ² - { (1S) -2, 2, 2-trifluoro-1- [ 4' - (methylsulfonyl) -1, 1' -biphenyl-4-yl]Synthesis of ethyl } -L-leucinamide

Step 1: (3S) -3- [ (tert-butoxycarbonyl) amino group]Preparation of benzyl (4-hydroxybutyrate)

N- (tert-butoxycarbonyl) -L-aspartic acid 4-benzyl ester (30g) was dissolved in dimethoxyethane (90mL) and the solution was cooled to-5 ℃. N-methylmorpholine (10.32mL) was added followed by isobutyl chloroformate (12.66mL) so that the reaction temperature was kept below-10 ℃. The mixture was aged for 0.5 hours. The solid was filtered off quickly and washed with dimethoxyethane (90 mL). The filtrate was cooled to-50 ℃ and a solution of sodium borohydride (4.4g) in water (45mL) was slowly added thereto so that the reaction temperature was maintained between-30 ℃ and-15 ℃. Then, water (500mL) was added thereto so that the reaction temperature was maintained below-15 ℃. The mixture was filtered, and the solid was washed with water (400mL) and dried to give benzyl (3S) -3- [ (tert-butoxycarbonyl) amino ] -4-hydroxybutyrate.

¹H NMR(CD₃COCD₃)δ7.3-7.45(5H，m)，5.85-5.95(1H，NH)，5.15(2H，s)，3.95-4.1(2H，m)，3.5-3.7(2H，m)，2.55-2.75(2H，m)，1.4(9H，s).

Step 2: [ (4S) -2-oxo-1, 3-oxazolidin-4-yl]Preparation of benzyl acetate

To a solution of the alcohol from step 1 (95.7g) in dichloroethane (925mL) was added pyridine (625mL) and the mixture was cooled to 0-5 ℃. Anhydrous p-toluene sulfonic anhydride (105.7g) was added thereto, the mixture was warmed to room temperature and stirred for 1 hour, and then it was heated to 90 ℃ and heating was continued for 2 hours. The mixture was cooled, diluted with dichloromethane (1000mL) and washed with 1N HCl (3X 600 mL). The organic layer was washed with brine, dried over sodium sulfate and the solvent removed in vacuo. The residue is treated with SiO ₂Purifying by chromatography with ethyl acetate and hexane in a ratio of 1: 1, and eluting with ethyl acetate to obtain [ (4S) -2-oxo-1, 3-oxazolidin-4-yl group]And (3) benzyl acetate.

¹H NMR(CD₃SOCD₃)δ7.8(1H，NH)，7.3-7.45(5H，m)，5.05-5.15(2H，m)，4.4-4.5(1H，m)，4.1-4.2(1H，m)，4.0-4.05(1H，m)，3.6-3.8(2H，m).

And step 3: preparation of (4S) -4- (2-hydroxy-2-methylpropyl) -1, 3-oxazolidin-2-one

Methylmagnesium bromide (227mL, 3M in ether) was added to a mixture of toluene (340mL) and THF (340mL) at-20 ℃. A warm THF solution (170mL) of the ester from step 2 (40g) was then added dropwise thereto while maintaining the temperature below-10 ℃. The mixture was aged for 2 hours, then slowly added to a mixture of water (1000mL) and acetic acid (200mL), and the resulting mixture was stirred at room temperature for 2 hours. The aqueous layer was separated and the organic layer was washed with water (2)X 200mL) was extracted. The product was extracted from the combined aqueous layers with dichloromethane and a continuous extractor. The dichloromethane extract was evaporated to dryness using heptane as a co-solvent to azeotrope the acetic acid. The residue is treated with SiO₂Is purified by chromatography eluting with ethanol and dichloromethane (1: 30) to give (4S) -4- (2-hydroxy-2-methylpropyl) -1, 3-oxazolidin-2-one.

¹H NMR(CD₃COCD₃)δ6.1-6.4(1H，NH)，4.45-4.55(1H，m)，4.1-4.2(1H，m)，3.95-4.05(1H，m)，3.7(1H，s)，1.65-1.85(2H，m)，1.25(6H，m).

And 4, step 4: preparation of (4S) -4- (2-fluoro-2-methylpropyl) -1, 3-oxazolidin-2-one

A solution of the alcohol from step 3 (47.8g) in methylene chloride (100mL) was added to a solution of (diethylamino) sulfur trifluoride (48.5g) in methylene chloride (500mL) at-70 ℃. The mixture was warmed to room temperature and stirred for 1 hour. The mixture was then carefully added to 0 ℃ NaHCO₃Saturated aqueous solution (800 mL). The organic layer was separated and washed with saturated NaHCO₃Washing the mixture with an aqueous solution. The aqueous layer was further extracted with dichloromethane (100mL), and the combined dichloromethane layers were dried and concentrated. The residue is treated with SiO₂Purification by chromatography with ethyl acetate and hexane (1: 5) followed by ethyl acetate afforded (4S) -4- (2-fluoro-2-methylpropyl) -1, 3-oxazol-2-one.

¹H NMR(CD₃SOCD₃)δ7.6(1H，NH)，4.4-4.5(1H，m)，3.95-4.05(1H，m)，3.9-3.95(1H，m)，1.8-1.95(2H，m)，1.25-1.4(6H，2s).

And 5: preparation of (2S) -2-amino-4-fluoro-4-methylpentan-1-ol

To a solution of the fluoro derivative from step 4 (21.0g) in 90% aqueous ethanol (216mL) was added potassium hydroxide (21.9 g). The mixture was heated to reflux for 4 hours and then cooled to room temperature. The mixture was then concentrated and co-evaporated with toluene (3X 300 mL). The residue was dissolved in dichloromethane (500mL) and stirred for 0.5 h. The suspension was filtered through celite and washed with dichloromethane (3 × 100 mL). The filtrate was concentrated to dryness to give (2S) -2-amino-4-fluoro-4-methylpentan-1-ol.

¹H NMR(CD₃OD)δ3.4-3.5(1H，m)，3.2-3.3(1H，m)，3.0-3.1(1H，m)，1.5-1.7(2H，m)，1.35(3H，s)，1.3(3H，s).

Step 6: (2S) -1- { [ tert-butyl (dimethyl) silyl]Oxy } -4-fluoro-4-methylpentane-2-amine Preparation of

The amino alcohol from step 5 (21.0g) was dissolved in dichloromethane (300mL) and the solution was cooled to 0 ℃. To this were added 4- (dimethylamino) pyridine (0.051g) and tert-butyldimethylsilyl chloride (21g), followed by triethylamine (25 mL). The mixture was stirred at room temperature overnight. The reaction mixture was slowly poured into a saturated aqueous solution of ammonium chloride at 0 ℃ and extracted with dichloromethane (3X 300 mL). The organic layer was washed with brine, dried over sodium sulfate and the solvent removed in vacuo to give (2S) -1- { [ tert-butyl (dimethyl) silyl ] oxy } -4-fluoro-4-methylpentane-2-amine.

¹H NMR(CD₃OD)δ3.6-3.65(1H，m)，3.4-3.5(1H，m)，3.1-3.2(1H，m)，1.6-1.8(2H，m)，1.35-1.45(6H，m)，0.93(9H，s)，0.1(6H，s).

And 7: ((2S) -1- { [ tert-butyl (dimethyl) silyl)]Oxy } -4-fluoro-4-methyl-N- [ (1E) - 2, 2, 2-trifluoroethylene]Preparation of pentane-2-amine

To the amine from step 6 (31.5g) in benzene (126mL) was added trifluoroacetaldehyde-methanol (21.6 mL). The solution was heated at reflux overnight and water was collected using a Dean-Stark trap. Will be provided withThe reaction mixture was cooled to room temperature and concentrated to dryness. The residue is treated with SiO ₂Purification, eluting with 4% ethyl acetate in hexanes to give (2S) -1- { [ tert-butyl (dimethyl) silyl]Oxy } -4-fluoro-4-methylpentane-2-amine.

¹H NMR(CD₃COCD₃)δ7.9-7.95(1H，m)，3.75-3.85(1H，m)，3.7-3.75(1H，m)，3.53-3.6(1H，m)，1.9-2.0(2H，m)，1.3-1.4(6H，m)，0.9(9H，s)，0.1(3H，s)，0.05(3H，s).

And 8: (2S) -2- { [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl]Amino } -4-fluoro-4-methylpentane Preparation of (E) -1-alcohols

To a solution of 1, 4-dibromobenzene (0.26g) in THF (4mL) at-75 deg.C was added n-BuLi (0.42mL, 2.5M in hexanes) and the mixture was aged for 20 minutes. To this was added the imine from step 7 (0.329g) in THF (2ml) and the mixture was aged for 2 hours. Then, the mixture was added to water (50mL), NH₄Cl (1g) and crushed ice. It was extracted with ethyl acetate (2 × 25mL) and the combined ethyl acetate layers were dried and then evaporated to dryness.

The same procedure was repeated on a larger scale with 1, 4-dibromobenzene (1.2g), n-BuLi (1.84mL) and imine (1.38g) and the reaction mixture was treated as above. The combined residues from both preparations were dissolved in THF (10mL) and cooled to 0 ℃. Tetra-n-butylammonium fluoride (6mL of a 1M solution in THF) was added thereto and the mixture was stirred at +5 ℃ for 16 h. The mixture was poured into a mixture of water (50mL), ammonium chloride (1g) and crushed ice and the organic layer was separated. The aqueous phase was further extracted with ethyl acetate (2 × 15mL) and the combined organic layers were dried and concentrated. The residue is treated with SiO ₂Purification was performed eluting with ethyl acetate and hexane (1: 5) to give (2S) -2- { [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl]Amino } -4-fluoro-4-methylpentan-1-ol.

¹H NMR(CD₃COCD₃)δ7.65(2H，m)，7.5(2H，m)，4.5-4.6(1H，m)，3.8(1H，m)，3.6(1H，m)，3.3-3.4(1H，m)，2.85-2.0(1H，m)，2.55(1H，m)，1.7-1.9(2H，s)，1.3-1.4(6H，m).

And step 9: n is a radical of ² - [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl radical]-N ¹ - (1-cyanocyclopropyl) -4-fluoro Preparation of (E) -L-leucinamide

H is to be₅IO₆/CrO₃Suspension of (3 mL, 0.44M in CH)₃In CN; note) was cooled to 0 ℃ and CH of the alcohol from step 8(1.55g) was added dropwise thereto₃CN (5mL) solution. The mixture was stirred at 0-5 ℃ for 3.5 hours. It was poured over Na of pH 4 with vigorous stirring₂HPO₄(200mL) and the mixture was extracted with diethyl ether (3X 50 mL). The combined ether extracts were washed with water and brine (1: 1) and then diluted NaHSO₃The aqueous solution and brine were washed. The mixture was dried over sodium sulfate, filtered and the solvent evaporated to dryness to give N- [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl)]4-fluoro-L-leucine, which can be used as such in the next step.

Note oxidizing reagent (H)₅IO₆/CrO₃) Was prepared as described in Tetrahedron Letters39(1998)5323-₃CN (containing 0.5% water); no water was added.

Diisopropylethylamine (4.2mL) was added to a suspension of the above acid (1.5g), 1-amino-1-cyclopropanecarbonitrile hydrochloride (1.18g), O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (1.94g) and dimethylformamide (5mL) at 0 ℃ and the mixture was reacted at room temperature for 48 hours. It was then poured onto ice and dilute aqueous ammonium chloride. The mixture was extracted with ethyl acetate and diethyl ether (1: 1) and the combined organic layers were extracted with dilute Na pH3 ₂HPO₄And brine. The solution was evaporated to dryness and the residue was purified using SiO₂Was purified by chromatography, eluting with ethyl acetate and hexane (1: 2) to give N with sufficient purity for the next step²- [ (1S) -l- (4-bromophenyl) -2, 2, 2-trifluoroethyl radical]-N¹- (1-cyanocyclopropyl) -4-fluoro-L-leucinamide.

¹H NMR(CD₃COCD₃)δ8.15(1H，NH)，7.6(2H，m)，7.45(2H，m)，4.35-4.45(1H，m)，3.45-3.55(1H，m)，1.9-2.1(2H，m)，1.75-1.85(1H，NH)，1.35-1.55(8H，m)，1.1-1.15(1H，m)，0.95-1.05(1H，m).

Step 10: n is a radical of ¹ - (1-cyanocyclopropyl) -4-fluoro-N ² - { (1S) -2, 2, 2-trifluoro-1- [ 4' - (methylthio) - 1, 1' -Biphenyl-4-yl]Preparation of ethyl } -L-leucinamide

A nitrogen stream was passed over the bromide from step 9 (0.338g), 4- (methylthio) phenylboronic acid (0.252g), 2M Na₂CO₃A mixture of aqueous solution (0.8mL) and DMF (4mL) was aerated for 15 minutes. Then adding PdCl thereto₂dppf (0.1g) and the reaction was warmed to 85 ℃ and stirred under nitrogen for 5 hours. The mixture was cooled to room temperature, diluted with ethyl acetate (10mL) and poured onto water (50mL) and ice. The ethyl acetate layer was separated and further extracted with ethyl acetate. The combined ethyl acetate extracts were dried and the solvent was removed in vacuo. The residue is treated with SiO₂Purifying by chromatography, eluting with ethyl acetate and hexane (1: 2) to give N ¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylthio) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide.

¹H NMR(CD₃COCD₃)δ8.15(1H，NH)，7.1-7.2(4H，m)，7.5-7.55(2H，m)，7.35-7.4(2H，m)，4.3-4.4(1H，m)，3.45-3.55(1H，m)，2.75-2.8(1H，NH)，2.5(3H，s)，1.9-2.05(2H，m)，1.3-1.5(8H，m)，1.0-1.1(1H，m)，0.85-0.95(1H，m).

Step 11: n is a radical of ¹ - (1-cyanocyclopropyl) -4-fluoro-N ² - { (1S) -2, 2, 2-trifluoro-1- [ 4' - (methylsulfonyl) amide 1, 1' -Biphenyl-4-yl]Preparation of ethyl } -L-leucinamide

To a solution of the sulfide from step 10 (0.265g) in toluene (5mL) and dichloromethane (5mL) at 0 deg.C was added Na₂WO₄·2H₂O (0.002g) and n-BU₄NHSO₄(0.01 g). Then 30% hydrogen peroxide (0.137mL) was slowly added thereto and the mixture was stirred at room temperature for 3 hours. The mixture was slowly poured onto a mixture of ice, dilute aqueous sodium thiosulfate solution and ethyl acetate. The organic layer was separated and the aqueous layer was further extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate and the solvent removed in vacuo to give a residue, which was washed with SiO₂It was purified using ethyl acetate, hexane and dichloromethane (1: 0.1) as eluent. Trituration of the residue with diethyl ether gave N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -1, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl ]Ethyl } -L-leucinamide.

¹H NMR(CD₃COCD₃)δ8.2(1H，NH)，8.05-8.1(2H，m)，7.95-8.0(2H，m)，7.8(2H，m)，7.65(2H，m)，4.35-4.45(1H，m)，3.5-3.6(1H，m)，3.2(3H，s)，2.8-2.9(1H，NH)，1.9-2.1(2H，m)，1.3-1.5(8H，m)，1.05-1.15(1H，m)，0.9-1.0(1H，m).

Example 16

(4S)-N ¹ - (1-cyanocyclopropyl) -5, 5, 5-trifluoro-N ² - { (1S) -2, 2, 2-trifluoro-1- [ 4' - (methylsulfonyl) -1, 1' -biphenyl-4-yl]Synthesis of ethyl } -1-leucinamide

Step 1: preparation of 5, 5, 5-trifluoroleucine hydrochloride

A racemic diastereoisomeric mixture of ethyl N-benzoyl-5, 5, 5-trifluoroleucine (10.0g, 31.5mmol) prepared according to Ojima et al (J.org.chem., 1989, 54, 4511-4522.) was refluxed in 6M hydrochloric acid (100mL) for 16 h. After cooling, the mixture was taken up in Et₂O was washed and concentrated in vacuo to give a racemic diastereoisomeric mixture of 5, 5, 5-trifluoroleucine hydrochloride.

¹H NMR (methanol-d)₄)δ4.10(m，1H)，2.65(m，1H)，2.35-1.80(m，2H)，1.25(m，3H).

Step 2: (4S) -N- [ (benzyloxy) carbonyl]-5, 5, 5-trifluoro-L-leucine methyl ester and (4R) -N- [ (benzyl) Oxy) carbonyl]-5, 5, 5-trifluoro-L-leucine methyl ester

To 5, 5, 5-Trifluoroleucine HCl salt (from step 1 above) in H₂To a cold (0 ℃) solution of O (30mL) was added 1M aqueous NaOH (60mL, 60mmol) followed by acetic anhydride (3.5mL, 36.7 mmol). The mixture was stirred at room temperature for 30 minutes to 1 hour. After acidification with 6M aqueous HCl (6mL), the mixture was extracted with EtOAc (6 ×). The combined EtOAc extracts were washed with brine and dried (MgSO) ₄) And (4) concentrating. The residue was taken up in hexane: Et₂O (1: 1) was volatilized to give N-acetyl-5, 5, 5-trifluoroleucine as a white solid.

To the solution of N-acetyl-5, 5, 5-trifluoroleucine (4.2g, 18.5mmol) in H₂To the suspension in O (35mL) was added 1M aqueous NaOH (18.5mL, 18.5mmol) and the mixture was stirred for 15 to 30 minutes to give a homogeneous solution. Acylase I (EC3.5.1.14, from Sigma, Cat. # A3010; 55mg) was added thereto and the mixture was stirred at room temperature overnight. Crude NMR of a small aliquot (evaporated under vacuum) indicated a 53: 47 ratio of starting material to product. It was then acidified with 6M aqueous HCl (. about.3.5 mL) and acidified with EtOAc (4X, with a small amount of H)₂O washed each EtOAc extract). The combined EtOAc extracts were washed with brine and dried (MgSO)₄) And concentrated to give crude N-acetyl-5, 5, 5-trifluoro-D-leucine, [ alpha ] as a pale yellow solid]_D＝+27.6⁰(c 1.5, EtOH). The aqueous layer was concentrated under vacuum and dried under vacuum overnight to give 5, 5, 5-trifluoro-L-leucine, which was possibly contaminated with NaCl and HCl salt, [ alpha ] -, as a solution]_D＝--4.1⁰(c 0.77，H₂O)。

To stirred 5, 5, 5-trifluoro-L-leucine (12g) in H at 0 deg.C ₂To a solution of O (150mL) was added benzyl chloroformate (4.8mL, 34mol), to which was then added dropwise an aqueous 1M NaOH solution (120mL, 120 mmol). More benzyl chloroformate (4.8mL, 34mmol) was added thereto. The mixture was stirred at 0 ℃ and the pH of the mixture became 7. The mixture was washed with Et₂O (2x) was washed and acidified with hydrochloric acid. The aqueous layer was extracted with EtOAc (3X) and dried (Na)₂SO₄) And concentrated in vacuo to give N- [ (benzyloxy) carbonyl]-5, 5, 5-trifluoro-L-leucine. The crude acid thus prepared was dissolved in Et₂Et in O with diazomethane₂And treating the mixture by using the O solution. Purifying by silica gel chromatography with hexane: Et₂O (7: 3) to give (4S) -N- [ (benzyloxy) carbonyl as a less polar fraction]-5, 5, 5-trifluoro-L-leucine methyl ester.

¹H NMR (acetone-d)₆)δ7.45-7.25(m，5H)，6.86(d，1H)，5.10(m，2H)，4.38(m，1H)，3.70(s，3H)，2.45(m，1H)，2.05(m，1H)，1.85(m，1H)，1.16(d，3H).

Additional elution gave (4R) -N- [ (benzyloxy) carbonyl ] -5, 5, 5-trifluoro-L-leucine ester as a more polar fraction with a small amount of benzyl alcohol contamination.

¹H NMR (acetone-d)₆)δ7.40-7.25(m，5H)，6.86(d，1H)，5.08(s，2H)，4.35(m，1H)，3.70(s，3H)，2.54(m，1H)，2.20(m，1H)，1.75(m，1H)，1.16(d，3H).

And step 3: (2S, 4S) -2-amino-5, 5, 5-trifluoro-4-methylpentan-1-ol

To (4S) -N- [ (benzyloxy) carbonyl at room temperature]-5, 5, 5-trifluoro-L-leucine methyl ester (5.4g, 16.2mmol) in EtOH (150mL) LiCl (2.8g, 66mol) was added and the mixture was stirred for 10 to 15 minutes, then NaBH was added thereto ₄(2.5g, 66 mmol). The mixture was stirred at room temperature for 6 h. In use H₂After dilution with O (60mL), the reaction was quenched with 6M hydrochloric acid (18 mL). Then adding H thereto₂O and the mixture was extracted with EtOAc (2 ×). The combined EtOAc extracts were washed with brine and dried (Na)₂SO₄) And concentrated to give crude benzyl (1S, 3S) -4, 4, 4-trifluoro-1- (hydroxymethyl) -3-methylbutylcarbamate.

The above alcohol was dissolved in EtOH (150mL) and 10% Pd/C (-500mg) was added thereto. The mixture is reacted with hydrogen₂Stir overnight under atmosphere (hydrogen balloon). The catalyst was filtered off over celite and the filtrate was concentrated to give the title compound as a colorless oil.

¹H NMR (methanol-d)₄)δ3.48(dd，1H)，3.38(dd，1H)，2.85(m，1H)，2.50(m，1H)，1.62-1.40(m，2H)，1.12(d，3H).

And 4, step 4: (2S, 4S) -1- { [ tert-butyl (dimethyl) methaneSilane radical]Oxy } -5, 5, 5-trifluoro-4-methyl- N- [ (1E) -2, 2, 2-trifluoroethylene]Pentane-2-amines

(2S, 4S) -2-amino-5, 5, 5-trifluoro-4-methylpentan-1-ol (2.6g, 15.2mmol) was converted to the title compound according to the procedures described in steps 1 and 2 of example 8.

¹H NMR (acetone-d)₆)δ7.98(m，1H)，3.80(m，1H)，3.60(m，2H)，2.18(m，1H)，1.98(m，1H)，1.65(m，1H)，1.12(d，3H)，0.88(s，9H)，0.06(s，3H)，0.02(s，3H).

And 5: (2S, 4S) -2- { [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl]Amino } -5, 5, 5-trifluoro- 4-methylpentan-1-ol

To 1, 4-dibromobenzene (7.0g, 29.7mmol) in cold (-78 ℃ C.) Et₂A solution of 2.5M n-BuLi in hexane (7.0mL, 17.5mmol) was added dropwise to a solution of O (75mL) and the mixture was stirred at-78 deg.C for 2 h. Reacting (2S, 4S) -1- { [ tert-butyl (dimethyl) silyl]Oxy } -5, 5, 5-trifluoro-4-methyl-N- [ (1E) -2, 2, 2-trifluoroethylene]Pentane-2-amine (3.7g, 10.1mmol) in a small amount of Et₂A solution in O was added to it and the mixture was stirred at-78 ℃ for 1 hour. Then using H₂The reaction was quenched with EtOAc and dried (MgSO)₄) And concentrated.

The crude product from above was dissolved in THF (20mL) and HOAc (0.3mL) was added to it. After addition of a 1M solution of tetrabutylammonium fluoride in THF (20mL, 20mmol), the mixture was stirred at room temperature overnight. The solvent is evaporated off in vacuo and the residue is taken up in H₂O was diluted and extracted with EtOAc. The EtOAc extract was washed with brine and dried (MgSO)₄) And (4) concentrating. Purification by silica gel chromatography eluting with hexanes: EtOAc (4: 1) afforded the title compound as a pale yellow oil.

¹H NMR (acetone-d)₆)δ7.60(d，2H)，7.48(d，2H)，4.58(m，1H)，3.80(t，1H)，3.45(m，2H)，2.90(m，1H)，2.70(m，1H)，2.25(m，1H)，1.75(m，1H)，1.45(m，1H)，1.14(d，3H).

Step 6: (4S) -N- [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl group ]-5, 5, 5-trifluoro-L-leucine

The title compound was prepared from (2S, 4S) -2- { [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl ] amino } -5, 5, 5-trifluoro-4-methylpentan-1-ol as described in example 15, step 9.

¹H NMR (acetone-d)₆)δ7.58(d，2H)，7.46(d，2H)，4.46(m，1H)，3.58(dd，1H)，2.80(m，1H)，1.92(m，1H)，1.72(m，1H)，1.20(d，3H).

And 7: (4S) -N ² - [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl radical]-N ¹ - (1-cyanocyclopropyl) - 5, 5, 5-trifluoro-L-leucinamide

The title compound was prepared from (4S) -N- [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl ] -5, 5, 5-trifluoro-L-leucine as described in example 15, step 9.

¹H NMR (acetone-d)₆)δ8.20(br s，1H)，7.59(d，2H)，7.43(d，2H)，4.34(m，1H)，3.48(m，1H)，2.78(m，1H)，1.85(m，1H)，1.55(m，1H)，1.39(m，2H)，1.14(d，3H)，1.15-0.90(m，2H).

MS(+ESI)：486，488[M+1]⁺.

And 8: (4S) -N ¹ - (1-cyanocyclopropyl) -5, 5, 5-trifluoro-N ² { (1S) -2, 2, 2-trifluoro-1- [ 4' - (methylen) Alkylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl-L-leucinamide

From (4S) -N as described in steps 10 and 11 of example 15²- [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl radical]-N¹- (1-cyanocyclopropyl) -5, 5, 5-trifluoro-L-leucinamide.

[α]_D+66 ° (c 0.5, acetone).

¹H NMR (acetone-d)₆)δ8.20(br s，1H)，8.03(d，2H)，7.94(d，2H)，7.78(d，2H)，7.62(d，2H)，4.41(m，1H)，3.52(m，1H)，3.17(s，3H)，2.88(m，1H)，1.98(m，1H)，1.58(m，1H)，1.35(m，2H)，1.16(d，3H)，1.15-0.85(m，2H).

MS(+ESI)：562[M+1]⁺.

Example 17

Synthesis of N-benzyl-1- (benzyloxy) -4-fluoro-4-methylpentane-2-amine

Step 1: preparation of N- (tert-butoxycarbonyl) -4-methylene norvaline

To a solution of dehydro-L-leucine (2.00g, 15.48mmol) and di-tert-butyl dicarbonate (10.14g, 46.4mmol) in THF (ca. 100mL) and water (ca. 50mL) was added triethylamine (12.94mL, 92.8 mmol). The reaction mixture was stirred at room temperature overnight. Citric acid (about 100mL of 1M aqueous solution) was added thereto and the product was extracted into about 400mL of dichloromethane. The organic phase was dried over sodium sulfate, filtered and concentrated by rotary evaporation. Purification by silica gel chromatography using 0-10% methanol in dichloromethane as eluent gave the title compound.

Step 2: preparation of tert-butyl 1- (hydroxymethyl) -3-methylbut-3-enylcarbamate

To Boc-dehydro-L-leucine (2.84g, 12.4mmol) and 4-methylmorpholine (1.36mL, 12.4mmol) equilibrated to-10 deg.C in the absence ofIsobutyl chloroformate (1.61mL, 12.4mmol) was added dropwise to a solution in aqueous THF (40 mL). The reaction was stirred for 30 minutes and the precipitate was removed by filtration. The filtrate was equilibrated at 0 ℃ and a solution of sodium borohydride (0.938g, 24.8mmol) in about 10mL of water was added dropwise with stirring. The reaction was allowed to return to room temperature and stirred for an additional 1 hour. The reaction was quenched with saturated aqueous sodium bicarbonate and the product extracted into ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated by rotary evaporation to give the title compound. MS (+ ESI): 216.1[ M-boc- +1]⁺

And step 3: benzyl {1- [ (benzyloxy) methyl group]Preparation of tert-butyl (3-methylbut-3-enyl) carbamate Prepare for

To a solution of Boc-dehydro-L-leucinol (2.56g, 11.91mmol) and benzyl bromide (3.54mL, 29.8mmol) in DMF (50mL) was added sodium hydride (1.19g, 60% dispersion in mineral oil, 29.8mmol) and the reaction was stirred for 3 hours. Additional benzyl bromide (3.54mL) and sodium hydride dispersion (1.19g) were added and the reaction was stirred for an additional 16 hours. Water (about 100mL) was added and extracted twice, and the product was extracted into dichloromethane (100 mL). The organic phases were combined and washed twice with about 100mL of water. The organic phase was dried over magnesium sulfate, filtered and dried by rotary evaporation. Purification by silica gel chromatography eluting with a gradient of 0-5% ethyl acetate in hexane afforded the title compound.

And 4, step 4: preparation of N-benzyl-1- (benzyloxy) -4-fluoro-4-methylpentane-2-amine

A solution of 70% hydrogen fluoride in pyridine (3.75mL) was equilibrated to 0 ℃ in a polypropylene vessel. N-benzyl-boc- (L) -leucinol benzyl ether (1.52g, 3.85mmol) was added and the reaction mixture was stirred for 6 hours. The reaction vessel was equilibrated with an ice bath and allowed to react for 5 days. The reaction was quenched by the addition of ice water and the product was extracted into dichloromethane. Purification by silica gel chromatography eluting with a gradient of 0-10% methanol in dichloromethane afforded the title compound.

MS(+ESI)：316.0[M+1]⁺

Example 18

(2S) -5, 5, 5-trifluoro-2- ({ (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl] Synthesis of Ethyl } amino) pentanoic acid cyanomethyl amide

Step 1: preparation of methyl 2-benzyloxycarbonylamino-5, 5, 5-trifluoro-pent-2-enoate

N- (benzyloxycarbonyl) - α -phosphonoglycine trimethyl ester and DBU were dissolved in anhydrous dichloromethane (50mL) and the reaction mixture was cooled to-30 ℃. To the cooled and stirred solution was added 3, 3, 3-trifluoropropionaldehyde (1 eq) dropwise and the reaction was stirred at-30 ℃ for an additional hour and then at room temperature overnight. Dichloromethane (about 100mL) was added and the organic layer was washed with HCl (about 100mL) and then saturated brine (about 100 mL). The organic phase was washed with MgSO ₄Drying, filtration and concentration by rotary evaporation. The crude product was purified by chromatography on silica gel with a gradient elution of 10-30% ethyl acetate in hexane to give 2-benzyloxycarbonylamino-5, 5, 5-trifluoro-pent-2-enoic acid methyl ester as a white crystalline solid.

MS(+ESI)：318.0[M+1]⁺

Step 2: preparation of methyl (S) -2-benzyloxycarbonylamino-5, 5, 5-trifluoropentanoate

In a Parr hydrogenation vessel 2-benzyloxycarbonylamino-5, 5, 5-trifluoropent-2-enoic acid methyl ester (15.37g, 48.5mmol) was dissolved in anhydrous ethanol (100 mL). The solution was sparged with a stream of nitrogen and then (+) Duphos (350mg) was added thereto. The reaction mixture was placed on a Parr hydrogenation apparatus and the headspace was evacuated and then pressurized with 50psi hydrogen. This process was repeated seven times, then pressurized with 50psi hydrogen and stirred on a parr apparatus overnight. The reaction mixture was then concentrated by rotary evaporation, dissolved in 1: 1 ethyl acetate: hexane and filtered through a bed of silica to remove crystals. The filtrate was concentrated by rotary evaporation to give crude methyl (S) -2-benzyloxycarbonylamino-5, 5, 5-trifluoropentanoate, which was used without further purification.

And step 3: preparation of (S) - (4, 4, 4-trifluoro-1-hydroxymethyl-butyl) -carbamic acid benzyl ester

(2S) -2-benzyloxycarbonylamino-5, 5, 5-trifluoropentanoic acid methyl ester from step 2 was dissolved in anhydrous THF (400 mL). LiBH is added dropwise thereto with stirring₄(2.11g in 100mL of anhydrous THF) and the solution was stirred at room temperature overnight. The reaction mixture was concentrated by rotary evaporation and 400mL of water was added thereto. The pH was then adjusted to 2 by addition of concentrated HCl and the product was extracted into ethyl acetate. The organic phase was washed twice with water and MgSO₄Drying, filtration and concentration by rotary evaporation gave crude (S) - (4, 4, 4-trifluoro-1-hydroxymethyl-butyl) -carbamic acid benzyl ester.

MS(-ESI)：290.2[M-1]^-

And 4, step 4: [1- (tert-butyl-dimethyl-silanyloxymethyl) -4, 4, 4-trifluoro-butyl]-carbamic acid Preparation of benzyl esters

To a solution of (S) - (4, 4, 4-trifluoro-1-hydroxymethyl-butyl) -carbamic acid benzyl ester (13.89g, 47.7mmol) and triethylamine (7.32mL, 52.5mmol) in DMF (60mL) was added dropwise a solution of tert-butyldimethylsilyl chloride (7.91g in 40mL DMF) at room temperature with stirring. The solution was allowed to stir at room temperature overnight. Then the The reaction mixture was concentrated by rotary evaporation and ethyl acetate was added thereto. The organic phase was washed twice with water and MgSO₄Drying, filtering and drying by rotary evaporation. The crude product was purified by chromatography on silica gel using 10% ethyl acetate in hexane as eluent to give [1- (tert-butyl-dimethyl-silanyloxymethyl) -4, 4, 4-trifluoro-butyl) as a white crystalline solid]-carbamic acid benzyl ester.

MS(+ESI)：406.2[M+1]⁺

And 5: (2S) -1- { [ tert-butyl (dimethyl) silyl]-oxy } -5, 5, 5-trifluoro-pentan-2-amine Preparation of

In a Parr hydrogenation vessel [1- (tert-butyldimethyl-silylmethyl) -4, 4, 4-trifluorobutyl]Benzyl carbamate was dissolved in absolute ethanol (100mL) and the solution was sparged with nitrogen. 10% palladium on charcoal (1.8g) was added and the vessel was placed on a Parr hydrogenation apparatus. The headspace of the vessel was evacuated and then pressurized with 50psi hydrogen. This process was repeated a second time and the vessel was pressurized with 50psi hydrogen and then stirred on the apparatus overnight. By usingThe catalyst was removed by filtration and the reaction mixture was concentrated by rotary evaporation to give (2S) -1- { [ tert-butyl (dimethyl) silyl ]-oxy } -5, 5, 5-trifluoro-pentan-2-amine.

MS(+ESI)：272.1[M+1]⁺

Step 6: (2S) -1- { [ tert-butyl (dimethyl) silyl]Oxy } -5, 5, 5-trifluoro-N- [ (1E) - 2, 2, 2-trifluoroethylene]Preparation of pentane-2-amine

A solution of (2S) -1- { [ tert-butyl (dimethyl) silyl ] oxy } -5, 5, 5-trifluoropentan-2-amine (3.00g, 11.06mmol) and trifluoroacetaldehyde-ethanol (1.6g, 11.1mmol) in benzene (20mL) was refluxed for 2 hours, during which time water was collected again in the Dean-Stark trap. The solvent was removed under vacuum to give crude (2S) -1- { [ tert-butyl (dimethyl) silyl ] oxy } -5, 5, 5-trifluoro-N- [ (1E) -2, 2, 2-trifluoroethylene ] pentan-2-amine.

MS(+ESI)：352.2[M+1]⁺

And 7: (2S) -2- [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl group]Amino group]-5, 5, 5-trifluoropentan-1- Preparation of alcohols

n-BuLi (2.5M in hexane, 21.4mL) was added dropwise to a stirred solution of 1, 4-dibromobenzene (12.6g) in dry ether (80mL) at-30 ℃ and the reaction mixture was stirred for 30 minutes. Then, (2S) -1- { [ tert-butyl (dimethyl) silyl group was added dropwise thereto]Oxy } -5, 5, 5-trifluoro-N- [ (1E) -2, 2, 2-trifluoroethylene]A solution of pentane-2-amine (3.75g, 10.7mmol) in dry diethyl ether (30mL) was allowed to warm to room temperature and stir for 16 h. The reaction mixture was then quenched with 100mL of water. The organic phase was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated by rotary evaporation to give the crude product which was purified by silica gel chromatography using 1% ethyl acetate in hexane as eluent to give (S) - [1- (4-bromophenyl) -2, 2, 2-trifluoro-ethyl ]- [1- (tert-butyl-dimethyl-silanyloxymethyl) -4, 4, 4-trifluoro-butyl]Amine (1.8 g). Reacting (S) - [1- (4-bromophenyl) -2, 2, 2-trifluoro-ethyl]- [1- (tert-butyl-dimethyl-silanyloxymethyl) -4, 4, 4-trifluoro-butyl]The amine was dissolved in THF (50mL) and cooled to 0 deg.C, and tert-butylammonium fluoride (10.6mL, 1M in THF) was added dropwise thereto. The reaction mixture was allowed to warm to room temperature and stirred for 4 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution, then ethyl acetate was added and the mixture was shaken vigorously. The organic layer was separated, washed twice with brine, dried over magnesium sulfate and filtered. The solvent was removed by rotary evaporation. Obtaining a residue from SiO₂Purifying with 20-25% ethyl acetate in hexane as eluentIt was eluted with a gradient of reagents to give (2S) -2- { [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl)]Amino } -5, 5, 5-trifluoropentan-1-ol.

MS(+ESI)：393.9，395.8[M+1]+

And 8: (2S) -5, 5, 5-trifluoro-2- ({ (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl -4-yl]Preparation of ethyl } amino) pentan-1-ol

A nitrogen stream was passed over (2S) -2- { [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl ]Amino } -5, 5, 5-trifluoropentan-1-ol (0.55g), 2- (4-methanesulfonyl-phenyl) -4, 4, 5, 5-tetramethyl- [1, 3, 2]Dioxaborole (0.59g), 2.5M K₂CO₃(2.75mL) and DMF (0.91mL) for 20 minutes. Then adding thereto [1, 1' -bis (diphenylphosphino) ferrocene ] oxide]Palladium (II) (1: 1 complex with dichloromethane, 34mg), the vessel is sealed, the reaction is warmed to 85 ℃ and stirred under nitrogen for 5 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50mL) and water (50mL) and shaken vigorously. The ethyl acetate layer was separated, washed three times with water, dried over magnesium sulfate and filtered. Removing the solvent to leave a residue, using SiO₂Purified by chromatography with a gradient elution of 10-30% ethyl acetate in hexane. The appropriate fractions were subjected to rotary evaporation to give (2S) -5, 5, 5-trifluoro-2- ({ (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } amino) pentan-1-ol.

And step 9: (2S) -5, 5, 5-trifluoro-2- ({ (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl -4-yl]Preparation of ethyl } amino) pentanoic acid

Stock suspensions of oxidizing agents were prepared by stirring periodic acid (2.28g) and chromium trioxide (4.6g) in aqueous acetonitrile (0.75% water) to produce a total volume of 22.8mL of suspension. This oxidant suspension (4.22mL) was then added dropwise to a stirred solution of (2S) -5, 5, 5-trifluoro-2- ({ (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl ] ethyl } amino) pentan-1-ol (0.35g, 0.74mmol) in aqueous acetonitrile (3.7mL) while maintaining the temperature at 0-5 ℃. After 1 hour, the reaction mixture was warmed to room temperature and stirred for a further 4 hours. The reaction was quenched with aqueous sodium hydrogen phosphate (6g/100mL), then toluene was added thereto, and the mixture was shaken vigorously. The organic phase was washed with 1: 1 brine: water, then with aqueous sodium bisulfite (2.2g/50mL), then brine. The organic layer was dried over sodium sulfate, filtered and dried by rotary evaporation. The crude product was purified by chromatography on silica gel using 5-10% methanol in dichloromethane as eluent to give (2S) -5, 5, 5-trifluoro-2- ({ (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl ] ethyl } amino) pentanoic acid.

MS(-ESI)：482.0[M-1]^-

Step 10: (2S) -5, 5, 5-trifluoro-2- ({ (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -bi-ethyl Phenyl-4-yl]Preparation of Ethyl } amino) pentanoic acid cyanomethylamides

(2S) -5, 5, 5-trifluoro-2- ({ (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl ] ethyl } amino) pentanoic acid (0.55g, 0.114mmol), aminoacetonitrile hydrochloride (21mg, 0.228mmol) and HATU (43mg, 0.114mmol) were dissolved in DMF (2ml) and the reaction mixture was cooled to-20 ℃. Diisopropylethylamine (0.10mL, 0.57mmol) was added thereto and the reaction mixture was stirred at-20 ℃ for 3 hours, then at room temperature for 16 hours. Ethyl acetate (about 30mL) and water (about 30mL) were added and the mixture was shaken vigorously. The organic layer was washed with water, dried over magnesium sulfate, and filtered. The filtrate was dried by rotary evaporation and the residue was purified by chromatography on silica gel using 30% ethyl acetate in hexane as eluent to give (2S) -5, 5, 5-trifluoro-2- ({ (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl ] ethyl } amino) pentanoic acid cyanomethyl amide as a white solid.

MS(+ESI)：522.3[M+1]⁺

¹H NMR(CDCl₃)δ8.0-8.053(2H，d)，7.74-7.78(2H，d)，7.63-7.66.(2H，d)，7.48-7.51(2H，d)，6.94-7.00(1H，bt，NH)，4.06-4.22(3H，m)，3.36-3.43(1H，m)，2.21-2.37(3H，m)，1.88-2.03(2H，m).¹⁹F NMR(CDCl₃)δ-66.74--66.83(3F，t)，-74.14--74.17(3F，d).

Example 19

N ¹ - (cyanomethyl) -N ² - { (S) - (4-fluorophenyl) [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl] Synthesis of methyl } -L-leucinamide

Step 1: (S) -2- [ (4-Fluorobenzylidene) -amino]Preparation of (E) -4-methylpentan-1-ol

A mixture of (L) -leucinol (1.13g, 9.67mmol) and 4-fluorobenzaldehyde (1.20g, 9.67mmol) was dissolved in benzene (30mL) and stirred at reflux for 1 h with removal of water using a Dean-Stark apparatus. (S) -2- [ (4-Fluorobenzylidene) -amino ] -4-methylpentan-1-ol is isolated by concentration in vacuo and used without further purification.

Step 2: (2S) -2- { (R) - [ (4-bromophenyl) - (4-fluorophenyl) -methyl]-amino } -4-methylpentan-1-ol Preparation of

To a solution of 1, 4-dibromobenzene (11.4g, 48.35mmol) in diethyl ether (120mL) was added n-butyllithium (24.2mL, 2.0M in cyclohexane) at-30 ℃ over 10 minutes. Will be provided withThe reaction mixture is stirred for 45 minutes, whereupon (S)2- [ (4-fluorobenzylidene) -amino group is added dropwise]-a solution of 4-methylpent-1-ol (up to 2.16g, 9.67mmol, from the previous step) in diethyl ether (30 mL). After 2 hours, during which time the reaction mixture was warmed to 0 ℃, water (200mL) was added thereto. The product was extracted with ethyl acetate (150mL), washed with brine (100mL), and MgSO ₄Drying, filtration, concentration in vacuo, and purification with a short plug of silica gel (eluting with 20% ethyl acetate/hexanes) provided (2S) -2- { (R) - [ (4-bromophenyl) - (4-fluorophenyl) -methyl]-amino } -4-methylpentan-1-ol.

MS(+APCI)：380，382[M+1]⁺

¹H NMR(CDCl₃)：δ0.91(d，6H)，1.22(m，1H)，1.43(m，1H)，1.61(m，1H)，2.62(m，1H)，3.28(m，1H)，3.63(m，1H)，4.95(s，1H)；7.00(m，2H)，7.22(d，2H)，7.2(m，2H)，7.44(d，2H).

And step 3: (2S) -2- { (R) - [ (4-bromophenyl) - (4-fluorophenyl) -methyl]Process for preparing (E) -amino) -4-methylpentanoic acid Preparation of

(2S) -2- { (R) - [ (4-bromophenyl) - (4-fluorophenyl) -methyl ] -was added at 0-5 deg.C over 20 min](iv) -amino } -4-methylpentan-1-ol (3.28g, 8.65mmol) in acetonitrile (50mL) containing water (0.375mL) was added periodic acid and chromium oxide [ VI ]]A solution in acetonitrile (50 mL: as described in Tetrahedron Letters, 1998, vol.39, p.5323-5326) was prepared by mixing 11.4 g of H₅IO₆And 23mg CrO₃Dissolved in 100mL CH₃CN and stirred at room temperature for 2 hours). The reaction mixture was stirred overnight while warming to room temperature. To this was added disodium hydrogen phosphate (1.8g/100mL of water). The reaction mixture was extracted with toluene (150mL), washed with 1: 1 brine/water (50mL), freshly prepared sodium bisulfite solution (2g/50mL water), brine (50mL), and MgSO₄Drying, filtering, vacuum concentrating, and purifying with a short plug of silica gel (elution with 30% ethyl acetate/hexane) To remove non-polar impurities, followed by elution with 50% ethyl acetate/dichloromethane) to give (2S) -2- { (R) - [ (4-bromophenyl) - (4-fluorophenyl) -methyl]-amino } -4-methylvaleric acid.

And 4, step 4: (2S) -2- { (R) - [ (4-bromophenyl) - (4-fluorophenyl) -methyl]-amino } -4-methylpentanoic acid cyanogen ester Preparation of methyl amides

To (2S) -2- { (R) - [ (4-bromophenyl) - (4-fluorophenyl) -methyl-l at-10 deg.C]To a solution of-amino } -4-methylvaleric acid (1.17g, 2.86mmol) in THF (20mL) was added 4-methylmorpholine (0.315mL, 2.86mmol) and isobutyl chloroformate (0.371mL, 2.86 mmol). The reaction mixture was stirred for 10 minutes, whereupon aminoacetonitrile hydrochloride (0.318g, 3.43mmol) was added thereto followed by 4-methylmorpholine (0.315mL, 2.86 mmol). The solution was stirred for 90 minutes. Ethyl acetate (30mL) and aqueous disodium hydrogen phosphate (30mL) were added. The organic phase was separated, washed with brine, and MgSO₄Drying and evaporating to dryness. The product was purified using a short plug of silica gel (10-50% ethyl acetate/hexanes gradient) to provide (2S) -2- { (R) - [ (4-bromophenyl) - (4-fluorophenyl) -methyl]-amino } -4-methylpentanoic acid cyanomethylamide.

And 5: n is a radical of ¹ - (cyanomethyl) -N ² - { (S) - (4-fluorophenyl) [4 '- (methylsulfonyl) -1, 1' -biphenyl-4- Base of]Preparation of methyl } -L-leucinamide

The reaction product of (2S) -2- { (R) - [ (4-bromophenyl) - (4-fluorophenyl) -methyl]-amino } -4-methylpentanoic acid cyanomethylamide (0.27g, 0.636mmol), 2- (4-methanesulfonylphenyl) -4, 4, 5, 5-tetramethyl- [1, 3, 2]A mixture of dioxaborole (0.177g, 0.626mmol) and potassium carbonate (0.703mL of a 2.0M solution) in DMF (5mL) was degassed. To this was added [1, 1' -bis (diphenylphosphino) ferrocene]A complex of palladium (II) dichloride and dichloromethane (27mg, 0.038mm0 l). Heating the reaction mixture to 80-85 deg.C in a sealed tubeHeating was continued for 3 hours at room temperature, and then it was cooled to room temperature. To this was added ethyl acetate (15 mL). The reaction mixture was washed with brine (10mL), saturated NaHCO₃The aqueous solution (10mL), brine (10mL) was washed with MgSO₄/DARCO activated carbon/silica gel filtration, concentration in vacuo, purification by preparative TLCElution with 5% ethyl acetate/dichloromethane afforded N¹- (cyanomethyl) -N²- { (S) - (4-fluorophenyl) [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Methyl } -L-leucinamide.

¹H NMRδ(CDCl₃)：0.77(d，3H)，0.9(d，3H)；1.38(m，1H)，1.57(m，1H)，1.71(m，1H)，2.01(br s，1H)，3.09(s，3H)，3.09(m，1H)，4.07(m，2H)，4.89(1H，s)，7.03(m，2H)，7.21(m，1H)，7.33(m，2H)，7.42(d，2H)，7.53(m，2H)，7.68(d，2H)，7.97(d，2H).

Example 20

(2S) -2- { (S) - [ (2, 4-difluoro-phenyl) - (4' -methanesulfonyl-biphenyl-4-yl) -methyl radical]Synthesis of (E) -amino) -4-methylpentanoic acid cyanomethyl amide

Step 1: (2S) -2- [ (2, 4-difluorobenzylidene) -amino]Preparation of (E) -4-methylpentan-1-ol

A solution of (S) - (+) -leucinol (2.47g, 21mmol) and 2, 4-difluorobenzaldehyde (3g, 21mmol) in benzene (50mL) was heated at reflux for 4h during which time water was collected with a Dean-Stark trap. The solvent was evaporated in vacuo to give (2S) -2- [ (2, 4-difluorobenzylidene) -amino ] -4-methylpentan-1-ol.

¹H NMR(CD₃SOCD₃)δ8.18(s，1H)，7.51(d，1H)，6.81(d，2H)，4.6(br s，1H)，3.8-3.2(m，3H)，1.6-1.2(m，3H)，0.9-0.8(m，6H).

Step 2: (2S) -2- { (S) - [ (4-bromophenyl) - (2, 4-difluorophenyl) -methyl]-amino group]-4-methylpentane-1- Preparation of alcohols

To a solution of 1, 4-dibromobenzene (24.5g, 100mmol, 5eq) in anhydrous ether (200mL) at-30 ℃ under a nitrogen atmosphere was added n-BuLi (64.75mL, 1.6M in hexane, 5 eq.) and the mixture was stirred for 1 h. To this was added slowly 2- [ (2, 4-difluorobenzylidene) -amino group at-30 deg.C]-4-methylpentan-1-ol (5g, 20mmol) in dry ether. After stirring for 4h, the reaction was quenched with water. The ether layer was washed with saturated NaCl solution and MgSO₄And (5) drying. The solvent was removed under reduced pressure and the crude product used 500cm³Purification by flash column chromatography on silica gel using 8: 2 hexane: EtOAc as the eluent gave (2S) -2- { (S) - [ (4-bromophenyl) - (2, 4-difluorophenyl) -methyl ]-amino } -4-methylpentan-1-ol.

¹H NMR(CD₃SOCD₃)δ7.31(dd，2H)，7.05(d，1H)，6.94(dd，2H)，6.63(d，1H)，6.54(d，1H)，5.02(s，1H)，4.45(t，1H)，3.5-3.3(m，2H)，2.3(s，1H)，2.15(s，1H)，1.85(m，1H)，1.18-1.4(m，2H)，0.9-0.8(m，6H).

And step 3: (2S) -2- { (S) - [ (4-bromophenyl) - (2, 4-difluoro-phenyl) -methyl]-amino } -4-methylvaleric acid Preparation of

Oxidation of 2- { [ (4-bromophenyl) - (2, 4-difluorophenyl) -methyl ] -amino } -4-methylpentan-1-ol by the method described in example 19, step 3 gave (2S) -2- { (S) - [ (4-bromophenyl) - (2, 4-difluoro-phenyl) -methyl ] -amino } -4-methylpentanoic acid as a cream-colored solid.

And 4, step 4: (2S) -2- { (S) - [ (4-bromophenyl) - (2, 4-difluorophenyl) -methyl]-amino group]-4-methylpentanoic acid Preparation of cyanomethyl amides

Coupling of (2S) -2- { (S) - [ (4-bromophenyl) - (2, 4-difluorophenyl) -methyl ] -amino } -4-methyl-pentanoic acid with aminoacetonitrile using the procedure described in example 19, step 4 gave (2S) -2- { (S) - [ (4-bromophenyl) - (2, 4-difluorophenyl) -methyl ] -amino } -4-methylpentanoic acid cyanomethylamide as a white solid.

¹H NMR(CD₃SOCD₃)δ7.31(dd，2H)，7.05(d，1H)，6.94(dd，2H)，6.63(d，1H)，6.54(d，1H)，4.92(s，1H)，4.14(t，2H)，3.32(m，1H)，3.19(m，1H)，2.98(m，1H)，1.85(m，1H)，1.46(m，1H)，0.9-0.8(m，6H).

And 5: (2S) -2- { (S) - [ (2, 4-difluorophenyl) - (4' -methanesulfonyl-biphenyl-4-yl) -methyl]- Preparation of amino } -4-methylpentanoic acid cyanomethylamide

Suzuki coupling with (2S) -2- { (S) - [ (4-bromophenyl) - (2, 4-difluorophenyl) -methyl ] -amino } -4-methylpentanoic acid cyanomethylamide using the procedure described in step 5, example 19 gave (2S) -2- { (S) - [ (2, 4-difluorophenyl) - (4' -methanesulfonyl-biphenyl-4-yl) -methyl ] -amino } -4-methylpentanoic acid cyanomethylamide as a white solid.

¹H NMR(CD₃SOCD₃)δ8.01(dd，2H)，7.8(dd，2H)，7.35(dd，2H)，7.11(dd，2H)，7.03(d，1H)，6.93(d，2H)，6.62(d，1H)，6.55(d，1H)，5.0(s，1H)，4.13(t，2H)，3.35(m，1H)，3.0(m，1H)，2.99(m，1H)，2.85(s，3H)，1.84(m，1H)，1.45(m，1H)，0.9-0.8(m，6H).

Example 21

N ² - [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl radical]-N ¹ - (1-cyanocyclopropyl) -L-norvalinamideSynthesis of (2)

Step 1: (S) - [1- (tert-butyldimethylsiloxymethyl) -butyl]- (2, 2, 2-trifluoroethylene) Preparation of the amino-amines

A mixture of (S) -1- (tert-butyldimethylsilyloxymethyl) -butylamine (27g, 126mmol) and trifluoroacetaldehyde acetal-methanol (17.2g, 132mmol) in benzene (250mL) was heated at reflux with removal of water using a Dean-Stark trap. After 2 hours, no more water was collected. The reaction mixture was cooled and concentrated to give (S) - [1- (tert-butyldimethylsilyloxymethyl) -butyl ] - (2, 2, 2-trifluoroethylene) -amine, which, due to its volatility, could be used in the next step without further purification or drying for a long time.

Step 2: (2S) - (S) - [1- (4-bromophenyl) -2, 2, 2-trifluoroethyl group]- [1- (tert-butyldimethylsilane) Oxymethyl) -butyl]Preparation of amines

To a solution of dibromobenzene (63.7g, 270mmol) in diethyl ether (600mL) was added n-BuLi (108mL, 2.5M in hexane) over 15 minutes at-30 ℃ via an addition funnel. The solution was warmed to-10 ℃ over 35 minutes and then cooled back to-30 ℃. To this was added (S) - [1- (tert-butyldimethylsilyloxymethyl) -butyl in diethyl ether (200mL) over 20 minutes ]- (2, 2, 2-trifluoroethylene) -amine (35.12g, 108 mmol). The reaction mixture was stirred for 1 hour while warming to 0 ℃. Water (200mL) was added. The organic phase was separated, washed with brine (200mL), MgSO₄Drying, filtering, evaporating to dryness to obtain (2S) - (S) - [1- (4-bromophenyl) -2, 2, 2-trifluoroethyl group]- [1- (tert-butyldimethylsilyloxymethyl) -butyl]Amine, which is used directly in the next step without further purification.

And step 3: (2S) -2- [ (S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethylamino]Preparation of pentan-1-ol

To (2S) - (S) - [1- (4-bromophenyl) -2, 2, 2-trifluoro-ethyl]- [1- (tert-butyldimethylsilyloxymethyl) -butyl]To a solution of amine (49.58g, 109mmol) in THF (200mL) was added tetrabutylammonium fluoride (110mL, 1.0M solution). The reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with water (2 × 100mL), brine (100mL), evaporated to dryness and purified by flash column chromatography eluting the less polar material with 3% ethyl acetate/hexane followed by 40% ethyl acetate/hexane. The product-containing fractions were combined, concentrated to a volume of 300mL, washed with 0.25M citric acid (200mL), brine (100mL), and MgSO ₄Drying, filtering and evaporating to obtain (2S) -2- [ (S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethylamino]-pentan-1-ol. This material was used directly in the next step without further purification. TLC (30% ethyl acetate/hexane) R_f＝0.28。

And 4, step 4: (2S) -2- [ (S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethylamino]Preparation of valeric acid

To crude (2S) -2- [ (S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethylamino group at-78 ℃ over 1 hour]To a solution of pentan-1-ol (37.1g, 109mmol) in anhydrous acetonitrile (500mL) was added a solution of periodic acid (71.7g) and chromium trioxide (144mg) in anhydrous acetonitrile (630 mL). The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure to a volume of about 500 mL. Citric acid solution (22g in 250mL H) was added to it₂O) and the mixture was extracted with ethyl acetate (800 mL). With freshly prepared NaHSO₃(2X 200mL, 25g of solid dissolved in 200mL of water) and brine (300mL), and the solution was washed with MgSO₄Drying, filtration and evaporation gave a pale orange solid which was triturated with 5% ethyl acetate/hexane to give (2S) -2- [ (S) -1- (4)-bromophenyl) -2, 2, 2-trifluoroethylamino ]-valeric acid. The residue was purified by concentrating the mother liquor in diethyl ether and NaHCO₃Partitioning the aqueous layer, acidifying the aqueous layer with citric acid, extracting with ethyl acetate, and separating with MgSO 4₄Drying, filtration and evaporation of the solvent gave additional acid.

And 5: n is a radical of ² - [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl radical]-N ¹ - (1-cyanocyclopropyl) -L-n-propyl Preparation of valinamides

Reacting (2S) -2- [ (S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethylamino]A mixture of valeric acid (19.0g, 53.6mmol), 1-aminocyclopropanecarbonitrile hydrochloride (12.71g, 107mmol, synthesized according to the method described in O' Donnell, M.J. et al, Synthesis, 1984, 127 & 128), and HATU (22.42g, 59.0mmol) was dissolved in DMF (200mL) and cooled to-78 ℃. Diisopropylethylamine (37.35mL, 214mmol) was added thereto, and after stirring for 1 hour, the cooling bath was removed, followed by addition of saturated NaHCO thereto₃(300 mL). The product was extracted with ethyl acetate (500mL), brine (100mL), 0.25M citric acid (200mL), saturated NaHCO₃(200mL), brine (200mL), washed with MgSO₄dried/DARCO, filtered over silica and evaporated to dryness. After elution, the residue was passed through another short silica plug, using 10% ethyl acetate/dichloromethane as mobile phase, the product was concentrated and recrystallized from ether/hexane to give N ²- [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl radical]-N' - (1-cyanocyclopropyl) -L-norvalinamide.

MS(-ESI)：416，418[M-1]^-

¹H NMR(CDCl₃)：δ0.97(3H，t)，0.98(m，1H)，1.07(m，1H)，1.41(m，2H)，1.49(m，2H)，1.62(m，1H)，1.72(m，1H)，3.27(1H，m)，1.04(m，1H)，7.1(br s，1H)，1.24(d，2H)，7.75(d，2H).

Example 22

N ¹ - (1-cyanocyclopropyl) -N ² - { (1S) -2, 2, 2-trifluoro-1- [ 4' - (methylsulfonyl) -1, 1' -biphenyl-4-yl]Synthesis of ethyl } -L-norvalinamide

In a thick-walled flask, adding N²- [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl radical]-N¹- (1-cyanocyclopropyl) -L-norvalinamide (6.46g, 15.44mmol), 4-methanesulfonylphenyl-boronic acid (3.40g, 16.98mmol), and 2M K₂CO₃The mixture (19.3mL) was dissolved in DMF (75 mL). The reaction mixture was degassed, and [1, 1' -bis (diphenylphosphino) ferrocene was added thereto]Palladium (II) dichloride complex with dichloromethane (0.678g, 0.926 mmol). The flask was sealed, heated at 80-85 ℃ for 3 hours, cooled, and diluted with ethyl acetate (300 mL). The solution was washed with 1: 1 water/brine (200mL), passed over a silica (base) DARCO, and MgSO₄The (top) triple plug was filtered, concentrated in vacuo, and purified using a silica gel plug (elution with 50-70% ethyl acetate/hexanes). The product was then purified by recrystallization from ethyl acetate/hexane to give the title compound.

MS(+ESI)：494[M+1]⁺

¹H NMR(CDCl₃)：δ0.97(t，3H)，0.98(m，1H)，1.1(m，1H)，1.42(m，2H)，1.29(m，2H)，1.63(m，1H)，1.77(m，1H)，3.13(s，3H)，3.28(dd，1H)，4.17(q，1H)，7.21(br s，1H)，7.47(d，2H)，7.63(d，2H)，7.78(d，2H)，8.02(d，2H).

Example 23

N ² - [1- (4-bromophenyl) -2, 2, 2-trifluoroethyl group]-N ¹ Synthesis of (cyanomethyl) -L-norvalinamide

N²- [1- (4-bromophenyl) -2, 2, 2-trifluoroethyl group]-N¹- (cyanomethyl) -L-norvalinamide compounds with N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Prepared in a similar manner as ethyl } -L-norvalinamide using aminoacetonitrile in the coupling step with (2S) -2- [ (S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethylamino]-coupling with valeric acid.

MS(+ESI)：392，394[M+1]⁺

Example 24

N ¹ - (cyanomethyl) -N ² - { (1S) -2, 2, 2-trifluoro-1- [ 4' - (methylsulfonyl) -1, 1' -biphenyl-4-yl]Synthesis of ethyl } -L-norvalinamide

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]The ethyl } -L-norvalinamide is reacted with N¹- (1-cyanocyclopropyl) -N²-{(1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Prepared in a similar manner to ethyl } -L-norvalinamide using the above-mentioned N in a Suzuki coupling²- [1- (4-bromophenyl) -2, 2, 2-trifluoroethyl group]-N¹- (cyanomethyl) -L-norvalinamide for coupling with 4-methanesulfonylphenyl boronic acid or pinacol boronic acid ester. Alternatively, the compound may be prepared by the following method: in the presence of [1, 1' -bis (diphenylphosphino) ferrocene ](2S) - (S) - [1- (4-bromophenyl) -2, 2, 2-trifluoro-ethyl in the case of a palladium (II) dichloride complex with dichloromethane, according to the procedure described above]- [1- (tert-butyldimethylsilyloxymethyl) -butyl]Suzuki coupling between amine and 4-methanesulfonylphenylboronic acid, followed by cleavage of the silyl group with tetrabutylammonium fluoride, and H₅IO₆/CrO₃(see above) to give (2S) -2- [ (S) -2, 2, 2-trifluoro-1- (4' -methanesulfonylbiphenyl-4-yl) -ethylamino]-pentanoic acid, coupling the product with aminoacetonitrile hydrochloride in the presence of HATU/diisopropylethylamine/DMF to give the title compound.

MS(+ESI)：468[M+1]⁺

Example 25

N ¹ - (cyanomethyl) -N ² - { (1R) -2, 2, 2-trifluoro-1- [ 4' - (methylsulfonyl) -1, 1' -biphenyl-4-yl]Synthesis of ethyl } -L-norvalinamide

Step 1: preparation of (4S) -4-propyl-2-trifluoromethyl oxazolidine

(L) -norvalinol hydrochloride (5.25g, 37.60mmol) and trifluoroacetaldehyde-methanol (5mL, 37.6mmol) were heated at reflux in the presence of triethylamine (5.26mL, 37.6mmol) in benzene (100mL) and water was collected using a Dean-Stark apparatus. After 3 hours, the reaction mixture was cooled, diluted with ether (100mL), filtered and evaporated to dryness to give (4S) -4-propyl-2-trifluoromethyloxazolidine, which was used without further purification.

Step 2: (2S) -2- [1- (4-bromophenyl) -2, 2, 2-trifluoroethylamino]Preparation of pentan-1-ol

Butyllithium (41mL of a 2.0M solution in cyclohexane) was added to a solution of 1, 4-dibromobenzene (19.3g, 81.89mmol) in diethyl ether (250mL) at-30 ℃ over 10 minutes. After 1 hour, a solution of (4S) -4-propyl-2-trifluoromethyloxazolidine (3.00g, 16.38mmol) in diethyl ether (50mL) was added thereto over 30 minutes via an addition funnel. After stirring for 90 minutes, water (100mL) was added thereto. The organic phase was washed with brine (100mL) and MgSO₄Dried, filtered and evaporated to dryness. The residue was purified with a silica gel plug (elution with 10-30% ethyl acetate/hexanes). According to at 0.98ppm (¹H NMR) of the sample, and (2S) -2- [1- (4-bromophenyl) -2, 2, 2-trifluoroethylamino group was observed]Pentan-1-ol in CF₃About a 2: 1 mixture of diastereomers on the residue.

And step 3: n is a radical of ¹ - (cyanomethyl) -N ² - { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl -4-yl]Ethyl } -L-norvalinamide and N ¹ - (cyanomethyl) -N ² - { (1R) -2, 2, 2-trifluoro-1- [ 4' - (methylsulfonyl) -1, 1' -biphenyl-4-yl]Preparation of ethyl } -L-norvalinamide

(2S) -2- [1- (4-bromophenyl) -2, 2, 2-trifluoroethylamino]Synthesis of valeric acid and addition thereofThe operation of the synthesis of the aminoacetonitrile adduct is similar to that of the preparation of N²- [1- (4-bromophenyl) -2, 2, 2-trifluoroethyl group]-N¹- (cyanomethyl) -L-norvalinamide) in the same manner as described above. With N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Suzuki coupling of the product to N-norvalinamide in the same manner as described for ethyl-L-norvalinamide¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-norvalinamide and N¹- (cyanomethyl) -N²- { (1R) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]2: 1 mixture of ethyl } -L-norvalinamide by preparative TLCIt is separated out.

MS(+ESI)：468[M+1]⁺

Example 26

N ¹ - (cyanomethyl) -N ² - {1- [4 '- (4-cyclopropylpiperazin-1-yl) -1, 1' -biphenyl-4-yl] Synthesis of (E) -2, 2, 2-trifluoroethyl } -L-norvalinamide

The title compound is prepared by reacting 4-cyclopropylpiperazine phenyl bromide with (2) -2- {2, 2, 2-trifluoro-1- [4- (4, 4, 5, 5-tetramethyl- [1, 3, 2-]Bioxaborolan-2-yl) -phenyl ]-ethylamino } -pentanoic acid cyanomethylamide in the presence of [1, 1' -bis (diphenylphosphino) ferrocene as described above]Suzuki cross-coupling with palladium (II) dichloride complex with dichloromethane, followed by preparative TLCPurification was performed to prepare.

MS(+ESI)：514[M+1]⁺

Example 27

N ² - { (1S) -1- [4 '- (aminosulfonyl) -1, 1' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -N ¹ Synthesis of (1-cyanocyclopropyl) -L-norvalinamide

The title compound is prepared by¹- (cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Prepared in a similar manner to ethyl } -L-norvalinamide (example 24)

MS(+ESI)：495[M+1]⁺

¹H NMR(CDCl₃)：δ0.97(3H，t).0.98(m^*，1H)；1.08(m，1H)，1.42(m，2H)，1.44(m，2H)，1.57-1.8(m，4H)，3.28(m，1H)，4.16(q，1H)，4.9(br s^*，1H)，7.2(s，1H)，7.43(d，2H)，7.6(d，2H)，7.72(d，2H)，7.99(d，2H).

Example 28

(2S) -2- [ (1S) -1- (4' -acetylbiphenyl-4-yl) -2, 2, 2-trifluoroethylamino] Preparation of (1-cyanocyclopropyl) -amide (E) -pentanoic acid

The title compound is prepared by¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-norvalinamide A similar process is described, using 4-acetylphenylboronic acid and N²- [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl radical]-N¹In the presence of [1, 1' -bis (diphenylphosphino) ferrocene ] between (1-cyanocyclopropyl) -L-norvalinamide ]-dichloropalladium (II) with dichloromethane complex by Suzuki cross-coupling.

MS(+ESI)：458[M+1]⁺，480[M+1+Na]⁺

¹H NMR(CDCl₃)：δ0.97(t，3H)，0.98(m，1H)，1.-7(m，1H)，1.42(m，2H)，1.57(s，2H)，1.63(m，1H)，1.78(m，1H)，2.33(s，3H)，3.33(dd，1H)，4.17(q，1H)，7.21(br s，1H)，7.43(d，2H)，7.65-7.69(2xd，4H)，8.03(d，2H).

Example 29

(2S) -2- [ (1S) -1- (2 ', 4' -difluorobiphenyl-4-yl) -2, 2, 2-trifluoroethylamino] Preparation of pentanoic acid (1-cyanocyclopropyl) -amide

The title compound is prepared by¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-norvalinamide A similar process to that described is carried out by reacting 2, 4-difluorophenylboronic acid with N²- [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl radical]-N¹In the presence of [1, 1 'between- (1-cyanocyclopropyl) -L-norvalinamide'Di (diphenylphosphino) ferrocene]-palladium (II) dichloride in complex with dichloromethane, by Suzuki cross-coupling.

MS(+ESI)：452[M+1]⁺，474[M+1+Na]⁺

¹H NMR(CDCl₃)：δ0.90(m，1H)，0.97(t，3H)，1.04(m，1H)，1.41-1.5(m，4H)，1.62(m，1H)，1.78(m，1H)，2.19(br s，1H)，3.32(dd，1H)，4.13(dd，1H)，6.95(m，2H)，7.19(br s，1H)，7.41(m，3H)，7.53(d，2H).

Example 30

(2S) -2- [ (1S) -1- (3 ', 4' -difluorobiphenyl-4-yl) -2, 2, 2-trifluoroethylamino] Synthesis of (1-cyanocyclopropyl) -amide (E) -pentanoate

The title compound is prepared by¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-norvalinamide A similar process to that described is carried out by reacting 3, 4-difluorophenylboronic acid with N ²- [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl radical]-N¹Presence of 1, 1' -bis (diphenylphosphino) ferrocene between- (1-cyanocyclopropyl) -L-norvalinamide]-dichloropalladium (II) with dichloromethane complex by Suzuki cross-coupling.

MS(+ESI)：452[M+1]⁺，474[M+1+Na]⁺

¹H NMR(CDCl₃)：δ0.97(t，3H)，0.98(m，1H)，1.07(m，1H)，1.42(m，2H)，1.5(m，2H)，1.62(m，1H)，1.77(m，1H)，2.18(br s，1H)，3.29(dd，1H)，4.17(q，1H)，7.21(brs，1H)，7.13-7.3(m，2H)，7.38(m，1H)，7.42(d，2H)，7.57(d，2H).

Example 31

(2S) -2- [ (1S) -1- (3 '-chloro-4' -fluorobiphenyl-4-yl) -2, 2, 2-trifluoroethylamino] Preparation of (1-cyano-cyclopropyl) -amide-pentanoic acid

The title compound is prepared by¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-norvalinamide A similar process is described, using 3-chloro-4-fluorophenylboronic acid and N²- [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl radical]-N¹In the presence of [1, 1' -bis (diphenylphosphino) -ferrocene ] between (1-cyanocyclopropyl) -L-norvalinamide]Prepared by Suzuki cross-coupling in the case of a complex of palladium (II) dichloride with dichloromethane.

MS(+ESI)：468[M+1]⁺

¹H NMR(CDCl₃)：δ0.99(t，3H)，1.00(m，1H)，1.08(m，1H)，1.42(m，2H)，1.51(m，2H)，1.62(m，1H)，1.79(m，1H)，2.19(br s，1H)，3.33(dd，1H)，4.17(q，1H)，7.21(m，2H)，7.42(m，3H)，7.57(d，2H)，7.62(m，1H).

Example 32

(2S) -2- [ (1S) -2, 2, 2-trifluoro-1- (4' -methylbiphenyl-4-yl) -ethylamino] Synthesis of (1-cyanocyclopropyl) -amide (E) -pentanoate

The title compound is prepared by¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl ]Ethyl } -L-norvalinamide A similar procedure is described for p-tolylboronic acid and N²- [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl radical]-N¹In the presence of [1, 1' -bis (diphenylphosphino) ferrocene ] between (1-cyanocyclopropyl) -L-norvalinamide]-palladium (II) dichloride in complex with dichloromethane, by Suzuki cross-coupling.

MS(+ESI)：430[M+1]⁺

¹H NMR(CDCl₃)δ0.90(m，1H)，0.98(t，3h)，1.02(m，1H)1.4-1.5(m，4H)，1.62(m，1H)，1.69(m，1H)，2.19(br s，1H)，2.41(s，3H)，3.35(dd，1H)，4.1(q，1H)，7.21(s，1H)7.24(d，2H)，7.38(d，2H)，7.46(d，2H)，7.60(d，2H).

Example 33

(2S) -2- [ (1S) -1- (4' -cyanobiphenyl-4-yl) -2, 2, 2-trifluoroethylamino] Synthesis of (1-cyanocyclopropyl) -amide (E) -pentanoate

The title compound is prepared by¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-norvalinamide A similar process is described, using 4-cyanophenylboronic acid and N²- [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl radical]-N¹In the presence of [1, 1' -bis (diphenylphosphino) ferrocene ] between (1-cyanocyclopropyl) -L-norvalinamide]-palladium (II) dichloride in complex with dichloromethane, by Suzuki cross-coupling.

MS(+ESI)：441[M+1]⁺

Example 34

(2S) -2- { (S) - [ (4-bromophenyl) -thiazol-2-yl-methyl]-amino } Synthesis of (E) -4-methylpentanoic acid cyanomethyl amide

Step 1: preparation of 3-methyl-3- (tosyl-oxymethyl) oxetane

P-toluenesulfonyl chloride (57.2g, 300mmol) was dissolved in anhydrous pyridine (400mL) under a nitrogen atmosphere. 3-methyl-3- (hydroxymethyl) oxetane (20.4g, 200mmol) was added slowly and the solution stirred for 1.5 h. Crushed ice (400g) was then added thereto and the mixture was stirred vigorously for a further 0.5 h. The white precipitate was then collected on Whatman filter paper #1 and washed with cold water. The product was dried under high vacuum to give 3-methyl-3- (tosyl-oxymethyl) oxetane (oxetane tosylate) as a white oxetane tosylate powder.

¹H NMR(CDCl₃)δ7.81(d，2H)，7.37(d，2H)，4.37(m，4H)，4.11(s，2H)，2.46(s，3H)，1.31(s，3H).

Step 2: (2S) -2-benzyloxycarbonylamino-4-methyl-pentanoic acid 3-methyloxetan-3-ylmethylmeth-yl Preparation of the base esters

Mixing Cbz-L-leucine (2g, 7.5mmol) and Cs₂CO₃(1.46g, 4.5mmol, 0.6eq) was dissolved in water (20 mL). The water was then removed under vacuum and the resulting oil was freeze dried for 12h to give a white solid. To this solid was added 3-methyl-3- (tosyl)Yl-oxymethyl) oxetane (oxetanemethanesulfonate) (1.8g, 4.5mmol), and NaI (224mg, 1.5mmol, 0.2 eq) in DMF (35mL) and allowed to stir under nitrogen for 48 h. Then, DMF was removed under vacuum, the resulting solid was dissolved in EtOAc (60mL) and washed with 10% NaHCO ₃It was washed (20mL) and saturated NaCl (10mL) with MgSO₄Drying is carried out. The solvent was removed under reduced pressure to give a yellow oil, 200cm³Flash column chromatography on silica gel eluting with 3: 1 hexanes: EtOAc as the eluent afforded (2S) -2-benzyloxycarbonylamino-4-methyl-pentanoic acid 3-methyloxetan-3-ylmethyl ester (Cbz-Leu oxetanyl ester) as a yellow thick oil.

¹H NMR(CD₃SOCD₃)7.75(d，1H)，7.26-7.38(m，5H)，5.05(s，2H)，4.0-4.4(m，8H)，1.45-1.7(m，3H)，1.25(s，3H)，0.85-0.9(m，6H).

And step 3: [ 3-methyl-1- (4-methyl-2, 6, 7-trioxa-bicyclo [2.2.2 ]]Oct-1-yl) -butyl]-aminomethyl Preparation of benzyl esters of acids

(2S) -2-benzyloxycarbonylamino-4-methyl-pentanoic acid 3-methyloxetan-3-ylmethyl ester (Cbz-Leu oxetanyl ester) (2g, 5.7mmol) was dissolved in anhydrous CH under nitrogen₂Cl₂(10 mL). BF mixing₃.Et₂O (40. mu.l, 0.3mmol, 0.054 equiv.) with anhydrous CH₂Cl₂(1mL) was diluted and added to the reaction flask. The reaction was allowed to warm to room temperature and stirred for 12 h. Triethylamine (335. mu.l, 3.3mmol, 0.58 eq.) was added and the reaction was stirred for an additional 30 minutes, then concentrated to a thick oil. The crude product was redissolved in EtOAc (15mL) with 3% NH₄Cl (10mL), saturated NaCl (10mL), washed with (MgSO) ₄) Drying and evaporating to dryness. This reaction produced a colorless thick oil which crystallized on standing to give [ 3-methyl-1- (4-methyl-2, 6, 7-trioxa-bicyclo [ 2.2.2: -l- ] -3-methyl-1- (4-methyl-2, 6, 7-trioxa-bicyclo [ -2.2.2 [ -l- ]]Oct-1-yl) -butyl]-aminomethylAcid benzyl ester, (Cbz-Leu-OBO ester).

¹H NMR(CD₃SOCD₃)7.25-7.35(br m，5H)，6.88(d，1H)，5.05(s，2H)，3.80(s，6H)，3.7(m，1H)1.2-1.6(m，3H)，0.75-0.85(m，6H)，0.70(s，3H).

And 4, step 4: 3-methyl-1- (4-methyl-2, 6, 7-trioxa-bicyclo [2.2.2]Oct-1-yl) -butylamine

To a solution of [ 3-methyl-1- (4-methyl-2, 6, 7-trioxa-bicyclo [2.2.2] oct-1-yl) -butyl ] -carbamic acid benzyl ester (3.2g, 9.2mmol) in anhydrous EtOH (30mL) under nitrogen was added 10% Pd in activated carbon (320mg, 10%). The reaction mixture was hydrogenated at 50psi for 6 hours. The reaction was checked by TLC and the mixture was filtered through celite. The solvent was removed to give 3-methyl-1- (4-methyl-2, 6, 7-trioxa-bicyclo [2.2.2] oct-1-yl) -butylamine as a white solid.

¹H NMR(CD₃SOCD₃)3.80(s，6H)，3.2-3.4(br s，3H)，1.75(m，1H)，1.0-1.4(m，2H)，0.75-0.90(m，6H)，0.75(s，3H).

And 5: [ 3-methyl-1- (4-methyl-2, 6, 7-trioxa-bicyclo [2.2.2]]Oct-1-yl) -butyl]-thiazoles Preparation of (E) -2-ylmethyleneamines

A solution of 3-methyl-1- (4-methyl-2, 6, 7-trioxa-bicyclo [2.2.2] oct-1-yl) -butylamine (1.9g, 8.8mmol) and thiazole-2-carbaldehyde (998mg, 8.8mmol) in benzene was refluxed for 3 hours using a Dean-Stark trap during which time water was collected and the remaining residue was evaporated under reduced pressure to give [ 3-methyl-1- (4-methyl-2, 6, 7-trioxa-bicyclo [2.2.2] oct-1-yl) -butyl ] -thiazol-2-ylmethylene amine as an orange solid.

¹H NMR(CD₃SOCD₃)8.4(s，1H)，7.97(d，1H)，7.84(d，1H)，3.82(s，6H)，3.4(m，1H)，1.7(m，1H)，1.5(m，1H)，1.3(m，1H)，0.9(m，6H)，0.75(s，3H).

Step 6: [ (4-bromo-phenyl) -thiazol-2-yl-methyl]- [ 3-methyl-1- (4-methyl-2, 6, 7-trioxa- Bicyclo [2.2.2]Oct-1-yl) -butyl]Preparation of amines

To a solution of dibromobenzene (760mg, 3.2mmol) in dry ether at-30 deg.C was added a solution of 2.5Mn-BuLi in hexane (1.3mL, 3.2 mmol). After stirring for 1 hour, [ 3-methyl-1- (4-methyl-2, 6, 7-trioxa-bicyclo [2.2.2 ] in 5mL of anhydrous ether was slowly added thereto]Oct-1-yl) -butyl]-solution of thiazol-2-ylmethylene-amine (500mg, 1.6 mmol). The reaction mixture was stirred at the same temperature for 2 hours, and then the reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated NaCl and MgSO₄And (5) drying. The solvent was evaporated under vacuum. The crude product was purified by flash column chromatography: using EtOAc as eluent, the [ (4-bromo-phenyl) -thiazol-2-yl-methyl ] was obtained as a light yellow solid]- [ 3-methyl-1- (4-methyl-2, 6, 7-trioxa-bicyclo [2.2.2 ]]Oct-1-yl) -butyl]-an amine.

¹H NMR(CD₃SOCD₃)7.64(d，1H)，7.59(d，1H)，7.5(d，2H)，7.28(d，2H)，5.68(s，1H)，3.82(s，6H)，3.3(m，1H)，2.65(m，1H)，1.95(m，1H)，1.4(m，1H)，1.2(m，1H)，0.9(d，3H)，0.75(s，3H)，0.7(d，3H).

And 7: (2S) -2- { (S) - [ (4-bromophenyl) -thiazol-2-yl-methyl]Preparation of (E) -amino) -4-methylvaleric acid Prepare for

To [ (4-bromo-phenyl) -thiazol-2-yl-methyl]- [ 3-methyl-1- (4-methyl-2, 6, 7-trioxa-bicyclo [2.2.2 ] ]Oct-1-yl) -butyl]Amine (500mg, 1.06mmol) in THF (20mL) and water (18mL) 1N HCl (3.5mL) was added. The reaction mixture was stirred for 2 h. After TLC examination showed disappearance of starting material, Li (OH) H was added thereto₂O (280.2mg, 6.3 equivalents) and stirred at room temperature for 2 hours. Then 1N H was added theretoCl to adjust pH to 4-6, extracting the product with EtOAC, and the organic layer with MgSO₄Drying is carried out. The solvent was evaporated to give (2S) -2- { (S) - [ (4-bromophenyl) -thiazol-2-yl-methyl-l as a yellow solid]-amino } -4-methylvaleric acid.

And 8: (2S) -2- ((S) - [ (4-bromophenyl) -thiazol-2-yl-methyl)]-amino) -4-methylpentanoic acid cyano Preparation of methylamides

Coupling of (2S) -2- { (S) - [ (4-bromophenyl) -thiazol-2-yl-methyl ] -amino } -4-methyl-pentanoic acid with aminoacetonitrile (2 equivalents, 1 equivalent excess) in the presence of HATU (1 equivalent) and diisopropylethylamine (4 equivalents) gave (2S) -2- { (S) - [ (4-bromophenyl) -thiazol-2-yl-methyl ] -amino } -4-methylpentanoic acid cyanomethylamide as a cream solid.

¹H NMR(CD₃SOCD₃)8.73(t，1H)，7.66(d，1H)，7.64(d，1H)，7.5(dd，2H)，7.25(dd，2H)4.92(d，1H)，4.14(t，2H)，3.32(s，1H)，3.19(m，1H)，2.98(m，1H)，1.85(m，1H)，1.46(m，1H)，0.9-0.85(m，6H).

Example 35

(2S)2- { (S) - [ (4-bromophenyl) -thiazol-2-yl-methyl]-amino } -4-methylvaleric acid Synthesis of (1-cyanocyclopropyl) -amide

The title compound was prepared by a method analogous to the preparation described in example 34, via coupling of (2S) -2- { (S) - [ (4-bromophenyl) -thiazol-2-yl-methyl ] -amino } -4-methylvaleric acid with 1-aminocyclopropanecarbonitrile in the presence of HATU and diisopropylamine. The synthesis of (2S) -2- { (S) - [ (4-bromophenyl) -thiazol-2-yl-methyl ] -amino } -4-methylpentanoic acid was performed by adding bromophenyl lithium (generated in situ from 1, 4-dibromobenzene and n-butyllithium) to the imine condensation product between thiazole-2-carbaldehyde and 3-methyl-1- (4-methyl-2, 6, 7-trioxa-bicyclo [2.2.2] oct-1-yl) -butylamine (L-leucine OBO ester, prepared according to the method described in example 34), followed by deprotection of the orthoester.

¹H NMR(CDCl₃)：δ0.82(d，3H)，0.95(d，3H)，1.04(m，2H)，1.46-1.62(m，4H)，1.80(m，1H)，3.12(dd，1H)，4.95(s，1H)，7.22(s，1H)，7.23-7.25(d，2H)，7.31(m，2H)，7.47(d，2H)，7.74(m，1H).

Example 36

(2S) -2- { (S) - [ (2 ', 4' -difluorobiphenyl-4-yl) -thiazol-2-yl-methyl]-amino } Preparation of (1-cyanocyclopropyl) -amide-4-methylpentanoic acid

The title compound was prepared by Suzuki cross-coupling between (2S) -2- { (S) - [ (4-bromophenyl) -thiazol-2-yl-methyl ] -amino } -4-methylpentanoic acid (1-cyanocyclopropyl) -amide and 2, 4-difluorophenylboronic acid in the presence of a complex of [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (II) with dichloromethane.

¹H NMR(CDCl₃)：δ0.84(d，3H)，0.97(d，3H)，1.03(m，2H)，1.47(m，2H)，1.57-1.62(m，4H)，1.95(m，1H)，3.27(dd，1H)，5.02(s，1H)，6.93(m，2H)，7.32(m，1H)，7.39(m，1H)，7.42(m，3H)，7.48(d，2H)，7.77(d，1H).

Example 37

(2S) -2- { (S) - [ (4' -methanesulfonylbiphenyl-4-yl) -thiazol-2-yl-methyl] Combination of (1-cyanocyclopropyl) -amide of (amino) -4-methylpentanoic acidBecome into

The title compound is prepared by a method analogous to that described for the preparation of (2S) -2- { (S) - [ (2 ', 4' -difluorobiphenyl-4-yl) -thiazol-2-yl-methyl ] -amino } -4-methylpentanoic acid (1-cyanocyclopropyl) -amide, prepared by Suzuki cross-coupling between (2S) -2- { (S) - [ (4-bromophenyl) -thiazol-2-yl-methyl ] -amino } -4-methylpentanoic acid (1-cyanocyclopropyl) -amide and 4-methanesulfonylphenylboronic acid in the presence of a complex of [1, 1' -bis (diphenylphosphino) -ferrocene ] dichloropalladium (II) with dichloromethane.

MS(-ESI)：521[M-1]^-

Example 38

N ¹ - (1-cyanocyclopropyl) -4, 4-difluoro-N ² - { (1S) -2, 2, 2-trifluoro-1- [ 4' - (methylsulfonyl) -1, 1' -biphenyl-4-yl]Synthesis of ethyl } -L-norvalinamide

Step 1: preparation of N- ((benzyloxy) carbonyl) -3-iodo-L-alanine methyl ester

To a solution of carbonylbenzyloxy-L-serine (25g, 104mmol) in ethyl acetate (200mL) was added a solution of diazomethane in diethyl ether until a pale yellow color was maintained. The solvent was evaporated under vacuum. To the residue were added N, N-dimethylformamide (400mL) and methyltriphenoxyphosphonium iodide (50g, 110 mmol). The mixture was stirred for 15 minutes, then methanol (15mL) was added to it, then the mixture was poured onto 20% sodium thiosulfate and extracted with 1: 1 ethyl acetate: hexane (2L). The organic layer was washed with water, brine (3 ×), dried over magnesium sulfate, filtered and the solvent evaporated in vacuo. The residue was purified by silica gel chromatography eluting with ethyl acetate and hexane. The resulting compound was triturated with ether/hexane, filtered and air dried to give N- ((benzyloxy) carbonyl) -3-iodo-L-alanine methyl ester.

Step 2: preparation of N- ((benzyloxy) carbonyl) -4-oxo-L-norvaline methyl ester

A mixture of N- ((benzyloxy) carbonyl) -3-iodo-L-alanine methyl ester from step 1 (10g, 27.5mmol), zinc-copper couple (3.3g) in benzene (110mL) and N, N-dimethylacetamide (7.4mL) was sonicated in a sonication bath for 2 hours. During this time, 3 parts of 1, 2-dibromoethane (0.24mL) and trimethylchlorosilane (0.17mL) were added thereto. To this mixture was then added bis (triphenylphosphine) palladium chloride (0.958g, 1.4mmol) and acetyl chloride (2.5mL, 35.2mmol) and the mixture was heated at 70 ℃ for 2 h. After cooling to room temperature, the mixture was filtered over celite with ethyl acetate, then the organic layer was washed with saturated ammonium chloride solution, brine (2 ×), dried over magnesium sulfate, filtered and the solvent was evaporated in vacuo. The residue was purified by silica gel chromatography using ethyl acetate and hexane to give N- ((benzyloxy) carbonyl) -4-oxo-L-norvaline methyl ester.

And step 3: preparation of N- ((benzyloxy) carbonyl) -4, 4-difluoro-L-norvaline methyl ester

To a solution of N- ((benzyloxy) carbonyl) -4-oxo-L-norvaline methyl ester (1.3g, 4.65mmol) in dichloromethane (20mL) and methanol (0.019mL) at 0 deg.C was slowly added DAST (2.46 mL). The ice bath was removed and replaced with a hot water bath (57 ℃). The hot water bath was replaced three times and the mixture was then stirred at room temperature overnight. The mixture was slowly poured into cold saturated NaHCO ₃Extracting with ethyl acetate, and adding brineWashed, dried over magnesium sulfate, filtered and the solvent evaporated in vacuo. The residue was purified by silica gel chromatography using ethyl acetate and hexane to give N- ((benzyloxy) carbonyl) -4, 4-difluoro-L-norvaline methyl ester.

And 4, step 4: preparation of benzyl (1S) -3, 3-difluoro-1- (hydroxymethyl) butylcarbamate

To a solution of N- ((benzyloxy) carbonyl) -4, 4-difluoro-L-norvaline methyl ester (1.59g, 5.29mmol) in ethanol (50mL) was added lithium chloride (919mg) and the mixture was stirred for 10 min. Sodium borohydride (820mg) was slowly added thereto, and the mixture was stirred for 2 hours. Then, another portion of sodium borohydride (100mg) was added thereto and stirring was continued for 30 minutes. The mixture was diluted with water (20mL), slowly neutralized with 1N HCl, and then an additional aliquot of water was added. The mixture was extracted with ethyl acetate (2 ×), washed with brine, dried over magnesium sulfate, filtered and the solvent evaporated in vacuo to give benzyl (1S) -3, 3-difluoro-1- (hydroxymethyl) butylcarbamate.

And 5: preparation of (2S) -1- ((tert-butyl (dimethyl) silyl) oxy) -4, 4-difluoropentane-2-amine Prepare for

To a solution of benzyl (1S) -3, 3-difluoro-1- (hydroxymethyl) butylcarbamate (from step 4) in ethanol (25mL) was added palladium on charcoal (10%, 150mg) and the mixture was taken up in H₂Stirring was carried out under an atmosphere (hydrogen balloon) for 2 hours. Dichloromethane was added thereto and the mixture was filtered through celite. The solvent was evaporated under vacuum. The residue was dissolved in methylene chloride (15mL) and triethylamine (1mL), to which were added N, N-dimethylaminopyridine (10mg) and chloro-tert-butyldimethylsilane (844 mg). The mixture was stirred overnight, then water and brine were added thereto. The mixture was extracted with ethyl acetate (2 ×), washed with brine, dried over magnesium sulfate, filtered and the solvent evaporated in vacuo to give (2S) -1- ((tert-butyl (dimethyl) silyl) oxy) -4, 4-difluoropentan-2-amine.

Step 6: (2S) -1- ((tert-butyl (dimethyl) silyl) oxy) -4, 4-difluoro-N- ((1E) -2, 2, 2- Preparation of trifluoroethylene) pentan-2-amine

A solution of (2S) -1- ((tert-butyl (dimethyl) silyl) oxy) -4, 4-difluoropentane-2-amine from step 5 with trifluoroacetaldehyde-methanol (80%, 0.9mL) in benzene (20mL) was refluxed overnight using a Dean-Strak apparatus. The solvent was removed in vacuo and the residue was purified by chromatography on silica gel using ethyl acetate and hexane to give (2S) -1- ((tert-butyl (dimethyl) silyl) oxy) -4, 4-difluoro-N- ((1E) -2, 2, 2-trifluoroethylene) pentan-2-amine.

And 7: (2S) -2- (((1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl) amino) -4, 4-difluoropentan-1- Preparation of alcohols

To a solution of 1, 4-dibromobenzene (330mg) in THF (5.2mL) at-78 deg.C was added a solution of 2.5Mn-BuLi in hexane (0.52 mL). Then, a solution of (2S) -1- ((tert-butyl (dimethyl) silyl) oxy) -4, 4-difluoro-N- ((1E) -2, 2, 2-trifluoroethylene) pentan-2-amine (333mg) in THF (5.2mL) was added thereto. The mixture was stirred at-78 ℃ for 45 minutes, then poured into cold saturated ammonium chloride, extracted with ethyl acetate (2 ×), washed with brine, dried over magnesium sulfate, filtered and the solvent evaporated in vacuo. The residue was dissolved in THF (10mL) cooled in an ice/water bath and tetra-n-butylammonium fluoride (1M in THF, 1.5mL) was added thereto. The mixture was stirred at 0 ℃ for 1 hour, poured onto cold water, extracted with ethyl acetate (2 ×), washed with brine, dried over magnesium sulfate, filtered and the solvent evaporated in vacuo to give (2S) -2- (((1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl) amino) -4, 4-difluoropentan-1-ol.

And 8: n is a radical of ² - [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl radical ]-N ¹ - (1-cyanocyclopropyl) -4, 4- Preparation of difluoro-L-norvalinamide

(2S) -2- ((1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl) amino) -4, 4-difluoropentan-1-ol was converted to the title compound by the method described in example 15, step 9.

And step 9: n is a radical of ¹ - (1-cyanocyclopropyl) -4, 4-difluoro-N ² - { (1S) -2, 2, 2-trifluoro-1- [ 4' - (methylthio) methane 1, 1' -Biphenyl-4-yl]Preparation of ethyl } -L-norvalinamide

N is reacted using the procedure described in step 10 of example 15²- [ (IS) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl)]-N¹- (1-cyanocyclopropyl) -4, 4-difluoro-L-norvalinamide was converted to the title compound.

Step 10: n is a radical of ¹ - (1-cyanocyclopropyl) -4, 4-difluoro-N ² - { (1S) -2, 2, 2-trifluoro-1- [ 4' - (methylsulfonyl) Acyl) -1, 1' -biphenyl-4-yl]Preparation of ethyl } -L-norvalinamide

N is reacted by the method described in step 11 of example 15¹- (1-cyanocyclopropyl) -4, 4-difluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylthio) -1, 1' -biphenyl-4-yl]Ethyl } -L-norvalinamide was converted to the title compound.

The following compounds were synthesized using experimental methods similar to those listed above.

Name (R)	Characterization of features
		N1- (cyanomethyl) -N' 2, 2, 2-trifluoro-1-phenylethyl) -L-leucinamide	MS(+ESI)：328.3[M+1]
N1- (cyanomethyl) -N- [2, 2, 2-trifluoro-1- (4-fluoro-3-methylphenyl) ethyl]-L-leucinamide	MS(+ESI)：360.2[M+1]
		N1- (cyanomethyl) -N- [ (1R) -2, 2, 2-trifluoro-1- (4-pyridin-3-ylphenyl) ethyl]-L-leucinamide	MS(+ESI)：405.1[M+1]
N1- (cyanomethyl) -N- [ (1S) -2, 2, 2-trifluoro-1- (4-pyridin-3-ylphenyl) ethyl]-L-leucinamide	MS(+ESI)：405.1[M+1]
		N1- (cyanomethyl) -N- [ (1R) -2, 2, 2-trifluoro-1- (4-pyridin-4-ylphenyl) ethyl]-L-leucinamide	MS(+ESI)：405.1[M+1]
N1- (cyanomethyl) -N- [ (1S) -2, 2, 2-trifluoro-1- (4-pyridin-4-ylphenyl) ethyl]-L-leucinamide	MS(+ESI)：405.1[M+1]
		N1- (cyanomethyl) -N- [ (1R) -2, 2, 2-trifluoro-1- (4- { [4- (2-fluoroethyl) piperazin-1-yl]Carbonyl } phenyl) ethyl]-L-leucinamide	MS(+ESI)：486.3[M+1]
N1- (cyanomethyl) -N- [2, 2, 2-trifluoro-1- (4- { [4- (2-fluoroethyl) piperazin-1-yl group]Carbonyl } phenyl) ethyl]-L-leucinamide	MS(+ESI)：486.2[M+1]
		N- [1- (1, 1' -Biphenyl-4-yl) -2, 2, 2-trifluoroethyl group]-N1- (cyanomethyl) -L-leucinamide	MS(+ESI)：404.2[M+1]
N1- (cyanomethyl) -N- {2, 2, 2-trifluoro-1- [4- (3-hydroxy-3-methylbut-1-ynyl) phenyl]Ethyl-L-leucinamide	MS(+ESI)：410.2[M+1]

N1- (cyanomethyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4- (3-hydroxy-3-methylbutyl) phenyl]Ethyl-L-leucinamide	MS(+ESI)：436.2[M+Na]，414.2[M+1]
		N- [ (1S) -1- (4-bromophenyl) -2, 2, 3, 3, 3-pentafluoropropyl radical]-N1- (cyanomethyl) -L-leucinamide	MS(+ESI)：458.1，456.1[M+1]
N1- (cyanomethyl) -N- [ (1S) -2, 2, 3, 3, 3-pentafluoro-1- (4-pyridin-4-ylphenyl) propyl]-L-leucinamide	MS(+ESI)：455.2[M+1]
		N1- (cyanomethyl) -N- [ (1S) -2, 2, 2-trifluoro-1- (4 '-fluoro-1, 1' -biphenyl-4-yl) ethyl]-L-leucinamide	MS(+ESI)：422.2[M+1]
N1- (cyanomethyl) -N- ((1S) -2, 2, 2-trifluoro-1- {4- [ (1E) -3-hydroxy-3-methylbut-1-enyl)]Phenyl } ethyl) -L-leucinamide	MS(+ESI)：434.1[M+Na]
		N1- (cyanomethyl) -N- { (1S) -2, 2, 3, 3, 3-Pentafluoro-1- [4 '- (methylthio) -1, 1' -Biphenyl-4-yl]Propyl } -L-leucinamide	MS(+ESI)：500.1[M+Na]
N1- (cyanomethyl) -N-{(1S)-2，2，33, 3-Pentafluoro-1- [4 '- (methylsulfonyl) -1, 1' -Biphenyl-4-yl]Propyl } -L-leucinamide	MS(+ESI)：532.1[M+Na]
		N1- (cyanomethyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4- (1-oxidopyridin-3-yl) phenyl]Ethyl-L-leucinamide	MS(+ESI)：421.2[M+Na]
N1- (cyanomethyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4- (morpholin-4-ylcarbonyl) phenyl]Ethyl-L-leucinamide	MS(+ESI)：441.3[M+1]
		N1- (cyanomethyl) -N- [ (1S) -2, 2, 2-trifluoro-1- (4- { [ methoxy (methyl) amino group]Carbonyl } phenyl) ethyl]-L-leucinamide	MS(+ESI)：415.1[M+1]

N1- (cyanomethyl) -N- [ (1S) -2, 2, 2-trifluoro-1- (4-thiophen-3-ylphenyl) ethyl]-L-leucinamide	MS(-ESI)：388.3[M-21]
		N1- (cyanomethyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4- (4-methylpyridin-2-yl) phenyl]Ethyl-L-leucinamide	MS(-ESI)：397.2[M-21]
N1- (cyanomethyl) -N - { (1S) -2, 2, 2-trifluoro-1- [4- (5-methylpyridin-2-yl) phenyl]Ethyl-L-leucinamide	MS(-ESI)：397.4[M-21]
		N1- (cyanomethyl) -N- { (1S) -1- [4- (3, 5-Dimethylisoxazol-4-yl) phenyl]-2, 2, 2-trifluoroethyl } -L-leucinamide	MS(-ESI)：401.4[M-21]
N- [ (1S) -1- (4 '-cyano-1, 1' -biphenyl-4-yl) -2, 2, 2-trifluoroethyl radical]-N1- (cyanomethyl) -L-leucinamide	MS(-ESI)：407.4[M-21]
		N1- (cyanomethyl) -N- [ (1S) -1- (3 ', 4 ' -difluoro-1, 1 ' -biphenyl-4-yl) -2, 2, 2-trifluoroethyl radical]-L-leucinamide	MS(-ESI)：418.4[M-21]
4' - {1- [1- (cyanomethyl-carbamoyl) -3-methyl-butylamino]-2, 2, 2-trifluoro-ethyl } -biphenyl-2-carboxylic acid methyl ester	MS(-ESI)：440.5[M-21]
		4′-{1-[1- (cyanomethyl-carbamoyl) -3-methyl-butylamino]-2, 2, 2-trifluoro-ethyl } -biphenyl-3-carboxylic acid methyl ester	MS(-ESI)：440.4[M-21]
N1- (cyanomethyl) -N- [ (1S) -1- (3 ', 4 ' -dimethoxy-1, 1 ' -biphenyl-4-yl) -2, 2, 2-trifluoroethyl radical]-L-leucinamide	MS(-ESI)：442.5[M-21]
		N1- (cyanomethyl) -N- { (1S) -2, 2, 2-trifluoro-1- [2 '- (trifluoromethyl) -1, 1' -biphenyl-4-yl]Ethyl-L-leucinamide	MS(-ESI)：450.4[M-21]
N1- (cyanomethyl) -N- [ (1S) -1- (3 ', 4 ' -dichloro-1, 1 ' -biphenyl-4-yl) -2, 2, 2-trifluoro-l	MS(-ESI)：450.4[M-21]

Ethyl radical]-L-leucinamide
		N1- (cyanomethyl) -N- [ (1S) -2, 2, 2-trifluoro-1- (3' -methyl)Acyl-1, 1' -biphenyl-4-yl) ethyl ]-L-leucinamide	MS.(-ESI)：410.2[M-21]
N- { (1S) -1- [4- (5-Bromopyridin-3-yl) phenyl]-2, 2, 2-trifluoroethyl } -N1- (cyanomethyl) -L-leucinamide	MS(-ESI)：461.4[M-21]
		N1- (cyanomethyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4 '- (trifluoromethoxy) -1, 1' -biphenyl-4-yl]Ethyl-L-leucinamide	MS(-ESI)：466.4[M-21]
N1- (cyanomethyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4- (1H-indol-4-yl) phenyl]Ethyl-L-leucinamide	MS(-ESI)：421.5[M-21]
		N1- (cyanomethyl) -N- [ (1S) -2, 2, 2-trifluoro-1- (4-pyrimidin-5-ylphenyl) ethyl]-L-leucinamide	MS(-ESI)：384.4[M-21]
N1- (cyanomethyl) -N- { (1S) -2, 2, 2-trifluoro-1- (4-quinolin-3-ylphenyl) ethyl } -L-leucinamide	MS(-ESI)：433.5[M-21]
		4' - {1- [1- (cyanomethyl-carbamoyl) -3-methyl-butylamino]-2, 2, 2-trifluoro-ethyl } -biphenyl-4-carboxylic acid methyl ester	MS(-ESI)：440.4[M-21]
N1- (cyanomethyl) -N- [ (1S) -2, 2, 2-trifluoro-1- (4-pyrimidin-2-ylphenyl) ethyl]-L-leucinamide	MS(-ESI)：384.4[M-21]
		N1- (cyanomethyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4- (3-furyl) phenyl]Ethyl-L-leucinamide	MS(-ESI)：372.4[M-21]
N1- (cyanomethyl) -N- ((1S) -2, 2, 2-trifluoro-1-4- [3- (trifluoromethyl) pyridin-2-yl)]Phenyl) ethyl) -L-leucinamide	MS(-ESI)：451.4[M-21]

N1- (cyanomethyl) -N- { (1S) -2, 2, 2-trifluoro-1- {4- [4- (trifluoromethyl) pyridin-2-yl]Phenyl } ethyl } -L-leucinamide	MS(-ESI)：451.4[M-21]
		N1- (cyanomethyl) -N- { (1S) -2, 2, 2-trifluoro-1- {4 - [5- (trifluoromethyl) pyridin-2-yl]Phenyl } ethyl } -L-leucinamide	MS(-ESI)：451.4[M-21]
N1- (cyanomethyl) -N- { (1S) -2, 2, 2-trifluoro-1- (3 '-methoxy-1, 1' -biphenyl-4-yl) ethyl } -L-leucinamide	MS(-ESI)：412.4[M-21]
		N- { (1S) -1- [4 ' - (acetylamino) -3 ' -fluoro-1, 1 ' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -N1- (cyanomethyl) -L-leucinamide	MS(-ESI)：457.4[M-21]
N1- (cyanomethyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4- (3-methylthiophen-2-yl) phenyl]Ethyl-L-leucinamide	MS(-ESI)：402.4[M-21]
		N1- (cyanomethyl) -N- { (1S) -2, 2, 2-trifluoro-1- (3 '-fluoro-1, 1' -biphenyl-4-yl) ethyl } -L-leucinamide	MS(-ESI)：400.4[M-21]
N- { (1S) -1- [4- (5-acetylthiophen-2-yl) phenyl]-2, 2, 2-trifluoroethyl } -N1- (cyanomethyl) -L-leucinamide	MS(-ESI)：430.4[M-21]
		N- [ (1S) -1- (3 '-acetyl-1, 1' -biphenyl-4-)Yl) -2, 2, 2-trifluoroethyl]-N1- (cyanomethyl) -L-leucinamide	MS(-ESI)：424.4[M-21]
N1- (cyanomethyl) -N- { (1S) -2, 2, 2-trifluoro-1- [3 '- (trifluoromethyl) -1, 1' -biphenyl-4-yl]Ethyl-L-leucinamide	MS(-ESI)：450.4[M-21]
		N1- (cyanomethyl) -N- { (1S) -2, 2, 2-trifluoro-1- (5 ' -fluoro-2 ' -methoxy-1, 1 ' -biphenyl-4-yl) ethyl } -L-leucinamide	MS(-ESI)：430.4[M-21]
N1- (cyanomethyl) -N- [ (1S) -1- (3 ', 5 ' -difluoro-1, 1 ' -biphenyl-4-yl) -2, 2, 2-trifluoro-l	MS(-ESI)：418.4[M-21]

Ethyl radical]-L-leucinamide
		N1- (cyanomethyl) -N- { (1S) -2, 2, 2-trifluoro-1- (2 ', 3', 5 '-trifluoro-1, 1' -biphenyl-4-yl) ethyl } -L-leucinamide	MS(-ESI)：436.4[M-21]
3- (4' - {1- [1- (cyanomethyl-carbamoyl) -3-methyl-butylamino]-2, 2, 2-trifluoro-ethyl } -biphenyl-3-yl) acrylic acid	MS(-ESI)：452.5[M-21]
		N- { (1S) -1- [4- (9-anthracenyl) phenyl]-2, 2, 2-trifluoroethyl } -N1- (cyanomethyl) -L-leucinamide	MS(-ESI)：482.5[M-21]
N- [ (1S) -1- (4 '-benzoyl-1, 1' -biphenyl-4-yl) -2, 2, 2-trifluoroethyl radical]-N1- (cyanomethyl) -L-leucinamide	MS(-ESI)：486.5[M-21]
		N- [ (1S) -1- (3 ' -acetyl-4 ' -hydroxy-1, 1 ' -biphenyl-4-yl) -2, 2, 2-trifluoroethyl radical]-N1- (cyanomethyl) -L-leucinamide	MS(-ESI)：440.5[M-21]
N1- (cyanomethyl) -N- { (1S) -1- [2 '- (cyanomethyl) -1, 1' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -L-leucinamide	MS(-ESI)：421.4[M-21]
		N1- (cyanomethyl) -N- {2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl radical} -L-leucinamide	MS(+APCI)：482.2[M+1]
N1- (cyanomethyl) -N- {2, 2, 2-trifluoro-1- [4 '- (methylsulfinyl) -1, 1' -biphenyl-4-yl]Ethyl-L-leucinamide	MS(+APCI)：466.1[M+1]
		N1- (cyanomethyl) -N- [2, 2, 2-trifluoro-1- (4-morpholin-4-ylphenyl) ethyl]-L-leucinamide	MS(+ESI)：413.2[M+1]
N1- (cyanomethyl) -N- { (1R) -2, 2, 2-trifluoro-1- [4- (6-methylpyridin-3-yl) phenyl ]Ethyl-L-leucinamide	MS(+APCI)：419.2[M+1]

N1- (cyanomethyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4- (6-methylpyridin-3-yl) phenyl]Ethyl-L-leucinamide	MS(+APCI)：419.0[M+1]
		N1- (cyanomethyl) -N- [2, 2, 2-trifluoro-1- (5-phenylthiophen-2-yl) ethyl]-L-leucinamide	MS(+ESI)：409.4[M+1]
N1- (cyanomethyl) -N- [2, 2, 2-trifluoro-1- (4-quinolin-8-ylphenyl) ethyl]-L-leucinamide	MS(+ESI)：419.0[M+1]
		N1- (cyanomethyl) -N- [ (1S) -2, 2, 2-trifluoro-1- (4-pyridin-2-ylphenyl) ethyl]-L-leucinamide	MS(+ESI)：455.2[M+1]
N- {1- [4 '- (aminosulfonyl) -1, 1' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -N1- (cyanomethyl) -L-leucinamide	MS(+ESI)：483.2[M+1]
		N- { (1S) -1- [4 '- (aminosulfonyl) -1, 1' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -N1- (cyanomethyl) -L-leucinamide	MS(+ESI)：483.2[M+1]
N1- (cyanomethyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl-L-leucinamide	MS(+ESI)：482.3[M+1]
		N1- (cyanomethyl) -N- { (1S) -2, 2, 2-trifluoro-1- [ 4' - (methylen)Thio) -1, 1' -biphenyl-4-yl]Ethyl-L-leucinamide	MS(+ESI)：450.2[M+1]
N- [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl radical]-N1- (cyanomethyl) -L-leucinamide	MS(+ESI)：407.2/408.2[M+1]/[M+2]
		N1- (cyanomethyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4 '- (morpholin-4-ylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl-L-leucinamide	MS(+ESI)：553.2[M+1]

N1- (cyanomethyl) -N - { (1S) -2, 2, 2-trifluoro-1- [4 '- (isopropylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl-L-leucinamide	MS(+APCI)：510.3[M+1]
		N- { (1S) -1- [4 '- (aminosulfonyl) -1, 1' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -N1- (cyanomethyl) -L-leucinamide	MS(+ESI)：483.2[M+1]
N- ((1S) -1- { 4' - [ (acetylamino) sulfonyl group]-1, 1' -biphenyl-4-yl } -2, 2, 2-trifluoroethyl) -N1- (cyanomethyl) -L-leucinamide	MS(+APCI)：525.4[M+1]
		N1- (cyanomethyl) -N- { (1S) -2, 2, 2-trifluoro-1- [2 ' -methyl-4 ' - (methylsulfonyl) -1, 1 ' -biphenyl-4-yl]Ethyl-L-leucinamide	MS(+ESI)：496.2[M+1]
N- [1- (5-bromothien-2-yl) -2, 2, 2-trifluoroethyl group]-N1- (cyanomethyl) -L-leucinamide	MS(+ESI)：413.2[M+1]
		N- [1- (4-bromophenyl) -2, 2, 2-trifluoroethyl group]-N1- (cyanomethyl) -L-leucinamide	MS(-ESI)：403.9，405.9[M+1]
4- (4' - {1- [1- (cyanomethyl-carbamoyl) -3-methyl-butylamino]-2, 2, 2-trifluoro-ethyl } -biphenyl-4-yl) -piperazine-1-carboxylic acid tert-butyl ester	MS(+ESI)：588.2[M+1]
		N1- (cyanomethyl) -N- [2, 2, 2-trifluoro-1- (4 '-piperazin-1-yl-1, 1' -biphenyl-4-yl) ethyl]-L-leucinamide	MS(+ESI)：488.3[M+1]
N1- (cyanomethyl) -N- (2, 2, 2-trifluoro-1- { 4' - [4- (2-hydroxyethyl) piperazin-1-yl]-1, 1' -biphenyl-4-yl } ethyl) -L-leucinamide	MS(+APCI)：532.3[M+1]
		N1- (cyanomethyl) -N- (2, 2, 2-trifluoro-1- { 4' -4- (2-hydroxy-2-methylpropyl) piperazine-	MS(+APCI)：559.9[M+1]

1-yl } -1, 1' -biphenyl-4-yl } ethyl) -L-leucinamide
		N1- (cyanomethyl) -N- (1- {4- [ (dimethylamino) carbonyl group]Phenyl } -2, 2, 2-trifluoroethyl) -L-leucinamide	MS(+ESI)：399.2[M+1]
N1- (cyanomethyl) -N- (1- {4- [ (cyclopropylamino) carbonyl]Phenyl } -2, 2, 2-trifluoroethyl) -L-leucinamide	MS(+ESI)：411.2[M+1]
		4- {1- [1- (cyanogen)Ylmethyl-carbamoyl) -3-methyl-butylamino]-2, 2, 2-trifluoro-ethyl } benzoic acid	MS(-ESI)：370.2[M-1]
N1- (cyanomethyl) -N- (2, 2, 2-trifluoro-1- { 4' - [4- (2-fluoroethyl) piperazin-1-yl]-1, 1' -biphenyl-4-yl } ethyl) -L-leucinamide	MS(+ESI)：534.3[M+1]
		N1- (cyanomethyl) -N- (2, 2, 2-trifluoro-1- {4- [ (4-methylpiperazin-1-yl) carbonyl]Phenyl } ethyl) -L-leucinamide	MS(+ESI)：454.3[M+1]
N1- (cyanomethyl) -N- [2, 2, 2-trifluoro-1- (4- { [4- (2-hydroxy-2-methylpropyl) piperazin-1-yl group]Carbonyl } phenyl) ethyl]-L-leucinamide	MS(+ESI)：512.3[M+1]
		N1- (cyanomethyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4- (2-methyl-1, 3-thiazol-4-yl) phenyl]Ethyl-L-leucinamide	MS(+ESI)：425.1[M+1]
N- {1- [4- (3-tert-butyl-1, 2, 4-triazin-5-yl) phenyl]-2, 2, 2-trifluoroethyl } -N1- (cyanomethyl) -L-leucinamide	MS(+ESI)：463.2[M+1]
		N1- (cyano radicals)Methyl) -N- [2, 2, 2-trifluoro-1- (4- {2- [3- (methylsulfonyl) phenyl group]-1, 3-thiazol-4-yl } phenyl) ethyl]-L-leucinamide	MS(+ESI)：565.1[M+1]

N1- (cyanomethyl) -N- ((1S) -2, 2, 2-trifluoro-1- {4- [2- (1H-pyrazol-4-yl) -1, 3-thiazol-4-yl)]Phenyl } ethyl) -L-leucinamide	MS(+ESI)：477.1[M+1]
		N1- (cyanomethyl) -N- (2, 2, 2-trifluoro-1- { 4' - [4- (methylsulfonyl) piperazin-1-yl]-1, 1' -biphenyl-4-yl } ethyl) -L-leucinamide	MS(+ESI)：566.3[M+1]
N- [1- (3-bromophenyl) -2, 2, 2-trifluoroethyl group]-N1- (cyanomethyl) -L-leucinamide	MS(+ESI)：406.0，408.1[M+1]
		N1- (cyanomethyl) -N- {2, 2, 2-trifluoro-1- [4 '- (methylthio) -1, 1' -biphenyl-3-yl]Ethyl-L-leucinamide	MS(+ESI)：450.1[M+1]
N1- (cyanomethyl) -N- [2, 2, 2-trifluoro-1- (3-pyridin-4-ylphenyl) ethyl]-L-leucinamide	MS(+ESI)：405.1[M+1]
		N1- (cyanomethyl) -N- [2, 2, 2-trifluoro-1- (4 '-piperazin-1-yl-1, 1' -biphenyl-3-yl) ethyl]-L-leucinamide	MS(+ESI)：488.3[M+1]
N1- (cyanomethyl) -N- {2, 2, 2-trifluoro-1- (4 '- (methylsulfonyl) -1, 1' -biphenyl-3-yl) ethyl } -L-leucinamide	MS(+ESI)：482.2[M+1]
		N- (cyanomethyl) -1- [ (2, 2, 2-trifluoro-1-phenylethyl) amino]Cyclohexanecarboxamide	MS(-ESI)：337[M-1]
1- { [1- (4-bromophenyl) -2, 2, 2-trifluoroethyl group]Amino } -N- (cyanomethyl) cyclohexanecarboxamide	MS(+ESI)：418，420[M+1]
		N- (cyanomethyl) -1- { [2, 2, 2-trifluoro-1- (4 '-piperazin-1-yl-1, 1' -biphenyl-4-yl) ethyl]Amino-cyclohexanecarboxamides	MS(+ESI)：500[M+1]
N1- (cyanomethyl) -N-[2，2，2-trifluoro-1- (4-piperidin-4-ylphenyl) ethyl ]-L-leucine	MS(+ESI)：411[M+1]

Amides of carboxylic acids
		N1- (cyanomethyl) -N- {2, 2, 2-trifluoro-1- [4- (4-pyridin-2-ylpiperazin-1-yl)]Phenyl radical]Ethyl-L-leucinamide	MS(+ESI)：489[M+1]
N- [1- (4-bromophenyl) -2, 2, 2-trifluoroethyl group]-N1- (cyanomethyl) -3-cyclopropylalaninamide	MS(+ESI)：404，406[[M+1]
		N1- (cyanomethyl) -3-cyclopropyl-N- [2, 2, 2-trifluoro-1- (4-pyridin-4-ylphenyl) ethyl]Alanine amides	MS(+ESI)：403[M+1]
N1- (cyanomethyl) -N- [2, 2, 2-trifluoro-1- (4 '-pyridin-4-yl-1, 1' -biphenyl-4-yl) ethyl]-L-leucinamide	MS(+ESI)：481[M+1]
		N1- (cyanomethyl) -N- [ (1R) -2, 2, 2-trifluoro-1- (1, 3-thiazol-2-yl) ethyl]-L-leucinamide	MS(+ESI)：335[M+1]
N1- (cyanomethyl) -N- [ (1S) -2, 2, 2-trifluoro-1- (4 '-methoxy-1, 1' -biphenyl-4-yl) ethyl]-L-leucinamide	MS(+ESI)：434[M+1]
		N1- (cyanomethyl) -N- [ (1S) -2, 2, 2-trifluoro-1- (4-methoxyphenyl) ethyl]-L-leucinamide	MS(+ESI)：358[M+1]
N1- (cyanomethyl) -N- [ (1S) -2, 2, 2-trifluoro-1- (4 '-pyridin-4-yl-1, 1' -biphenyl-4-yl) ethyl]-L-leucinamide	MS(+ESI)：481[M+1]
		N1- (cyanomethyl) -N- [ (1S) -2, 2, 2-trifluoro-1- (4-phenoxyphenyl) ethyl]-L-leucinamide	MS(+ESI)：420[M+1]
N- [ (1S) -1- (4 '-bromo-1, 1' -biphenyl-4-yl) -2, 2, 2-trifluoroethyl radical]-N' - (cyanomethyl) -L-leucinamide	MS(+ESI)：482，484[M+1]

N- { (1S) -1- [4- (4-Chloropyridin-3-yl) phenyl]-2, 2, 2-trifluoroethyl } -N 1- (cyanomethyl) -L-leucinamide	MS(+ESI)：439[M+1]
		N- { (1S) -1- [4 ' - (acetylamino) -2 ' -methyl-1, 1 ' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -N1- (cyanomethyl) -L-leucinamide	MS(+ESI)：475[M+1]
N- [ (1S) -1- (1, 1' -biphenyl-4-yl) -2, 2, 2-trifluoroethyl radical]-N1- (cyanomethyl) -L-leucinamide	MS(+ESI)：404[M+1]
		N1- (cyanomethyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4- (6-methoxypyridin-3-yl) phenyl]Ethyl-L-leucinamide	MS(+ESI)：435[M+1]
N1- (cyanomethyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4- (6-methoxypyridin-2-yl) phenyl]Ethyl-L-leucinamide	MS(+ESI)：435[M+1]
		N1- (cyanomethyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4 "- (methylsulfonyl) -1, 1': 4 ', 1' -terphenyl-4-yl]Ethyl-L-leucinamide	MS(+ESI)：558[M+1]
N- [1- (4-bromophenyl) -2, 2, 2-trifluoroethyl group]-N1- (cyanomethyl) -3- (1-methylcyclopropyl) alaninamide	MS(+ESI)：418，420[M+1]
		N1- (cyanomethyl) -3- (1-methylcyclopropyl) -N- {2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl alaninamide	MS(+ESI)：494[M+1]
N1- (cyanomethyl) -3- (1-methylcyclopropyl) -N- {2, 2, 2-trifluoro-1- [4 '- (methylthio) -1, 1' -biphenyl-4-yl]Ethyl alaninamide	MS(+ESI)：462[M+1]

N1- (cyanomethyl) -N- [ (1S) -2, 2, 2-trifluoro-1- (4 '-methyl-1, 1' -biphenyl-4-yl)) Ethyl radical]-L-leucinamide	MS(+ESI)：418[M+1]
		N- [ (1S) -1- (4 '-acetyl-1, 1' -biphenyl-4-yl) -2, 2, 2-trifluoroethyl radical ]-N1- (cyanomethyl) -L-leucinamide	MS(+ESI)：446[M+1]
N1- (cyanomethyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4 '- (hydroxymethyl) -1, 1' -biphenyl-4-yl]Ethyl-L-leucinamide	MS(+ESI)：434[M+1]
		N1- (cyanomethyl) -N- { (1R) -2, 2, 2-trifluoro-1- [4- (1-oxidopyridin-4-yl) phenyl]Ethyl-L-leucinamide	MS(+ESI)：421.4[M+1]
N1- (cyanomethyl) -N- {2, 2, 2-trifluoro-1- [4- (1-oxidopyridin-4-yl) phenyl]Ethyl-L-leucinamide	MS(+ESI)：421.4[M+1]
		N1- (cyanomethyl) -N- (2, 2, 2-trifluoro-1- {4- [6- (1-hydroxy-1-methylethyl) -1-oxidopyridin-3-yl)]Phenyl } ethyl) -L-leucinamide	MS(+ESI)：479.3[M+1]
N1- (cyanomethyl) -N-(2，2，2-trifluoro-1- {4- [6- (methylsulfonyl) pyridin-3-yl]Phenyl } ethyl) -L-leucinamide	MS(+ESI)：483.2[M+1]
		N1- (cyanomethyl) -N- (2, 2, 2-trifluoro-1- {4- [2- (4-methylpiperazin-1-yl) -1, 3-thiazol-4-yl)]Phenyl } ethyl) -L-leucinamide	MS(+ESI)：509.2[M+1]
N- [1- (4-bromophenyl) -2, 2, 2-trifluoroethyl group]-N1- (1-cyanocyclopropyl) -L-leucinamide	MS(+ESI)：434.2[M+1]，MS(+ESI)：432.0[M+1]
		N1- (cyanomethyl) -N- [2, 2, 2-trifluoro-1- (4-piperazin-1-ylphenyl) ethyl]-L-leucinamide	MS(+ESI)：412.2[M+1]

N- {1- [3 '- (acetylamino) -1, 1' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -N1- (cyanomethyl) -L-leucinamide	MS(+ESI)：461.2[M+1]
		N1- (cyanomethyl) -N- {2, 2, 2-trifluoro-1- [4- (4-propylpiperazin-1-yl) phenyl]Ethyl-L-leucinamide	MS(+ESI)：454.3[M+1]
N1- (cyanomethyl) -N- {2, 2, 2-trifluoro-1- [4- (piperazin-1-ylcarbonyl) phenyl]Ethyl-L-leucinamide	MS(+ESI)：440.2[M+1]
		N1- (cyanomethyl) -N- [2, 2, 2-trifluoro-1- (4- { [4- (2-hydroxyethyl) piperazin-1-yl group]Carbonyl } phenyl) ethyl]-L-leucinamide	MS(+ESI)：484.3[M+1]
N1- (cyanomethyl) -N- [ (1S) -2, 2, 2-trifluoro-1- (4- {3- [3- (trifluoromethyl) phenyl]-1, 2, 4-oxadiazol-5-yl } phenyl) ethyl]-L-leucinamide	MS(+ESI)：540.1[M+1]
		4- {1- [1- (cyanomethyl-carbamoyl) -3-methyl-butylamino]-2, 2, 2-trifluoro-ethyl } -benzoic acid methyl ester	MS(+ESI)：386.2[M+1]
N1- (cyanomethyl) -N- ((1S) -2, 2, 2-trifluoro-1- {4- [ (E) -2-quinolin-2-ylvinyl)]Phenyl } ethyl) -L-leucinamide	MS(+ESI)：481.3[M+1]
		N1- (cyanomethyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4- (3-methyl-1, 2, 4-oxadiazol-5-yl) phenyl]Ethyl-L-leucinamide	MS(+ESI)：553.3[M+1]
N- ((1S) -1- {4- [3- (5-bromopyridin-3-yl) -1, 2, 4-oxadiazol-5-yl)]Phenyl } -2, 2, 2-trifluoroethyl) -N1- (cyanomethyl) -L-leucinamide	MS(+ESI)：553.3[M+1]，MS(+ESI)：551.1[M+1]
		N- [ (1S) -1- (4-benzoylphenyl) -2, 2, 2-trifluoroethyl radical]-N1- (cyanomethyl) -L-leucinamide	MS(+ESI)：432.3[M+1]

N1- (cyanomethyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4- (thien-2-ylcarbonyl) phenyl]Ethyl-L-leucinamide	MS(+ESI)：438.3[M+1]
		N1- (cyanomethyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4- (1, 3-thiazol-2-ylcarbonyl) phenyl ]Ethyl-L-leucinamide	MS(+ESI)：439.2[M+1]
N1- (cyanomethyl) -N- [ (1S) -2, 2, 2-trifluoro-1- (4- { (Z) -2- [4- (methylsulfonyl) phenyl]Vinyl } phenyl) ethyl]-L-leucinamide	MS(+ESI)：508.2[M+1]
		N1- (cyanomethyl) -N- [ (1S) -2, 2, 2-trifluoro-1- (4- { (E) -2- [4- (methylsulfonyl) phenyl]Vinyl } phenyl) ethyl]-L-leucinamide	MS(+ESI)：508.2[M+1]
N1- (cyanomethyl) -N- [ (1S) -2, 2, 2-trifluoro-1- (4-isobutyrylphenyl) ethyl]-L-leucinamide	MS(+ESI)：398.2[M+1]
		N- { (1S) -1- [4- (4-bromo-1, 3-thiazol-2-yl) phenyl]-2, 2, 2-trifluoroethyl } -N1- (cyanomethyl) -L-leucinamide	MS(+ESI)：491.1[M+1]，MS(+ESI)：489.0[M+1]
N1- (cyanomethyl) -N- [ (1S) -1- (4-cyanophenyl) -2, 2, 2-trifluoroethyl radical]-L-leucinamide	MS(+ESI)：353.2[M+1]
		N1- (cyanomethyl) -N- [ (1S) -1- (4-ethynylphenyl) -2, 2, 2-trifluoroethyl radical]-L-leucinamide	MS(+ESI)：352.1[M+1]
N1- (cyanomethyl) -N- [ (1S) -2, 2, 2-trifluoro-1- (2 '-fluoro-1, 1' -biphenyl-4-yl) ethyl]-L-leucinamide	MS(+ESI)：422.3[M+1]
		N1- (cyanomethyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4- (1, 3-thiazol-2-yl) phenyl]Ethyl-L-leucinamide	MS(+ESI)：411.1[M+1]

N1- (cyanomethyl) -N- {2, 2, 2-trifluoro-1- [4 '- (methylthio) -1, 1' -biphenyl-4-yl]Ethyl-L-leucinamide	MS(+ESI)：450.2[M+1]
		N1- (cyanomethyl) -N- {2, 2, 2-trifluoro-1- [4- (2-methylquinolin-7-yl) phenyl]Ethyl-L-leucinamide	MS(+ESI)：469.2[M+1]
N1- (cyanomethyl) -N - {2, 2, 2-trifluoro-1- [4-(1H-indol-5-yl) phenyl]Ethyl-L-leucinamide	MS(+ESI)：443.2[M+1]
		N1- (cyanomethyl) -N- {1- [4 '- (dimethylamino) -1, 1' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -L-leucinamide	MS(+ESI)：447.2[M+1]
N1- (cyanomethyl) -N- [ (1S) -1- (4- { [ (cyanomethyl) amino]Carbonyl } phenyl) -2, 2, 2-trifluoroethyl]-L-leucinamide	MS(+APCI)：410.2[M+1]
		N1- (cyanomethyl) -N- [ (1R) -1- (4- { [ (cyanomethyl) amino]Carbonyl } phenyl) -2, 2, 2-trifluoroethyl]-L-leucinamide	MS(+APCI)：410.2[M+1]
N1- (cyanomethyl) -N- {2, 2, 2-trifluoro-1- [3 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl-L-leucinamide	MS(+APCI)：482.1[M+1]
		4' - {1- [1- (cyanomethyl-carbamoyl) -3-methyl-butylamino]-2, 2, 2-trifluoro-ethyl } -biphenyl-4-carboxylic acid	MS(+APCI)：448.0[M+1]
4' - {1- [1- (cyanomethyl-carbamoyl) -3-methyl-butylamino]-2, 2, 2-trifluoro-ethyl } -biphenyl-4-carboxylic acid methoxy groupMethyl-amides	MS(+APCI)：491.2[M+1]
		N1- (cyanomethyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4- ({ [4- (methylsulfonyl) benzyl)]Thio } methyl) phenyl]Ethyl-L-leucinamide	MS(+APCI)：542.3[M+1]

N- { (1S) -1- [4- (5-Chloropyridin-2-yl) phenyl]-2, 2, 2-trifluoroethyl } -N1- (cyanomethyl) -L-leucinamide	MS(+APCI)：439.1[M+1]
		N- { (1S) -1- [3- (aminosulfonyl) -4 '-bromo-1, 1' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -N 1- (cyanomethyl) -L-leucinamide	MS (+ APCI): 561.1 and 563.1[ M +1 ]]
N- { (1S) -1- [4 ' -bromo-3 ' - (methylsulfonyl) -1, 1 ' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -N1- (cyanomethyl) -L-leucinamide	MS (+ APCI): 560.1 and 562.1[ M +1 ]]
		N1- (cyanomethyl) -N- ((1S) -2, 2, 2-trifluoro-1- {4- [ 5-methyl-6- (methylsulfonyl) pyridin-3-yl)]Phenyl } ethyl) -L-leucinamide	MS(+ESII)：497.2[M+1]
N- [ (1S) -1- (4- { 5-chloro-3- [4- (methylsulfonyl) phenyl]Pyridin-2-yl } phenyl) -2, 2, 2-trifluoroethyl]-N1- (cyanomethyl) -L-leucinamide	MS(+ESI)：593.2[M+1]
		N1- (cyanomethyl) -N- ((1S) -2, 2, 2-trifluoro-1- {4- [ (phenylthio) methyl group]Phenyl } ethyl) -L-leucinamide	MS(+APCI)：450.0[M+1]
N1- (cyanomethyl) -N- ((1S) -2, 2, 2-trifluoro-1- { 4' - [ (trifluoromethyl) sulfonyl group]-1, 1' -biphenyl-4-yl } ethyl) -L-leucinamide	MS(+APCI)：536.1[M+1]
		N1- (cyanomethyl) -N- [ (1S) -2, 2, 2-trifluoro-1- (4- { [ (4-fluorobenzoyl) amino]Methyl } phenyl) ethyl]-L-leucinamide	MS(+APCI)：479.1[M+1]
N1- (cyanomethyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4- (methylsulfonyl) phenyl]Ethyl-L-leucinamide	MS(+APCI)：406.1[M+1]

N1- (1-cyanocyclopropyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl-L-leucinamide	MS(+APCI)：508.2[M+1]
		N1- (cyanomethyl) -N- { (1S) -1- [4 '- (ethylsulfonyl) -1, 1' -biphenyl-4-yl ]-2, 2, 2-trifluoroethyl } -L-leucinamide	MS(+ARCI)：496.1[M+1]
N- ((1S) -1- {4- [ ({ [3- (2-chloro-6-fluorophenyl) -5-methylisoxazol-4-yl)]Carbonyl } amino) methyl]Phenyl } -2, 2, 2-trifluoroethyl) -N1- (cyanomethyl) -L-leucinamide	MS(+APCI)：594.4[M+1]
		N- ((1S) -1- {4- [ (9-chloro-3-methyl-4-oxoisoxazolo [4, 3-c)]Quinolin-5 (4H) -yl) methyl]Phenyl } -2, 2, 2-trifluoroethyl) -N1- (cyanomethyl) -L-leucinamide	MS(+APCI)：574.3[M+1]
N1- (cyanomethyl) -N-{(1S)-2，22-trifluoro-1- [4 ' -methoxy-3 ' - (methylsulfonyl) -1, 1 ' -biphenyl-4-yl]Ethyl-L-leucinamide	MS(+APCI)：512.2[M+1]
		N- { (1S) -1- [4 "-chloro-4 '- (methylsulfonyl) -1, 1': 2 ', 1' -terphenyl-4-yl]-2, 2, 2-trifluoroethyl } -N1- (cyanomethyl) -L-leucinamide	MS(+APCI)：592.2[M+1]
N1- (cyanomethyl) -N- { (1S) -2, 2, 2-trifluoro-1- [2 ' -methoxy-4 ' - (methylsulfonyl) -1, 1 ' -biphenyl-4-yl]Ethyl-L-leucinamide	MS(+APCI)：512.2[M+1]
		N- { (1S) -1- [2 ' -chloro-4 ' - (methylsulfonyl) -1, 1 ' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -N1- (cyanomethyl) -L-leucinamide	MS (+ APCI): 516.3 and 518.2[ M +1 ]]

N1- (cyanomethyl) -N- ((1S) -2, 2, 2-trifluoro-1- { 4' - [ (2-hydroxyethyl) thio)]-1, 1' -biphenyl-4-yl } ethyl) -L-leucinamide	MS(-ESI)：478.1[M-1]
		N1- (cyanomethyl) -N- { (1S) -2, 2, 2-trifluoro-1- [3 ' -fluoro-4 ' - (methylsulfonyl) -1, 1 ' -biphenyl-4-yl ]Ethyl-L-leucinamide	MS(+APCI)：500.1[M+1]
N1- (cyanomethyl) -N- ((1S) -2, 2, 2-trifluoro-1- { 4' - [ (2-hydroxyethyl) sulfonyl]-1, 1' -biphenyl-4-yl } ethyl) -L-leucinamide	MS(+APCI)：512.3[M+1]
		N1- (cyanomethyl) -N- { (1S) -2, 2, 2-trifluoro-1- [3 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl-L-leucinamide	MS(+APCI)：482.1[M+1]
N1- (cyanomethyl) -N- { (1S) -2, 2, 2-trifluoro-1- [ 4' - ({2- [ methoxy (methyl) amino)]-2-oxoethyl } sulfonyl) -1, 1' -biphenyl-4-yl]Ethyl-L-leucinamide	MS(+APCI)：569.3[M+1]
		N1- (cyanomethyl) -N- ((1S) -2, 2, 2-trifluoro-1- { 4' - [ (2-hydroxy-2-methylpropyl) sulfonyl)]-1, 1' -biphenyl-4-yl } ethyl) -L-leucinamide	MS(+APCI)：540.2[M+1]
N- { (1S) -1- [ 4' - (aminosulfonyl) -1, 1-Biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -N1- (1-cyanocyclopropyl) -L-leucinamide	MS(+APCI)：506.2[M+1]
		N- { (4-bromophenyl) [4- (methylsulfonyl) phenyl]Methyl } -N1- (cyanomethyl) -L-leucinamide	MS(+ESI)：492.0，494.0[M+1]
N1- (cyanomethyl) -N- { [4- (methylsulfonyl) phenyl][4 '- (methylthio) -1, 1' -bi-ethyl	MS(-ESI)：534.2[M-1]

Phenyl-4-yl]methyl-L-leucinamide
		N1- (cyanomethyl) -N- { [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl][4- (methylsulfonyl) phenyl group]methyl-L-leucinamide	MS(+ESI)：568.2[M+1]
N1- (1-cyanocyclopropyl) -N- [ (1S) -2, 2, 2-trifluoro-1- (4-methylphenyl) ethyl ]-L-leucinamide	MS(+ESI)：368.4[M+1]
		N1- (1-cyanocyclopropyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4- (1H-pyrazol-3-yl) phenyl]Ethyl-L-leucinamide	MS(+APCI)：420.1[M+1]
N1- (1-cyanocyclopropyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4- (2-methyl-1, 3-oxazol-4-yl) phenyl]Ethyl-L-leucinamide	MS(+ESI)：435.4[M+1]
		N1- (cyanomethyl) -N- [ (1S) -2, 2, 2-trifluoro-1- (4-pyrazin-2-ylphenyl) ethyl]-L-leucinamide	MS(+ESI)：406.2[M+1]
N1- (cyanomethyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4- (2-methylpyridin-4-yl) phenyl]Ethyl-L-leucinamide	MS(+ESI)：419.2[M+1]
		N1- (cyanomethyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4- (4-methylpyridin-3-yl) phenyl]Ethyl-L-leucinamide	MS(+ESI)：419.2[M+1]
N1- (1-cyanocyclopropyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4- (1H-pyrazol-4-yl) phenyl]Ethyl-L-leucinamide	MS(+APCI)：420.1[M+1]
		N1- (1-cyanocyclopropyl) -N- [ (1S) -2, 2, 2-trifluoro-1- (4-pyridin-4-ylphenyl) ethyl]-L-leucinamide	MS(+ESI)：431.1[M+1]
N- [ (1S) -1- (3' -acetyl-1, 1-biphenyl) -4-yl]=2, 2, 2-trifluoroethyl]-N' - (1-cyanocyclopropyl) -L-leucinamide	MS(+ESI)：472.2[M+1]

N1- (1-cyanocyclopropyl) -N- [ (1S) -2, 2, 2-trifluoro-1- (3 ' -fluoro-4 ' -methyl-1, 1 ' -biphenyl-4-yl) ethyl]-L-leucinamide	MS(+ESI)：462.1[M+1]
		N1- (1-cyanocyclopropyl) -N- ((1S) -2, 2, 2-trifluoro-1- {5- [4- (1-hydroxy-1-methylethyl) phenyl]Pyridin-2-yl } ethyl) -L-leucinamide	MS(+ESI)：489.6[M+1]
N1- (cyanomethyl) -N-{(1S)-22, 3, 3, 3-pentafluoro-1- [4 '- (1-hydroxy-1-methylethyl) -1, 1' -biphenyl-4-yl]Propyl } -L-leucinamide	MS(+ESI)：512.2[M+1]
		N1- (1-cyanocyclopropyl) -N- [ (1S) -2, 2, 3, 3, 3-pentafluoro-1- (4 '-methyl-1, 1' -biphenyl-4-yl) propyl]-L-leucinamide	MS(+ESI)：494.1[M+1]
N1- (cyanomethyl) -N- { (1S) -2, 2, 3, 3, 3-Pentafluoro-1- [4- (6-methoxypyridin-3-yl) phenyl]Propyl } -L-leucinamide	MS(+ESI)：485.2[M+1]
		N1- (cyanomethyl) -N- [ (1S) -2, 2, 3, 3, 3-pentafluoro-1- (2 '-fluoro-1, 1' -biphenyl-4-yl) propyl]-L-leucinamide	MS(+ESI)：472.2[M+1]
N1- (1-cyanocyclopropyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4 ' -methoxy-3 ' - (methylsulfonyl) -1, 1 ' -biphenyl-4-yl]Ethyl-L-leucinamide	MS(+ESI)：538.1[M+1]
		N- { (1S) -1- [3 ' - (aminosulfonyl) -4 ' -methoxy-1, 1 ' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -N1- (1-cyanocyclopropyl) -L-leucinamide	MS(+ESI)：539.1[M+1]
N1- (1-cyanocyclopropyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4- (6-methoxypyridin-3-yl) phenyl]Ethyl-L-leucinamide	MS(+APCI)：461.3[M+1]

N1- (cyanomethyl) -N- { (1S) -2, 2, 3, 3, 3-Pentafluoro-1- [4- (5-methylpyridin-2-yl) phenyl]Propyl } -L-leucinamide	MS(+ESI)：469.2[M+1]
		N1- (1-cyanocyclopropyl) -N- ((1S) -2, 2, 2-trifluoro-1- {4- [5- (methylsulfonyl) pyridin-2-yl)]Phenyl } ethyl) -L-leucinamide	MS(+APCI)：509.2[M+1]
N1- (1-cyanocyclopropyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4- (5-methylpyridin-2-yl) phenyl]Ethyl-L-leucinamide	MS(+APCI)：446.1[M+1]
		N1- (cyanomethyl) -4-fluoro-N- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl-L-leucinamide	MS(+ESI)：500.1[M+1]
N1- (1-cyanocyclopropyl) -4-fluoro-N- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl-L-leucinamide	MS(+ESI)：526.1[M+1]
		N1- (1-cyanocyclopropyl) -4-fluoro-N- { (1S) -2, 2, 2-trifluoro-1- [2 ' -methyl-4 ' - (methylsulfonyl) -1, 1 ' -biphenyl-4-yl]Ethyl-L-leucinamide	MS(+ESI)：540.1[M+1]
N1- (1-cyanocyclopropyl) -N- { (1S) -2, 2, 2-trifluoro-1- [5- (1H-pyrazol-3-yl) pyridin-2-yl]Ethyl-L-leucinamide	MS(+APCI)：421.0[M+1]
		N1- (1-cyanocyclopropyl) -N- [ (1S) -2, 2, 2-trifluoro-1- (5-quinolin-5-ylpyridin-2-yl) ethyl]-L-leucinamide	MS(+APCI)：482.3[M+1]
N1- (1-cyanocyclopropyl) -N- [ (1S) -2, 2, 2-trifluoro-1- (5-quinolin-6-ylpyridin-2-yl) ethyl]-L-leucinamide	MS(+APCI)：482.3[M+1]

N1- (1-cyanocyclopropyl) -N- { (1S) -2, 2-difluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl-L-leucinamide	1H NMR(CD3COCD3)δ8.15(1H，m)，8.0(2H，d)，7.95(2H，d)，7.75(2H，d)，7.55(2H，d)，6.1(1H，dt)，4.0-4.1(1H，m)，3.25-3.35(1H，m)，3.15(3H，s)，2.4-2.5(1H，m)，1.8-1.9(1H，m)，1.4-1.55(4H，m)，0.85-1.05(8H，m).
		N- [ (1S) -1- (4 '-acetyl-1, 1' -biphenyl-4-yl) -2, 2, 3, 3, 3-pentafluoropropyl radical]-N1- (1-cyanocyclopropyl) -L-leucinamide	MS(+ESI)：522.3[M+1]
N- [ (1S) -1- (1, 1' -biphenyl-4-yl) -2, 2, 2-trifluoroethyl radical ]-N1- (1-cyanocyclopropyl) -L-leucinamide	MS(+ESI)：430.2[M+1]
		N- { (1S) -1- [4 '- (aminosulfonyl) -1, 1' -biphenyl-4-yl]-2, 2, 3, 3, 3-pentafluoropropyl } -N1- (1-cyanocyclopropyl) -L-leucinamide	MS(-ESI)：557.2[M-1]
N1- (1-cyanocyclopropyl) -N- { (1S) -1- [4- (1-ethoxyvinyl) phenyl]-2, 2, 2-trifluoroethyl } -L-leucinamide	MS(-ESI)：422.2[M-1]
		N- [ (1S) -1- (4-acetylphenyl) -2, 2, 2-trifluoroethyl radical]-N1- (1-cyanocyclopropyl) -L-leucinamide	MS(+ESI)：396.0[M+1]
N1- (1-cyanocyclopropyl) -N- [ (1S) -2, 2, 2-trifluoro-1- (4-isopropylphenyl) ethyl]-L-leucinamide	MS(+ESI)：396.2[M+1]
		N1- (1-cyanocyclopropyl) -N- [ (1S) -2, 2, 2-trifluoro-1-phenylethyl]-L-leucinamide	MS(+ESI)：354.0[M+1]
N1- (1-cyanocyclopropyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4- (1-hydroxy-1-methylethyl) phenyl]Ethyl-L-leucinamide	MS(+ESI)：434.3[M+Na]
		N1- (1-cyanocyclopropyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4- (1-methylcyclopropyl)	MS(+ESI)：408.2[M+1]

Phenyl radical]Ethyl-L-leucinamide
		N1- (1-cyanocyclopropyl) -N- [ (1S) -2, 2, 2-trifluoro-1- (2 ', 4', 6 '-trimethyl-1, 1' -biphenyl-4-yl) ethyl]-L-leucinamide	MS(+ESI)：472.2[M+1]
N- [ (1S) -1- (6-Chloropyridin-3-yl) -2, 2, 2-trifluoroethyl radical]-N1- (1-cyanocyclopropyl) -L-leucinamide	MS(+ESI)：389.3[M+1]
		N- { (1S) -1- [5- (4-acetylphenyl) pyridin-2-yl]-2, 2, 2-trifluoroethyl } -N1- (1-cyanocyclopropyl) -L-leucinamide	MS(+ESI)：473.2[M+1]
N- { (1S) -1- [6- (4-acetylphenyl) pyridin-3-yl]-2, 2, 2-trifluoroethyl } -N1- (1-cyanocyclopropyl) -L-leucinamide	MS(+ESI)：473.2[M+1]
		N- { (1S) -1- [5- (3-acetylphenyl) pyridin-2-yl]-2, 2, 2-trifluoroethyl } -N1- (1-cyanocyclopropyl) -L-leucinamide	MS(+ESI)：473.4[M+1]
N1- (1-cyanocyclopropyl) -N- ((1S) -2, 2, 2-trifluoro-1- {5- [4- (1-hydroxyethyl) phenyl]Pyridin-2-yl } ethyl) -L-leucinamide	MS(+ESI)：475.5[M+1]
		N- [ (1S) -1- (1, 1' -biphenyl-4-yl) -2, 2, 3, 3, 3-pentafluoropropyl radical]-N1- (cyanomethyl) -L-leucinamide	MS(-ESI)：452.2[M-1]
N- [ (1S) -1- (4 '-acetyl-1, 1' -biphenyl-4-yl) -2, 2, 3, 3, 3-pentafluoropropyl radical]-N1- (cyanomethyl) -L-leucinamide	MS(+ESI)：495.83[M+1]
		N- [ (1S) -1- (1, 1' -biphenyl-4-yl) -2, 2, 3, 3, 3-pentafluoropropyl radical]-N1- (1-cyanocyclopropyl) -L-leucinamide	MS(+ESI)：479.8[M+1]
N- (1-benzyl-2, 2, 2-trifluoroethyl) -N1- (1-cyanocyclopropyl) -L-leucinamide	MS(-APCI)：366.1[M-1]

N- [ (1S) -1- (4-tert-butylphenyl) -2, 2, 2-trifluoroethyl radical]-N1- (1-cyanocyclopropyl) -L-leucinamide	MS(+APCI)：410.2[M+1]
		N- [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl radical]-N1- (cyanomethyl) -4-methyl-L-leucinamide	MS(+APCI)：420.2[M+1]
N- [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl radical]-N1- (1-cyanocyclopropyl) -4-methyl-L-leucinamide	MS(+APCI)：446.1[M+1]
		N1- (1-cyanocyclopropyl) -N- ((1S) -2, 2, 2-trifluoro-1- {4- [2- (1H-pyrazol-4-yl) -1, 3-thiazol-4-yl) ]Phenyl } ethyl) -L-leucinamide	MS(+APCI)：503.2[M+1]
N1- (1-cyanocyclopropyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4- (2-methyl-1, 3-thiazol-4-yl) phenyl]Ethyl-L-leucinamide	MS(+ESI)：451.2[M+1]
		N1- (1-cyanocyclopropyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4- (2-methylpyridin-4-yl) phenyl]Ethyl-L-leucinamide	MS(+ESI)：445.2[M+1]
N1- (1-cyanocyclopropyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4- (2-methylpyridin-3-yl) phenyl]Ethyl-L-leucinamide	MS(+ESI)：445.1[M+1]
		N1- (1-cyanocyclopropyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4- (6-methylpyridin-2-yl) phenyl]Ethyl-L-leucinamide	MS(+ESI)：445.2[M+1]
N- [ (1S) -1- (3 '-acetyl-1, 1' -biphenyl-4-yl) -2, 2, 2-trifluoroethyl radical]-N1- (1-cyanocyclopropyl) -4-fluoro-L-leucinamide	MS(+ESI)：490.3[M+1]
		N1- (1-cyanocyclopropyl) -4-fluoro-N- { (1S) -2, 2, 2-trifluoro-1- [4- (1H-pyrazol-3-yl) phenyl]Ethyl-L-leucinamide	MS(+ESI)：438.3[M+1]

N1- [ (1S) -1-cyanoethyl]-N- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl-L-leucinamide	MS(+ESI)：496.3[M+1]
		N1- [ (1S) -1-cyano-3- (methylthio) propyl]-N- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl-L-leucinamide	MS(+ESI)：556.3[M+1]
N1- [ (1S) -1-cyano-3- (methylsulfonyl) propyl]-N- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl ]Ethyl-L-leucinamide	MS(+ESI)：588.2[M+1]
		N- [ (1S) -1- (4-bromophenyl) -2, 2, 3, 3, 3-pentafluoropropyl radical]-N1- (1-cyanocyclopropyl) -L-leucinamide	MS(+ESI)：482，484[M+1]
N1- (cyanomethyl) -N- { (1S) -2, 2, 3, 3, 3-Pentafluoro-1- [4- (6-methoxypyridin-2-yl) phenyl]Propyl } -L-leucinamide	MS(+ESI)：485[M+1]
		N- [ (1S) -1- (5-Bromopyridin-2-yl) -2, 2, 2-trifluoroethyl radical]-N1- (cyanomethyl) -L-leucinamide	MS(+ESI)：407，409[M+1]
N1- (cyanomethyl) -N- ((1S) -2, 2, 2-trifluoro-1- {5- [4- (methylsulfonyl) phenyl]Pyridin-2-yl } ethyl) -L-leucinamide	MS(+ESI)：483[M+1]
		N1- (1-cyanocyclopropyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4 '- (1-hydroxy-1-methylethyl) -1, 1' -biphenyl-4-yl]Ethyl-L-leucinamide	MS(+ESI)：488[M+1]
N1- (cyanomethyl) -N- [ (1S) -2, 2, 2-trifluoro-1- (6 'methyl-3, 3' -bipyridin-6-yl) ethyl]-L-leucinamide	MS(+ESI)：420[M+1]

N1- (1-cyanocyclopropyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4- (6-methoxypyridin-2-yl) phenyl]Ethyl-L-leucinamide	MS(+ESI)：461[M+1]
		N1- (cyanomethyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4- (6-oxo-1, 6-dihydropyridin-2-yl) phenyl]Ethyl-L-leucinamide	MS(+ESI)：421[M+1]
(4S)-N1- (cyanomethyl) -5, 5, 5-trifluoro-N- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl-L-leucinamide	MS(+ESI)：536[M+1]
		(4S)-N1- (1-cyanocyclopropyl) -5, 5, 5-trifluoro-N - { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl-L-leucinamide	MS(+ESI)：562[M+1]
(4S)-N1- (cyanomethyl) -5, 5, 5-trifluoro-N- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylthio) -1, 1' -biphenyl-4-yl]Ethyl-L-leucinamide	MS(+ESI)：504[M+1]
		(4S)-N1- (1-cyanocyclopropyl) -5, 5, 5-trifluoro-N- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylthio) -1, 1' -biphenyl-4-yl]Ethyl-L-leucinamide	MS(+ESI)：530[M+1]
(4S)-N- [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl radical]-N1- (cyanomethyl) -5, 5, 5-trifluoro-L-leucinamide	MS(+ESI)：460，462[M+1]
		(4S)-N- [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl radical]-N1- (1-cyanocyclopropyl) -5, 5, 5-trifluoro-L-leucinamide	MS(+ESI)：486，488[M+1]
N- { (1S) -1- [4- (6-Aminopyridin-3-yl) phenyl]-2, 2, 2-trifluoroethyl } -N1- (cyanomethyl) -L-leucinamide	MS(+ESI)：420[M+1]

N- [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl radical]-N1- (1-cyanocyclopropyl) -4-fluoro-L-leucinamide	MS(+ESI)：450，452[M+1]
		N1- (cyanomethyl) -N- { (1S) -2, 2, 3, 3, 3-Pentafluoro-1- [4- (6-methylpyridin-3-yl) phenyl]Propyl } -L-leucinamide	MS(+ESI)：468.8[M+1]
N1- (1-cyanocyclopropyl) -N- { (1S) -2, 2, 3, 3, 3-Pentafluoro-1- [4- (6-methylpyridin-3-yl) phenyl]Propyl } -L-leucinamide	MS(+ESI)：494.8[M+1]
		N1- (1-cyanocyclopropyl) -N-{(1S)-22, 2-trifluoro-1- [4- (6-methylpyridin-3-yl) phenyl]Ethyl-L-leucinamide	MS(+ESI)：445.0[M+1]
N1- (cyanomethyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4 '- (1-hydroxyethyl) -1, 1' -biphenyl-4-yl]Ethyl-L-leucinamide	MS(+ESI)：447.8[M+1]
		N1- (cyanomethyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4 '- (2, 2, 2-trifluoro-1-hydroxyethyl) -1, 1' -biphenyl-4-yl]Ethyl-L-leucinamide	MS(+ESI)：501.8[M+1]
N1- (1-cyanocyclopropyl) -N- { (1S) -2, 2, 3, 3, 3-Pentafluoro-1- [4 '- (methylthio) -1, 1' -Biphenyl-4-yl]Propyl } -L-leucinamide	MS(+ESI)：526.1[M+1]
		N1- (1-cyanocyclopropyl) -N- { (1S) -2, 2, 3, 3, 3-Pentafluoro-1- [4 '- (1-hydroxy-1-methylethyl) -1, 1' -biphenyl-4-yl]Propyl } -L-leucinamide	MS(+ESI)：538.3[M+1]
N1- (1-cyanocyclopropyl) -N- { (1S) -2, 2, 3, 3, 3-Pentafluoro-1- [4 '- (methylsulfonyl) -1, 1' -Biphenyl-4-yl]Propyl } -L-leucinamide	MS(+ESI)：558.2[M+1]

(4R)-N1- (cyanomethyl) -5, 5, 5-trifluoro-N- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl-L-leucinamide	MS(+ESI)：536.1[M+1]
		(4R)-N1- (1-cyanocyclopropyl) -5, 5, 5-trifluoro-N- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl-L-leucinamide	MS(+ESI)：562.1[M+1]
N1- (cyanomethyl) -N- [ (1S) -2, 2, 3, 3, 3-pentafluoro-1- (4 '-methyl-1, 1' -biphenyl-4-yl) propyl]-L-leucinamide	MS(+ESI)：468.2[M+1]
		N1- (cyanomethyl) -N- { (1S) -2, 2, 3, 3, 3-Pentafluoro-1- [4- (1, 3-thiazol-2-yl) phenyl ]Propyl } -L-leucinamide	MS(+ESI)：461.0[M+1]
N1- (1-cyanocyclopropyl) -N- { (1S) -1- (4-ethynylphenyl) -2, 2, 3, 3, 3-pentafluoropropyl } -L-leucinamide	MS(+ESI)：428.1[M+1]
		N1- (cyanomethyl) -N- { (1S) -1- [4- (cyclopropylethynyl) phenyl]-2, 2, 2-trifluoroethyl } -L-leucinamide	MS(+ESI)：392.3[M+1]
N1- (1-cyanocyclopropyl) -N- { (1S) -1- [4- (cyclopropylethynyl) phenyl]-2, 2, 2-trifluoroethyl } -L-leucinamide	MS(+ESI)：418.3[M+1]
		N1- (cyanomethyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4- (5-methyl-1, 3-thiazol-2-yl) phenyl]Ethyl-L-leucinamide	MS(+ESI)：425.3[M+1]
N1- (1-cyanocyclopropyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4- (1, 3-thiazol-2-yl) phenyl]Ethyl-L-leucinamide	MS(+ESI)：437.1[M+1]
		N1- (1-cyanocyclopropyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4- (5-methyl-1, 3-thiazol-2-yl) phenyl]Ethyl-L-leucinamide	MS(+ESI)：451.2[M+1]

N1- (1-cyanocyclopropyl) -N- { (1S) -1- [4- (cyclopropylethynyl) phenyl]-2, 2, 3, 3, 3-pentafluoropropyl } -L-leucinamide	MS(+ESI)：468.2[M+1]
		N1- (1-cyanocyclopropyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4- (4-methyl-1, 3-thiazol-2-yl) phenyl]Ethyl-L-leucinamide	MS(+ESI)：451.2[M+1]
N1- (cyanomethyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4- (4-methyl-1, 3-thiazol-2-yl) phenyl]Ethyl-L-leucinamide	MS(+ESI)：425.3[M+1]
		N1- (cyanomethyl) -N- { (1S) -1- [4- (4, 5-dimethyl-1, 3-thiazol-2-yl) phenyl ]-2, 2, 2-trifluoroethyl } -L-leucinamide	MS(+ESI)：439.3[M+1]
N1- (1-cyanocyclopropyl) -N- { (1S) -1- [4 '- (ethylsulfonyl) -1, 1' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -4-fluoro-L-leucinamide	MS(+ESI)：540.1[M+1]
		N1- (1-cyano)Cyclopropyl) -4-fluoro-N- [ (1S) -2, 2, 2-trifluoro-1- (4-pyridin-3-ylphenyl) ethyl]-L-leucinamide	MS(+ESI)：449.2[M+1]
N1- (1-cyanocyclopropyl) -4-fluoro-N- { (1S) -2, 2, 2-trifluoro-1- [4 ' -methoxy-3 ' - (methylsulfonyl) -1, 1 ' -biphenyl-4-yl]Ethyl-L-leucinamide	MS(+ESI)：556.3[M+1]
		N- [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl radical]-N1- (cyanomethyl) -L-alaninamide	MS(+APCI)：363.8，365.8[M+1]
N- { { (1S) -1- [4 '- (aminosulfonyl) -1, 1' -biphenyl-4-yl]-2, 2, 3, 3, 3-pentafluoropropyl } -N1- (cyanomethyl) -L-leucinamide	MS(+APCI)：533.2[M+1]
		N1- (cyanomethyl) -N- ((1S) -2, 2, 3, 3, 3-Pentafluoro-1- { 4' - [ (2-hydroxy-2-)	MS(+APCI)：590.4[M+1]

Methylpropyl) sulfonyl]-1, 1' -biphenyl-4-yl } propyl) -L-leucinamide
		N1- (cyanomethyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl-L-alaninamide	MS(+APCI)：440.1[M+1]
N1- (cyanomethyl) -N- { (1S) -2, 2, 3, 3, 3-Pentafluoro-1- [4 '- (isopropylsulfonyl) -1, 1' -biphenyl-4-yl]Propyl } -L-leucinamide	MS(+APCI)：560.2[M+1]
		N1- (1-cyano-1-methylethyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl ]Ethyl-L-leucinamide	MS(+APCI)：510.2[M+1]
N1- (1-cyanocyclopropyl) -N- ((1S) -2, 2, 2-trifluoro-1- (4' - [ (2-hydroxy-2-methylpropyl) sulfonyl)]-1, 1' -biphenyl-4-yl } ethyl) -L-leucinamide	MS(+APCI)：566.4[M+1]
		N1- (1-cyanocyclopropyl) -N- { (1S) -2, 2, 2-trifluoro-1- [2 ' -methyl-4 ' - (methylsulfonyl) -1, 1 ' -biphenyl-4-yl]Ethyl-L-leucinamide	MS(+APCI)：522.3[M+1]
N1- (1-cyanocyclopropyl) -N- { (1S) -1- [4 '- (ethylsulfonyl) -1, 1' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -L-leucinamide	MS(+APCI)：522.3[M+1]
		N- { (1S) -1- [4 '- (aminosulfonyl) -1, 1' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -N1- (1-cyanocyclopropyl) -4-fluoro-L-leucinamide	MS(+APCI)：527.3[M+1]
N1- (cyanomethyl) -N- { (S) - [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl][4- (trifluoromethoxy) phenyl group]methyl-L-leucinamide	MS(-ESI)：572.2[M-1]And 573.3

Cyclopentan-2-yl) phenyl](Thien-2-yl) methyl]-L-leucinamide
		N- { (R) - (4-bromophenyl) [4- (trifluoromethoxy) phenyl]Methyl } -N1- (cyanomethyl) -L-leucinamide	MS(-ESI)：496.1[M-1]
N1- (cyanomethyl) -N- { (S) - [4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl][4- (trifluoromethoxy) phenyl group]methyl-L-leucinamide	MS (+ APCI): 545.2 and 546.3[ M +1 ]]
		N- [ (S) - (4-bromophenyl) (2-furyl) methyl ]-N1- (cyanomethyl) -L-leucinamide	MS (+ APCI): 404.1 and 405.3[ M +1 ]]
N1- (cyanomethyl) -N- { (S) -2-Furanyl [4 '- (methylsulfonyl) -1, 1' -Biphenyl-4-yl]methyl-L-leucinamide	MS(+APCI)：479.2[M+1]
		N- [1- (4-bromophenyl) -2, 2, 2-trifluoroethyl group]-N1- (cyanomethyl) -L-norvalinamide	MS(+ESI)：392，394[M+1]
N- { (R) - (4-bromophenyl) [4- (trifluoromethyl) phenyl]Methyl } -N1- (cyanomethyl) -L-leucinamide	MS (+ APCI): 482.1 and 481.2[ M +1 ]]
		N1- (cyanomethyl) -N- {1- [4 '- (4-cyclopropylpiperazin-1-yl) -1, 1' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -L-norvalinamide	MS(+ESI)：514[M+1]
N- [ (R) - (4-bromophenyl) (4-chlorophenyl) methyl]-N1- (cyanomethyl) -L-leucinamide	MS (+ APCI): 482.1 and 481.2[ M +1 ]]
		N1- (cyanomethyl) -N- {2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-norvalinamide	MS(+ESI)：468[M+1]
N- [ (S) - (4-bromophenyl) (3-methylthiophen-2-yl) methyl]-N1- (cyanomethyl) -L-leucinamide	LC/MS，M-1：432.0.

N- [ (S) - (4-bromophenyl) (thiophen-3-yl) methyl]-N1- (cyanomethyl) -L-leucinamide	LC/MS，M-1：418.2.
		N1- (cyano radicals)Methyl) -N- { (S) - (2, 4-difluorophenyl) [ 4' - (methylsulfonyl) -biphenyl-4-yl]methyl-L-leucinamide	MS(+APCI)525.3，524.3[M-1]And 526.4[ M +1 ]].1H NMR(CDSOCD)δ8.01(dd，2H)，7.8(dd，2H)，7.35(dd，2H)，7.11(dd，2H)，7.03(d，1H)，6.93(d，2H)，6.62(d，1H)，6.55(d，1H)，5.0(s，1H)，4.13(t，2H)，3.35(m，1H)，3.0(m，1H)，2.99(m，1H)，2.85(s，3H)，1.84(m，1H)，1.45(m，1H)，0.9-0.8(m，6H).
N1- (cyanomethyl) -N- [ (S) - [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl ](Thien-3-yl) methyl]-L-leucinamide	1HNMR(d-dmso)：δ8.62(1H，t)，7.95(2H，d)，7.85(2H，m)，7.65(2H，d)，7.49(2H，d)，7.47(2H，m)，7.10(1H，dd)，4.80(1H，d)，4.13(2H，m)，3.24(3H，s)，3.05(1H，m)，2.65(1H，m)，1.8(1H，m)，1.45(1H，m)，1.30(1H，m)，0.84(3H，d)，0.76(3H，d).LC/MS，M-1：493.5.
		N1- (cyanomethyl) -N- [ (S) - [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl](3-methylthiophen-2-yl) methyl]-L-leucinamide	LC/MS，M-1：507.5
N1- (cyanomethyl) -N- [ (S) - [4 '- (4-cyclopropylpiperazin-1-yl) -1, 1' -biphenyl-4-yl](3-methylthiophen-2-yl) methyl]-L-leucinamide	LC/MS，M+1：556.1，M-1：554.0
		N1- (cyanomethyl) -N-[(S)-[4′- (4-cyclopropylpiperazin-1-yl) -1, 1' -biphenyl-4-yl](Thien-3-yl) methyl]-L-leucinamide	LC/MS，M-1：540.1
N- [1- (4-bromophenyl) -2, 2, 2-trifluoroethyl group]-N1- (cyanomethyl) -5, 5, 5-trifluoro-L-norvalinamide	MS(+ESI)：446.1，448.1[M+1]
		N1- (cyanomethyl) -5, 5, 5-trifluoro-N- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-norvalinamide	MS(+ESI)：522.3[M+1]
N- [ (S) - (4-bromophenyl) (3-methylthiophene-)	LC/MS，M-1：460.1.

2-yl) methyl]-N1- (1-cyanocyclopropyl) -L-leucinamide
		N1- (1-cyanocyclopropyl) -N- [ (S) - [4 '(methylsulfonyl) -1, 1' -biphenyl-4-yl]Methylthiophen-2-yl]Methyl radical]-L-leucinamide	1HNMR(d-dmso)：δ8.96(1H，s)，7.96(2H，d)，7.87(2H，d)，7.69(2H，d)，7.45(2H，d)，7.31(1H，d)，7.76(1H，d)，4.98(1H，s)，3.24(3H，s)，3.10(1H，m)，2.5(1H，d)，2.09(3H，s)，1.85(1H，m)，1.50(2H，m)，1.40(1H，m)，1.25(1H，m)，1.10(2H，m)，0.86(3H，d)，0.83(3H，d).LC/MS，M-1：534.2.
N1- (cyanomethyl) -N- { (S) -3-furyl [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl } methyl } -L-leucinamide	MS (+ APCI): 479.2 and 478.3[ M-1 ]]
		N1- (1-cyanocyclopropyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl ]Ethyl } -L-norvalinamide	MS(+ESI)：494[M+1].1H NMR(CDCl)：δ0.97(t，3H)，0.98(m，1H)，1.1(m，1H)，1.42(m，2H)，1.29(m，2H)，1.63(m，1H)，1.77(m，1H)，3.13(s，3H)，3.28(dd，1H)，4.17(q，1H)，7.21(br s，1H)，7.47(d，2H)，7.63(d，2H)，7.78(d，2H)，8.02(d，2H).
N- [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl radical]-N1- (1-cyanocyclopropyl) -L-norvalinamide	MS(-ESI)：416，418[M-1]1H NMR(CDCl)：δ0.97(3H，t)，0.98(m，1H)，1.07(m，1H)，1.41(m，2H)，1.49(m，2H)，1.62(m，1H)，1.72(m，1H)，3.27(1H，m)，1.04(m，1H)，7.1(br s，1H)，1.24(d，2H)，7.75(d，2H).
		N- [ (S) - (4-bromophenyl) (4-bromothien-2-yl) methyl]-N1- (cyanomethyl) -L-leucinamide	1HNMR(d-dmso)：δ8.69(1H，t)，7.52(1H，m)，7.49(2H，d)，7.31(2H，d)，7.00(1H，d)，4.91(1H，s)，4.14(2H，m)，3.15(1H，m)，2.81(1H，dd)，1.85(1H，m)，1.45(1H，m)，1.30(1H，m)，0.86(3H，d)0.82(3H，d).
N- [ (S) - (4-bromophenyl) (thiophen-3-yl) methyl]-N1- (I-cyanocyclopropyl) -L-leucinamide	LC/MS，M-1：443.8

N1- (cyanomethyl) -N- ((S) - [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl)]{4- [4- (methylsulfonyl) phenyl]Thien-2-yl methyl) -L-leucinamide	1HNMR(d-dmso)：δ8.75(1H，t)，7.90(9H，m)，7.70(2H，d)，7.57(3H，m)，5.06(1H，s)，4.18(2H，m)，3.23(3H，s)，3.22(1H，m)，3.19(3H，s)，2.85(1H，d)，1.90(1H，m)，1.50(1H，m)，1.35(1H，m)，0.89(3H，d)，0.85(3H，d).LC/MS，M-1：648.1.
		N1- (1-cyanocyclopropyl) -N- [ (S) - [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl](Thien-3-yl) methyl]-L-leucinamide	LC/MS，M+1：522.3，M-1：521.4.
N- { (1S) -1- [4 '- (aminosulfonyl) -1, 1' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -N1- (1-cyanocyclopropyl) -L-norvalinamide	MS(+ESI)：495[M+1].1H NMR(CDCl)：δ0.97(3H，t).0.98(m，1H)；1.08(m，1H)，1.42(m，2H)，1.44(m，2H)，1.57-1.8(m，4H)，3.28(m，1H)，4.16(q，1H)，4.9(br s，1H)，7.2(s，1H)，7.43(d，2H)，7.6(d，2H)，7.72(d，2H)，7.99(d，2H).
		N- [ (S) - (4-bromophenyl) (4-bromothien-2-yl) methyl]-N1- (1-cyanocyclopropyl) -L-leucinamide	LC/MS，M-1：526.2.
N- [ (S) - [4 '- (aminosulfonyl) -1, 1' -biphenyl-4-yl](Thien-3-yl) methyl]-N1- (1-cyanocyclopropyl) -L-leucinamide	LC/MS，M-1：521.4.
		N- [ (S) - [4 '- (aminosulfonyl) -1, 1' -biphenyl-4-yl](Thien-3-yl) methyl]-N1- (cyanomethyl) -L-leucinamide	1HNMR(d-dmso)：δ8.63(1H，t)，7.84(2H，d)，7.79(2H，d)，7.63(2H，d)，7.47(2H，d)，7.40(2H，m)，7.09(1H，dd)，4.81(1H，d)，4.13(2H，m)，3.05(1H，m)，2.65(1H，dd)，1.80(1H，m)，1.45(1H，m)，0.85(3H，d)，0.76(3H，d).LC/MS，M-1：495.4.
N1- (1-cyanocyclopropyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4 ' -methoxy-3 ' - (methylsulfonyl) -1, 1 ' -biphenyl-4-yl ]Ethyl } -L-norvalinamide	MS(+ESI)：524.2[M+1]
		N1- (1-cyanocyclopropyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4- (2-methylpyridin-4-yl) phenyl]Ethyl } -L-norvalinamide	MS(+ESI)：431.0[M+1]

N1- (1-cyanocyclopropyl) -5, 5, 5-trifluoro-N- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-norvalinamide	MS(+ESI)：548.3[M+1]
		N1- (1-cyanocyclopropyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4- (1H-pyrazol-3-yl) phenyl]Ethyl } -L-norvalinamide	MS(+ESI)：406.3[M+1]
N1- (1-cyanocyclopropyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4 '- (1-hydroxy-1-methylethyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-norvalinamide	MS(+ESI)：474.2[M+1](100％).1HNMR(400MHz，DMSO-d6)：δ7.6(m，8H)7.4(m，1H)7.25(s，1H)5.2(s，1H)4.1(m，2H)3.3(m，1H)2.05(s，1H)1.75(m，1H)1.6(s，6H)1.4(m，2H)1.25(t，2H)1.0(m，4H).
		N1- (1-cyanocyclopropyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4- (5-methylpyridin-2-yl) phenyl]Ethyl } -L-norvalinamide	1HNMR(d-dmso)：δ8.72(1H，s)，8.48(1H，m)，8.02(2H，d)，7.84(1H，d)，7.67(1H，dd)，7.46(2H，d)，4.30(1H，m)，3.13(1H，m)，2.85(1H，dd)，2.33(3H，s)，1.46(2H，m)，1.32(4H，m)，0.88(1H，m)，0.86(3H，t)，0.73(1H，m).LC/MS，M+1：431.2.
2- { [ (4-bromo-phenyl) -pyridin-4-yl-methyl]-amino } -pentanoic acid cyanomethyl-amide	MS (+ APCI): 400.9 and 401.2[ M +1 ]]
		2- { [ (4-bromo-phenyl) -thiazol-2-yl-methyl]-amino } -pentanoic acid cyanomethyl-amide	MS (+ APCI): 407.1 and 406[ M +1]
(2S) -2- [ (S) -1- (4' -acetylbiphenyl-4-yl) -2, 2, 2-trifluoroethylamino]-pentanoic acid (1-cyanocyclopropyl) -amide	MS(+ESI)：458[M+1]，480[M+1+Na].1H NMR(CDCl)：δ0.97(t，3H)，0.98(m，1H)，1.7(m，1H)，1.42(m，2H)，1.57(s，2H)，1.63(m，1H)，1.78(m，1H)，2.33(s，3H)，3.33(dd，1H)，4.17(q，1H)，7.21(br s，1H)，7.43(d，2H)，7.65-7.69(2xd，4H)，8.03(d，2H).
		(2S) -2- [ (S) -1- (2 ', 4' -difluorobiphenyl-4-yl) -2, 2, 2-trifluoroethylamino]-pentanoic acid (1-cyanocyclopropyl) -amide	MS(+ESI)：452[M+1]，474[M+1+Na].1H NMR(CDCl)：δ0.90(m，1H)，0.97(t，3H)，1.04(m，1H)，1.41-1.5(m，4H)，1.62(m，1H)，1.78(m，1H)，2.19(br s，1H)，3.32(dd，1H)，4.13(dd，1H)，6.95(m，2H)，7.19(br s，1H)，7.41(m，3H)，7.53(d，2H).

(2S) -2- [ (S) -1- (3 ', 4' -difluorobiphenyl-4-yl) -2, 2, 2-trifluoroethylamino]-pentanoic acid (1-cyanocyclopropyl) -amide	MS(+ESI)：452[M+1]，474[M+1+Na].1H NMR(CDCl)：δ0.97(t，3H)，0.98(m，1H)，1.07(m，1H)，1.42(m，2H)，1.5(m，2H)，1.62(m，1H)，1.77(m，1H)，2.18(br s，1H)，3.29(dd，1H)，4.17(q，1H)，7.21(br s，1H)，7.13-7.3(m，2H)，7.38(m，1H)，7.42(d，2H)，7.57(d，2H).
		(2S) -2- [ (S) -1- (3 '-chloro-4' -fluorobiphenyl-4-yl) -2, 2, 2-trifluoroethylamino]-pentanoic acid (1-cyano-cyclopropyl) -amide	MS(+ESI)：468[M+1].1H NMR(CDCl)：δ0.99(t，3H)，1.00(m，1H)，1.08(m，1H)，1.42(m，2H)，1.51(m，2H)，1.62(m，1H)，1.79(m，1H)，2.19(br s，1H)，3.33(dd，1H)，4.17(q，1H)，7.21(m，2H)，7.42(m，3H)，7.57(d，2H)，7.62(m，1H).
(2S) -2- [ (S) -2, 2, 2-trifluoro-1- (4' -methanesulfonylamino-biphenyl-4-yl) -ethylamino]-pentanoic acid (1-cyano-cyclopropyl) -amide	MS(-ESI)：507.0[M-1]
		(2S) -2- { (S) - [ (4-bromo-phenyl) -thiazol-2-yl-methyl]-amino } -4-methylpentanoic acid cyanomethyl-amide	MS (+ APCI): 479.2 and 478.3[ M-1 ]]
N1- (1-cyanocyclopropyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4 '-chloro-1, 1' -biphenyl-4-yl]Ethyl } -L-norvalinamide	MS(+ESI)：450.1[M+1]
		N1- (1-cyanocyclopropyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4 ' -chloro-3 ' -methyl-1, 1 ' -biphenyl-4-yl]Ethyl } -L-norvalinamide	MS(+ESI)：464.2[M+1]
N1- (1-cyanocyclopropyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4 ' -chloro-2 ' -methyl-1, 1 ' -biphenyl-4-yl]Ethyl } -L-norvalinamide	MS(+ESI)：464.3[M+1]
		(2S) -2- { (S) -2, 2, 2-trifluoro-1- [4- (1H-indol-5-yl) -phenyl]-ethylammoniaYl } -pentanoic acid (1-cyano-cyclopropyl) -amide	MS(+ESI)：455.1[M+1]
(2S) -2- [ (S) -2, 2, 2-trifluoro-1- (3' -methanesulfonylamino-biphenyl-4-yl) -ethylamino ]-pentanoic acid (1-cyano-cyclopropyl) -acyl	MS(+ESI)：509.2[M+1]

Amines as pesticides
		N1- (1-cyanocyclopropyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4 '-trifluoro-1, 1' -biphenyl-4-yl]Ethyl } -L-norvalinamide	MS(+ESI)：434.4[M+1]
N1- (1-cyanocyclopropyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4 ' -fluoro-3 ' -methyl-1, 1 ' -biphenyl-4-yl]Ethyl } -L-norvalinamide	MS(+ESI)：448.2[M+1]
		N1- (1-cyanocyclopropyl) -N- { (1S) -2, 2, 2-trifluoro-1- [3 ' -fluoro-4 ' -methyl-1, 1 ' -biphenyl-4-yl]Ethyl } -L-norvalinamide	MS(+ESI)：448.3[M+1]
N1- (1-cyanocyclopropyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4 '-trifluoromethoxy-1, 1' -biphenyl-4-yl]Ethyl } -L-norvalinamide	MS(+ESI)：500.1[M+1]
		(2S) -2- [ (S) -2, 2, 2-trifluoro-1- (4' -methylbiphenyl-4-yl) -ethylamino]-pentanoic acid (1-cyanocyclopropyl) -amide	MS(+ESI)：430[M+1].1H NMR(CDCl)δ0.90(m，1H)，0.98(t，3h)，1.02(m，1H)1.4-1.5(m，4H)，1.62(m，1H)，1.69(m，1H)，2.19(br s，1H)，2.41(s，3H)，3.35(dd，1H)，4.1(q，1H)，7.21(s，1H)7.24(d，2H)，7.38(d，2H)，7.46(d，2H)，7.60(d，2H).
(2S) -2- [ (S) -1- (4' -cyanobiphenyl-4-yl) -2, 2, 2-trifluoroethylamino]-pentanoic acid (1-cyanocyclopropyl) -amide	MS(+ESI)：441[M+1]
		N1- (1-cyanocyclopropyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4 '-methoxy-1, 1' -biphenyl-4-yl]Ethyl } -L-norvalinamide	MS(+ESI)：446.3[M+1]
N1- (1-cyanocyclopropyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4- (benzo [1, 3 ]]Dioxol-5-yl) phenyl]Ethyl } -L-norvalinamide	MS(+ESI)：460.1[M+1]
		N1- (1-cyanocyclopropyl) -N- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methoxycarbonyl) -1, 1' -biphenyl-4-yl ]Ethyl } -L-n-valine	MS(+ESI)：474.3[M+1]

Amides of carboxylic acids
		(2S) -2- { (S) - [ (4-bromophenyl) -thiazol-2-yl-methyl]-amino } -4-methylpentanoic acid (1-cyanocyclopropyl) -amide	MS(-ESI)：445，447[M-1].NMR(CDCl)：δ0.82(d，3H)，0.95(d，3H)，1.04(m，2H)，1.46-1.62(m，4H)，1.80(m，1H)，3.12(dd，1H)，4.95(s，1H)，7.22(s，1H)，7.23-7.25(d，2H)，7.31(m，2H)，7.47(d，2H)，7.74(m，1H).
(2S) -2- { (S) - [ (4' -methanesulfonyl-biphenyl-4-yl) -thiazol-2-yl-methyl]-amino } -4-methyl-pentanoic acid cyanomethyl-amide	MS(+APCI)：418.9，420.9[M-1]
		(2S) -2- [ (S) -2, 2, 2-trifluoro-1- (4' -trifluoromethyl-biphenyl-4-yl) -ethylamino]-pentanoic acid (1-cyano-cyclopropyl) -amide	MS(+APCI)：483.3[M+1]
(2S) -2- [ (S) -2, 2, 2-trifluoro-1- (2' -trifluoromethyl-biphenyl-4-yl) -ethylamino]-pentanoic acid (1-cyano-cyclopropyl) -amide	MS(+APCI)：483.3[M+1]
		(2S) -2- { (S) - [ (2 ', 4' -difluorobiphenyl-4-yl) -thiazol-2-yl-methyl]-amino } -4-methylpentanoic acid (1-cyanocyclopropyl) -amide	MS(-ESI)：479[M-1].1H NMR(CDCl)：δ0.84(d，3H)，0.97(d，3H)，1.03(m，2H)，1.47(m，2H)，1.57-1.62(m，4H)，1.95(m，1H)，3.27(dd，1H)，5.02(s，1H)，6.93(m，2H)，7.32(m，1H)，7.39(m，1H)，7.42(m，3H)，7.48(d，2H)，7.77(d，1H).
(2S) -2- { (S) - [ (4' -methanesulfonylbiphenyl-4-yl) -thiazol-2-yl-methyl]-amino } -4-methylpentanoic acid (1-cyanocyclopropyl) -amide	MS(-ESI)：521[M-1].
		N1- (1-cyanocyclopropyl) -4-fluoro-N- [ (1S) -2, 2, 2-trifluoro-1- (4-quinolin-6-ylphenyl) ethyl]-L-leucinamide	MS(+APCI)：499.4[M+1]+
N1- (1-cyanocyclopropyl) -4-fluoro-N- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfinyl) -1, 1' -biphenyl-4-yl]Ethyl-L-leucinamide	MS(+APCI)：510.1[M+1]+
		N- [ (1S) -1- (4 '-acetyl-1, 1' -biphenyl-4-yl) -2, 2, 2-trifluoroethyl radical]-N1- (1-cyano)	MS(+ESI)：472.1[M+1]+

Cyclopropyl) -L-leucinamide
		N1- (1-cyanocyclopropyl) -N- [ (1S) -2, 2, 2-trifluoro-1- (4-quinolin-6-ylphenyl) ethyl]-L-leucinamide	MS(+ESI)：482[M+1]+
N- [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl radical]-N1- (1-cyanocyclopropyl) -4, 4-difluoro-L-norvalinamide	MS(+ESI)：454.1，456.2[M+1]+
		N1- (1-cyanocyclopropyl) -4, 4-difluoro-N- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylthio) -1, 1' -biphenyl-4-yl]Ethyl } -L-norvalinamide	MS(+ESI)：498.3[M+1]+
N1- (1-cyanocyclopropyl) -4, 4-difluoro-N- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-norvalinamide	MS(+ESI)：530.3[M+1]+

Pharmaceutical composition

As a specific embodiment of the present invention, 100mgN is paired with sufficiently finely pulverized lactose¹- (cyanomethyl) -N²- [2, 2, 2-trifluoro-1- (4 '-piperazin-1-yl-1, 1' -biphenyl-4-yl) ethyl]L-leucinamide to give a total amount of 580 to 590mg, with which hard gelatin capsule size 0 is filled.

The compounds disclosed in this application show activity in the following assays. Furthermore, the compounds disclosed herein have enhanced pharmacological properties relative to previously disclosed compounds.

Cathepsin K assay

A series of dilutions (1/3) from 500. mu.M to as low as 0.0085. mu.M of test compound were prepared in Dimethylsulfoxide (DMSO). Then 2. mu.L of DMSO was taken from each dilution and added to 50. mu.L of assay buffer (MES, 50mM (pH 5.5); EDTA, 2.5 mM; DTT, 2.5mM and 10% DMSO) and 25. mu.L of human cathepsin K (0.4nM) in assay buffer. The assay solution was mixed with a shaker plate for 5-10 seconds and incubated at room temperature for 15 minutes. Z-Leu-Arg-AMC (8. mu.M) in 25. mu.L assay buffer was added to the assay solution. Hydrolysis of the coumarin leaving group (AMC) was then followed by fluorescence spectroscopy (Ex. lamda. times.355 nm; Em. lamda. times.460 nm) for 10 minutes. Percent inhibition was calculated by fitting a standard mathematical model of the dose response curve to the experimental values.

Cathepsin L assay

A series of dilutions (1/3) from 500. mu.M to as low as 0.0085. mu.M of test compound were prepared in Dimethylsulfoxide (DMSO). Then 2. mu.L of DMSO was taken from each dilution and added to 50. mu.L of assay buffer (MES, 50mM (pH 5.5); EDTA, 2.5 mM; DTT, 2.5mM and 10% DMSO) and 25. mu.L of human cathepsin L (0.5nM) in assay buffer. The assay solution was mixed with a shaker plate for 5-10 seconds and incubated at room temperature for 15 minutes. Z-Leu-Arg-AMC (8. mu.M) in 25. mu.L assay buffer was added to the assay solution. Hydrolysis of the coumarin leaving group (AMC) was then followed by fluorescence spectroscopy (Ex. lamda. times.355 nm; Em. lamda. times.460 nm) for 10 minutes. Percent inhibition was calculated by fitting a standard mathematical model of the dose response curve to the experimental values.

Cathepsin B assay

A series of dilutions (1/3) from 500. mu.M to as low as 0.0085. mu.M of test compound were prepared in Dimethylsulfoxide (DMSO). Then 2. mu.L of DMSO was taken from each dilution and added to 50. mu.L of assay buffer (MES, 50mM (pH 5.5); EDTA, 2.5 mM; DTT, 2.5mM and 10% DMSO) and 25. mu.L of human cathepsin B (0.4nM) in assay buffer. The assay solution was mixed with a shaker plate for 5-10 seconds and incubated at room temperature for 15 minutes. Z-Leu-Arg-AMC (8. mu.M) in 25. mu.L assay buffer was added to the assay solution. Hydrolysis of the coumarin leaving group (AMC) was then followed by fluorescence spectroscopy (Ex. lamda. times.355 nm; Em. lamda. times.460 nm) for 10 minutes. Percent inhibition was calculated by fitting a standard mathematical model of the dose response curve to the experimental values.

Cathepsin S assay

A series of dilutions (1/3) from 500. mu.M to as low as 0.0085. mu.M of test compound were prepared in Dimethylsulfoxide (DMSO). Then 2. mu.L of DMSO was taken from each dilution and added to 50. mu.L of assay buffer (MES, 50mM (pH 5.5); EDTA, 2.5 mM; DTT, 2.5mM and 10% DMSO) and 25. mu.L of human cathepsin S (20nM) in assay buffer. The assay solution was mixed with a shaker plate for 5-10 seconds and incubated at room temperature for 15 minutes. Z-Leu-Arg-AMC (8. mu.M) in 25. mu.L assay buffer was added to the assay solution. Hydrolysis of the coumarin leaving group (AMC) was then followed by fluorescence spectroscopy (Ex. lamda. times.355 nm; Em. lamda. times.460 nm) for 10 minutes. Percent inhibition was calculated by fitting a standard mathematical model of the dose response curve to the experimental values.

Claims (28)

1. A compound of the formula:

wherein R is¹Is hydrogen, C_1-6Alkyl or C_2-6Alkenyl, wherein the alkyl and alkenyl are optionally substituted with 1 to 6 halogens, C_3-6Cycloalkyl, -SR⁹、-SR¹²、-SOR⁹、-SOR¹²、-SO₂R⁹、-SO₂R¹²、-SO₂CH(R¹²)(R¹¹)、-OR¹²、-OR⁹、-N(R¹²)₂Aryl, heteroaryl or heterocyclyl, wherein said aryl, heteroaryl and heterocyclyl are optionally substituted with one or two substituents independently selected from C_1-6Alkyl, halogen, hydroxyalkyl, hydroxy, alkoxy or keto;

R²is hydrogen, C_1-6Alkyl or C_2-6Alkenyl, wherein the alkyl and alkenyl are optionally substituted with 1 to 6 halogens, C_3-6Cycloalkyl, -SR⁹、-SR¹²、-SOR⁹、-SOR¹²、-SO₂R⁹、-SO₂R¹²、-SO₂CH(R¹²)(R¹¹)、-OR¹²、-OR⁹、-N(R¹²)₂Aryl, heteroaryl or heterocyclyl, wherein said aryl, heteroaryl and heterocyclyl are optionally substituted with one or two substituents independently selected from C_1-6Alkyl, halogen, hydroxyalkyl, hydroxy, alkoxy or keto;

or R¹And R²May form a C group together with the carbon atom to which it is attached_3-8A cycloalkyl or heterocyclyl ring, wherein said ring system is optionally substituted with one or two substituents independently selected from C_1-6Alkyl, hydroxyalkyl, haloalkyl, or halogen;

R³is hydrogen, C_1-6Alkyl or C_2-6Alkenyl, wherein the alkyl and alkenyl are optionally substituted by C _3-6Cycloalkyl or 1 to 6 halogen;

R⁴is hydrogen, C_1-6Alkyl or C_2-6Alkenyl, wherein the alkyl and alkenyl are optionally substituted by C_3-6Cycloalkyl or 1 to 6 halogen;

or R³And R⁴May form a C group together with the carbon atom to which it is attached_3-8Cycloalkyl ring, C_5-8A cycloalkenyl ring, or a 5-to 7-membered heterocyclyl, wherein said cycloalkyl, cycloalkenyl and heterocyclyl are optionally substitutedOne or two are independently selected from C_1-6Alkyl, halogen, hydroxyalkyl, hydroxy, alkoxy or keto;

R⁵selected from hydrogen or C substituted by 1-6 halogens_1-6An alkyl group;

R⁶is aryl, heteroaryl, C_1-6Haloalkyl, arylalkyl or heteroarylalkyl, wherein said aryl, heteroaryl, arylalkyl and heteroarylalkyl are optionally substituted with one, two or three independently selected from halogen, C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-6Cycloalkyl, haloalkoxy, -SR⁹、-SR¹²、-SOR⁹、-SOR¹²、-SO₂R⁹、-SO₂R¹²、-SO₂CH(R¹²)(R¹¹)、-OR¹²、-N(R¹⁰)(R¹¹) Cyano, or optionally by-SO₂R¹²Substituted with a substituent of the substituted aryl;

each D is independently C_1-3Alkyl radical, C_2-3Alkenyl radical, C_2-3Alkynyl, aryl, heteroaryl, C_3-8Cycloalkyl or heterocyclyl, wherein each of said aryl, heteroaryl, cycloalkyl and heterocyclyl, which may be monocyclic or bicyclic, may optionally be substituted by 1 to 5 substituents independently selected from C on carbon or a heteroatom _1-6Alkyl, haloalkyl, halogen, keto, alkoxy, -SR⁹、-SR¹²、-OR⁹、-OR¹²、N(R¹²)₂、-SO₂R⁹or-SO₂R¹⁰Substituted with the substituent(s);

R⁷is hydrogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy, halogen, nitro, cyano, aryl, heteroaryl, C_3-8Cycloalkyl, heterocyclyl, -C (O) OR¹⁰、-C(O)OSi[CH(CH₃)₂]₃、-OR⁹、-OR¹⁰、-C(O)R¹⁰、-R¹⁰C(O)R⁹、-C(O)R⁹、-C(O)N(R^a)(R^b)、-C(O)N(R¹²)(R¹²)、-C(O)N(R¹⁰)(R¹¹)、-C(R¹⁰)(R¹¹)OH、-SR¹²、-SR⁹、-R¹⁰SR⁹、-R⁹、-C(R⁹)₃、-C(R¹⁰)(R¹¹)N(R⁹)₂、-NR¹⁰C(O)NR¹⁰S(O)₂R⁹、-SO₂R¹²、-SO(R¹²)、-SO₂R⁹、-SO_mN(R^c)(R^d)、-SO_mCH(R¹⁰)(R¹¹)、-SO₂N(R¹⁰)C(O)(R¹²)、-SO₂(R¹⁰)C(O)N(R¹²)₂、-OSO₂R¹⁰、-N(R¹⁰)(R¹¹)、-N(R¹⁰)C(O)N(R¹⁰)(R⁹)、-N(R¹⁰)C(O)R⁹、-N(R¹⁰)C(O)R¹⁰、-N(R¹⁰)C(O)OR¹⁰、-N(R¹⁰)SO₂(R¹⁰)、-C(R¹⁰)(R¹¹)NR¹⁰C(R¹⁰)(R¹¹)R⁹、-C(R¹⁰)(R¹¹)N(R¹⁰)R⁹、-C(R¹⁰)(R¹¹)N(R¹⁰)(R¹¹)、-C(R¹⁰)(R¹¹)SC(R¹⁰)(R¹¹)(R⁹)、R¹⁰S-、-C(R^a)(R^b)NR^aC(R^a)(R^b)(R⁹)、-C(R^a)(R^b)N(R^a)(R^b)、-C(R^a)(R^b)C(R^a)(R^b)N(R^a)(R^b)、-C(O)C(R^a)(R^b)N(R^a)(R^b)、-C(R^a)(R^b)N(R^a)C(O)R⁹、-C(O)C(R^a)(R^b)S(R^a)、C(R^a)(R^b)C(O)N(R^a)(R^b)、-B(OH)₂、-OCH₂O-or 4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl; wherein said group is optionally substituted on carbon or heteroatom by 1 to 5 substituents independently selected from C_1-6Alkyl, halogen, keto, cyano, haloalkyl, hydroxyalkyl, -OR⁹、-NO₂、-NH₂、-NHS(O)₂R⁸、-R⁹SO₂R¹²、-SO₂R¹²、-SO(R¹²)、-SR¹²、-SR⁹、-SO_mN(R^c)(R^d)、-SO_mN(R¹⁰)C(O)(R¹²)、-C(R¹⁰)(R¹¹)N(R¹⁰)(R¹¹)、-C(R¹⁰)(R¹¹)OH、-COOH、-C(R^a)(R^b)C(O)N(R^a)(R^b)、-C(O)(R^a)(R^b)、-N(R¹⁰)C(R¹⁰)(R¹¹)(R⁹)、-N(R¹⁰)CO(R⁹)、-NH(CH₂)₂OH、-NHC(O)OR¹⁰、-Si(CH₃)₃Heterocyclyl, aryl, or heteroaryl;

R⁸is hydrogen or C_1-6An alkyl group;

or R⁴And R⁸May form together with any atom attached to or between them a 4-to 10-membered heterocyclyl ring system, wherein said ring system, which may be mono-or bicyclic, is optionally substituted by one or two groups independently selected from C_1-6Alkyl, halogen, hydroxyalkyl, hydroxy, keto, -OR¹⁰、-SR¹⁰or-N (R)¹⁰)₂Substituted with the substituent(s);

R⁹selected from hydrogen, aryl (C)_1-4) Alkyl, heteroaryl (C)_1-4) Alkyl radical, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl (C)_1-4) Alkyl, and heterocyclic group (C)_1-4) Alkyl, wherein the group may optionally be substituted with one, two, or three independently selected from halogen, alkoxy, or-SO ₂R¹²Substituted with the substituent(s);

R¹⁰is hydrogen or C_1-6An alkyl group;

R¹¹is hydrogen or C_1-6An alkyl group;

R¹²is hydrogen or is optionally substituted by one, two, or three groups independently selected from halogen, alkoxy, -cyano, -NR¹⁰or-SR¹⁰C substituted by a substituent of (3)_1-6An alkyl group;

R^ais hydrogen, C_1-6Alkyl, (C)_1-6Alkyl) aryl, (C)_1-6Alkyl) hydroxy, -O (C)_1-6Alkyl), hydroxy, halogen, aryl, heteroaryl, C_3-8Cycloalkyl, heterocyclyl, wherein said alkyl, aryl, heteroaryl, C_3-8The cycloalkyl and heterocyclyl groups may optionally be mono-, di-, or tri-independently selected from C on carbon or heteroatom_1-6Alkyl or halogen;

R^bis hydrogen, C_1-6Alkyl, (C)_1-6Alkyl) aryl, (C)_1-6Alkyl) hydroxy, alkoxy, hydroxy, halogen, aryl, heteroaryl, C_3-8Cycloalkyl, heterocyclyl, wherein said alkyl, aryl, heteroaryl, C_3-8The cycloalkyl and heterocyclyl groups may optionally be mono-, di-, or tri-independently selected from C on carbon or heteroatom_1-6Alkyl or halogen;

or R^aAnd R^bMay form a C together with the carbon atoms to which they are attached or between them_3-8Cycloalkyl ring or C_3-8A heterocyclyl ring wherein said 3-8 membered ring system may optionally be substituted with one or two substituents independently selected from C _1-6Alkyl and halogen;

R^cis hydrogen OR is optionally substituted by one, two, OR three independently selected from halogen OR-OR⁹C substituted by a substituent of (3)_1-6An alkyl group;

R^dis hydrogen OR is optionally substituted by one, two, OR three independently selected from halogen OR-OR⁹C substituted by a substituent of (3)_1-6An alkyl group;

or R^cAnd R^dMay form a C together with or between the nitrogen atoms to which they are attached_3-8A heterocyclyl ring, which may optionally be substituted by one or two substituents independently selected from C_1-6Alkyl, halogen, hydroxyalkyl, hydroxy, alkoxy or keto;

n is independently selected from an integer from 0 to 3;

each m is independently selected from an integer from 0 to 2.

2. The compound of claim 1, wherein R is R, and pharmaceutically acceptable salts, stereoisomers and N-oxide derivatives thereof¹Is hydrogen, and R²Is hydrogen, or R¹And R²May form a C group together with the carbon atom to which it is attached_3-8A cycloalkyl ring, wherein said ring system is optionally substituted by one or two substituents selected from C_1-6Alkyl or halogen.

3. The compound of claim 2, wherein R is R, and pharmaceutically acceptable salts, stereoisomers and N-oxide derivatives thereof³Is C which may be optionally substituted by 1 to 6 halogen _1-6Alkyl, and R⁴Is hydrogen.

4. A compound according to claim 3, wherein R is R, and pharmaceutically acceptable salts, stereoisomers and N-oxide derivatives thereof³Is n-propyl, isobutyl, 2-fluoro-2-methylpropyl, 2-trifluoromethylpropyl, 3-fluoro-2- (2-fluoromethyl) propyl, 2-difluoroethyl, 2-difluoropropyl, 3, 3, 3-trifluoropropyl, or 2, 2-dichloroethyl, and R is⁴Is hydrogen.

5. A compound according to claim 3, wherein R is R, and pharmaceutically acceptable salts, stereoisomers and N-oxide derivatives thereof⁵Is hydrogen, and R⁶Is aryl or heteroaryl, wherein said aryl or heteroaryl may optionally be substituted by one, two or three groups selected from halogen or-SO₂R¹²Substituted with the substituent(s).

6. A compound according to claim 3, wherein R is R, and pharmaceutically acceptable salts, stereoisomers and N-oxide derivatives thereof⁵Is hydrogen, and R⁶Is C substituted by 1-6 halogen_1-6An alkyl group.

7. The compound of claim 6, wherein R is R, and pharmaceutically acceptable salts, stereoisomers and N-oxide derivatives thereof⁵Is hydrogen, having R⁶Is trifluoromethyl or 3, 3, 3, 2, 2-pentafluoroethyl.

8. The compound of claim 6, wherein N is 2, each D is independently aryl or heteroaryl, and R is ⁷is-SO_mCH(R¹⁰)(R¹¹l) or-SO_m(R^c)(R^d)，R^cAnd R^dEach independently is hydrogen or C_1-6An alkyl group.

9. The compound of claim 1, selected from:

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- (2, 2, 2-trifluoro-1-phenylethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- [2, 2, 2-trifluoro-l- (4-fluoro-3-methylphenyl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1R) -2, 2, 2-trifluoro-1- (4-pyridin-3-ylphenyl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (4-pyridin-3-ylphenyl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1R) -2, 2, 2-trifluoro-1- (4-pyridin-4-ylphenyl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (4-pyridin-4-ylphenyl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1R) -2, 2, 2-trifluoro-1- (4- { [4- (2-fluoroethyl) piperazin-1-yl]Carbonyl } phenyl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- [2, 2, 2-trifluoro-1 (4- { [4- (2-fluoroethyl) piperazin-1-yl group]Carbonyl } phenyl) ethyl]-L-leucinamide;

N²- [1- (1, 1' -Biphenyl-4-yl) -2, 2, 2-trifluoroethyl group ]-N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- {2, 2, 2-trifluoro-l- [4- (3-hydroxy-3-methylbut-1-ynyl) phenyl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (3-hydroxy-3-methylbutyl) phenyl]Ethyl } -L-leucinamide;

N²- [ (1S) -1- (4-bromophenyl) -2, 2, 3, 3, 3-pentafluoropropyl radical]-N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 3, 3, 3-pentafluoro-1- (4-pyridin-4-ylphenyl) propyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (4 '-fluoro-1, 1' -biphenyl-4-yl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- ((1S) -2, 2, 2-trifluoro-1- {4- [ (lE) -3-hydroxy-3-methylbut-1-enyl)]Phenyl } ethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 3, 3, 3-Pentafluoro-1- [4 '- (methylthio) -1, 1' -Biphenyl-4-yl]Propyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 3, 3, 3-Pentafluoro-1- [4 '- (methylsulfonyl) -1, 1' -Biphenyl-4-yl]Propyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (1-oxidopyridin-3-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (morpholin-4-ylcarbonyl) phenyl ]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (4- { [ methoxy (methyl) amino group]Carbonyl } phenyl) ethyl]-L-leucineAn amide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (4-thiophen-3-ylphenyl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (4-methylpyridin-2-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (5-methylpyridin-2-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 2-trifluoro-l- (2 '-fluoro-l, l' -biphenyl-4-yl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -1- [4- (3, 5-Dimethylisoxazol-4-yl) phenyl]-2, 2, 2-trifluoroethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (hydroxymethyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N²- [ (1S) -1- (4 '-cyano-1, 1' -biphenyl-4-yl) -2, 2, 2-trifluoroethyl radical]-N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -1- (3 ', 4 ' -difluoro-1, 1 ' -biphenyl-4-yl) -2, 2, 2-trifluoroethyl radical]-L-leucinamide;

4' - { l- [1- (cyanomethyl-carbamoyl) -3-methyl-butylamino ] -2, 2, 2-trifluoro-ethyl } biphenyl-2-carboxylic acid methyl ester;

4' - {1- [1- (cyanomethyl-carbamoyl) -3-methyl-butylamino ] -2, 2, 2-trifluoro-ethyl } biphenyl-3-carboxylic acid methyl ester;

N¹- (cyanomethyl) -N²- [ (1S) -l- (3 ', 4 ' -dimethoxy-1, 1 ' -biphenyl-4-yl) -2, 2, 2-trifluoroethyl radical]-L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [2 '- (trifluoromethyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -1- (3 ', 4 ' -dichloro-1, 1 ' -biphenyl-4-yl) -2,2, 2-trifluoroethyl group]-L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (3 '-formyl-1, 1' -biphenyl-4-yl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (2-oxo-2, 3-dihydro-1, 3-benzothiazol-6-yl) phenyl]Ethyl } -L-leucinamide;

N²- { (1S) -1- [4- (5-Bromopyridin-3-yl) phenyl]-2, 2, 2-trifluoroethyl } -N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-l- [4 '- (trifluoromethoxy) -l, l' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (1H-indol-4-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (4-pyrimidin-5-ylphenyl) ethyl ]-L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (4-quinolin-3-ylphenyl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (1, 3-thiazol-2-yl) phenyl]Ethyl } -L-leucinamide;

4' - {1- [1- (cyanomethyl-carbamoyl) -3-methyl-butylamino ] -2, 2, 2-trifluoro-ethyl } biphenyl-4-carboxylic acid methyl ester;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (4-pyrimidin-2-ylphenyl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (3-methylpyridin-2-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-l- [4- (3-furyl) phenyl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- ((1S) -2, 2, 2-trifluoro-1- {4- [3- (trifluoromethyl) pyridin-2-yl]Phenyl group } BYl) -L-leucinamide;

N¹- (cyanomethyl) -N²- ((1S) -2, 2, 2-trifluoro-1- {4- [4- (trifluoromethyl) pyridin-2-yl]Phenyl } ethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- ((1S) -2, 2, 2-trifluoro-1- {4- [5- (trifluoromethyl) pyridin-2-yl]Phenyl } ethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (3 '-methoxy-1, 1' -biphenyl-4-yl) ethyl ]-L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (3 '-methoxy-1, 1' -biphenyl-4-yl) ethyl]-L-leucinamide;

N²- { (1S) -1- [4 ' - (acetylamino) -3 ' -fluoro-1, 1 ' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (3-methylthiophen-2-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (3 '-fluoro-1, 1' -biphenyl-4-yl) ethyl]-L-leucinamide;

N²- { (1S) -1- [4- (5-acetylthiophen-2-yl) phenyl]-2, 2, 2-trifluoroethyl } -N¹- (cyanomethyl) -L-leucinamide;

N²- [ (1S) -1- (3 '-acetyl-1, 1' -biphenyl-4-yl) -2, 2, 2-trifluoroethyl radical]-N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [3 '- (trifluoromethyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (5 ' -fluoro-2 ' -methoxy-1, 1 ' -biphenyl-4-yl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -1- (3 ', 5 ' -difluoro-1, 1 ' -biphenyl-4-yl) -2, 2, 2-trifluoroethyl radical]-L-leucinamide;

N¹- (cyanomethyl) -N ²- [ (1S) -2, 2, 2-trifluoro-1- (2 ', 3', 5 '-trifluoro-1, 1' -biphenyl-4-yl) ethyl]-L-leucinamide;

3- (4' - {1- [1- (cyanomethyl-carbamoyl) -3-methyl-butylamino ] -2, 2, 2-trifluoro-ethyl } -biphenyl-3-yl) -acrylic acid;

N²- { (1S) -1- [4- (9-anthracenyl) phenyl]-2, 2, 2-trifluoroethyl } -N¹- (cyanomethyl) -L-leucinamide;

N²- [ (1S) -1- (4 '-benzoyl-1, 1' -biphenyl-4-yl) -2, 2, 2-trifluoroethyl radical]-N¹- (cyanomethyl) -L-leucinamide;

N²- [ (1S) -1- (3 ' -acetyl-4 ' -hydroxy-1, 1 ' -biphenyl-4-yl) -2, 2, 2-trifluoroethyl radical]-N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -1- [2 '- (cyanomethyl) -1, 1' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- {2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- {2, 2, 2-trifluoro-1- [4 '- (methylsulfinyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- [2, 2, 2-trifluoro-1- (4-morpholin-4-ylphenyl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- { (1R) -2, 2, 2-trifluoro-1- [4- (6-methylpyridin-3-yl) phenyl ]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (6-methylpyridin-3-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- [2, 2, 2-trifluoro-1- (5-phenylthiophen-2-yl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- [2, 2, 2-trifluoro-1- (4-quinolin-8-ylphenyl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (4-pyridin-2-ylphenyl) ethyl]-L-leucinamide;

N²- {1- [4 '- (aminosulfonyl) -1, 1' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -N¹- (cyanomethyl) -L-leucinamide;

N²- { (1S) -1- [4 '- (aminosulfonyl) -1, 1' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylthio) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N²- [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl radical]-N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- { (lR) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (morpholin-4-ylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (isopropylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N²- { (1S) -1- [4 '- (aminosulfonyl) -1, 1' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -N¹- (cyanomethyl) -L-leucinamide;

N²- ((1S) -1- { 4' - [ (acetylamino) sulfonyl group]-1, 1' -biphenyl-4-yl } -2, 2, 2-trifluoroethyl) -N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-l- [2 ' -methyl-4 ' - (methylsulfonyl) -1, 1 ' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N²- [1- (5-bromothien-2-yl) -22, 2-trifluoroethyl radical]-N¹- (cyanomethyl) -L-leucinamide;

N²- [1- (4-bromophenyl) -2, 2, 2-trifluoroethyl group]-N¹- (cyanomethyl) -L-leucinamide;

4- (4' - {1- [1- (cyanomethyl-carbamoyl) -3-methyl-butylamino ] -2, 2, 2-trifluoro-ethyl } -biphenyl-4-yl) -piperazine-l-carboxylic acid tert-butyl ester;

N¹- (cyanomethyl) -N²- [2, 2, 2-trifluoro-1- (4 '-piperazin-1-yl-1, 1' -biphenyl-4-yl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N ²- (2, 2, 2-trifluoro-1- { 4' - [4- (2-hydroxyethyl) piperazin-1-yl]-1, 1' -biphenyl-4-yl } ethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- (2, 2, 2-trifluoro-1- { 4' - [4- (2-hydroxy-2-methylpropyl) piperazin-1-yl]-1, 1' -biphenyl-4-yl } ethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- (1- {4- [ (dimethylamino) carbonyl group]Phenyl } -2, 2, 2-trifluoroethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- [2, 2, 2-trifluoro-1- (4 '-piperazin-1-yl-1, 1' -biphenyl-4-yl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- (1- {4- [ (cyclopropylamino) carbonyl]Phenyl } -2, 2, 2-trifluoroethyl) -L-leucinamide;

4- {1- [1- (cyanomethyl-carbamoyl) -3-methyl-butylamino ] -2, 2, 2-trifluoro-ethyl } -benzoic acid;

N¹- (cyanomethyl) -N²- (2, 2, 2-trifluoro-l- { 4' - [4- (2-fluoroethyl) piperazin-1-yl]-L, L' -biphenyl-4-yl } ethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- (2, 2, 2-trifluoro-1- {4- [ (4-methylpiperazin-1-yl) carbonyl]Phenyl } ethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- [2, 2, 2-trifluoro-1- (4- { [4- (2-hydroxy-2-methylpropyl) piperazin-1-yl group]Carbonyl } phenyl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-l- [4- (2-methyl-1, 3-thiazol-4-yl) phenyl ]Ethyl } -L-leucinamide;

N²- {1- [4- (3-tert-butyl-1, 2, 4-triazin-5-yl) phenyl]-2, 2, 2-trifluoroethyl } -N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- [2, 2, 2-trifluoro-1- (4- {2- [3- (methylsulfonyl) phenyl group]-1, 3-thiazol-4-yl } phenyl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- ((1S) -2, 2, 2-trifluoro-1- {4- [2- (lH-pyrazol-4-yl) -l, 3-thiazol-4-yl]Phenyl } ethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- (2, 2, 2-trifluoro-1- {4 '- {4- (methylsulfonyl) piperazin-1-yl } -1, 1' -biphenyl-4-yl } ethyl) -L-leucinamide;

N²- [ l- (3-bromophenyl) -2, 2, 2-trifluoroethyl group]-N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- {2, 2, 2-trifluoro-1- [4 '- (methylthio) -1, 1' -biphenyl-3-yl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- [2, 2, 2-trifluoro-l- (3-pyridin-4-ylphenyl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- [2, 2, 2-trifluoro-1- (4 '-piperazin-1-yl-1, 1' -biphenyl-3-yl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- {2, 2, 2-trifluoro-l- [4 '- (methylsulfonyl) -1, 1' -biphenyl-3-yl]Ethyl } -L-leucinamide;

n- (cyanomethyl) -1- [ (2, 2, 2-trifluoro-1-phenylethyl) amino ] cyclohexanecarboxamide;

1- { [1- (4-bromophenyl) -2, 2, 2-trifluoroethyl ] amino } -N- (cyanomethyl) cyclohexanecarboxamide;

1- { [2, 2, 2-trifluoro-1- (4 '-piperazin-1-yl-1, 1' -biphenyl-4-yl) ethyl ] amino } cyclohexanecarboxamide;

N¹- (cyanomethyl)-N²- [2, 2, 2-trifluoro-1- (4-piperidin-4-ylphenyl) ethyl group]-L-leucinamide;

N¹- (cyanomethyl) -N²- {2, 2, 2-trifluoro-1- [4- (4-pyridin-2-ylpiperazin-1-yl) phenyl]Ethyl } -L-leucinamide;

N²- [1- (4-bromophenyl) -2, 2, 2-trifluoroethyl group]-N¹- (cyanomethyl) -3-cyclopropylalaninamide;

N¹- (cyanomethyl) -3-cyclopropyl-N²- [2, 2, 2-trifluoro-1- (4-pyridin-4-ylphenyl) ethyl](ii) an alaninamide;

N¹- (cyanomethyl) -N²- [2, 2, 2-trifluoro-1- (4 '-pyridin-4-yl-1, 1' -biphenyl-4-yl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1R) -2, 2, 2-trifluoro-l- (1, 3-thiazol-2-yl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (4 '-methoxy-1, 1' -biphenyl-4-yl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (4-methoxyphenyl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (4 '-pyridin-4-yl-1, 1' -biphenyl-4-yl) ethyl ]-L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (4-phenoxyphenyl) ethyl]-L-leucinamide;

N²- [ (1S) -1- (4 '-bromo-1, 1' -biphenyl-4-yl) -2, 2, 2-trifluoroethyl radical]-N¹- (cyanomethyl) -L-leucinamide;

N²- { S } -1- [4- (4-chloropyridin-3-yl) phenyl]-2, 2, 2-trifluoroethyl } -N¹- (cyanomethyl) -L-leucinamide;

N²- { (1S) -1- [4 ' - (acetylamino) -2 ' -methyl-1, 1 ' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -N¹- (cyanomethyl) -L-leucinamide;

N²- [ (1S) -1- (1, 1' -biphenyl-4-yl) -2, 2, 2-trifluoroethyl radical]-N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (6-methoxypyridin-3-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (6-methoxypyridin-2-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-l- [4 "- (methylsulfonyl) -l, 1': 4 ', 1' -terphenyl-4-yl]Ethyl } -L-leucinamide;

N²- [ (1S) -I- (4-bromophenyl) -2, 2, 2-trifluoroethyl radical]-N¹- (cyanomethyl) -3- (1-methylcyclopropyl) -L-alaninamide;

N¹- (cyanomethyl) -3- (1-methylcyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl ]Ethyl } -L-alaninamide;

N¹- (cyanomethyl) -3- (1-methylcyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1 ' - [4 ' - (methylthio) -1, 1 ' -biphenyl-4-yl]Ethyl } -L-alaninamide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (4 '-methyl-1, 1' -biphenyl-4-yl) ethyl]-L-leucinamide;

N²- [ (1S) -1- (4 '-acetyl-1, 1' -biphenyl-4-yl) -2, 2, 2-trifluoroethyl radical]-N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-l- [4 '- (hydroxymethyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N²- [1- (4-bromophenyl) -2, 2, 2-trifluoroethyl group]-N¹- (cyanomethyl) -D-leucinamide;

N¹- (cyanomethyl) -N²- {2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -D-leucinamide;

N¹- (cyanomethyl) -N²- {2-2, 2-trifluoro-1- [4 '- (morpholin-4-ylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -D-leucineAn amide;

N¹- (cyanomethyl) -N²- (2, 2, 2-trifluoro-l- { 4' - [ (methylamino) sulfonyl group]-1, 1' -biphenyl-4-yl } ethyl) -D-leucinamide;

N¹- (cyanomethyl) -N²- { (1R) -2, 2, 2-trifluoro-1- [4- (1-oxidopyridin-4-yl) phenyl]Ethyl } L-leucinamide;

N¹- (cyanomethyl) -N²- {2, 2, 2-trifluoro-1- [4- (1-oxidopyridin-4-yl) phenyl ]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- (2, 2, 2-trifluoro-1- {4- [6- (1-hydroxy-1-methylethyl) -1-oxidopyridin-3-yl)]Phenyl } ethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- (2, 2, 2-trifluoro-1- {4- [6- (methylsulfonyl) pyridin-3-yl]Phenyl } ethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- (2, 2, 2-trifluoro-1- {4- [2- (4-methylpiperazin-1-yl) -1, 3-thiazol-4-yl)]Phenyl } ethyl) -L-leucinamide;

N²- [1- (4-bromophenyl) -2, 2, 2-trifluoroethyl group]-N¹- (1-cyanocyclopropyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- [2, 2, 2-trifluoro-1- (4-piperazin-1-ylphenyl) ethyl]-L-leucinamide;

N²- {1- [3 '- (acetylamino) -1, 1' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- {2, 2, 2-trifluoro-1- [4- (4-propylpiperazin-1-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- {2, 2, 2-trifluoro-1- [4- (piperazin-1-ylcarbonyl) phenyl]ethyl-L-leucinamide;

N¹- (cyanomethyl) -N²- [2, 2, 2-trifluoro-1- (4- { [4- (2-hydroxyethyl) piperazin-1-yl group]Carbonyl } phenyl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (4- {3- [3- (trifluoromethyl) methyl ) Phenyl radical]-1, 2, 4-oxadiazol-5-yl } phenyl) ethyl]-L-leucinamide;

4- {1- [1- (cyanomethyl-carbamoyl) -3-methyl-butylamino ] -2, 2, 2-trifluoro-ethyl } -benzoic acid methyl ester;

N¹- (cyanomethyl) -N²- ((1S) -2, 2, 2-trifluoro-1- {4- [ (E) -2-quinolin-2-ylvinyl)]Phenyl } ethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (3-methyl-1, 2, 4-oxadiazol-5-yl) phenyl]Ethyl } -L-leucinamide;

N²- ((1S) -1- {4- [3- (5-bromopyridin-3-yl) -1, 2, 4-oxadiazol-5-yl)]Phenyl } -2, 2, 2-trifluoroethyl) -N¹- (cyanomethyl) -L-leucinamide;

N²- [ (1S) -1- (4-benzoylphenyl) -2, 2, 2-trifluoroethyl radical]-N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (thien-2-ylcarbonyl) phenyl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (1, 3-thiazol-2-ylcarbonyl) phenyl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (4- { (Z) -2- [4- (methylsulfonyl) phenyl]Vinyl } phenyl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (4- { (E) -2- [4- (methylsulfonyl) phenyl ]Vinyl } phenyl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (4-isobutyrylphenyl) ethyl]-L-leucinamide;

N²- { (1S) -1- [4- (4-bromo-1, 3-thiazol-2-yl) phenyl]-2, 2, 2-trifluoroethyl } -N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -1- (4-cyanophenyl) -2, 2, 2-trifluoroethyl radical]-L-leucinamide;

N¹- (cyanoformazan)Radical) -N²- [ (1S) -1- (4-ethynylphenyl) -2, 2, 2-trifluoroethyl radical]-L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (2 '-fluoro-1, 1' -biphenyl-4-yl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-l- [4- (1, 3-thiazol-2-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- {2, 2, 2-trifluoro-1- [4 '- (methylthio) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- {2, 2, 2-trifluoro-1- [4- (2-methylquinolin-7-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- {2, 2, 2-trifluoro-1- [4- (lH-indol-5-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- {1- [4 '- (dimethylamino) -1, 1' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -L-leucinamide;

N¹- (cyanomethyl) -N ²- [ (1S) -1- (4- { [ (cyanomethyl) amino]Carbonyl } phenyl) -2, 2, 2-trifluoroethyl]-L-leucinamide;

N¹- (cyanomethyl) N²- [ (1R) -1- (4- { [ (cyanomethyl) amino]Carbonyl } phenyl) -2, 2, 2-trifluoroethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- {2, 2, 2-trifluoro-1- [3 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

4' - {1- [ l- (cyanomethyl-carbamoyl) -3-methyl-butylamino ] -2, 2, 2-trifluoro-ethyl } -biphenyl-4-carboxylic acid;

4' - {1- [1- (cyanomethyl-carbamoyl) -3-methyl-butylamino ] -2, 2, 2-trifluoro-ethyl } -biphenyl-4-carboxylic acid methoxy-methyl-amide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- ({ [4- (methylsulfonyl) benzyl)]Thio } methyl) phenyl]Ethyl } -L-leucinamide;

N²-{(1S) -1- [4- (5-Chloropyridin-2-yl) phenyl]-2, 2, 2-trifluoroethyl } -N¹- (cyanomethyl) -L-leucinamide;

N²- { (1S) -1- [3 ' - (aminosulfonyl) -4 ' -bromo-1, 1 ' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -N¹- (cyanomethyl) -L-leucinamide;

N²- { (1S) -1- [4 ' -bromo-3 ' - (methylsulfonyl) -1, 1 ' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N ²- ((1S) -2, 2, 2-trifluoro-1- {4- [ 5-methyl-6- (methylsulfonyl) pyridin-3-yl)]Phenyl } ethyl) -L-leucinamide;

N²- [ (1S) -1- (4- { 5-chloro-3- [4- (methylsulfonyl) phenyl]Pyridin-2-yl } phenyl) -2, 2, 2-trifluoroethyl]-N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- ((1S) -2, 2, 2-trifluoro-l- {4- [ (phenylthio) methyl group]Phenyl } ethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- ((1S) -2, 2, 2-trifluoro-1- { 4' - [ (trifluoromethyl) sulfonyl group]-1, 1' -biphenyl-4-yl } ethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 2-trifluoro-1 (4- { [ (4-fluorobenzoyl) amino]Methyl } phenyl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (methylsulfonyl) phenyl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -1- [4 '- (ethylsulfonyl) -1, 1' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -L-leucinamide;

N²- ((1S) -1- {4- [ ({ [3- (2-chloro-6-fluorophenyl) -5-methylisoxazol-4-yl)]Carbonyl } amino) methyl]Phenyl } -2, 2, 2-trifluoroethyl) -N¹- (cyanomethyl) -L-leucinamide;

N²- ((1S) -1- {4- [ (9-chloro-3-methyl-4-oxoisoxazolo [4, 3-c)]Quinolin-5 (4H) -yl) methylphenyl]-2, 2, 2-trifluoroethyl } -N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 ' -methoxy-3 ' - (methylsulfonyl) -1, 1 ' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N²- { (1S) -1- [4 "-chloro-4 '- (methylsulfonyl) -1, 1': 2 ', 1' -terphenyl-4-yl]-2, 2, 2-trifluoroethyl } -N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [2 ' -methoxy-4 ' - (methylsulfonyl) -1, 1 ' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N²- { (1S) -1- [2 ' -chloro-4 ' - (methylsulfonyl) -1, 1 ' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- ((1S) -2, 2, 2-trifluoro-1- { 4' - [ (2-hydroxyethyl) thio)]-1, 1' -biphenyl-4-yl } ethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [3 ' -fluoro-4 ' - (methylsulfonyl) -1, 1 ' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- ((1S) -2, 2, 2-trifluoro-1- { 4' - [ (2-hydroxyethyl) sulfonyl]-1, 1' -biphenyl-4-yl } ethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [3 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [ 4' - ({2- [ methoxy (methyl) amino)]-2-oxoethyl } sulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- ((1S) -2, 2, 2-trifluoro-l- { 4' - [ (2-hydroxy-2-methylpropyl) sulfonyl)]-1, 1' -biphenyl-4-yl } ethyl) -L-leucinamide;

N²- { (1S) -1- [4 '- (aminosulfonyl) -1, 1' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -N¹- (1-cyanocyclopropyl) -L-leucinamide;

N²- [ (4-bromophenyl) (2, 4, 6-trifluorophenyl) methyl]-N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- ([ (4-pyridin-4-ylphenyl) (2, 4, 6-trifluorophenyl) methyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- [ [4- (4-fluorobenzyl) phenyl group](phenyl) methyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- { phenyl [4- (pyridin-3-ylmethyl) phenyl]Methyl } -L-leucinamide;

N²- { (4-bromophenyl) [4- (methylsulfonyl) phenyl]Methyl } -N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- { [4- (methylsulfonyl) phenyl][4 '- (methylthio) -1, 1' -biphenyl-4-yl ]Methyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- { [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl][4- (methylsulfonyl) phenyl group]Methyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- [2, 2, 2-trichloro-1- (4-glycolylphenyl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- [ 2-fluoro-1- (fluoromethyl) -1-phenylethyl group]-L-leucinamide;

N¹- (cyanomethyl) -N²- {2, 2, 2-trifluoro-1- [4- (pyrrolidin-1-ylacetyl) phenyl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- {2, 2, 2-trifluoro-1- [4- (piperazin-l-ylcarbonyl) phenyl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- (2, 2, 2-trifluoro-1- {4- [2- (4-methylpiperazin-1-yl) -1, 3-thiazol-4-yl)]Phenyl } ethyl) -L-leucinamide;

N¹- (1-cyanocyclopropyl) -3- (1-methylcyclopropyl))-N²- (2, 2, 2-trifluoro-1- {4- [1- (2-hydroxyethyl) propyl group]Phenyl } ethyl) -L-alaninamide;

N²- [ [4- (4-tert-butylpiperazin-1-yl) phenyl group](pentafluorophenyl) methyl group]-N¹- (cyanomethyl) -L-leucinamide;

1- {4- [4- (4-methylpiperazin-1-yl) phenyl ] ethyl } piperidine-2-carboxamide;

N²- [ [4- (4-tert-butylpiperazin-1-yl) phenyl group](pyridin-2-yl) methyl]-N¹- (cyanomethyl) -L-leucinamide;

N²- [ [4- (4-tert-butylpiperazin-1-yl) phenyl group ][5- (trifluoromethyl) pyridin-2-yl]Methyl radical]-N¹- (cyanomethyl) -L-leucinamide;

(4S) -N- (cyanomethyl) -4-methyl-1- [ (1S) -1- (4-piperazin-1-ylphenyl) ethyl ] -L-prolinamide;

(4S) -N- (cyanomethyl) -4-methyl-1- [ (1R) -1- (4-piperazin-1-ylphenyl) ethyl ] -L-prolinamide;

n- (cyanomethyl) -1- [ (1S) -1- (4-piperazin-1-ylphenyl) ethyl ] -L-prolinamide;

n- (cyanomethyl) -1- [ (lR) -1- (4-piperazin-1-ylphenyl) ethyl ] -L-prolinamide;

n- (cyanomethyl) -4, 4-difluoro-1- [ (1S) -1- (4-piperazin-1-ylphenyl) ethyl ] -L-prolinamide;

N¹- (1-cyanocyclopropyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (4-methylphenyl) ethyl]-L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (1H-pyrazol-3-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (2-methyl-1, 3-oxazol-4-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (4-pyrazin-2-ylphenyl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (2-methylpyridin-4-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (4-methylpyridin-3-yl) phenyl ]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-l- [4- (1H-pyrazol-4-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (4-pyridin-4-ylphenyl) ethyl]-L-leucinamide;

N²- [ (1S) -1- (3 '-acetyl-1, 1' -biphenyl-4-yl) -2, 2, 2-trifluoroethyl radical]-N¹- (1-cyanocyclopropyl) -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (3 ' -fluoro-4 ' -methyl-1, 1 ' -biphenyl-4-yl) ethyl]-L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- ((1S) -2, 2, 2-trifluoro-1- {5- [4- (1-hydroxy-l-methylethyl) phenyl]Pyridin-2-yl } ethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 3, 3, 3-Pentafluoro-1- [4 '- (1-hydroxy-1-methylethyl) -1, 1' -biphenyl-4-yl]Propyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- [ (1S) -2, 2, 3, 3, 3-pentafluoro-1- (4 '-methyl-1, 1' -biphenyl-4-yl) propyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 3, 3, 3-Pentafluoro-1- [4- (6-methoxypyridin-3-yl) phenyl]Propyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 3, 3, 3-pentafluoro-1- (2 '-fluoro-1, 1' -biphenyl-4-yl) propyl ]-L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 ' -methoxy-3 ' - (methylsulfonyl) -1, 1 ' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N²- { (1S) -1- [3 ' - (aminosulfonyl) -4 ' -methoxy-1, 1 ' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -N¹- (1-cyanocyclopropyl) -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (6-methoxypyridin-3-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 3, 3, 3-Pentafluoro-1- [4- (5-methylpyridin-2-yl) phenyl]Propyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- ((1S) -2, 2, 2-trifluoro-1- {4- [5- (methylsulfonyl) pyridin-2-yl)]Phenyl } ethyl) -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (5-methylpyridin-2-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [2 ' -methyl-4 ' - (methylsulfonyl) -1, 1 ' -biphenyl-4-yl ]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-l- [5- (1H-pyrazol-3-yl) pyridin-2-yl]Ethyl } -L-leucinamide;

N¹- [ (1-cyanocyclopropyl) -N²- [ (1S) -2, 2, 2-trifluoro-l- (5-quinolin-5-ylpyridin-2-yl) ethyl]-L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (5-quinolin-6-ylpyridin-2-yl) ethyl]-L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2-difluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N²- [ (1S) -1- (4 '-acetyl-1, 1' -biphenyl-4-yl) -2, 2, 3, 3, 3-pentafluoropropyl radical]-N¹- (1-cyanocyclopropyl) -L-leucinamide;

N²- [ (1S) -1- (1, 1' -biphenyl-4-yl) -2, 2, 2-trifluoroethyl radical]-N¹- (1-cyanocyclopropyl) -L-leucinamide;

N²- { (1S) -1- [4 '- (aminosulfonyl) -1, 1' -biphenyl-4-yl]-2, 2, 3, 3, 3-pentafluoropropyl } -N¹- (1-cyanocyclopropyl) -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -1- [4- (1-ethoxyvinyl) phenyl]-2, 2, 2-trifluoroethyl } -L-leucinamide;

N²- [ (1S) -1- (4-acetylphenyl) -2, 2, 2-trifluoroethyl radical]-N¹- (1-cyanocyclopropyl) -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (4-isopropylphenyl) ethyl ]-L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- [ (1S) -2, 2, 2-trifluoro-1-phenylethyl]-L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (1-hydroxy-1-methylethyl) phenyl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (1-methylcyclopropyl) phenyl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (2 ', 4', 6 '-trimethyl-1, 1' -biphenyl-4-yl) ethyl]-L-leucinamide;

N²- [ (1S) -1- (6-Chloropyridin-3-yl) -2, 2, 2-trifluoroethyl radical]-N¹- (1-cyanocyclopropyl) -L-leucinamide;

N²- { (1S) -1- [5- (4-acetylphenyl) pyridin-2-yl]-2, 2, 2-trifluoroethyl } -N¹- (1-cyanocyclopropyl) -L-leucinamide;

N²- { (1S) -1- [6- (4-acetylphenyl) pyridin-3-yl]-2, 2, 2-trifluoroethyl } -N¹- (1-cyanocyclopropyl) -L-leucinamide;

N²- [ (1S) -1- [5- (3-acetylphenyl) pyridin-2-yl]-2, 2, 2-trifluoroethyl]-N¹- (1-cyano)Cyclopropyl) -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- ((1S) -2, 2, 2-trifluoro-1- {5- [4- (1-hydroxyethyl) phenyl]Pyridin-2-yl } ethyl) -L-leucinamide;

N²- [ (1S) -1- (1, 1' -biphenyl-4-yl) -2, 2, 3, 3, 3-pentafluoropropyl radical ]-N¹- (cyanomethyl) -L-leucinamide;

N²- [ (1S) -1- (4 '-acetyl-1, 1' -biphenyl-4-yl) -2, 2, 3, 3, 3-pentafluoropropyl radical]-N¹- (cyanomethyl) -L-leucinamide;

N²- [ (1S) -1- (1, 1' -biphenyl-4-yl) -2, 2, 3, 3, 3-pentafluoropropyl radical]-N¹- (1-cyanocyclopropyl) -L-leucinamide;

N²- (1-benzyl-2, 2, 2-trifluoroethyl) -N¹- (1-cyanocyclopropyl) -L-leucinamide;

N²- [ (1S) -1- (4-tert-butylphenyl) -2, 2, 2-trifluoroethyl radical]-N¹- (1-cyanocyclopropyl) -L-leucinamide;

N²- [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl radical]-N¹- (cyanomethyl) -4-methyl-L-leucinamide;

N²- [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl radical]-N¹- (1-cyanocyclopropyl) -4-methyl-L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- ((1S) -2, 2, 2-trifluoro-1- {4- [2- (lH-pyrazol-4-yl) -1, 3-thiazol-4-yl)]Phenyl } ethyl) -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (2-methyl-1, 3-thiazol-4-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-l- [4- (2-methylpyridin-4-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (2-methylpyridin-3-yl) phenyl ]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1-[4- (6-methylpyridin-2-yl) phenyl]Ethyl } -L-leucinamide;

N²- [ (1S) -1- (3 '-acetyl-1, 1' -biphenyl-4-yl) -2, 2, 2-trifluoroethyl radical]-N¹- (1-cyanocyclopropyl) -4-fluoro-L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4- (lH-pyrazol-3-yl) phenyl]Ethyl } -L-leucinamide;

N¹- [ (1S) -1-cyanoethyl]-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- [ (1S) -1-cyano-3- (methylthio) propyl]-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- [ (1S) -1-cyano-3- (methylsulfonyl) propyl]-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N²- [ (1S) -1- (4-bromophenyl) -2, 2, 3, 3, 3-pentafluoropropyl radical]-N¹- (1-cyanocyclopropyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 3, 3, 3-Pentafluoro-1- [4- (6-methoxypyridin-2-yl) phenyl]Propyl } -L-leucinamide;

N²- [ (1S) -1- (5-Bromopyridin-2-yl) -2, 2, 2-trifluoroethyl radical]-N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- ((1S) -2, 2, 2-trifluoro-1- {5- [4- (methylsulfonyl) phenyl]Pyridin-2-yl } ethyl) -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (1-hydroxy-1-methylethyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (6 '-methyl-3, 3' -bipyridin-6-yl) ethyl]-L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4-(6-methoxypyridin-2-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (6-oxo-1, 6-dihydropyridin-2-yl) phenyl]Ethyl } -L-leucinamide;

(4S)-N¹- (cyanomethyl) -5, 5, 5-trifluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

(4S)-N¹- (1-cyanocyclopropyl) -5, 5, 5-trifluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

(4S)-N¹- (cyanomethyl) -5, 5, 5-trifluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylthio) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

(4S)-N¹- (1-cyanocyclopropyl) -5, 5, 5-trifluoro-N { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylthio) -1, 1' -biphenyl-4-yl ]Ethyl } -L-leucinamide;

(4S)-N²- [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl radical]-N¹- (cyanomethyl) -5, 5, 5-trifluoro-L-leucinamide;

(4S)-N²- [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl radical]-N¹- (1-cyanocyclopropyl) -5, 5, 5-trifluoro-L-leucinamide;

N²- { (1S) -1- [4- (6-Aminopyridin-3-yl) phenyl]-2, 2, 2-trifluoroethyl } -N¹- (cyanomethyl) -L-leucinamide;

N²- [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl radical]-N¹- (1-cyanocyclopropyl) -4-fluoro-L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 3, 3, 3-Pentafluoro-1- [4- (6-methylpyridin-3-yl) phenyl]Propyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 3, 3, 3-Pentafluoro-1- [4- (6-methylpyridin-3-yl) phenyl]Propyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-TrisFluoro-1- [4- (6-methylpyridin-3-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (1-hydroxyethyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (2, 2, 2-trifluoro-1-hydroxyethyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²{ (1S) -2, 2, 3, 3, 3-Pentafluoro-1- [4 '- (methylthio) -1, 1' -Biphenyl-4-yl ]Propyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 3, 3, 3-Pentafluoro-1- [4 '- (1-hydroxy-1-methylethyl) -1, 1' -biphenyl-4-yl]Propyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 3, 3, 3-Pentafluoro-1- [4 '- (methylsulfonyl) -1, 1' -Biphenyl-4-yl]Propyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 3, 3, 3-Pentafluoro-1- [4- (6-methoxypyridin-2-yl) phenyl]Propyl } -L-leucinamide;

(4R)-N¹- (cyanomethyl) -5, 5, 5-trifluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

(4R)N¹- (1-cyanocyclopropyl) -5, 5, 5-trifluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- [ (1S) -2, 2, 3, 3, 3-pentafluoro-1- (4 '-methyl-1, 1' -biphenyl-4-yl) propyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 3, 3, 3-Pentafluoro-1- [4- (1, 3-thiazol-2-yl) phenyl]Propyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- [ (1S) -1- (4-ethynylphenyl) -2, 2, 3, 3, 3-pentafluoropropyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -1- [4- (cyclopropylethynyl) phenyl ]-2, 2, 2-trifluoroethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -1- [4- (cyclopropylethynyl) phenyl]-2, 2, 2-trifluoroethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (5-methyl-1, 3-thiazol-2-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-l- [4- (1, 3-thiazol-2-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- (4- (5-methyl-1, 3-thiazol-2-yl) phenyl) ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -1- [4- (cyclopropylethynyl) phenyl]-2, 2, 3, 3, 3-pentafluoropropyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (4-methyl-1, 3-thiazol-2-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (4-methyl-1, 3-thiazol-2-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -1- [4- (4, 5-dimethyl-1, 3-thiazol-2-yl) phenyl]-2, 2, 2-trifluoroethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -1- [4 '- (ethylsulfonyl) -1, 1' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -4-fluoro-L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- [ (1S) -2, 2, 2-trifluoro-1- (4-pyridin-3-ylphenyl) ethyl]-L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-l- [4 ' -methoxy-3 ' - (methylsulfonyl) -1, 1 ' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N²-[(1S)-1- (4-bromophenyl) -2, 2, 2-trifluoroethyl]-N¹- (cyanomethyl) -L-alaninamide;

N²- { (1S) -1- [4 '- (aminosulfonyl) -1, 1' -biphenyl-4-yl]-2, 2, 3, 3, 3-pentafluoropropyl } -N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- ((1S) -2, 2, 3, 3, 3-Pentafluoro-1- { 4' - [ (2-hydroxy-2-methylpropyl) sulfonyl)]-1, 1' -biphenyl-4-yl } propyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-alaninamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 3, 3, 3-Pentafluoro-1- [4 '- (isopropylsulfonyl) -1, 1' -biphenyl-4-yl]Propyl } -L-leucinamide;

N¹- (1-cyano-1-methylethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- ((1S) -2, 2, 2-trifluoro-1- { 4' - [ (2-hydroxy-2-methylpropyl) sulfonyl) ]-1, 1' -biphenyl-4-yl } ethyl) -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [2 ' -methyl-4 ' - (methylsulfonyl) -1, 1 ' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -1- [4 '- (ethylsulfonyl) -1, 1' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -L-leucinamide;

N²- { (1S) -1- [4 '- (aminosulfonyl) -1, 1' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -N¹- (1-cyanocyclopropyl) -4-fluoro-L-leucinamide;

N¹- (cyanomethyl) -N²- { (S) - [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl][4- (trifluoromethoxy) phenyl group]Methyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- { (S) - [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl](thiophene)-2-yl) methyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- [ (S) - [4 '-piperazin-4-ium-1-yl-1, 1' -biphenyl-4-yl](Thien-2-yl) methyl]-L-leucinamide mesylate;

N¹- (cyanomethyl) -N²- { (S) - (4-fluorophenyl) [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Methyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- { (S) - [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl][4- (trifluoromethyl) phenyl group]Methyl } -L-leucinamide;

N²- { (S) - (4-chlorophenyl) [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl ]Methyl } -N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-norvalinamide;

N²- [ (S) - (4-bromophenyl) (thiophen-2-yl) methyl]-N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- [ (S) - [4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl](Thien-2-yl) methyl]-L-leucinamide;

N²- { (R) - (4-bromophenyl) [4- (trifluoromethoxy) phenyl]Methyl } -N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- { (S) - [4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl][4- (trifluoromethoxy) phenyl group]Methyl } -L-leucinamide;

N²- [ (S) - (4-bromophenyl) (2-furyl) methyl]-N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- { (S) -2-Furanyl [4 '- (methylsulfonyl) -1, 1' -Biphenyl-4-yl]Methyl } -L-leucinamide;

N²- [1- (4-bromophenyl) -2, 2, 2-trifluoroethyl group]-N¹- (cyanomethyl) -L-norvalinamide;

N²- { (R) - (4-bromobenzene)Radical) [4- (trifluoromethyl) phenyl]Methyl } -N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- {1- [4 '- (4-cyclopropylpiperazin-1-yl) -1, 1' -biphenyl-4-yl ]-2, 2, 2-trifluoroethyl } -L-norvalinamide;

N²- [ (R) - (4-bromophenyl) (4-chlorophenyl) methyl]-N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- {2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-norvalinamide;

N²- [ (S) - (4-bromophenyl) (3-methylthiophen-2-yl) methyl]-N¹- (cyanomethyl) -L-leucinamide;

N²- [ (S) - (4-bromophenyl) (thiophen-3-yl) methyl]-N¹- (cyanomethyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- { (S) - (2, 4-difluorophenyl) [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Methyl } -L-leucinamide;

N¹- (cyanomethyl) -N²- [ (S) - [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl](Thien-3-yl) methyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- [ (S) - [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl](3-methylthiophen-2-yl) methyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- [ (S) - [4 '- (4-cyclopropylpiperazin-1-yl) -1, 1' -biphenyl-4-yl](3-methylthiophen-2-yl) methyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- [ (S) - [4 '- (4-cyclopropylpiperazin-1-yl) -1, 1' -biphenyl-4-yl](Thien-3-yl) methyl]-L-leucinamide;

N²- [1- (4-bromophenyl) -2, 2, 2-trifluoroethyl group]-N¹- (cyanomethyl) -5, 5, 5-trifluoro-L-norvalinamide;

N¹- (cyanomethyl) -5, 5, 5-trifluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-norvalinamide;

N²- [ (S) - (4-bromophenyl) (3-methylthiophen-2-yl) methyl]-N¹- (1-cyanocyclopropyl) -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- [ (S) - [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl](3-methylthiophen-2-yl) methyl]-L-leucinamide;

N¹- (cyanomethyl) -N²- { (S) -3-furyl [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Methyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-norvalinamide;

N²- [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl radical]-N¹- (cyanocyclopropyl) -L-norvalinamide N²- [ (S) - (4-bromophenyl) (4-bromothien-2-yl) methyl]-N¹- (cyanomethyl) -L-leucinamide;

N²- [ (S) - (4-bromophenyl) (thiophen-3-yl) methyl]-N' - (1-cyanocyclopropyl) -L-leucinamide;

N¹- (cyanomethyl) -N²- ((S) - [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl)]{4- [4- (methylsulfonyl) phenyl]Thien-2-yl } methyl) -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- [ (S) - [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl ](Thien-3-yl) methyl]-L-leucinamide;

N²- { (1S) -1- [4 '- (aminosulfonyl) -1, 1' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -N¹- (1-cyanocyclopropyl) -L-norvalinamide;

N²- [ (S) - (4-bromophenyl) (4-bromothien-2-yl) methyl]-N¹- (1-cyanocyclopropyl) -L-leucinamide;

N²- [ (S) - [4 '- (aminosulfonyl) -1, 1' -biphenyl-4-yl](Thien-3-yl) methyl]-N¹- (1-cyanocyclopropyl) -L-leucinamide;

N²- [ (S) - [4 '- (aminosulfonyl) -1, 1' -biphenyl-4-yl](Thien-3-yl) methyl]-N¹- (cyanomethyl) -L-leucylAn amine;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 ' -methoxy-3 ' - (methylsulfonyl) -1, 1 ' -biphenyl-4-yl]Ethyl } -L-norvalinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (2-methylpyridin-4-yl) phenyl]Ethyl } -L-norvalinamide;

N¹- (1-cyanocyclopropyl) -5, 5, 5-trifluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-norvalinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (lH-pyrazol-3-yl) phenyl]Ethyl } -L-norvalinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (1-hydroxy-1-methylethyl) -1, 1' -biphenyl-4-yl ]Ethyl } -L-norvalinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (5-methylpyridin-2-yl) phenyl]Ethyl } -L-norvalinamide;

2- { [ (4-bromo-phenyl) -pyridin-4-yl-methyl ] -amino } -pentanoic acid cyanomethyl-amide;

2- { [ (4-bromo-phenyl) -thiazol-2-yl-methyl ] -amino } -pentanoic acid cyanomethyl-amide;

(2S) -2- [ (S) -1- (4' -acetylbiphenyl-4-yl) -2, 2, 2-trifluoroethylamino ] -pentanoic acid (1-cyanocyclopropyl) -amide;

(2S) -2- [ (S) -1- (2 ', 4' -difluorobiphenyl-4-yl) -2, 2, 2-trifluoroethylamino ] -pentanoic acid (1-cyanocyclopropyl) -amide;

(2S) -2- [ (S) -1- (3 ', 4' -difluorobiphenyl-4-yl) -2, 2, 2-trifluoroethylamino ] -pentanoic acid (1-cyanocyclopropyl) -amide;

(2S) -2- [ (S) -1- (3 '-chloro-4' -fluorobiphenyl-4-yl) -2, 2, 2-trifluoroethylamino ] -pentanoic acid (1-cyano-cyclopropyl) -amide;

(2S) -2- [ (S) -2, 2, 2-trifluoro-1- (4' -methanesulfonylamino-biphenyl-4-yl) -ethylamino ] -pentanoic acid (1-cyano-cyclopropyl) -amide;

(2S) -2- { (S) - [ (4-bromo-phenyl) -thiazol-2-ylmethyl ] -amino } -4-methylpentanoic acid cyanomethyl-amide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 '-chloro-1, 1' -biphenyl-4-yl ]Ethyl } -L-norvalinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 ' -chloro-3 ' -methyl-1, 1 ' -biphenyl-4-yl]Ethyl } -L-norvalinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 ' -chloro-2 ' -methyl-1, 1 ' -biphenyl-4-yl]Ethyl } -L-norvalinamide;

(2S) -2- { (S) -2, 2, 2-trifluoro-1- [4- (lH-indol-5-yl) -phenyl ] -ethylamino } -pentanoic acid (1-cyano-cyclopropyl) -amide;

(2S) -2- [ (S) -2, 2, 2-trifluoro-1- (3' -methanesulfonylamino-biphenyl-4-yl) -ethylamino ] -pentanoic acid (1-cyano-cyclopropyl) -amide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 '-fluoro-1, 1' -biphenyl-4-yl]Ethyl } -L-norvalinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 ' -fluoro-3 ' -methyl-l, l ' -biphenyl-4-yl]Ethyl } -L-norvalinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [3 ' -fluoro-4 ' -methyl-1, 1 ' -biphenyl-4-yl]Ethyl } -L-norvalinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 '-trifluoromethoxy-1, 1' -biphenyl-4-yl]Ethyl } -L-norvalinamide;

(2S) -2- [ (S) -2, 2, 2-trifluoro-1- (4' -methylbiphenyl-4-yl) -ethylamino ] -pentanoic acid (1-cyanocyclopropyl) -amide;

(2S) -2- [ (S) -1- (4' -cyanobiphenyl-4-yl) -2, 2, 2-trifluoroethylamino ] -pentanoic acid (1-cyanocyclopropyl) -amide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 '-methoxy-1, 1' -biphenyl-4-yl]Ethyl } -L-norvalinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4- (benzo [1, 3 ]]Dioxol-5-yl) phenyl]Ethyl } -L-norvalinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methoxycarbonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-norvalinamide;

(2S) -2- { (S) - [ (4-bromophenyl) -thiazol-2-yl-methyl ] -amino } -4-methylvaleric acid (1-cyanocyclopropyl) -amide;

(2S) -2- { (S) - [ (4' -methanesulfonyl-biphenyl-4-yl) -thiazol-2-yl-methyl ] -amino } -4-methyl-pentanoic acid cyanomethyl-amide;

(2S) -2- [ (S) -2, 2, 2-trifluoro-1- (4' -trifluoromethyl-biphenyl-4-yl) -ethylamino ] -pentanoic acid (1-cyano-cyclopropyl) -amide;

(2S) -2- [ (S) -2, 2, 2-trifluoro-1- (2' -trifluoromethyl-biphenyl-4-yl) -ethylamino ] -pentanoic acid (1-cyano-cyclopropyl) -amide;

(2S) -2- { (S) - [ (2 ', 4' -difluorobiphenyl-4-yl) -thiazol-2-yl-methyl ] -amino } -4-methylpentanoic acid (1-cyanocyclopropyl) -amide;

(2S) -2- { (S) - [ (4' -methanesulfonylbiphenyl-4-yl) -thiazol-2-yl-methyl ] -amino } -4-methylvaleric acid (1-cyanocyclopropyl) -amide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4- (1-oxo-2, 3-dihydro-1-benzothien-5-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -1- [4- (l, 1-dioxido-2, 3-dihydro-1-benzothien-5-yl) phenyl]-2, 2, 2-trifluoroethyl } -4-fluoro-L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -1- [4- (1, 1-dioxido-2, 3-dihydro-1, 2-benzisothiazol-5-yl) phenyl]-2, 2, 2-trifluoroethyl } -4-fluoro-L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfinyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -1- [4- (1, 1-dioxido-3-oxo-2, 3-dihydro-1, 2-benzisothiazol-5-yl) phenyl]-2, 2, 2-trifluoroethyl } -4-fluoro-L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [2 '- (1-hydroxy-1-methylethyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4, 4-difluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl ]Ethyl } -L-norvalinamide;

N¹- (cyanomethyl) -4, 4-difluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-norvalinamide;

N¹- (cyanomethyl) -4-fluoro-N²- { (1S) -2, 2, 2-trichloro-l- [4 '- (methylsulfonyl) -l, l' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trichloro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4, 4-difluoro-N²- { (1S) -2, 2, 2-trichloro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-norvalinamide;

N¹- (cyanomethyl) -4, 4-difluoro-N²- { (1S) -2, 2, 2-trichloro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-norvalinamide;

(2S) -N- (cyanomethyl) -4, 4-difluoro-2- ({ (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl ] ethyl } amino) butanamide;

(2S) -N- (1-cyanocyclopropyl) -4, 4-difluoro-2- ({ (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl ] ethyl } amino) butanamide;

(2S) -N- (1-cyanocyclopropyl) -4, 4-difluoro-2- ({ (1S) -2, 2, 2-trichloro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl ] ethyl } amino) butanamide;

(2S) -N- (cyanomethyl) -4, 4-difluoro-2- ({ (1S) -2, 2, 2-trichloro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl ] ethyl } amino) butanamide;

(2S) -4, 4-dichloro-N- (cyanomethyl) -2- ({ (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl ] ethyl } amino) butanamide;

(2S) -4, 4-dichloro-N- (1-cyanocyclopropyl) -2- ({ (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl ] ethyl } amino) butanamide;

(2S) -4, 4-dichloro-N- (1-cyanocyclopropyl) -2- ({ (1S) -2, 2, 2-trichloro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl ] ethyl } amino) butanamide;

(2S) -4, 4-dichloro-N- (cyanocyclopropyl) -2- ({ (1S) -2, 2, 2-trichloro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl ] ethyl } amino) butanamide;

N²- [ (1S) -1- (1, 1' -biphenyl-4-yl) -2, 2, 2-trifluoroethyl radical]-N¹- (1-cyanocyclopropyl) -4-fluoro-L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [3 '- (1-hydroxyethyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- [ (1S) -2, 2, 2-trifluoro-1- (4 '-methyl-1, 1' -biphenyl-4-yl) ethyl]-L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- [ (1S) -2, 2, 2-trifluoro-1- [3 '- (1-hydroxy-1-methylethyl) -1, 1' -biphenyl-4-yl]Ethyl radical]-L-leucinamide;

N²- [ (1S) -1- (4 '-acetyl-1, 1' -biphenyl-4-yl) -2, 2, 2-trifluoroethyl radical]-N¹- (1-cyanocyclopropyl) -4-fluoro-L-leucinamide;

N²- [ (1S) -1- (2 '-acetyl-1, 1' -biphenyl-4-yl) -2, 2, 2-trifluoroethyl radical]-N¹- (1-cyanocyclopropyl) -4-fluoro-L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (1-hydroxyethyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [2 '- (1-hydroxyethyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (1-hydroxy-1-methylethyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [2 '- (1-hydroxy-1-methylethyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- {5- [4- (methylsulfonyl) phenyl]Pyridin-2-yl } ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N ²- ((1S) -2, 2, 2-trifluoro-1- {6- [4- (methylsulfonyl) phenyl]Pyridin-3-yl } ethyl) -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- [ (1S) -2, 2, 2-trifluoro-1- (4- {6- [ (methylsulfonyl) amino group]Pyridin-3-yl } phenyl) ethyl]-L-leucinamide;

N¹- (cyanomethyl) -4-fluoro-N²- [ (1S) -2, 2, 2-trifluoro-1- (4- {6- [ (methylsulfonyl) amino group]Pyridin-3-yl } phenyl) ethyl]-L-leucinamide;

N¹- (1-cyanobutyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyano-2-cyclopropylethyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyano-2-pyridin-3-ylethyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-l- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyano-3-hydroxy-3-methylbutyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4- (1-oxo-1, 3-dihydro-2-benzofuran-5-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -1- [4- (3, 3-dimethyl-1-oxo-1, 3-dihydro-2-benzofuran-5-yl) phenyl]-2, 2, 2-trifluoroethyl } -4-fluoro-L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -1- [4- (3, 3-diethyl-1-oxo-1, 3-dihydro-2-benzofuran-5-yl) phenyl]-2, 2, 2-trifluoroethyl } -4-fluoro-L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4- (3-oxo-1, 3-dihydro-2-benzofuran-5-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -1- [4- (1, 1-dimethyl-3-oxo-1, 3-dihydro-2-benzofuran-5-yl) phenyl]-2, 2, 2-trifluoroethyl } -4-fluoro-L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -1- [4- (1, 1-diethyl-3-oxo-1, 3-dihydro-2-benzofuran-5-yl) phenyl]-2, 2, 2-trifluoroethyl } -4-fluoro-L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (3-oxo-1, 3-dihydro-2-benzofuran-5-yl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -1- [4 '- (1, 1-dimethyl-3-oxo-1, 3-dihydro-2-benzofuran-5-yl) -1, 1' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -4-fluoro-L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -1- [4 '- (1, 1-diethyl-3-oxo-1, 3-dihydro-2-benzofuran-5-yl) -1, 1' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -4-fluoro-L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-l- [4 '- (1-oxo-1, 3-dihydro-2-benzofuran-5-yl) -1, 1' -biphenyl-4-yl]Ethyl-L-leucinamide；

N¹- (1-cyanocyclopropyl) -N²- { (1S) -1- [4 '- (3, 3-dimethyl-1-oxo-1, 3-dihydro-2-benzofuran-5-yl) -1, 1' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -4-fluoro-L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -1- [4 '- (3, 3-diethyl-1-oxo-1, 3-dihydro-2-benzofuran-5-yl) -1, 1' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -4-fluoro-L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4- (5-oxo-2, 5-dihydrofuran-3-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -1- [4- (2, 2-dimethyl-5-oxo-2, 5-dihydrofuran-3-yl) phenyl]-2, 2, 2-trifluoroethyl } -4-fluoro-L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -1- [4- (2, 2-diethyl-5-oxo-2, 5-dihydrofuran-3-yl) phenyl-2, 2, 2-trifluoroethyl ]-4-fluoro-L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- {4- (2-oxo-2, 5-dihydrofuran-3-yl) phenyl } ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -1- [4- (5, 5-dimethyl-2-oxo-2, 5-dihydrofuran-3-yl) phenyl]-2, 2, 2-trifluoroethyl } -4-fluoro-L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -1- [4- (5, 5-diethyl-2-oxo-2, 5-dihydrofuran-3-yl) phenyl]-2, 2, 2-trifluoroethyl } -4-fluoro-L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4- (5-oxo-4-oxaspiro [2.4 ]]Hept-6-en-7-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4- (6-oxo-5-oxaspiro [3.4 ]]Oct-7-en-8-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4- (5-oxo-4-oxaspiro [2.4 ]]Hept-6-en-6-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4- (6-oxo-5-oxaspiro [3.4 ]]Oct-7-en-7-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- [ (1S) -2, 2, 2-trifluoro-1- (4-quinolin-6-ylphenyl) ethyl ]-L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfinyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N²- [ (1S) -1- (4 '-acetyl-1, 1' -biphenyl-4-yl) -2, 2, 2-trifluoroethyl radical]-N¹- (1-cyanocyclopropyl) -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (4-quinolin-6-ylphenyl) ethyl]-L-leucinamide;

N²- [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl radical]-N¹- (1-cyanocyclopropyl) -4, 4-difluoro-L-norvalinamide;

N¹- (1-cyanocyclopropyl) -4, 4-difluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylthio) -1, 1' -biphenyl-4-yl]Ethyl } -L-norvalinamide;

N¹- (1-cyanocyclopropyl) -4, 4-difluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-norvalinamide;

N¹- [ (1S) -1-cyano-3- (methylsulfonyl) propyl]-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- [ (1S) -2, 2, 2-trifluoro-1- (4-quinolin-6-ylphenyl) ethyl]-L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfinyl) -1, 1' -biphenyl-4-yl ]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (1-hydroxyethyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N²- [ (1S) -1- (4 '-acetyl-1, 1' -biphenyl-4-yl) -2, 2, 2-trifluoroethyl radical]-N¹- (1-cyanocyclopropyl) -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (4-quinolin-6-ylphenyl) ethyl]-L-leucinamide;

N²- [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl radical]-N¹- (1-cyanocyclopropyl) -4, 4-difluoro-L-norvalinamide;

N¹- (1-cyanocyclopropyl) -4, 4-difluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylthio) -1, 1' -biphenyl-4-yl]Ethyl } -L-norvalinamide;

N¹- (1-cyanocyclopropyl) -4, 4-difluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-norvalinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- ((1S) -2, 2, 2-trifluoro-1- {4- [ 5-methyl-6- (methylsulfonyl) pyridin-3-yl)]Phenyl } ethyl) -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- ((1S) -2, 2, 2-trifluoro-1- {4- [6- (1-hydroxy-1-methylethyl) -5-methylpyridin-3-yl)]Phenyl } ethyl) -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N ²- [ (1S) -2, 2, 2-trifluoro-1- (4 '-fluoro-1, 1' -biphenyl-4-yl) ethyl]-L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [3 ' -methyl-4 ' - (methylsulfonyl) -1, 1 ' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4- (6-methylpyridin-3-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-TrisFluoro-1- [4 '- (methylthio) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (1-hydroxy-1-methylethyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4- (2-methylquinolin-7-yl) phenyl]Ethyl } -L-leucinamide;

N²- [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl radical]-N¹- (cyanomethyl) -4, 4-difluoro-L-norvalinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- ((1S) -2, 2, 2-trifluoro-1- { 4' - [ (1S) -1-hydroxyethyl]-1, 1' -biphenyl-4-yl } ethyl) -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- ((1S) -2, 2, 2-trifluoro-1- { 4' - [ (1R) -1-hydroxyethyl]-1, 1' -biphenyl-4-yl } ethyl) -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (trifluoroacetyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [5- (2-naphthalenyl) pyridin-2-yl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -4, 4-difluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylthio) -1, 1' -biphenyl-4-yl]Ethyl } -L-norvalinamide;

N¹- (cyanomethyl) -4, 4-difluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-norvalinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4- (5-methyl-1, 3-thiazol-2-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -1- [4- (1, 1-dioxido-3-oxo-2, 3-dihydro-1, 2-benzisothiazol-5-yl) phenyl]-2, 2, 2-trifluoroethyl } -4-fluoro-L-leucinamide;

N²- [ (4-bromophenyl) (phenyl) methyl]-N¹- (1-cyanocyclopropyl) -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- [ (1S) -2, 2, 2-trifluoro-1- (4 '-methyl-1, 1' -biphenyl-4-yl) ethyl]-L-leucinamide;

N²- [ (1S) -1- (1, 1' -biphenyl-4-yl) -2, 2, 2-trifluoroethyl radical]-N¹- (1-cyanocyclopropyl) -4-fluoro-L-leucinamide;

N²- { (1S) -1- [4- (5-Chloropyridin-2-yl) phenyl]-2, 2, 2-trifluoroethyl } -N¹- (1-cyanocyclopropyl) -4-fluoro-L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- [ (1S) -2, 2, 2-trifluoro-1- (4-pyridin-4-ylphenyl) ethyl]-L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- ((1S) -2, 2, 2-trifluoro-1- { 4' - [ (methylsulfonyl) amino group]-1, 1' -biphenyl-4-yl } ethyl) -L-leucinamide;

N²- [ (1S) -1- (4-bromophenyl) -2, 2-difluoroethyl]-N¹- (1-cyanocyclopropyl) -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2-difluoro-1- [4 '- (methylthio) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- [ (1S) -2, 2, 2-trifluoro-1- (4-pyrimidin-5-ylphenyl) ethyl]-L-leucinamide;

N²- [ (1S) -1- (4 '-acetyl-1, 1' -biphenyl-4-yl) -2, 2, 2-trifluoroethyl radical]-N¹- (1-cyanocyclopropyl) -4-fluoro-L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [3 '- (1-hydroxyethyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N²- [ (1S) -1- (4 '-acetyl-1, 1' -biphenyl-4-yl) -2, 2-difluoroethyl]-N¹- (1-cyanocyclopropyl) -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²-{(1S)-1-[4-(3，5-Dimethylisoxazol-4-yl) phenyl ]-2, 2, 2-trifluoroethyl } -4-fluoro-L-leucinamide;

N¹- [ (1S) -1-cyano-3- (methylsulfonyl) propyl]-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- [ (1S) -2, 2, 2-trifluoro-1- (4-quinolin-6-ylphenyl) ethyl]-L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfinyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (1-hydroxyethyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N²- [ (1S) -1- (4 '-acetyl-1, 1' -biphenyl-4-yl) -2, 2, 2-trifluoroethyl radical]-N¹- (1-cyanocyclopropyl) -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- [ (1S) -2, 2, 2-trifluoro-1- (4-quinolin-6-ylphenyl) ethyl]-L-leucinamide;

N²- [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl radical]-N¹- (1-cyanocyclopropyl) -4, 4-difluoro-L-norvalinamide;

N¹- (1-cyanocyclopropyl) -4, 4-difluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylthio) -1, 1' -biphenyl-4-yl]Ethyl } -L-norvalinamide;

N¹- (1-cyanocyclopropyl) -4, 4-difluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl ]Ethyl } -L-norvalinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- ((1S) -2, 2, 2-trifluoro-1- {4- [ 5-methyl-6- (methylsulfonyl) pyridin-3-yl)]Phenyl } ethyl) -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- ((1S) -2, 2, 2-trifluoro-1- {4- [6- (1-hydroxy-1-methylethyl) -5-methylpyridin-3-yl)]Phenyl } ethyl) -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- [ (1S) -2, 2, 2-trifluoro-1- (4 '-fluoro-1, 1' -biphenyl-4-yl) ethyl]-L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [3 ' methyl-4 ' - (methylsulfonyl) -1, 1 ' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4- (6-methylpyridin-3-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylthio) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (1-hydroxy-1-methylethyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4- (2-methylquinolin-7-yl) phenyl]Ethyl } -L-leucinamide;

N²- [ (1S) -1- (4-bromophenyl) -2, 2, 2-trifluoroethyl radical]-N¹- (cyanomethyl) -4, 4-difluoro-L-norvalinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- ((1S) -2, 2, 2-trifluoro-1- { 4' - [ (1S) -1-hydroxyethyl]-1, 1' -biphenyl-4-yl } ethyl) -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- ((1S) -2, 2, 2-trifluoro-1- { 4' - [ (1R) -1-hydroxyethyl]-1, 1' -biphenyl-4-yl } ethyl) -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-l- [4 '- (trifluoroacetyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2, 2-trifluoro-1- [5- (2-naphthalenyl) pyridin-2-yl]Ethyl } -L-leucinamide;

N¹- (cyanomethyl) -4, 4-difluoro-N²- { (1S) -2, 2, 2-trifluoro-l- [4 '- (methylthio) -1, 1'-biphenyl-4-yl]Ethyl } -L-norvalinamide;

N¹- (cyanomethyl) -4, 4-difluoro-N²- { (1S) -2, 2, 2-trifluoro-l- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-norvalinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4- (5-methyl-1, 3-thiazol-2-yl) phenyl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -1- [4- (1, 1-dioxido-3-oxo-2, 3-dihydro-1, 2-benzisothiazol-5-yl) phenyl ]-2, 2, 2-trifluoroethyl } -4-fluoro-L-leucinamide;

N²- [ (4-bromophenyl) (phenyl) methyl]-N¹- (1-cyanocyclopropyl) -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- [ (1S) -2, 2, 2-trifluoro-1- (4 '-methyl-1, 1' -biphenyl-4-yl) ethyl]-L-leucinamide;

N²- [ (1S) -1- (1, 1' -biphenyl-4-yl) -2, 2, 2-trifluoroethyl radical]-N¹- (1-cyanocyclopropyl) -4-fluoro-L-leucinamide;

N²- { (1S) -1- [4- (5-Chloropyridin-2-yl) phenyl]-2, 2, 2-trifluoroethyl } -N¹- (1-cyanocyclopropyl) -4-fluoro-L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- [ (1S) -2, 2, 2-trifluoro-1- (4-pyridin-4-ylphenyl) ethyl]-L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- ((1S) -2, 2, 2-trifluoro-1- { 4' - [ (methylsulfonyl) amino group]-1, 1' -biphenyl-4-yl } ethyl) -L-leucinamide;

N²- [ (1S) -1- (4-bromophenyl) -2, 2-difluoroethyl]-N¹- (1-cyanocyclopropyl) -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -2, 2-difluoro-1- [4 '- (methylthio) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- [ (1S) -2, 2, 2-trifluoro-1- (4-pyrimidin-5-ylphenyl) ethyl]-L-leucinamide;

N²- [ (1S) -1- (4 '-acetyl-1, 1' -biphenyl-4-yl) -2, 2, 2-trifluoroethyl radical ]-N¹- (1-cyanocyclopropyl) -4-fluoro-L-leucinamide;

N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [3 '- (1-hydroxyethyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide;

N²- [ (1S) -1- (4 '-acetyl-1, 1' -biphenyl-4-yl) -2, 2-difluoroethyl]-N¹- (1-cyanocyclopropyl) -L-leucinamide;

N¹- (1-cyanocyclopropyl) -N²- { (1S) -1- [4- (3, 5-Dimethylisoxazol-4-yl) phenyl]-2, 2, 2-trifluoroethyl } -4-fluoro-L-leucinamide;

and pharmaceutically acceptable salts, stereoisomers and N-oxide derivatives thereof.

10.N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide or a pharmaceutically acceptable salt thereof.

11.N¹- (1-cyanocyclopropyl) -4-fluoro-N²- { (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfinyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide or a pharmaceutically acceptable salt thereof.

12.N¹- (cyanomethyl) -N²{ (1S) -2, 2, 2-trifluoro-1- [4 '- (methylsulfonyl) -1, 1' -biphenyl-4-yl]Ethyl } -L-leucinamide or a pharmaceutically acceptable salt thereof.

13.N²- { (1S) -1- [4 '- (aminosulfonyl) -1, 1' -biphenyl-4-yl]-2, 2, 2-trifluoroethyl } -N¹(cyanomethyl) -L-leucinamide or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

15. A pharmaceutical composition prepared by combining a compound of claim 1 and a pharmaceutically acceptable carrier.

16. A method of making a pharmaceutical composition comprising combining a compound of claim 1 and a pharmaceutically acceptable carrier.

17. Use of a compound according to claim 1 in the manufacture of a medicament for inhibiting tissue protease activity in a mammal in need of such inhibition.

18. The use of claim 17, wherein the cathepsin activity is cathepsin K activity.

19. Use of a compound according to claim 1 for the preparation of a medicament selected from the group consisting of: osteoporosis, glucocorticoid-induced osteoporosis, Paget's disease, abnormally increased bone turnover, periodontal disease, tooth loss, bone fracture, rheumatoid arthritis, osteoarthritis, periprosthetic osteolysis, incomplete osteogenesis, metastatic bone disease, hypercalcemia of malignancy, or multiple myeloma.

20. The use of claim 19, wherein the disease is osteoporosis.

21. Use of a compound according to claim 1 for the manufacture of a medicament for treating a cathepsin dependent disorder in a mammal in need thereof.

22. A pharmaceutical composition comprising a compound of claim 1 and a compound selected from: an organic bisphosphonate, an estrogen receptor modulator, an estrogen receptor beta modulator, an androgen receptor modulator, an osteoclast proton atpase inhibitor, an HMG-CoA reductase inhibitor, an integrin receptor antagonist, or an osteoblast anabolic agent, and pharmaceutically acceptable salts and mixtures thereof.

23. A compound according to claim 1 and a compound selected from: use of an organic bisphosphonate, an estrogen receptor modulator, an androgen receptor modulator, an osteoclast proton atpase inhibitor, an HMG-CoA reductase alcohol inhibitor, an integrin receptor antagonist, or an osteoblast anabolic agent, and pharmaceutically acceptable salts and mixtures thereof, in the preparation of a medicament for the treatment or prevention of a disorder selected from the group consisting of: osteoporosis, glucocorticoid-induced osteoporosis, Paget's disease, abnormally increased bone turnover, periodontal disease, tooth loss, bone fracture, rheumatoid arthritis, osteoarthritis, periprosthetic osteolysis, incomplete osteogenesis, metastatic bone disease, hypercalcemia of malignancy, or multiple myeloma.

24. The use of claim 23, wherein the disease is osteoporosis.

25. A pharmaceutical composition comprising a compound of claim 1 and a compound selected from: an organic bisphosphonate, an estrogen receptor modulator, an estrogen receptor beta modulator, an androgen receptor modulator, an osteoclast proton ATPase inhibitor, an HMG-CoA reductase inhibitor, an integrin receptor antagonist, or an osteoblast anabolic agent, and pharmaceutically acceptable salts and mixtures thereof.

26. Use of a compound of claim 1 for the manufacture of a medicament for inhibiting bone resorption in a mammal in need thereof.

27. Use of a compound of claim 1 for the manufacture of a medicament for increasing bone mineral density in a mammal in need thereof.

28. Use of a compound of claim 1 for the manufacture of a medicament for reducing the risk of bone fracture in a mammal in need thereof.