KR100880133B1 - Octahydro-pyrrolo[3,4-c] derivatives and their use as antiviral compounds - Google Patents

Abstract

Chemokine receptor antagonists, particularly 3,7-diazabicyclo [3.3.0] octane compounds according to formula (I), are useful for the treatment or prevention of human immunodeficiency virus (HIV) infection, or for the treatment of AIDS or ARC. It is an antagonist of the receptor. The present invention also provides a method for treating a disease that is alleviated with CCR5 antagonists. The present invention includes pharmaceutical compositions and methods of using the therapeutic compounds of the seven rings. Also included in the present invention are methods for the preparation of compounds according to formula ( I ).

Description

Octahydro-pyrrolo [3,4-c] derivatives as antiviral compounds and uses thereof {OCTAHYDRO-PYRROLO [3,4-C] DERIVATIVES AND THEIR USE AS ANTIVIRAL COMPOUNDS

The present invention relates to octahydro-pyrrolo [3,4-c] pyrrole derivatives useful for the treatment of various disorders, including those involving the regulation of the CCR5 receptor. More particularly, the invention provides 3- (hexahydro-pyrrolo [3,4-c] pyrrole-2-yl) -1-phenyl-propylamine and [3- (hexahydro-pyrrolo [3,4-c ] Pyrrole-2-yl) -propyl] -phenyl-amine compound and related derivatives, compositions containing the same, the use of such derivatives and methods for preparing such compounds. Disorders that can be treated or prevented with the present derivatives include HIV and genetically related retroviral infections (and resulting AIDS), immune system diseases and inflammatory diseases.

[AM. Vandamme et al. ( Antiviral Chemistry & Chemotherapy , 1998 9: 187-203) disclose current HAART clinical treatment of HIV-1 infection in humans, comprising three or more drug combinations. High activity anti-retroviral therapy (HAART) typically consists of co-treatment with nucleoside reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI) and protease inhibitors (PI). These compounds inhibit the biochemical processes required for viral replication. In docile patients who have never been on medication, HAART is effective in reducing the progression and mortality of HIV-1 to AIDS. HAART dramatically changes the prognosis of HIV-infected individuals, but current cures, including very complex medication regimens, leave many shortcomings and potentially serious side effects (A. Carr and DA Cooper, Lancet 2000 356 (9239): 1423 -1430). Moreover, such multidrug treatments do not eliminate HIV-1, and long-term treatment usually results in multidrug resistance, limiting their effectiveness in long-term healing. The development of new drug therapies to provide better HIV-1 treatment is a priority.

Compounds of the invention modulate the activity of chemokine CCR5 receptors. Chemokines are large units of pre-inflammatory peptides that exert their pharmacological effects via G-protein-coupled receptors. The name "chemokine" is an abbreviation for "cheatogenic cytokine". Chemokines are white blood cell chemotactic protein units that can attract white blood cells to various tissues, which is an essential response to inflammation and infection. Human chemokines comprise approximately 50 small proteins that are structurally homologous, 50-120 amino acids (M. Baggiolini et al. , Annu. Rev. Immunol. 1997 15: 675-705).

CCR5 receptor modulators may be useful in the treatment of various inflammatory diseases and conditions, and in the treatment of infections by HIV-1 and genetically related retroviruses. As leukocyte chemotactic factors, chemokines play an indispensable role in attracting leukocytes to various tissues of the body, and the process is essential in both the body's response to inflammation and infection. Since chemokines and their receptors are central to the pathophysiology of inflammatory and infectious diseases, agents effective in regulating and preferably offsetting the activity of chemokines and their receptors are useful as therapeutic agents for such inflammatory and infectious diseases. The chemokine receptor CCR5 is particularly important in the name of treating inflammatory and infectious diseases. CCR5 is a receptor for chemokines, in particular for macrophage inflammatory proteins (MIP) called MIP-1a and MIP-1b, and for proteins (RANTES) which are normal T-cells that are regulated and expressed and secreted upon activation.

HIV-1 infects mononuclear cell-macrophage lineages and helper T-cell lymphocytes utilizing the high affinity interactions of the viral envelope glycoprotein (Env) with the CD-4 antigen. However, although CD-4 antigen appears to be necessary for cell entry, it is not sufficient and one or more other surface proteins are required to infect the cell (EA Berger et al. , Ann. Rev. Immunol). 1999 17: 657-700). It was subsequently found that the two chemokine receptors, CCR5 or CXCR4 receptors, along with CD4, are co-receptors required to infect cells with human immunodeficiency virus (HIV). The central role of CCR5 in the pathogenesis of HIV is estimated by the epidemiological confirmation of the potent disease-controlling effects of the naturally occurring allele CCR5 Δ32. The Δ32 mutation has a 32-base pair of deletions in the CCR5 gene, creating a nodule protein called Δ32. Compared to the general population, Δ32 / Δ32 homozygotes are quite common in exposed / uninfected individuals, suggesting the role of CCR5 in HIV cell entry (R. Liu et al. , Cell 1996 86 (3): 367-377). Samson et al. , Nature 1996 382 (6593): 722-725).

The HIV-1 capsular protein consists of two subunits: the surface subunit gp 120 and the dural subunit gp41. The two subunits are non-covalent and form the homotrimers that make up the HIV envelope. Each gp41 subunit contains two helical 7-valent repeating regions, HR1 and HR2 and a hydrophobic fusion region, at the C-terminus.

The CD-4 binding site at gp120 of HIV induces a change in placement at gp120 that produces or exposes a hidden CCR5 (or CXCR-4) binding site, and gp120 binds to CCR5 and / or CXCR-4 cell-surface receptors It appears to interact with CD4 molecules at the cell surface, undergoing a batch change that allows them. This bivalent interaction allows the viral membrane to be in close proximity to the target cell membrane, and a hydrophobic fusion region can be inserted into the target cell membrane. The change in placement in gp41 contacts the outer membrane of the target cell membrane with the viral membrane, which creates a fusion hole where viral RNA is injected into the cytoplasm. Thus, agents that can inhibit the binding between gp120 and chemokine receptors should prevent or alleviate infection in healthy individuals and slow or stop viral progression in infected patients (B. Tomkowicz and RG Collman, Expert Opin). .. Ther Targets 2004 8 (2 ): 65-78; JP Moore and RW Doms, Proc Nat Acad Sci USA, 2003 100 (19):.... 10598-10602).

Viral fusion and cell entry are complex multistep processes, each step providing the potential for therapeutic intervention. These steps include (i) CD-40-gp120 interactions, (ii) CCR5 and / or CXCR-4 interactions, and (iii) gp41 mediated membrane fusion. Each of these steps provides an opportunity for therapeutic intervention in the prevention or alleviation of HIV infection.

RANTES, a natural ligand for the CCR5 receptor, and aminooxypentane RANTES, a chemically modified analogue at the N-terminus, has been shown to block HIV entry into cells (G. Simmons et al. , Science 1997 276: 276-). 279). Soluble CD4 protein and synthetic derivatives (Smith, et al. , Science 1987 238: 1704-1707), dextran sulfate, Direct Yellow 50 dyes, Evans Blue, and certain azo dyes (US Pat) No. 5,468,469) has been shown to inhibit the replication of HIV. Some of these antiviral agents have been demonstrated to work by blocking the binding of HIV's outer membrane protein, gp120, to its target, which is the CD4 glycoprotein of the cell.

T20 (Entuvirtide) is a 36 amino acid peptide corresponding to residues 643-678 in the HR2 domain of gp41. T-20 traps transient intermediates formed by the interaction of gp120 and target cells, which inhibits viral replication and inhibits viral fusion (JM Kilby et al. , New Eng. J. med. 1998 4 (11): 1302-1307). T-20 has been approved for clinical use.

In addition to the potential of CCR5 modulators in the treatment of HIV infection, CCR5 receptors are important regulators of immune function, and the compounds of the present invention may prove very beneficial in the treatment of immune system disorders. An effective amount of a CCR5 antagonist compound of the invention is administered to a human being in need of treatment of solid organ transplant rejection, graft-versus-host disease, arthritis, rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis, psoriasis, asthma, allergies or multiple sclerosis Treatment is also possible.

Pharmacokinetic problems associated with large molecules, proteins and peptides have established a program to identify low molecular weight antagonists of CCR5. Attempts to identify chemokine modulators have been reviewed (W. Kazmierski et al. Biorg Med. Chem. 2003 11: 2663-76; L. Agrawal and G. Alkhatib, Expert Opin. Ther. Targets 2001 5 (3): 303- 326; Chemokine CCRS antagonists incorporating 4-aminopiperidine scaffold, Expert Opin. Ther. Patents 2003 13 (9): 1469-1473; MA Cascieri and MS Springer, Curr. Opin. Chem. Biol. 2000 4: 420-426, and there Citations).

Takeda's program first led to the achievement of TAK-779's sympathy (M. Shiraishi et al. , J. Med. Chem. 2000 43 (10): 2049-2063). Schering conducted a phase I / II clinical study of Sch-351125 and reported the progress of a phase I study of Sch-417690, a more powerful follow-up compound (SW McCrombie et al. , WO00066559; BM Baroudy et al. W000066558; A ... Palani et al, J. Med Chem 2001 44 (21): 3339-3342; JR Tagat et al, J. Med Chem 2001 44 (21):.... 3343-3346; JA Este, Cur Opin Invest Drugs 2002 3 (3): 379-383).

Merck has good affinity for the CCR5 receptor and potent-HIV activity (2S) -2- (3-chlorophenyl) -1-N- (methyl) -N- (phenylsulfonyl) amino] -4- [spiro (2,3-dihydrobenzothiophen-3,4'-piperidin-1'-yl) butane S-oxide ( 1 ) and related derivatives of trisubstituted pyrrolidine 2 and substituted piperidine 3 Preparation is initiated (PE Finke et al. , Bioorg. Med. Chem. Lett. , 2001 11: 265-270; PE Finke et al. , Bioorg. Med. Chem. Lett. , 2001 11: 2469-2475; PE Finke et al. , Bioorg.Med.Chem . Lett. , 2001 11: 2475-2479; JJ Hale et al. , Bioorg.Med.Chem . Lett. , 2001 11: 2741-22745; D. Kim et al. , Bioorg.Med . Chem. Lett. , 2001 11: 3099-3102).

WO0039125 (DR Armor et al. ) And W00190106 (M. Perros et al. ) Disclose heterocyclic compounds that are potent selective CCR5 antagonists. Clinical trials have been conducted with UK-427857, which shows activity against HIV-1 isolates and laboratory strains. (MJ Macartney et al., 43 ^rd Intersci. Conf. Antimicrob. Agents Chemother. (September 14-17, 2003, Addendum H-875)).

Due to their stiffness and ease of functionalization, bicyclic and tricyclic amines have proven to be useful skeletons in drug design. 3,7-diazabicyclo [3.3.0] octane ( 4 : R '= R "= H) based compounds are particularly migraine (as described in WO 98/06725 and WO 97/11945); antibiotics (WO 97 / 10223 and WO 96/25691), neuroleptics (described in WO 95/15327 and WO 95/13279); serotonin reuptake inhibitors (described in WO 96/07656); thrombin inhibitors ( Helv. Chim. Acta 2000 83: 855, Chem. & Biol. 1997 4: 287 and Angew. Chem. Int.Ed. Eng. 1995 34: 1739); Use in various medical applications is known, including J. Med. Chem. 1989 32: 1024. In addition, 3,7-diazabicyclo [3.3.0] octane compounds are used for glutamine-based gastrointestinal disorders (DE 39). 30 266 A1) WO 00/55143 discloses diamine compounds comprising a 3,7-diazabicyclo [3.3.0] octane compound bound to an oxazolone, which compound is α-1 adeno Receptor modulators. EP 1 122 257 (F. Ito et al. ) Discloses benzimidazole compounds bound to various bicyclic diamine compounds, including diazabicyclooctane, which compounds are ORL-1 receptor agonists. The receptor is an opioid receptor subtype.

WO 96/07656 (JM Schaus and RD Titus) discloses aralkyl substituted 3,7-diazabicyclo [3.3.0] octane compounds with selective reuptake inhibitory activity. WO 97/11945 (A. Madin) discloses a 3-substituted 3,7-diazabicyclo [3.3.0] octane compound, which has selective 5-HT _{1D □} activity and may be further substituted at the 7-position. . WO 01/44243 (D. Peters et al. ) Discloses a novel heteroaryl 3-substituted at the 7-position, which is a muscarinic and nicotinic receptor modulator, useful for the treatment of diseases associated with cholinergic degeneration . A substituted-diazabicycloalkane compound is disclosed. Preferred embodiments include 3,7-diazabicyclo [3.3.0] octane compound 4 , wherein R 'is a heteroaryl group and R "is a hydrogen, alkyl, aryl, aralkyl or fluorescent group.

WO 02/07523 A1 (R. Colon-Cruz et al. ) Discloses 3,7-diazabicyclo [3.3.0] octane compounds, which are antagonists of chemokine CCR2 and CCR3 receptors. MCP-1 is a natural ligand for the CCR2 receptor and its interaction with the ligand increases histamine release, calcium influx, cAMP activation, increases integrin expression, and is chemotactic for monocytes and macrophages. It is said to act as an argument. The compounds disclosed herein claim to be useful for the treatment of mononuclear cells, lymphocytes and leukocyte accumulation diseases, more specifically atherosclerosis, restenosis, gingivitis, psoriasis, rheumatoid arthritis, glomerulonephritis, Crohn's disease, encephalomyelitis and transplant rejection do. Preferred embodiments include compounds of general formula 5 .

WO 02/060902 A1 (M. Bjorsne et al. ) Discloses 3,7-diazabicyclo [3.3.0] octane compounds useful for the treatment of cardiac arrhythmias. Preferred embodiments include compounds of formula 6

The present invention containing a compound, CCR5 antagonist treatment and at least one carrier, diluent or excipient and the additional mixing the CCR5 antagonist compounds according to formula I of diseases which are relaxed by administration of a compound according to formula I of the formula I, It relates to a pharmaceutical composition for treating a disease.

One subject of the present invention is ( i ) a compound of formula (I) and pharmaceutically acceptable salts, hydrates, solvates and stereoisomers thereof:

[here:

X ¹ is selected from the group consisting of -C (= 0) R ³ , -S (= 0) ₂ R ³ and -C (= 0) OR ³ ;

X ² is ^{-C (= O) R 4,} -S (= O) 2 R 4, benzyl or -CH ₂ is selected from the group consisting of (pyridin-3-yl), the benzyl are halogen or C _{1 -3} Optionally substituted with alkyl;

One of R ¹ and R ² is

(i) phenyl optionally substituted with 1 to 4 substituents independently selected at each occurrence from the group consisting of halogen, C _1-6 alkyl and C _1-6 alkoxy;

(Ii) heteroaryl selected from the group consisting of pyridinyl, pyridinyl-N-oxide, pyrimidinyl and thiazolyl, wherein said heteroaryl is halogen, C _1-6 alkyl, C _1-6 haloalkyl and C ₁ Optionally substituted with 1 to 3 substituents independently selected from the group consisting of _-6 alkoxy);

The rest of R ¹ and R ² are hydrogen;

R ³ is selected from the group consisting of:

(i) phenyl optionally substituted with 1 to 4 substituents independently selected at each occurrence from the group consisting of:

(a) C _1-10 alkyl,

(b) C _1-10 heteroalkyl,

(c) C _1-6 haloalkyl,

(d) C _1-6 alkoxy,

(e) C _1-6 thioalkyl,

(f) amino,

(g) C _1-6 alkyl amino,

(h) C _1-6 dialkylamino,

(g) C _1-6 acylamino,

(i) carbamoyl, NC _1-6 alkylcarbamoyl or N, NC _1-6 dialkylcarbamoyl,

(j) ureido,

(k) nitro,

(l) cyano,

(m) halogen,

(n) C _1-6 alkylsulfonyl,

(o) sulfamoyl, NC _1-6 alkylsulfamoyl or N, NC _1-6 dialkylsulfamoyl,

(p) C _1-6 alkylsulfonamido or optionally substituted phenylsulfonamido,

(q) optionally substituted phenoxy,

(r) optionally substituted heteroaryloxy, and

(s) -Y (CH ₂ ) _n R ¹¹ wherein R ¹¹ is cyano, -CO ₂ R ¹² , -CONR ¹² R ¹³ , -SO ₂ N ¹² R ¹³ , -NHSO ₂ R ¹² and -NHSO ₂ NR ¹² R ¹³ ),

(t) CO ₂ R ¹² ,

(u) C _1-6 acyloxy,

(v) C _1-6 alkylcarbonyl, and

(w) C _1-6 haloalkoxy;

(Ii) phenyl C _1-6 alkyl, wherein phenyl is as described in (i) above;

(Iii) pyridinyl, pyridinyl-N-oxide, pyrimidinyl, pyrazinyl, pyridazinyl, isoxazolyl, isothiazolyl, pyrrolyl, furyl, thiazolyl, oxazolyl, pyrazolyl, oxdiazolyl , Thiadiazolyl, imidazolyl, triazolyl, tetrazolyl, indolyl, quinolinyl, isoquinolinyl, 2,4-dimethyl-6-oxo-6H-pyranyl and thienyl Heteroaryl (The heteroaryl is C _1-10 alkyl, phenyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 thioalkyl, C _1-6 alkoxycarbonyl, carbamoyl, acetyl, nitro Optionally substituted with 1 to 3 substituents independently selected in each case from the group consisting of cyano, amino, C _1-3 alkylamino, C _1-3 dialkylamino, N-morpholino, sulfamoyl and halogen being);

(Iii) heteroaryl C _1-6 alkyl (heteroaryl is as described above);

, 옥세타닐, 테트라히드로푸라닐, 테트라히드로피라닐, 티아졸리디닐, 옥사졸리디닐, 이소티아졸리디닐, 피페라지닐, 이미다졸리닐, 1,2,3,4-테트라히드로퀴놀리닐 및 N-메틸-1,2,3,4-테트라히드로이소퀴놀린-3-일로 이루어지는 군으로부터 선택되는 헤테로사이클 (상기 헤테로사이클은 C_1-6 알킬, 히드록시, C_1-6 알킬카르보닐, 카르바모일, 아미노, C_1-6 알킬아미노, C_1-6 디알킬아미노, 피리디닐 및 페닐아미노로 이루어지는 군으로부터 각 경우에 독립적으로 선택되는 1 내지 3 개의 치환기로 임의치환되고, 질소에 결합되어 있는 탄소에 있는 2 개의 수소는 산소 (옥소) 로 대체될 수 있음), 여기서:(v) IIa-f

, Oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, oxazolidinyl, isothiazolidinyl, piperazinyl, imidazolinyl, 1,2,3,4-tetrahydroquinolinyl And N-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl, wherein the heterocycle is C _1-6 alkyl, hydroxy, C _1-6 alkylcarbonyl, Optionally substituted with 1 to 3 substituents independently selected in each case from the group consisting of carbamoyl, amino, C _1-6 alkylamino, C _1-6 dialkylamino, pyridinyl and phenylamino and bonded to nitrogen Two hydrogens in the carbon can be replaced with oxygen (oxo), where:

R ⁸ is hydrogen, C _1-6 -alkyl, C _1-6 haloalkyl, C _1-6 heteroalkyl, phenyl-C _1-6 alkyl, C _1-3 alkoxy-C _1-6 alkyl, pyrimidine-2 -Day, COR ⁹ , COCHR ¹⁵ NHR ⁷ or SO ₂ R ¹⁰ ;

R ⁹ is selected from the group consisting of:

(i) independently from the group consisting of C _1-3 alkoxy, C _1-3 acyloxy, hydroxyl, phenyl, amino, C _1-6 alkylamino, C _1-6 dialkylamino and aminocarbonylpyridyl C _1-6 alkyl optionally substituted with one or two groups selected, wherein the aminocarbonylpyridyl may optionally be N-oxide and aminobenzoyl, wherein the phenyl or the benzoyl radical is amino, C _{1 -Optionally} substituted with one to three groups independently selected from the group consisting of _-6 alkylamino, C _1-6 dialkylamino, hydroxyl, halogen and C _1-3 alkoxy),

(Ii) phenyl optionally substituted with one or two groups independently selected from the group consisting of sulfamoyl, acetylamino, halogen, C _1-6 alkyl, C _1-6 haloalkyl, and C _1-6 alkoxy,

(Iii) NH ₂ , C _1-6 alkylamino, C _1-6 dialkylamino,

(Iii) C (= 0) NH ₂ , C (= 0) OC _1-6 alkyl, or C (= 0) OH;

(v) 1H indole-3-carbonyl,

(Iii) furyl, pyridinyl, or pyridinyl N-oxide,

(Iii) N-acetylpiperidin-4-yl,

(Ⅷ) furfuryl,

(Iii) C _3-8 cycloalkyl,

(x) C _1-6 haloalkyl,

(xi) phenyl C _1-3 alkyl, and,

(xii) C _1-6 alkoxy,

R ¹⁰ is selected from the group consisting of:

(i) C _1-6 alkyl,

(Ii) C _1-3 haloalkyl,

(Iii) C _3-8 cycloalkyl, and

(Iii) NH ₂ , C _1-3 alkylamino, C _1-3 dialkylamino;

(Iii) heterocycle C _1-6 alkyl (heterocycle as defined above);

(Iii) hydrogen;

(Iii) hydroxy, halogen, C _1-6 alkoxy, C _1-6 thioalkyl, C _1-6 acyloxy, C _1-6 alkoxycarbonyl, C _1-6 acylamino, NR ^14a R ^14b , cyano , C _1-6 alkylsulfonyl, phenyl, N-methyl-methyl-sulfonamido, N-piperidinyl, N-pyrrolidinyl, imidazolyl, 2-aza-bicyclo [2.2.1] hept- In each case with 1 to 3 substituents independently selected in each case from the group consisting of 2-yl, carbamoyl, C _1-6 alkoxycarbonyl, and optionally substituted phenyl as defined in R ³ (i) above Independently C _1-10 alkyl optionally substituted;

(Iii) C _3-7 cycloalkyl or [3.1.0] bicyclohexyl, 4-oxo-cyclohexyl or 3-oxo-cyclobutyl (the cycloalkyl being 1 to 4 fluorine, cyano, hydroxyl, C Optionally substituted with _1-3 alkyl or phenyl);

(x) C _1-3 alkyl-C _3-7 cycloalkyl, wherein said cycloalkyl is optionally substituted with 1 to 4 fluorine, C _1-3 alkyl or phenyl;

(xi) NR ^14a R ^14b ; And,

(xii) C (= 0) OR ^14c ;

R ⁴ is selected from the group consisting of:

(i) aryl selected from the group consisting of:

(a) Phenyl substituent as described for R ³ (i) (a) to (i) (w), C _1-6 haloalkoxy, pyridinyl, 2-oxo-pyrrolidin-1-yl, 2,5- Dimethyl-pyrrolidin-1-yl, 3-methyl-5-oxo-4,5-dihydro-pyrazol-1-yl and NR ^14a R ^14b (where R ^14a and R ^14b are the nitrogens to which they are attached) Together with (CH ₂ ) _r or [(CH ₂ ) ₂ X ³ (CH ₂ ) ₂ ], -NMe (CH ₂ ) ₂ OH), each occurrence of from 1 to 4 substituents independently selected from Phenyl optionally substituted;

(b) 2,3-dihydrobenzofuran-4-yl,

(c) benzofuran-4-yl,

(d) 2,3-dihydrobenzofuran-7-yl,

(e) quinolin-8-yl,

(f) 1,2,3,4-tetrahydro-isoquinolin-5-yl,

(g) N-acetyl-1,2,3,4-tetrahydro-isoquinolin-5-yl,

(h) N-Boc-1,2,3,4-tetrahydro-isoquinolin-5-yl,

(i) 1,2,3,4-tetrahydro-isoquinolin-8-yl,

(j) N-Boc-1,2,3,4-tetrahydro-isoquinolin-8-yl,

(k) isoquinolin-7-yl,

(l) 1H-indole-5-day,

(m) 2-acetyl-1,2,3,4-tetrahydro-isoquinolin-5-yl, and

(n) 6-fluoro-benzo [1,3] dioxin-8-yl, and

(o) quinolin-6-yl;

(Ii) phenyl C _1-6 alkyl (phenyl is as described above);

(Iii) pyridinyl, 2-azetidin-1-yl, pyridinyl N-oxide, pyrimidinyl, pyrazinyl, pyridazinyl, isoxazolyl, isothiazolyl, pyrrolyl, furyl, thiazolyl, oxa Zolyl, pyrazolyl, oxdiazolyl, thiadiazolyl, imidazolyl, triazolyl, tetrazolyl, indolyl, quinolyl, isoquinolyl, quinoxalin-2-yl, indazole, benzofuranyl, 4,5 , 6,7-tetrahydro-benzofuranyl, 2,4-dimethyl-6-oxo-6H-pyranyl, benzo [b] thiophenyl, 4,5,6,7-tetrahydroindazole, 1,4 , 5,6-tetrahydrocyclopentylpyrazolyl, imidazo [2,1-b] thiazolyl, 6-fluoro-4H-benzo [1,3] dioxin-8-yl, cinnoline-4-yl And heteroaryl selected from the group consisting of thienyl (wherein said heteroaryl is C _1-10 alkyl, in each case from the group consisting of substituents (i) (a) to (i) (w) described for R ³ above); Optionally substituted with 1 to 4 substituents independently selected from Carbonyl, benzyl, pyridinyl, 2-methyl-thiazolyl, acetyl, amino, C _1-6 alkylamino, C _1-6 dialkylamino, aminobenzyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 thioalkyl, C _1-6 alkylsulfonyl, C _1-6 alkoxycarbonyl, carboxyl, carbamoyl, nitro, cyano, ^{_{sulfamoyl, -OCH 2 CO 2 R 14c,}} -SCH 2 CO 2 Optionally substituted with 1 to 3 substituents independently selected at each occurrence from the group consisting of R ^14c and halogen;

(Iii) heteroaryl C _1-6 alkyl (heteroaryl is as described above);

(v) IIa-f , furyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, oxazolidinyl, piperazinyl, imidazoli as described in (v) of R ³ above. Nyl, N-benzyl-morpholine, N-methyl-1,2,3,4-tetrahydroquinolin-2-yl, 4,5-dihydro-pyrazolyl, and 1,2,3,4-tetrahydro Heterocycle selected from the group consisting of isoquinolinyl, wherein the heterocycle is C _1-6 alkyl, acetyl, hydroxy, C _1-6 alkylcarbonyl, C _1-6 alkoxycarbonyl, carbamoyl, amino, Two hydrogens on the carbon bonded to nitrogen optionally substituted with one to three substituents independently selected in each case from the group consisting of C _1-6 alkylamino, C _1-6 dialkylamino and phenylamino Oxygen (oxo) can be replaced);

(Iii) heterocycle C _1-6 alkyl (heterocycle as defined above);

(Iii) hydrogen;

(Iii) hydroxy, halogen, C _1-6 alkoxy, C _1-6 thioalkyl, acyloxy, C _1-6 acylamino, NR ^14a R ^14b , cyano, C _1-6 alkylsulfonyl, N-methyl 1 to 3 independently selected in each case from the group consisting of -methyl-sulfonamido, phenyl, N-piperidinyl, N-pyrrolidinyl, imidazolyl, carbamoyl and C _1-6 alkoxycarbonyl C _1-10 alkyl substituted with 4 substituents,

(Iii) C _3-7 cycloalkyl optionally substituted with 1 to 4 fluorine, C _1-3 alkyl or phenyl,

(x) C _1-3 alkyl-C _3-7 cycloalkyl optionally substituted with 1 to 4 fluorine, C _1-3 alkyl or phenyl; And,

(xi) NR ^14a R ^14b ;

R ⁵ is hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, methoxymethyl, —CO ₂ R ¹² or CONR ¹² R ¹³ ;

R ^5a is hydrogen or C _1-6 alkyl;

R ⁶ is independently selected from the group consisting of hydrogen, C _1-10 alkyl, hydroxy, C _1-6 alkoxy, C _1-3 hydroxyalkyl and C _1-3 alkoxy-C _1-3 alkyl;

R ⁷ is hydrogen or Boc;

R ¹² and R ¹³ are (i) independently hydrogen, C _1-6 alkyl or C _1-6 heteroalkyl, or (ii) when R ¹² and R ¹³ are both bonded to a nitrogen atom, May be C _2-5 alkylene;

R ^14a and R ^14b are (i) independently R ³ , or (ii) (CH ₂ ) _r or [(CH ₂ ) ₂ X ³ (CH ₂ ) ₂ ] when taken together with the nitrogen to which they are attached; ego;

R ^14c is hydrogen or C _1-6 alkyl;

R ¹⁵ is hydrogen, methyl, iso -propyl, iso -butyl, sec -butyl, -CH ₂ OH, -CH (OH) CH ₃ , -CH ₂ SH, -CH ₂ CH ₂ SMe,-(CH ₂ ) _S COR ¹⁶ where R ¹⁶ is -OH or -NH ₂ , s is 1 or 2,-(CH ₂ ) _t -NH ₂ , where t is 3 or 4,-(CH ₂ ) ₃ -NHC (= NH) NH ₂ , -CH ₂ C ₆ H ₅ , -CH ₂ -p -C ₆ H ₄ -OH, (3-indolinyl) methylene or (4-imidazolyl) methylene;

X ³ is -O-, -S (O) _p- , NR ^14c ;

Y is a direct bond, -0-, -S- or -NR ^12- ;

n is an integer from 1 to 6;

p is an integer from 0 to 2;

r is an integer from 3 to 6;

The compounds and compositions of the present invention are useful for treating diseases mediated by human immunodeficiency virus in humans. Compounds and compositions of the invention also include respiratory disorders including adult respiratory distress syndrome (ARDS), bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, rhinitis and chronic sinusitis It can be used for the treatment of disorders alleviated by antagonists. Diseases triggered by, affected by, or interrelated in some other way by T-cell trafficking in various organs can be treated with the compounds of the present invention. The compounds of the present invention may be useful for the treatment of such diseases, particularly those in which correlation with CCR5 or CCR5 chemokines is established, but the disease is not limited to: Crohn's disease and ulcerative colitis Inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, transplant rejection, especially kidney and lung allografts (but not limited to), endometriosis, type I diabetes, kidney disease, chronic pancreatitis, inflammatory lung disease or chronic heart failure. For a recent review of possible uses of chemokine and chemokine receptor blockers, see: Cascieri, MA, and Springer, MS, The chemokine / chemokine receptor family: potential and progress for therapeutic intervention, Curr. Opin. Chem. Biol. 2000 4 (4) : 420-7; AEI Proudfoot The Strategy of Blocking the Chemokine System to Combat Disease, Immunol. Rev. 2000 177: 246-256.

Further subjects of the invention are:

( Ii ) a compound of formula (I) and pharmaceutically acceptable salts, hydrates, solvates and stereoisomers thereof:

[here:

One of R ¹ and R ² is

Phenyl optionally substituted with 1 to 4 substituents independently selected at each occurrence from the group consisting of halogen and C _1-6 alkyl;

Heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl and thiazolyl, wherein said heteroaryl is 1 to 3 substituents independently selected from the group comprising halogen, C _1-6 alkyl and C _1-6 haloalkyl Optionally substituted);

The rest of R ¹ and R ² are hydrogen;

R ⁵ is hydrogen, C _1-6 alkyl methoxymethyl or C _1-3 hydroxyalkyl;

R ^5a is hydrogen, hydroxyl or C _1-6 alkyl;

R ⁶ is hydrogen, C _1-6 alkyl or C _1-3 hydroxyalkyl;

X ¹ is selected from the group consisting of -C (= 0) R ³ , -S (= 0) ₂ R ³ and -C (= 0) OR ³ ;

X ² is ^{-C (= O) R 4,} -S (= O) is selected from the group consisting of ₂ R ⁴ or benzyl, said benzyl is optionally substituted by halogen or C _{1 -3} alkyl;

R ³ is selected from the group consisting of:

Hydrogen, C _1-6 alkyl, —CH ₂ NH ₂ , —CH ₂ CH ₂ NH ₂ , —C (CH ₃ ) NH ₂ , —CH ₂ CH ₂ N (ethyl) ₂ , —N (CH ₃ ) ₂ , -N (CH ₂ CH ₃ ) ₂ , -N (iso-propyl) ₂ , -NCH ₃ -benzyl, -NHCH ₂ COOCH ₂ CH ₃ , -CH ₂ NHCOCH ₃ , CH ₂ CH ₂ CONH ₂ , -C (NH ₂ ) CH ₂ C (CH ₃ ) ₂ , -CH (NH ₂ ) CH (CH ₃ ) ₂ , -CH ₂ CN, -C _1-6 alkyl-OH, -CH ₂ CH ₂ COOCH ₃ , -C (CH ₃ ) ₂ OCOCH ₃ , -CH ₂ OCOCH ₃ , -CH ₂ SO ₂ CH ₃ , -CH ₂ (CH ₃ ) SO ₂ CH ₃ ,

Heteroalkyl (the heteroalkyl is optionally substituted with -NHCOCH ₃ ),

— (CH ₂ ) _t —C _3-8 cycloalkyl, wherein t is 0 to 2, wherein —C _3-8 cycloalkyl is C _1-6 alkyl, halogen, hydroxyl, cyano, oxo, phenyl Optionally substituted with 1 to 3 substituents independently selected from the group consisting of:

-(CHR ^m ) _u -phenyl, wherein R ^m is H, hydroxyl or C _1-6 alkyl, u is 0 to 3, said phenyl is C _1-10 alkyl, C _1-10 heteroalkyl, C Optionally selected from 1 to 6 substituents independently selected in each case from the group consisting of _1-6 haloalkyl, cyano, halogen, C _1-6 alkylsulfonyl, -SO ₂ NH ₂ , -NHCOCH ₃ or -COOCH ₃ Substituted),

Pyridinyl, pyridinyl-N-oxide, pyrimidinyl, pyrazinyl, pyridazinyl, isoxazolyl, isothiazolyl, pyrrolyl, furyl, thiazolyl, oxazolyl, pyrazolyl, oxdiazolyl, thiadia -(CH selected from the group consisting of zolyl, imidazolyl, triazolyl, tetrazolyl, indolyl, quinolinyl, isoquinolinyl, 2,4-dimethyl-6-oxo-6H-pyranyl and thienyl ₂ ) _v -heteroaryl, where v is 0 to 3 and said heteroaryl is C _1-10 alkyl, phenyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 thioalkyl, C ₁ Each case from the group consisting of _-6 alkoxycarbonyl, carbamoyl, acetyl, nitro, cyano, amino, C _1-3 alkylamino, C _1-3 dialkylamino, N-morpholino, sulfamoyl and halogen Optionally substituted with 1 to 3 substituents independently selected from

, 옥세타닐, 테트라히드로푸라닐, 테트라히드로피라닐, 티아졸리디닐, 옥사졸리디닐, 이소티아졸리디닐, 피페라지닐, 이미다졸리닐, 1,2,3,4-테트라히드로퀴놀리닐 및 N-메틸-1,2,3,4-테트라히드로이소퀴놀린-3-일로 이루어지는 군으로부터 선택되는 -(CHRⁿ)_w-헤테로사이클 (여기서, Rⁿ 은 수소 또는 C_1-6 알킬이고, w 는 0 내지 3 이고, IIa-f

, Oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, oxazolidinyl, isothiazolidinyl, piperazinyl, imidazolinyl, 1,2,3,4-tetrahydroquinolinyl And-(CHR ⁿ ) _w -heterocycle selected from the group consisting of N-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl, wherein R ⁿ is hydrogen or C _1-6 alkyl, w is 0 to 3,

The heterocycle consists of C _1-6 alkyl, hydroxy, C _1-6 alkylcarbonyl, carbamoyl, amino, C _1-6 alkylamino, C _1-6 dialkylamino, pyridinyl and phenylamino Optionally substituted with 1 to 3 substituents independently selected in each case from 2 hydrogens in the carbon bonded to nitrogen may be replaced with oxygen (oxo), wherein:

R ⁸ is hydrogen, C _1-6 -alkyl, C _1-6 haloalkyl, C _1-6 heteroalkyl, phenyl-C _1-6 alkyl, C _1-3 alkoxy-C _1-6 alkyl, pyrimidine-2 -Day, COR ⁹ , COCHR ¹⁵ NHR ⁷ or SO ₂ R ¹⁰ ;

R ⁹ is C _1-6 alkyl, C _1-6 haloalkyl, furanyl, C _1-6 alkoxy, C _3-5 cycloalkyl, C _1-6 alkylamino, -COO-C _1-6 alkyl, -COOH , -CH ₂ OCH ₂ OOH, -CH ₂ CH ₂ COOH;

R ¹⁰ is C _1-6 alkyl, C _1-6 dialkylamino, C _3-8 cycloalkyl;

R ⁷ is hydrogen or Boc;

R ¹⁵ is hydrogen or C _1-6 alkyl;

-NH- (CH ₂ ) _x -phenyl, wherein x is 0 or 1, said phenyl is C _1-6 alkyl, halogen, -OCF ₃ , heteroalkyl, haloalkyl, acetyl, dialkylamine, cyano, Optionally substituted with 1 to 3 substituents independently selected in each case from the group consisting of -COOH, COOCH ₂ CH ₃ ),

-NH (CH ₂ ) _y -heteroaryl, wherein y is 0 or 1, wherein the heteroaryl is 1 to 3 substituents independently selected at each occurrence from the group consisting of C _1-6 alkyl, halogen, haloalkyl Randomized to),

-NH-heterocycle, wherein the heteroaryl is optionally substituted with 1 to 2 substituents independently selected at each occurrence from the group consisting of -COCF ₃ , COOCH ₂ -phenyl,

-NH (CH ₂ ) _z -C _3-8 cycloalkyl, wherein z is 0 or 1;

R ⁴ is selected from the group consisting of:

C _1-6 alkyl, —CH ₂ CH ₂ CONH ₂ , —CH ₂ NCH ₃ SO ₂ CH ₃ , —CH (CH (CH ₃ ) ₂ ) NHCOCH ₃ ,

-(CH ₂ ) _e C _3-8 cycloalkyl, wherein e is 0 to 2, wherein said cycloalkyl is optionally substituted with 1 to 4 substituents independently selected at each occurrence from the group consisting of C _1-6 alkyl being),

, 또는

으로 이루어지는 군으로부터 각 경우에 독립적으로 선택되는 1 내지 4 개의 치환기로 임의치환됨),C _3-8 heterocycle, wherein the heterocycle is C _1-6 alkyl, hydroxyl, —CO—C _1-6 alkyl, oxo, benzyl,

, or

Optionally substituted with 1 to 4 substituents independently selected at each occurrence from the group consisting of:

으로 이루어지는 군으로부터 각 경우에 독립적으로 선택되는 1 내지 4 개의 치환기로 임의치환됨);-(CHR ^f ) _f -phenyl, wherein R ^f is hydrogen or -NHCOCH ₃ , f is 0 or 1, said phenyl is C _1-10 alkyl, C _1-10 heteroalkyl, C _1-6 haloalkyl , Cyano, halogen, C _1-6 alkylsulfonyl, NO ₂ , -CO-C _1-6 alkyl, -COOCH ₃ , COOC (CH ₃ ) ₃ , -NHSO ₂ CH ₃ , NH ₂ , -N (CH ₃ ) ₂ , -N (CH ₃ ) CH ₂ CH ₂ OH, -NHCOCH ₃ , -OCF ₃ -OCH ₂ COOH, pyridin-4-yl,

Optionally substituted with 1 to 4 substituents independently selected at each occurrence from the group consisting of;

(CH ₂ ) _g -heteroaryl, where g is 0 or 1,

및

으로 이루어지는 군으로부터 선택되고,The heteroaryl is furanyl, thiophenyl, isoxazolyl, thiazolyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl, benzofuranyl, pyranyl, pyridinyl, pyrimidinyl, synoxalinyl , Cinnalinel,

And

Selected from the group consisting of

벤질, 페닐로 이루어지는 군으로부터 각 경우에 독립적으로 선택되는 1 내지 4 개의 치환기로 임의치환되고, 상기 페닐은 C_1-6 알킬, 할로겐, C_1-6 알콕실, -COOCH₃ 로 이루어지는 1 내지 3 개의 치환기로 임의치환됨),The heteroaryl is C _1-6 alkyl, oxo, oxido, heteroalkyl, halogen, haloalkyl, methoxy-phenyl, haloalkyl, -NH ₂ , -N (CH ₃ ) ₂ , -NHCH ₂ -phenyl,- NHCOCH ₃ , cyano, -SO ₂ NH ₂ , -SO ₂ CH ₃ , -OCH ₂ COOCH ₃ , -OCH ₂ COOH, -SCH ₂ COOH, -COCH ₃ , -COOC (CH ₃ ) ₃ , -COOC (CH ₃ ) ₃ , -COOCH ₂ CH ₃ , -COOH, pyridin-4-yl,

Benzyl, is optionally substituted by one to four substituents independently selected at each occurrence from the group consisting of phenyl, said phenyl is from 1 to 3 consisting of C _1-6 alkyl, halogen, C _1-6 alkoxyl, -COOCH ₃ Optionally substituted with)

-(NR ^h )-(CH ₂ ) _h -phenyl, wherein R ^h is hydrogen or C _1-6 alkyl, h is 0 or 1, and the phenyl is one to three selected from C _1-6 alkyl Optionally substituted with a substituent).

( Ⅲ ). The compound according to (ii), and pharmaceutically acceptable salts, hydrates, solvates and stereoisomers thereof:

[R ² is phenyl, or pyridinyl, optionally substituted with 1 to 4 halogens;

R ¹ is hydrogen;

R ⁵ is hydrogen, C _1-6 alkyl or methoxymethyl, C _1-3 hydroxyalkyl;

R ^5a is hydrogen, hydroxyl or C _1-6 alkyl;

R ⁶ is hydrogen, C _1-6 alkyl or C _1-3 hydroxyalkyl;

X ¹ is selected from the group consisting of -C (= 0) R ³ , -S (= 0) ₂ R ^3, and -C (= 0) OR ³ ;

X ² is selected from the group consisting of —C (═O) R ⁴ , —S (═O) ₂ R ⁴ or benzyl, said benzyl optionally substituted with halogen or C _1-3 alkyl;

R ³ is selected from the group consisting of:

Hydrogen, C _1-6 alkyl, —CH ₂ NH ₂ , —CH ₂ CH ₂ NH ₂ , —C (CH ₃ ) NH ₂ , —CH ₂ CH ₂ N (ethyl) ₂ , —N (CH ₃ ) ₂ , -N (CH ₂ CH ₃ ) ₂ , -N (iso-propyl) ₂ , -NCH ₃ -benzyl, -NHCH ₂ COOCH ₂ CH ₃ , -NH-phenyl, -CH ₂ NHCOCH ₃ , CH ₂ CH ₂ CONH ₂ , -C (NH ₂ ) CH ₂ C (CH ₃ ) ₂ , -CH (NH ₂ ) CH (CH ₃ ) ₂ , -CH ₂ CN, -C _1-6 alkyl-OH, -CH ₂ CH ₂ COOCH ₃ , -C (CH ₃ ) ₂ OCOCH ₃ , -CH ₂ OCOCH ₃ , -CH ₂ SO ₂ CH ₃ , -CH ₂ (CH ₃ ) SO ₂ CH ₃ , heteroalkyl,

으로부터 선택되는 -(CH₂)_t-C_3-8 시클로알킬 (여기서, t 는 0 내지 2 이고, 상기 -C_3-8 시클로알킬은 C_1-6 알킬, 할로겐, 히드록실, 시아노, 옥소, 페닐로 이루어지는 군으로부터 독립적으로 선택되는 1 내지 3 개의 치환기로 임의치환됨),Cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl and

-(CH ₂ ) _t -C _3-8 cycloalkyl, wherein t is 0 to 2, wherein -C _3-8 cycloalkyl is C _1-6 alkyl, halogen, hydroxyl, cyano, oxo Optionally substituted with 1 to 3 substituents independently selected from the group consisting of phenyl),

-(CHR ^m ) _u -phenyl, wherein R ^m is H, hydroxyl or C _1-6 alkyl, u is 0 to 2, said phenyl is C _1-10 alkyl, C _1-10 heteroalkyl, C Optionally selected from 1 to 6 substituents independently selected in each case from the group consisting of _1-6 haloalkyl, cyano, halogen, C _1-6 alkylsulfonyl, -SO ₂ NH ₂ , -NHCOCH ₃ or -COOCH ₃ Substituted),

으로 이루어지는 군으로부터 선택되는 -(CH₂)_v-헤테로아릴 (여기서, v 는 0 내지 3 이고, 상기 헤테로아릴은 C_1-10 알킬, 할로겐, 페닐, C_1-6 알콕시, C_1-6 티오알킬, -NH₂, SO₂NH₂, -COCH₃, 옥소, 옥시도,

으로 이루어지는 군으로부터 각 경우에 독립적으로 선택되는 1 내지 3 개의 치환기로 임의치환됨),

-(CH ₂ ) _v -heteroaryl selected from the group consisting of: wherein v is 0 to 3 and said heteroaryl is C _1-10 alkyl, halogen, phenyl, C _1-6 alkoxy, C _1-6 thio Alkyl, -NH ₂ , SO ₂ NH ₂ , -COCH ₃ , oxo, oxido,

Optionally substituted with 1 to 3 substituents independently selected in each case from the group consisting of:

, 옥세타닐, 테트라히드로푸라닐, 테트라히드로피라닐, 티아졸리디닐, 옥사졸리디닐, 이소티아졸리디닐, 피페라지닐, 이미다졸리닐, 1,2,3,4-테트라히드로퀴놀리닐 및 N-메틸-1,2,3,4-테트라히드로이소퀴놀린-3-일로 이루어지는 군으로부터 선택되는 -(CHRⁿ)_w-헤테로사이클 (여기서, Rⁿ 은 수소 또는 C_1-6 알킬이고, w 는 0 내지 3 이고, IIa-f

, Oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, oxazolidinyl, isothiazolidinyl, piperazinyl, imidazolinyl, 1,2,3,4-tetrahydroquinolinyl And-(CHR ⁿ ) _w -heterocycle selected from the group consisting of N-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl, wherein R ⁿ is hydrogen or C _1-6 alkyl, w is 0 to 3,

The heterocycle consists of C _1-6 alkyl, hydroxy, C _1-6 alkylcarbonyl, carbamoyl, amino, C _1-6 alkylamino, C _1-6 dialkylamino, pyridinyl and phenylamino Optionally substituted with 1 to 3 substituents independently selected in each case from 2 hydrogens in the carbon bonded to nitrogen may be replaced with oxygen (oxo), wherein:

R ⁸ is hydrogen, C _1-6 -alkyl, C _1-6 haloalkyl, C _1-6 heteroalkyl, phenyl-C _1-6 alkyl, C _1-3 alkoxy-C _1-6 alkyl, pyrimidine-2 -Day, COR ⁹ , COCHR ¹⁵ NHR ⁷ or SO ₂ R ¹⁰ ;

R ⁹ is C _1-6 alkyl, C _1-6 haloalkyl, furanyl, C _1-6 alkoxy, C _3-5 cycloalkyl, C _1-6 alkylamino, -COO-C _1-6 alkyl, -COOH , -CH ₂ OCH ₂ OOH, -CH ₂ CH ₂ COOH;

R ¹⁰ is C _1-6 alkyl, C _1-6 dialkylamino, C _3-8 cycloalkyl;

R ⁷ is hydrogen or Boc;

R ¹⁵ is hydrogen or C _1-6 alkyl;

R ⁴ is selected from the group consisting of:

C _1-6 alkyl, —CH ₂ CH ₂ CONH ₂ , —CH ₂ NCH ₃ SO ₂ CH ₃ , —CH (CH (CH ₃ ) ₂ ) NHCOCH ₃ ,

— (CH ₂ ) _e C _3-8 cycloalkyl selected from cyclopropanyl, cyclobutanyl, cyclopentanyl, and cyclohexanyl, wherein e is 0 to 2 and said cycloalkyl consists of C _1-6 alkyl Optionally substituted with 1 to 4 substituents independently selected at each occurrence from the group),

, 또는

으로 이루어지는 군으로부터 각 경우에 독립적으로 선택되는 1 내지 4 개의 치환기로 임의치환됨),C _3-8 heterocycle, wherein the heterocycle is C _1-6 alkyl, hydroxyl, —CO—C _1-6 alkyl, oxo, benzyl,

, or

Optionally substituted with 1 to 4 substituents independently selected at each occurrence from the group consisting of:

으로 이루어지는 군으로부터 각 경우에 독립적으로 선택되는 1 내지 4 개의 치환기로 임의치환됨);-(CHR ^f ) _f -phenyl, wherein R ^f is hydrogen or -NHCOCH ₃ , f is 0 or 1, said phenyl is C _1-10 alkyl, C _1-10 heteroalkyl, C _1-6 haloalkyl , Cyano, halogen, C _1-6 alkylsulfonyl, NO ₂ , -CO-C _1-6 alkyl, -COOCH ₃ , COOC (CH ₃ ) ₃ , -NHSO ₂ CH ₃ , NH ₂ , -N (CH ₃ ) ₂ , -N (CH ₃ ) CH ₂ CH ₂ OH, -NHCOCH ₃ , -OCF ₃ -OCH ₂ COOH, pyridin-4-yl,

Optionally substituted with 1 to 4 substituents independently selected at each occurrence from the group consisting of;

및

으로 이루어지는 군으로부터 선택되고,(CH ₂ ) _g -heteroaryl, where g is 0 or 1 and said heteroaryl is furanyl, thiophenyl, isoxazolyl, thiazolyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl , Benzofuranyl, pyranyl, pyridinyl, pyrimidinyl, synoxalinyl, cinnolinyl,

And

Selected from the group consisting of

벤질, 페닐로 이루어지는 군으로부터 각 경우에 독립적으로 선택되는 1 내지 4 개의 치환기로 임의치환되고, 상기 페닐은 C_1-6 알킬, 할로겐, C_1-6 알콕실, -COOCH₃ 로 이루어지는 1 내지 3 개의 치환기로 임의치환됨),The heteroaryl is C _1-6 alkyl, oxo, oxido, heteroalkyl, halogen, haloalkyl, methoxy-phenyl, haloalkyl, -NH ₂ , -N (CH ₃ ) ₂ , -NHCH ₂ -phenyl,- NHCOCH ₃ , cyano, -SO ₂ NH ₂ , -SO ₂ CH ₃ , -OCH ₂ COOCH ₃ , -OCH ₂ COOH, -SCH ₂ COOH, -COCH ₃ , -COOC (CH ₃ ) ₃ , -COOC (CH ₃ ) ₃ , -COOCH ₂ CH ₃ , -COOH, pyridin-4-yl,

Benzyl, is optionally substituted by one to four substituents independently selected at each occurrence from the group consisting of phenyl, said phenyl is from 1 to 3 consisting of C _1-6 alkyl, halogen, C _1-6 alkoxyl, -COOCH ₃ Optionally substituted with)

-NH-phenyl, wherein the phenyl is optionally substituted with 1 to 3 substituents selected from C _1-6 alkyl.

( Ⅳ ). The compound according to (iii):

[X ¹ is C (= O) R ³ , where

R ³ is selected from the group consisting of:

Hydrogen, C _1-6 alkyl, —CH ₂ NH ₂ , —CH ₂ CH ₂ NH ₂ , —C (CH ₃ ) NH ₂ , —CH ₂ CH ₂ N (ethyl) ₂ , —N (CH ₃ ) ₂ , -N (CH ₂ CH ₃ ) ₂ , -N (iso-propyl) ₂ , -NCH ₃ -benzyl, -NHCH ₂ COOCH ₂ CH ₃ , -NH-phenyl, -CH ₂ NHCOCH ₃ , CH ₂ CH ₂ CONH ₂ , -C (NH ₂ ) CH ₂ C (CH ₃ ) ₂ , -CH (NH ₂ ) CH (CH ₃ ) ₂ , -CH ₂ CN, -C _1-6 alkyl-OH, -CH ₂ CH ₂ COOCH ₃ , -C (CH ₃ ) ₂ OCOCH ₃ , -CH ₂ OCOCH ₃ , -CH ₂ SO ₂ CH ₃ , -CH ₂ (CH ₃ ) SO ₂ CH ₃ , heteroalkyl,

으로부터 선택되는 -(CH₂)_t-C_3-8 시클로알킬 (여기서, t 는 0 내지 2 이고, 상기 -C_3-8 시클로알킬은 C_1-6 알킬, 할로겐, 히드록실, 시아노, 옥소, 페닐을 포함하는 군으로부터 독립적으로 선택되는 1 내지 3 개의 치환기로 임의치환됨),Cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl or

-(CH ₂ ) _t -C _3-8 cycloalkyl, wherein t is 0 to 2, wherein -C _3-8 cycloalkyl is C _1-6 alkyl, halogen, hydroxyl, cyano, oxo , Optionally substituted with 1 to 3 substituents independently selected from the group containing phenyl),

-(CHR ^m ) _u -phenyl, wherein R ^m is H, hydroxyl or C _1-6 alkyl, u is 0 to 2, said phenyl is C _1-10 alkyl, C _1-10 heteroalkyl, C Optionally selected from _1-6 haloalkyl, cyano, halogen, C _1-6 alkylsulfonyl, -SO ₂ NH ₂ , -NHCOCH ₃ or -COOCH ₃ with 1 to 4 substituents independently selected in each case Substituted),

으로 이루어지는 군으로부터 선택되는 -(CH₂)_v-헤테로아릴 (여기서, v 는 0 내지 3 이고, 상기 헤테로아릴은 C_1-10 알킬, 할로겐, 페닐, C_1-6 알콕시, C_1-6 티오알킬, -NH₂, SO₂NH₂, -COCH₃, 옥소, 옥시도,

으로 이루어지는 군으로부터 각 경우에 독립적으로 선택되는 1 내지 3 개의 치환기로 임의치환됨),

-(CH ₂ ) _v -heteroaryl selected from the group consisting of: wherein v is 0 to 3 and said heteroaryl is C _1-10 alkyl, halogen, phenyl, C _1-6 alkoxy, C _1-6 thio Alkyl, -NH ₂ , SO ₂ NH ₂ , -COCH ₃ , oxo, oxido,

Optionally substituted with 1 to 3 substituents independently selected in each case from the group consisting of:

, 옥세타닐, 테트라히드로푸라닐, 테트라히드로피라닐, 티아졸리디닐, 옥사졸리디닐, 이소티아졸리디닐, 피페라지닐, 이미다졸리닐, 1,2,3,4-테트라히드로퀴놀리닐 및 N-메틸-1,2,3,4-테트라히드로이소퀴놀린-3-일로 이루어지는 군으로부터 선택되는 -(CHRⁿ)_w-헤테로사이클 (여기서, Rⁿ 은 수소 또는 C_1-6 알킬이고, w 는 0 내지 3 이고, IIa-f

, Oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, oxazolidinyl, isothiazolidinyl, piperazinyl, imidazolinyl, 1,2,3,4-tetrahydroquinolinyl And-(CHR ⁿ ) _w -heterocycle selected from the group consisting of N-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl, wherein R ⁿ is hydrogen or C _1-6 alkyl, w is 0 to 3,

The heterocycle consists of C _1-6 alkyl, hydroxy, C _1-6 alkylcarbonyl, carbamoyl, amino, C _1-6 alkylamino, C _1-6 dialkylamino, pyridinyl and phenylamino Optionally substituted with 1 to 3 substituents independently selected in each case from 2 hydrogens in the carbon bonded to nitrogen may be replaced with oxygen (oxo), wherein:

R ⁸ is hydrogen, C _1-6 -alkyl, C _1-6 haloalkyl, C _1-6 heteroalkyl, phenyl-C _1-6 alkyl, C _1-3 alkoxy-C _1-6 alkyl, pyrimidine-2 -Day, COR ⁹ , COCHR ¹⁵ NHR ⁷ or SO ₂ R ¹⁰ ;

R ⁹ is C _1-6 alkyl, C _1-6 haloalkyl, furanyl, C _1-6 alkoxy, C _3-5 cycloalkyl, C _1-6 alkylamino, -COO-C _1-6 alkyl, -COOH , -CH ₂ OCH ₂ OOH, -CH ₂ CH ₂ COOH;

R ¹⁰ is C _1-6 alkyl, C _1-6 dialkylamino, C _3-8 cycloalkyl;

R ⁷ is hydrogen or Boc;

R ¹⁵ is hydrogen or C _1-6 alkyl).

( v ). The compound according to (iii), wherein X ¹ is S (═O) ₂ R ³ , wherein R ³ is phenyl optionally substituted with 1 to 3 halogens.

( Ⅵ ). The compound of (iii), wherein X ¹ is C (═O) OR ³ , wherein R ³ is C _1-6 alkyl.

( Ⅶ ). The compound according to (iii):

[X ² is C (= O) R ⁴ , where

R ⁴ is selected from the group consisting of:

C _1-6 alkyl, —CH ₂ CH ₂ CONH ₂ , —CH ₂ NCH ₃ SO ₂ CH ₃ , —CH (CH (CH ₃ ) ₂ ) NHCOCH ₃ ,

-(CH ₂ ) _e C _3-8 cycloalkyl, wherein e is 0 to 2, wherein said cycloalkyl is optionally substituted with 1 to 4 substituents independently selected at each occurrence from the group consisting of C _1-6 alkyl being),

, 또는

으로 이루어지는 군으로부터 각 경우에 독립적으로 선택되는 1 내지 4 개의 치환기로 임의치환됨),C _3-8 heterocycle, wherein the heterocycle is C _1-6 alkyl, hydroxyl, —CO—C _1-6 alkyl, oxo, benzyl,

, or

Optionally substituted with 1 to 4 substituents independently selected at each occurrence from the group consisting of:

으로 이루어지는 군으로부터 각 경우에 독립적으로 선택되는 1 내지 4 개의 치환기로 임의치환됨);-(CHR ^f ) _f -phenyl, wherein R ^f is hydrogen or -NHCOCH ₃ , f is 0 or 1, said phenyl is C _1-10 alkyl, C _1-10 heteroalkyl, C _1-6 haloalkyl , Cyano, halogen, C _1-6 alkylsulfonyl, NO ₂ , -CO-C _1-6 alkyl, -COOCH ₃ , COOC (CH ₃ ) ₃ , -NHSO ₂ CH ₃ , NH ₂ , -N (CH ₃ ) ₂ , -N (CH ₃ ) CH ₂ CH ₂ OH, -NHCOCH ₃ , -OCF ₃ -OCH ₂ COOH, pyridin-4-yl,

Optionally substituted with 1 to 4 substituents independently selected at each occurrence from the group consisting of;

및

으로 이루어지는 군으로부터 선택되고,(CH ₂ ) _g -heteroaryl, where g is 0 or 1 and said heteroaryl is furanyl, thiophenyl, isoxazolyl, thiazolyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl , Benzofuranyl, pyranyl, pyridinyl, pyrimidinyl, synoxalinyl, cinnolinyl,

And

Selected from the group consisting of

벤질, 페닐로 이루어지는 군으로부터 각 경우에 독립적으로 선택되는 1 내지 4 개의 치환기로 임의치환되고, 상기 페닐은 C_1-6 알킬, 할로겐, C_1-6 알콕실, -COOCH₃ 로 이루어지는 1 내지 3 개의 치환기로 임의치환됨),The heteroaryl is C _1-6 alkyl, oxo, oxido, heteroalkyl, halogen, haloalkyl, methoxy-phenyl, haloalkyl, -NH ₂ , -N (CH ₃ ) ₂ , -NHCH ₂ -phenyl,- NHCOCH ₃ , cyano, -SO ₂ NH ₂ , -SO ₂ CH ₃ , -OCH ₂ COOCH ₃ , -OCH ₂ COOH, -SCH ₂ COOH, -COCH ₃ , -COOC (CH ₃ ) ₃ , -COOC (CH ₃ ) ₃ , -COOCH ₂ CH ₃ , -COOH, pyridin-4-yl,

Benzyl, is optionally substituted by one to four substituents independently selected at each occurrence from the group consisting of phenyl, said phenyl is from 1 to 3 consisting of C _1-6 alkyl, halogen, C _1-6 alkoxyl, -COOCH ₃ Optionally substituted with)

-NH-phenyl, wherein the phenyl is optionally substituted with 1 to 3 substituents selected from C _1-6 alkyl.

( Ⅷ ). Compound (i) as follows:

[X ² is S (= O) ₂ R ⁴ , where

R ⁴ is phenyl optionally substituted with 1 to 3 C _1-6 alkyl, or

및

으로부터 선택되는 헤테로아릴이고, 상기 헤테로아릴은 C_1-6 알킬, 할로겐, -COOCH₃ 또는 페닐로 이루어지는 1 내지 4 개의 치환기로 임의치환됨].

And

Heteroaryl is optionally substituted from 1 to 4 substituents consisting of C _1-6 alkyl, halogen, —COOCH ₃ or phenyl.

( Ⅸ ). The compound according to (ii), and pharmaceutically acceptable salts, hydrates, solvates and stereoisomers thereof:

[R ¹ is phenyl optionally substituted with 1 to 4 substituents independently selected at each occurrence from the group consisting of halogen and C _1-6 alkyl, or

Heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl and thiazolyl, said heteroaryl being 1 to 3 substituents independently selected from the group consisting of halogen, C _1-6 alkyl and C _1-6 haloalkyl Optionally substituted with;

R ² is hydrogen;

R ⁵ is hydrogen or C _1-6 alkyl;

R ^5a is hydrogen, hydroxyl or C _1-6 alkyl;

R ⁶ is hydrogen or C _1-3 hydroxyalkyl;

X ¹ is selected from the group consisting of -C (= 0) R ³ , -S (= 0) ₂ R ³ ;

X ² is selected from the group consisting of —C (═O) R ⁴ , —S (═O) ₂ R ⁴ or benzyl;

R ³ is selected from the group consisting of:

C _1-6 alkyl, heteroalkyl, -phenyl-SO ₂ CH ₃ ,

-(CH ₂ ) _t -C _3-8 cycloalkyl selected from the group consisting of cyclopropanyl, cyclobutanyl, cyclopentanyl and cyclohexanyl, wherein t is 0 or 2 and the -C _3-8 cyclo Alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxyl and oxo),

또는

으로 이루어지는 군으로부터 선택되는 헤테로아릴 (여기서, v 는 0 내지 3 이고, 상기 헤테로아릴은 1 내지 3 개의 C_1-10 알킬로 임의치환됨),

or

Heteroaryl selected from the group consisting of: where v is 0 to 3 and said heteroaryl is optionally substituted with 1 to 3 C _1-10 alkyl,

, 옥세타닐, 테트라히드로푸라닐, 테트라히드로피라닐, 티아졸리디닐, 옥사졸리디닐, 이소티아졸리디닐, 피페라지닐, 이미다졸리닐, 1,2,3,4-테트라히드로퀴놀리닐 및 N-메틸-1,2,3,4-테트라히드로이소퀴놀린-3-일로 이루어지는 군으로부터 선택되는 헤테로사이클 (상기 헤테로사이클은 C_1-6 알킬, 히드록시, C_1-6 알킬카르보닐, 카르바모일, 아미노, C_1-6 알킬아미노, C_1-6 디알킬아미노, 피리디닐 및 페닐아미노로 이루어지는 군으로부터 각 경우에 독립적으로 선택되는 1 내지 3 개의 치환기로 임의치환되고, 질소에 결합되어 있는 탄소에 있는 2 개의 수소는 산소 (옥소) 로 대체될 수 있고, 여기서: IIa-f

, Oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, oxazolidinyl, isothiazolidinyl, piperazinyl, imidazolinyl, 1,2,3,4-tetrahydroquinolinyl And N-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl, wherein the heterocycle is C _1-6 alkyl, hydroxy, C _1-6 alkylcarbonyl, Optionally substituted with 1 to 3 substituents independently selected in each case from the group consisting of carbamoyl, amino, C _1-6 alkylamino, C _1-6 dialkylamino, pyridinyl and phenylamino and bonded to nitrogen The two hydrogens in the carbon can be replaced with oxygen (oxo), where:

R ⁸ is hydrogen, C _1-6 -alkyl, C _1-6 haloalkyl, C _1-6 heteroalkyl, phenyl-C _1-6 alkyl, C _1-3 alkoxy-C _1-6 alkyl, pyrimidine-2 -Day, COR ⁹ , COCHR ¹⁵ NHR ⁷ or SO ₂ R ¹⁰ ;

R ⁹ is C _1-6 alkyl, C _1-6 haloalkyl, furanyl, C _1-6 alkoxy, C _3-5 cycloalkyl, C _1-6 alkylamino, -COO-C _1-6 alkyl, -COOH , -CH ₂ OCH ₂ OOH, -CH ₂ CH ₂ COOH;

R ¹⁰ is C _1-6 alkyl, C _1-6 dialkylamino, C _3-8 cycloalkyl;

R ⁷ is hydrogen or Boc;

R ¹⁵ is hydrogen or C _1-6 alkyl;

-NH- (CH ₂ ) _x -phenyl, wherein x is 0 or 1, said phenyl is C _1-6 alkyl, halogen, -OCF ₃ , heteroalkyl, haloalkyl, acetyl, dialkylamine, cyano, Optionally substituted with 1 to 3 substituents independently selected in each case from the group consisting of -COOH, COOCH ₂ CH ₃ ),

-NH (CH ₂ ) _y -heteroaryl, wherein y is 0 or 1, wherein the heteroaryl is 1 to 3 substituents independently selected at each occurrence from the group consisting of C _1-6 alkyl, halogen, haloalkyl Randomized to),

-NH-heterocycle, wherein the heteroaryl is optionally substituted with 1 to 2 substituents independently selected at each occurrence from the group consisting of -COCF ₃ , COOCH ₂ -phenyl,

-NH (CH ₂ ) _z -C _3-8 cycloalkyl selected from cyclopropanyl, cyclobutanyl, cyclopentanyl and cyclohexanyl, wherein z is 0 or 1;

R ⁴ is selected from the group consisting of:

C _1-6 alkyl,

C _3-8 cycloalkyl selected from cyclopropanyl, cyclobutanyl, cyclopentanyl and cyclohexanyl, wherein said cycloalkyl is optionally substituted with 1 to 4 substituents consisting of C _1-6 alkyl,

으로부터 선택되는 C_3-8 헤테로사이클 (여기서, 상기 헤테로사이클은 C_1-6 알킬 및 -CO-C_1-6 알킬로 이루어지는 군으로부터 각 경우에 독립적으로 선택되는 1 내지 3 개의 치환기로 임의치환됨),Tetrahydrofuranyl and

C _3-8 heterocycle selected from wherein the heterocycle is optionally substituted with 1 to 3 substituents independently selected at each occurrence from the group consisting of C _1-6 alkyl and —CO-C _1-6 alkyl ),

으로 이루어지는 군으로부터 각 경우에 독립적으로 선택되는 1 내지 4 개의 치환기로 임의치환됨),Phenyl (wherein the phenyl is C _1-10 alkyl, C _1-10 heteroalkyl, C _1-6 haloalkyl, cyano, halogen, C _{1 -6} alkyl _{sulfonyl, NO 2, -CO-C 1} -6 alkyl, -COOCH ₃ , COOC (CH ₃ ) ₃ , -NHSO ₂ CH ₃ , NH ₂ , -N (CH ₃ ) ₂ , -N (CH ₃ ) CH ₂ CH ₂ OH, -NHCOCH ₃ , -OCF ₃ -OCH ₂ COOH, pyridin-4-yl,

Optionally substituted with 1 to 4 substituents independently selected at each occurrence from the group consisting of:

및

으로 이루어지는 군으로부터 선택되는 헤테로아릴 (상기 헤테로아릴은 C_{1 -6} 알킬, 옥소, 옥시도, 헤테로알킬, 할로겐, 할로알킬, 메톡시-페닐, 할로알킬, -NH₂, -N(CH₃)₂-, -NHCH₂-페닐, -NHCOCH₃, 시아노, -SO₂NH₂, -SO₂CH₃, -OCH₂COOCH₃, -OCH₂COOH, -SCH₂COOH, -COCH₃, -COOC(CH₃)₃, -COOC(CH₃)₃, -COOCH₂CH₃, -COOH, 피리딘-4-일,

, 벤질, 페닐 {상기 페닐은 C_1-6 알킬, 할로겐, C_1-6 알콕실, -COOCH₃ 로 이루어지는 1 내지 3 개의 치환기로 임의치환됨} 로 이루어지는 군으로부터 각 경우에 독립적으로 선택되는 1 내지 4 개의 치환기로 임의치환됨);Furanyl, thiophenyl, isoxazolyl, thiazolyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl, benzofuranyl, pyranyl, pyridinyl, pyrimidinyl, synoxalinyl, cynolinyl ,

And

Heteroaryl selected from the group consisting of (wherein the heteroaryl group is C _{1 -6} alkyl, oxo, oxido, heteroalkyl, halogen, haloalkyl, methoxy-phenyl, _{haloalkyl, -NH 2, -N (CH 3} ) _2- , -NHCH ₂ -phenyl, -NHCOCH ₃ , cyano, -SO ₂ NH ₂ , -SO ₂ CH ₃ , -OCH ₂ COOCH ₃ , -OCH ₂ COOH, -SCH ₂ COOH, -COCH ₃ , -COOC (CH ₃ ) ₃ , -COOC (CH ₃ ) ₃ , -COOCH ₂ CH ₃ , -COOH, pyridin-4-yl,

, Benzyl, phenyl, wherein said phenyl is independently selected in each case from the group consisting of 1 to 3 substituents consisting of C _1-6 alkyl, halogen, C _1-6 alkoxyl, -COOCH ₃ } Optionally substituted with 4 substituents);

-(NR ^h )-(CH ₂ ) _h -phenyl, wherein R ^h is hydrogen or C _1-6 alkyl, h is 0 or 1, and the phenyl is one to three selected from C _1-6 alkyl Optionally substituted with a substituent).

( x ). The compound according to (iii):

[X ¹ is C (= O) R ³ , where

R ³ is selected from the group consisting of:

C _1-6 alkyl, heteroalkyl, -phenyl-SO ₂ CH ₃ ,

-(CH ₂ ) _t -C _3-8 cycloalkyl selected from the group consisting of cyclopropanyl, cyclobutanyl, cyclopentanyl and cyclohexanyl, wherein t is 0 or 2 and the -C _3-8 cyclo Alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxyl and oxo),

또는

으로 이루어지는 군으로부터 선택되는 헤테로아릴 (여기서, v 는 0 내지 3 이고, 상기 헤테로아릴은 1 내지 3 개의 C_1-10 알킬로 임의치환됨),

or

Heteroaryl selected from the group consisting of: where v is 0 to 3 and said heteroaryl is optionally substituted with 1 to 3 C _1-10 alkyl,

, 옥세타닐, 테트라히드로푸라닐, 테트라히드로피라닐, 티아졸리디닐, 옥사졸리디닐, 이소티아졸리디닐, 피페라지닐, 이미다졸리닐, 1,2,3,4-테트라히드로퀴놀리닐 및 N-메틸-1,2,3,4-테트라히드로이소퀴놀린-3-일로 이루어지는 군으로부터 선택되는 헤테로사이클, IIa-f

, Oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, oxazolidinyl, isothiazolidinyl, piperazinyl, imidazolinyl, 1,2,3,4-tetrahydroquinolinyl And N-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl,

The heterocycle C _{1 -6} alkyl, hydroxy, C _{1 -6} alkylcarbonyl, carbamoyl, amino, C _{1 -6} alkylamino, C _{1 -6} dialkylamino, pyridinyl and phenylamino group consisting of Optionally substituted with 1 to 3 substituents independently selected in each case from 2 hydrogens in the carbon bonded to nitrogen may be replaced with oxygen (oxo), wherein:

R ⁸ is hydrogen, C _{1 -6} alkyl, C _{1 -6} haloalkyl, C _{1 -6} alkyl, heteroaryl, phenyl -C _{1 -6} alkyl, C _1-3 alkoxy -C _{1 -6} alkyl, pyrimidin-2- 1, COR ⁹ , COCHR ¹⁵ HR ⁷ or SO ₂ R ¹⁰ ego;

R ⁹ is C _{1 -6} alkyl, C _{1 -6} haloalkyl, furanyl, C _{1 -6} alkoxy, C _{3 -5} cycloalkyl, C _1-6 alkylamino, -COO-C _{1 -6} alkyl, -COOH , -CH ₂ OCH ₂ OOH, -CH ₂ CH ₂ COOH;

R ¹⁰ is C _{1 -6} alkyl, C _{1 -6} dialkylamino, C _{3 -8} cycloalkyl;

R ⁷ is hydrogen or Boc;

R ¹⁵ is hydrogen or C _{1 -6} alkyl;

-NH- (CH _{2) x} - phenyl (wherein x is 0 or 1, and said phenyl C _{1 -6} alkyl, halogen, -OCF _3, heteroalkyl, haloalkyl, acetyl, dialkyl amine, cyano, Optionally substituted with 1 to 3 substituents independently selected in each case from the group consisting of -COOH, COOCH ₂ CH ₃ ,

-NH (CH _{2) y} - heteroaryl (where, y is 0 or 1, and said heteroaryl is C _{1 -6} alkyl, 1 to 3 substituents independently selected at each occurrence from halogen, the group consisting of haloalkyl Is optionally substituted with

-NH-heterocycle, wherein the heteroaryl is optionally substituted with 1 to 2 substituents independently selected at each occurrence from the group consisting of -COCF ₃ , COOCH ₂ -phenyl,

-NH (CH ₂ ) _z -C _{3 -8} cycloalkyl selected from cyclopropanyl, cyclobutanyl, cyclopentanyl and cyclohexanyl, wherein z is 0 or 1.

(xi). in (ix) the following compounds:

X ¹ is —S (═O) ₂ R ³ , wherein R ³ is phenyl.

(xii). in (ix) the following compounds:

X ² is -C (= 0) R ⁴ ,

R ⁴ is selected from the group consisting of:

C _{1 -6} alkyl,

C _{3 -8} cycloalkyl (wherein the cycloalkyl is optionally substituted by one to four substituents consisting of a C _{1 -6-alkyl)} is selected from cycloalkyl propanil, cycloalkyl butanone carbonyl, cycloalkyl carbonyl fentanyl and cyclohexanone,

로부터 선택되는 C_{3 -8} 헤테로사이클 (여기서, 상기 헤테로사이클은 C_{1 -6} 알킬 및 -CO-C_{1 -6} 알킬로 이루어지는 군으로부터 각 경우에 독립적으로 선택되는 1 내지 3 개의 치환기로 임의치환됨), Tetrahydrofuranyl and

C _{3 -8} heterocycle is selected from (wherein said heterocyclic is optionally substituted with 1 to 3 substituents independently selected at each occurrence from the group consisting of C _{1 -6} alkyl and -CO-C _{1 -6} alkyl ),

으로 이루어지는 군으로부터 각 경우에 독립적으로 선택되는 1 내지 4 개의 치환기로 임의치환됨), Phenyl (wherein the phenyl is C _{1 -10} alkyl, C _{1 -10} alkyl, heteroaryl, C _{1 -6} haloalkyl, cyano, halogen, C _{1 -6} alkyl _{sulfonyl, NO 2, -CO-C 1} -6 Alkyl, -COOCH ₃ , COOC (CH ₃ ) ₃ , -NHSO ₂ CH ₃ , NH ₂ , -N (CH ₃ ) ₂ , -N (CH ₃ ) CH ₂ CH ₂ OH, -NHCOCH ₃ , -OCF _3- OCH ₂ COOH, pyridin-4-yl,

Optionally substituted with 1 to 4 substituents independently selected at each occurrence from the group consisting of:

및

로 이루어지는 군으로부터 선택되는 헤테로아릴 (여기서, 상기 헤테로아릴은 C_{1 -6} 알킬, 옥소, 옥시도, 헤테로알킬, 할로겐, 할로알킬, 메톡시-페닐, 할로알킬, -NH₂, -N(CH₃)₂, -NHCH₂-페닐, -NHCOCH₃, 시아노, -SO₂NH₂, -SO₂CH₃, -OCH₂COOCH₃, -OCH₂COOH, -SCH₂COOH, -COCH₃, -COOC(CH₃)₃, -COOC(CH₃)₃, -COOCH₂CH₃, -COOH, 피리딘-4-일,

, 벤질, 페닐 {상기 페닐은 C_{1 -6} 알킬, 할로겐, C_{1 -6} 알콕실, -COOCH₃ 로 이루어지는 1 내지 3 개의 치환기로 임의치환됨} 로 이루어지는 군으로부터 각 경우에 독립적으로 선택되는 1 내지 4 개의 치환기로 임의치환됨),Furanyl, thiophenyl, isoxazolyl, thiazolyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl, benzofuranyl, pyranyl, pyridinyl, pyrimidinyl, synoxalinyl, cinnaolinyl ,

And

Heteroaryl (wherein the heteroaryl is selected from the group consisting of is C _{1 -6} alkyl, oxo, oxido, heteroalkyl, halogen, haloalkyl, methoxy-phenyl, haloalkyl, -NH _2, -N (CH ₃ ) ₂ , -NHCH ₂ -phenyl, -NHCOCH ₃ , cyano, -SO ₂ NH ₂ , -SO ₂ CH ₃ , -OCH ₂ COOCH ₃ , -OCH ₂ COOH, -SCH ₂ COOH, -COCH ₃ ,- COOC (CH ₃ ) ₃ , -COOC (CH ₃ ) ₃ , -COOCH ₂ CH ₃ , -COOH, pyridin-4-yl,

, Benzyl, phenyl 1 is independently selected at each occurrence from the group consisting of {the phenyl is C _{1 -6} alkyl, halogen, C _{1 -6} alkoxyl, optionally substituted with one to three substituents consisting of a -COOCH _3} Optionally substituted with 4 substituents),

^{- (NR h) - (CH} 2) h - phenyl (wherein, R ^h is from 1 to 3 being hydrogen or C _{1 -6} alkyl, h is 0 or 1, and said phenyl is selected from C _{1 -6} alkyl Optionally substituted with a substituent).

(xiii). in (ix) the following compounds:

X ² is -S (= 0) ₂ R ⁴ ,

R ⁴ is phenyl optionally substituted by one to four substituents consisting of a C _{1 -6} alkyl, halogen, cyano, -COOCH ₃ and COOH, or

Isoxazolyl, pyrazolyl, furanyl, pyrrolyl, and a heteroaryl group selected from pyridinyl, wherein the heteroaryl is a C _{1 -6} alkyl, halogen, _{phenyl, -N (CH 3 O) 2} , -COOH, -COOCH Optionally substituted with 1 to 4 substituents consisting of ₃ and —COOCH ₂ CH ₃ .

In one embodiment of the invention, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^5a , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ^1O , R ¹¹ , R ¹² , R ¹³ , There is provided a compound according to formula I , wherein R ^14a , R ^14b , R ^14c , R ¹⁵ , R ¹⁶ , X ¹ , X ² , X ³ , Y, r, s, n and p are as defined above.

In the following embodiments of the invention, all substituent definitions are to take the best form as disclosed in the Summary of the Invention, unless limited to the description of the following embodiments.

In another embodiment of the invention, R ¹ is optionally substituted phenyl; X ¹ is —C (═O) R ³ or —SO ₂ R ³ ; X ² is -C (= 0) R ⁴ ; There is provided a compound according to formula I , wherein R ² , R ⁵ , R ^5a and R ⁶ are hydrogen.

In another embodiment of the invention, R ¹ is optionally substituted phenyl; X ¹ is -C (= 0) R ³ ; X ² is -C (= 0) R ³ ; R ³ is heterocycle as defined in section (v) of R ³ ; There is provided a compound according to formula I , wherein R ² , R ⁵ , R ^5a and R ⁶ are hydrogen.

In another embodiment of the invention, R ¹ is optionally substituted phenyl; X ¹ is -C (= 0) R ³ ; X ² is -C (= 0) R ⁴ ; R ³ is a heterocycle according to formula ( IIa-IId ) as defined in section (v) of R ³ ; R ⁴ is a phenyl or heteroaryl group wherein one or more, preferably two atom (s), adjacent to the atoms bonded to X ² are substituted carbon atoms, and R ² , R ⁵ , R ^5a and R ⁶ There is provided a compound according to formula I , which is hydrogen. Substituted carbon as used herein refers to carbon having a non-hydrogen substituent.

In another embodiment of the invention, R ¹ is 4-methyl-3-chloro-phenyl; X ¹ is -C (= 0) R ³ ; X ² is -C (= 0) R ⁴ ; R ³ is a heterocycle according to formula IIb or IIc as defined in section (v) of R ³ ; R ⁴ is 2,6-dimethyl-pyrimidin-5-yl, 2,6-dimethyl-pyridin-3-yl or 2,6-dimethyl-phenyl; There is provided a compound according to formula I , wherein R ² , R ⁵ , R ^5a and R ⁶ are hydrogen.

In another embodiment of the invention, R ¹ is 4-methyl-3-chloro-phenyl; X ¹ is -C (= 0) R ³ ; X ² is -C (= 0) R ⁴ ; R ³ is a heterocycle according to formula ( IIb) or ( IIc ) as defined in section (v), wherein the piperidinyl or pyrrolidinyl nitrogen atom is selected from -C (= 0) CH ₃ , -C (= 0) C ( ═O) OC _1-6 alkyl or substituted by —C (═O) C (═O) OH); R ⁴ is 2,6-dimethyl-pyrimidin-5-yl, 2,6-dimethyl-pyridin-3-yl or 2,6-dimethyl-phenyl; There is provided a compound according to formula I , wherein R ² , R ⁵ , R ^5a and R ⁶ are hydrogen.

In another embodiment of the invention, R ¹ is optionally substituted phenyl; X ¹ is C (═O) NR ^14a R ^14b or —S (═O) ₂ NR ^14a R ^14b ; X ² is -C (= 0) R ⁴ ; There is provided a compound according to formula I , wherein R ² , R ⁵ , R ^5a and R ⁶ are hydrogen.

In another embodiment of the invention, R ¹ is optionally substituted phenyl; X ¹ is C (═O) NR ^14a R ^14b or —S (═O) ₂ NR ^14a R ^14b , wherein R ^14a is optionally substituted phenyl and R ^14b is hydrogen; X ² is -C (= 0) R ⁴ ; Provided are compounds according to formula ( I) , wherein R ² , R ⁵ , R ^5a and R ⁶ are hydrogen. Unsubstituted phenyl refers to the substituents listed in the definition in section (i) of R ³ .

In another embodiment of the invention, R ¹ is 4-methyl-3-chloro-phenyl; X ¹ is C (═O) NR ^14a R ^14b or —S (═O) ₂ NR ^14a R ^14b , wherein R ^14a is phenyl substituted with carboxyl or C _1-6 alkoxycarbonyl and R ^14b is Soy); X ² is -C (= 0) R ⁴ ; There is provided a compound according to formula I , wherein R ² , R ⁵ , R ^5a and R ⁶ are hydrogen. Unsubstituted phenyl refers to the substituents listed in the definition in section (i) of R ³ .

In another embodiment of the invention, R ² is optionally substituted phenyl; X ¹ is —C (═O) R ³ or —SO ₂ R ³ ; X ² is -C (= 0) R ⁴ ; There is provided a compound according to formula I , wherein R ¹ , R ⁵ , R ^5a and R ⁶ are hydrogen.

In another embodiment of the invention, R ² is optionally substituted phenyl; X ¹ is -C (= 0) R ³ ; X ² is -C (= 0) R ⁴ ; There is provided a compound according to formula I , wherein R ¹ , R ⁵ , R ^5a and R ⁶ are hydrogen. In this embodiment, R ³ is optionally substituted aryl, optionally substituted cycloalkyl, 4-oxo-cyclohexyl, 3-oxo-cyclobutyl or tetrahydrofuranyl, and R ⁴ is a phenyl or heteroaryl group, wherein One or more, preferably two atom (s), adjacent atoms bonded to X ² are substituted carbon atoms.

In another embodiment of the invention, R ² is optionally substituted phenyl; X ¹ is -C (= 0) R ³ ; X ² is -C (= 0) R ⁴ ; There is provided a compound according to formula I , wherein R ¹ , R ⁵ , R ^5a and R ⁶ are hydrogen. In this embodiment, R ³ is cycloalkyl optionally substituted with 1 to 4 fluorine atoms, and R ⁴ is a phenyl or heteroaryl group (wherein one or more, preferably two atom (s) adjacent to the atom bonded to X ² ) Is a substituted carbon atom.

In another embodiment of the invention, R ² is optionally substituted phenyl; X ¹ is -C (= 0) R ³ ; X ² is -C (= 0) R ⁴ ; There is provided a compound according to formula I , wherein R ¹ , R ⁵ , R ^5a and R ⁶ are hydrogen. In this embodiment, R ³ is cyclopentyl, 4,4-difluorocyclohexyl or 3,3-difluorocyclobutyl, and R ⁴ is 2,6-dimethyl-pyrimidin-5-yl, 2, 6-dimethyl-pyridin-3-yl, 2,6-dimethyl-phenyl or III below.

In another embodiment of the invention, R ² is phenyl; X ¹ is -C (= 0) R ³ ; X ² is -C (= 0) R ⁴ ; There is provided a compound according to formula I , wherein R ¹ , R ⁵ , R ^5a and R ⁶ are hydrogen. In this embodiment, R ³ is cyclopentyl, 4,4-difluorocyclohexyl or 3,3-difluorocyclobutyl, and R ⁴ is 2,6-dimethyl-pyrimidin-5-yl, 2, 6-dimethyl-pyridin-3-yl, 2,6-dimethyl-phenyl or III .

In another embodiment of the invention there is provided a compound according to formula I selected from:

1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4 -c] pyrrole-2-yl] -propyl} -amide,

1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pipe Rolo [3,4-c] pyrrol-2-yl] -propyl} -amide,

[4-((3-Chloro-4-methyl-phenyl)-{3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4-c] Pyrrole-2-yl] -propyl} -carbamoyl) -piperidin-1-yl] -oxo-acetic acid; Compound with trifluoro-acetic acid,

Cyclopentanecarboxylic acid {(S) -1-phenyl-3- [5- (pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -propyl}- amides; Compound with trifluoro-acetic acid,

Cyclopentanecarboxylic acid {(S) -3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl]- 1-phenyl-propyl} -amide,

Cyclopentanecarboxylic acid {(S) -3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1 -Phenyl-propyl) -amide,

3- (3- (3-Chloro-4-methyl-phenyl) -3- {3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4 -c] pyrrole-2-yl] -propyl} -ureido) -benzoic acid; Compound with trifluoro-acetic acid

4,4-Difluoro-cyclohexanecarboxylic acid {(S) -3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4-c ] Pyrrole-2-yl] -1-phenyl-butyl} -amide, and

(5- {5-[(S) -3- (cyclopentanecarbonyl-amino) -3-phenyl-propyl] -hexahydropyrrolo [3,4-c] pyrrole-2-carbonyl} -4, 6-dimethyl-pyrimidin-2-yloxy) -acetic acid; Compound with trifluoro-acetic acid.

In another embodiment of the invention, a therapeutically effective amount of formula I wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^5a , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ^14a , R ^14b , R ^14c , R ¹⁵ , R ¹⁶ , X ¹ , X ² , X ³ , Y, r, s, n and p are as defined above) A method of treating or preventing human immunodeficiency virus (HIV) infection in a patient in need of the compound, or treating AIDS or ARC, is provided comprising administering a compound of to a patient in need thereof.

In another embodiment of the invention, a therapeutically effective amount of formula I wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^5a , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ^14a , R ^14b , R ^14c , R ¹⁵ , R ¹⁶ , X ¹ , X ² , X ³ , Y, r, s, n and p are as defined above) And co-administering a compound of and one or more of an HIV nucleoside reverse transcriptase inhibitor, an HIV non-nucleoside reverse transcriptase inhibitor, an HIV protease inhibitor or a viral fusion inhibitor to a patient in need thereof. Methods of treating or preventing human immunodeficiency virus (HIV) infection in a patient in need, or of treating AIDS or ARC are provided.

In another embodiment of the invention, a therapeutically effective amount of formula I wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^5a , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ^14a , R ^14b , R ^14c , R ¹⁵ , R ¹⁶ , X ¹ , X ² , X ³ , Y, r, s, n and p are as defined above) Compounds of and efavirens, nevirapine or delavirdine, zidovudine, didanosine, zalcitabine, stavudine; One or more of lamivudine, abakavir, adefovir and dipivoxil, saquinavir, ritonavir, nelpinavir, indinavir, amprenavir and lopinavir, or T-20, to a patient in need thereof Methods of treating or preventing human immunodeficiency virus (HIV) infection in a patient in need of the compound, including co-administration, or treating AIDS or ARC are provided.

In another embodiment of the invention there is provided a therapeutically effective amount of Formula I wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^5a , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ^14a , R ^14b , R ^14c , R ¹⁵ , R ¹⁶ , X ¹ , X ² , X ³ , Y, r, s, n and p are as defined above) Provided are methods of treating a mammal having a disease state that is alleviated by a CCR5 receptor antagonist, the method comprising administering the compound to a mammal in need thereof, wherein the disease state is a solid organ transplant rejection, transplantation formation Host disease, arthritis, rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis, psoriasis, asthma, allergies or multiple sclerosis).

In another embodiment of the invention, a therapeutically effective amount of formula I wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^5a , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ^14a , R ^14b , R ^14c , R ¹⁵ , R ¹⁶ , X ¹ , X ² , X ³ , Y, r, s, n and p are as defined above) A method of treating a mammal with a disease state that is alleviated by a CCR5 receptor antagonist, comprising co-administering a compound according to claim 1 and one or more other immune system modulators to a mammal in need thereof, wherein the disease state is Namely, solid organ transplant rejection, graft versus host disease, arthritis, rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis, psoriasis, asthma, allergies or multiple sclerosis).

In another embodiment of the invention, a therapeutically effective amount of formula I wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^5a , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ^14a , R ^14b , R ^14c , R ¹⁵ , R ¹⁶ , X ¹ , X ² , X ³ , Y, r, s, n and p are as defined above) A method of treating a mammal with a disease state that is alleviated by a CCR5 receptor antagonist, comprising co-administering a compound according to claim 1 and one or more other immune system modulators to a mammal in need thereof, wherein the disease state is Namely, solid organ transplant rejection, graft versus host disease, arthritis, rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis, psoriasis, asthma, allergies or multiple sclerosis).

In another embodiment of the invention, formula I , wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^5a , R ⁶ , mixed with one or more pharmaceutically acceptable carriers, diluents or excipients R ⁷ , R ⁸ , R ⁹ , R ^1O , R ¹¹ , R ¹² , R ¹³ , R ^14a , R ^14b , R ^14c , R ¹⁵ , R ¹⁶ , X ¹ , X ² , X ³ , Y, r, s , wherein n and p are as defined above), there is provided a pharmaceutical composition for the treatment or prevention of human immunodeficiency virus (HIV) infection, or for the treatment of AIDS or ARC.

In another embodiment of the invention, formula I , wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^5a , R ⁶ , mixed with one or more pharmaceutically acceptable carriers, diluents or excipients R ⁷ , R ⁸ , R ⁹ , R ^1O , R ¹¹ , R ¹² , R ¹³ , R ^14a , R ^14b , R ^14c , R ¹⁵ , R ¹⁶ , X ¹ , X ² , X ³ , Y, r, s , wherein n and p are as defined above, there is provided a pharmaceutical composition for treatment of a mammal having a disease state alleviated by a CCR5 receptor antagonist, wherein the disease state is a solid organ transplant Rejection, graft versus host disease, arthritis, rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis, psoriasis, asthma, allergies or multiple sclerosis).

In another embodiment of the invention, there is provided a reduction amination step, if any, including acylation with an acylating agent selected to provide the compounds disclosed herein, and removal of the protecting groups, wherein R ¹ is hydrogen and R ² Is optionally substituted phenyl or optionally substituted heteroaryl).

In another embodiment of the present invention, a chemical formula comprising the alkylation step, if present, removing a protecting group and acylating with an acylating agent selected to provide a compound disclosed herein, wherein R ² is hydrogen and R ¹ is any Is substituted phenyl or optionally substituted heteroaryl).

In another embodiment of the invention, there is provided a compound according to formula la , and pharmaceutically acceptable salts, hydrates, solvates and stereoisomers thereof:

[here:

X ¹ is -C (= O) R ³ , -S (= O) ₂ R ³ , -C (= O) OR ³ and -C (= 0) NHR ³ ; X ² is selected from the group consisting of —C (═O) R ⁴ , —S (═O) ₂ R ⁴ , or —CH ₂ -aryl; One of R ¹ and R ² is

(i) aryl optionally substituted with 1 to 4 substituents independently selected at each occurrence from the group consisting of: (a) C _1-10 alkyl, (b) C _1-10 heteroalkyl, (c) C _{1 -6} haloalkyl, (d) C _1-6 alkoxy, (e) C _1-6 thioalkyl, (f) amino, (g) C _1-6 alkyl amino, (h) C _1-6 dialkylamino, (g) C _1-6 acylamino, (i) carbamoyl, N-alkylcarbamoyl, N, N-dialkylcarbamoyl, (j) ureido, (k) nitro, (l) cyano , (m) halogen, (n) C _1-6 alkylsulfonyl, (o) sulfamoyl, N-alkylsulfamoyl or N, N-dialkylsulfamoyl, (p) alkylsulfonamido or optionally substituted phenylsulfone Amido, (q) optionally substituted aryloxy, (r) optionally substituted heteroaryloxy, and (s) -Y (CH ₂ ) _n R ¹¹ , wherein R ¹¹ is cyano, -CO ₂ R ¹² ,- CONR ¹² R ¹³ , -SO ₂ N ¹² R ¹³ , -NHSO ₂ R ¹² and -NHSO ₂ NR ¹² R ¹³ , wherein R ¹² and R ¹³ is (i) independently hydrogen, C _1-6 alkyl or C _1-6 heteroalkyl, or ( ii ) R ¹² and R ¹³ may be C _2-5 alkylene together when both are bonded to a nitrogen atom, and Y is —O—, —S—, or —NR ¹² — of a direct bond; or,

(ii) one of R ¹ and R ² is pyridinyl, pyridinyl-N-oxide, pyrimidinyl, pyrazinyl, pyridazinyl, isoxazolyl, isothiazolyl, pyrrolyl, thiazolyl and thienyl Heteroaryl selected from the group consisting of said heteroaryl optionally substituted with one to three substituents independently selected from the group of any substituents in (i) above; R ³ is selected from the group consisting of: (i) 1 to independently selected in each case from the group consisting of (i) (a) to (i) (s) described for R ¹ and R ² above; Aryl optionally substituted with four substituents, (ii) aryl is aryl C _1-6 alkyl as described in (i) above, (iii) pyridinyl, pyridinyl-N-oxide, pyrimidinyl, pyrazinyl , Pyridazinyl, isoxazolyl, isothiazolyl, pyrrolyl, thiazolyl, oxazolyl, pyrazolinyl, oxadiazolinyl, thiadiazolinyl, pyrazolyl, tetrazole, imidazolyl, triazolyl, tria Heteroaryl selected from the group consisting of zolyl, indolyl, quinolinyl, isoquinolinyl and thienyl, wherein the heteroaryl is C _1-10 alkyl, aryl, C _1-6 haloalkyl, C _1-6 Alkoxy, Independently selected in each case from the group consisting of C _1-6 thioalkyl, carbamoyl, nitro, cyano, amino, C _1-3 alkylamino, C _1-6 -dialkylamino, morpholino and halogen Optionally substituted with one to three substituents), (iv) heteroaryl is heteroaryl C _1-6 alkyl as described above, (v) IIa-f , furfuryl, oxetanyl, tetrahydrofuranyl, tetra Hydropyranyl, thiazolidinyl, oxazolidinyl, piperazinyl, imidazolinyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl and Heterocycle selected from the group consisting of 2-aza-bicyclo [2.2.1] heptanyl, wherein the heterocycle is C _1-6 alkyl, hydroxy, C _1-6 alkylcarbonyl, carbamoyl, amino , Independently selected in each case from the group consisting of alkylamino, dialkylamino and phenylamino Optionally substituted with three substituents, or two hydrogens at the carbon bonded to a nitrogen atom are replaced with oxygen (oxo), wherein: R ⁸ is hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 heteroalkyl, COR ⁹ or SO ₂ R ¹⁰ ; R ⁹ is (i) C _1-3 alkoxy, C _1-3 acyloxy, hydroxyl, phenyl, amino, C _1-6 alkylamino, C _1-6 dialkylamino, aminocarbonyl-pyridyl optionally substituted with C _1-6 alkyl from the group by one or two groups selected independently from a group consisting of (where the aminocarbonyl-pyridyl is optionally N- oxide and amino Benzoyl, wherein the phenyl or the benzoyl radical is optionally substituted with 1 to 3 groups independently selected from the group consisting of amino, alkylamino, dialkylamino, hydroxyl, halogen and C _1-3 alkoxy), (ii) sulfamoyl, acetylamino, halogen, C _1-6 alkyl, C _1-6 halogen Phenyl optionally substituted with one or two groups independently selected from the group consisting of roalkyl, and C _1-6 alkoxy, (iii) NH ₂ , C _1-3 alkylamino, C _1-3 dialkylamino, (iv ) C (= 0) NH ₂ , (v) 1H indole-3-carbonyl, (vi) furyl, pyridinyl, or pyridinyl N-oxide, (vii) N-acetylpiperidin-4yl, and (viii) selected from the group consisting of furfuryl; R ¹⁰ is (i) C _1-6 alkyl, (ii) C _1-3 haloalkyl, (iii) C _1-3 haloalkoxy, (iv) C _3-8 cycloalkyl, (v) C _1-3 alkoxy , Phenyl optionally substituted with halogen, nitro, acetamido, carboxy, and (vi) aralkyl, (vi) heterocyclyl C _1-6 alkyl, wherein heterocyclyl is as defined above, (vii ) Hydrogen, (viii) hydroxy, halogen, C _1-6 alkoxy, C _1-6 thioalkyl, acyloxy, C _1-6 acylamino, amino, alkylamino, dialkylamino, cyano, C _1-6 Alkylsulfonyl, C _1-6 sulfinyl, N-piperidinyl, N-pyrrolidinyl, imidazolyl, carbamoyl and alkoxycarbonyl substituted with 1 to 3 substituents independently selected in each case a C _1-6 alkyl, (ix) 1 to 4 fluorine, C _1-3 optionally substituted C _3-7 cycloalkyl, (x) 1 to 4 fluorine, C _1-3 alkyl or phenyl-alkyl or phenyl, an optionally substituted C _1-3 alkyl, -C _3-7 guneu consisting of cycloalkyl It is selected from; R ⁴ is (i) aryl optionally substituted with 1 to 4 substituents independently selected in each case from the group consisting of (i) (a) to (i) (s) described for R ¹ and R ² above; (ii) aryl C _1-6 alkyl as described above, (iii) pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, isoxazolyl, isothiazolyl, pyrrolyl, thiazolyl, oxazolyl , Pyrazolinyl, oxadiazolinyl, thiadiazolinyl, pyrazolyl, tetrazole, imidazolyl, triazolyl, triazolyl, indolyl, quinolinyl, isoquinolinyl, indazole, 4,5, Heteroaryl selected from the group consisting of 6,7-tetrahydroindazole, 1,4,5,6-tetrahydrocyclopentylpyrazolyl, imidazo [2,1-b] thiazolyl and thienyl, wherein Heteroaryl is C _1-10 alkyl, aryl, C _1-6 haloalkyl, C _1-6 alkoxy, Optionally substituted with 1 to 3 substituents independently selected at each occurrence from the group consisting of C _1-6 thioalkyl, carbamoyl, nitro, cyano, and halogen), (iv) heteroaryl is as described above Heteroaryl such as C _1-6 alkyl, (v) azetidinyl, azepinyl, furfuryl, oxetanyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, oxa Heterocycle selected from the group consisting of zolidinyl, piperazinyl, imidazolinyl, 1,2,3,4-tetrahydroquinolinyl and 1,2,3,4-tetrahydroisoquinolinyl, wherein _Wherein the heterocycle is independently selected in each case from the group consisting of C _1-6 alkyl, hydroxy, C _1-6 alkylcarbonyl, carbamoyl, amino, alkylamino, dialkylamino and phenylamino Optionally substituted with 3 substituents, or nitrogen Two hydrogens at the carbon bonded to the atom are replaced with oxygen (oxo)); (vi) heterocyclyl C _1-6 alkyl, wherein heterocyclyl is as defined above, (vii) hydrogen, (viii) hydroxy, halogen, C _1-6 alkoxy, C _1-6 thioalkyl , Acyloxy, C _1-6 acylamino, amino, alkylamino, dialkylamino, cyano, C _1-6 alkylsulfonyl, C _1-6 sulfinyl, N-piperidinyl, N-pyrrolidinyl, Imidazolyl, carbamoyl and alkoxycarbonyl with C _1-10 alkyl substituted with 1 to 3 substituents independently selected in each case, (ix) 1 to 4 fluorine, C _1-3 alkyl or phenyl an optionally substituted C _3-7 cycloalkyl, (x) is selected from 1 to 4 fluorine, C _1-3 group consisting of optionally substituted C _1-3 alkyl, -C _3-7 cycloalkyl-alkyl or phenyl; R ⁵ is hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 heteroalkyl, —CO ₂ R ¹² or CONR ¹² R ¹³ , R ⁶ is hydrogen, C _1-10 alkyl, hydroxy , C _1-6 alkoxy, C _1-3 hydroxyalkyl and C _1-3 alkoxy-C _1-3 alkyl; m is 1 to 2; n is 1 to 6; p is 0 to 2;

As used throughout this application, the phrase “a” or “an” refers to one or more of itself; For example, a compound refers to one or more compounds or at least one compound. As such, the terms “a” (or “an”), “one or more” and “at least one” may be used interchangeably herein.

The phrase “as defined above” refers to the first definition provided in the Summary of the Invention.

As used herein, the term “optionally” or “optionally” means that an event or situation described later may occur, but need not occur, and the description includes when an event or situation does and does not occur. do. For example, "optionally substituted" means that part may be hydrogen or a substituent.

The definitions described herein may be appended to form chemically-related combinations such as "heteroalkylaryl," "haloalkylheteroaryl," "arylalkylheterocyclyl," "alkylcarbonyl," "alkoxyalkyl" and the like. Consider that. The term-(ar) alkyl refers to either an unsubstituted alkyl or an aralkyl group. The term (hetero) aryl refers to an aryl or heteroaryl group.

The term "alkyl" as used herein refers to unbranched or branched, saturated, monovalent hydrocarbon residues having 1 to 10 carbon atoms. The term "lower alkyl" refers to a straight or branched chain hydrocarbon residue having 1 to 6 carbon atoms. "C _1-10 alkyl" as used herein refers to alkyl consisting of 1 to 10 carbons. One or more carbon atoms may be optionally replaced with oxygen, sulfur, substituted or unsubstituted nitrogen atom (s). Examples of alkyl groups include, but are not limited to, lower alkyl groups including methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, t-butyl or pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl It is not limited. The term (ar) alkyl or (heteroaryl) alkyl refers to an alkyl group optionally substituted by an aryl or heteroaryl group, respectively.

The definition above, when the term "alkyl" is used as another term below, such as in "phenylalkyl," or "hydroxyalkyl", is substituted with 1 to 2 substituents selected from other specifically-named groups It is considered to refer to an alkyl group as described. Thus, for example, "phenylalkyl" refers to an alkyl group having 1 to 2 phenyl substituents and thus includes benzyl, phenylethyl, and biphenyl. "Alkylaminoalkyl" is an alkyl group having 1 to 2 alkylamino substituents. "Hydroxyalkyl" means 2-hydroxyethyl, 2-hydroxypropyl, 1- (hydroxymethyl) -2-methylpropyl, 2-hydroxybutyl, 2,3-dihydroxybutyl, 2- (hydroxy Hydroxymethyl), 3-hydroxypropyl and the like. Thus, as used herein, the term "hydroxyalkyl" is used to define a subclass of a heteroalkyl group as defined above.

The term "alkylene" as used herein refers to a divalent saturated linear hydrocarbon radical having 1 to 8 carbon atoms or a branched saturated divalent hydrocarbon radical having 3 to 8 carbon atoms unless otherwise indicated. Examples of alkylene radicals include, but are not limited to, methylene, ethylene, propylene, 2-methyl-propylene, butylene, 2-ethylbutylene.

As used herein, the term “haloalkyl” refers to an unbranched or branched alkyl group as defined above, wherein one, two, three or more hydrogen atoms are replaced by halogen. Examples include 1-fluoromethyl, 1-chloromethyl, 1-bromomethyl, 1-iodomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, triiodomethyl, 1-fluoroethyl, 1-chloroethyl, 1-bromoethyl, 1-iodoethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2,2-dichloroethyl, 3-bro Parent propyl or 2,2,2-trifluoroethyl.

As used herein, the term “heteroalkyl” refers to an alkyl radical as defined herein, wherein one, two or three hydrogen atoms are selected from -OR ^a , -NR ^b R ^c , and -S (O) is substituted with a substituent independently selected from the group consisting of _n R ^d , wherein n is an integer from 0 to 2, wherein the point of attachment of the heteroalkyl radical is considered to be via a carbon atom (wherein R ^a is hydrogen, C _1-6 acyl, C _1-6 alkyl, C _3-8 cycloalkyl, or C _{3-8 cycloaryl} -C _1-6 alkyl; R ^b and R ^c are independently of each other hydrogen, C _1-6 acyl, C _1-6 alkyl, C _3-8 cycloalkyl, or C _3-8 cycloalkyl-C _1-6 alkyl; when n is 0, R ^d is hydrogen, C _1-6 alkyl, C _3-8 cyclo Alkyl, or C _3-8 cycloalkyl-C _1-6 alkyl, when n is 1 or 2, R ^d is C _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 cycloalkyl-C _{1 -6} alkyl, amino, C _1-6 acylamino, or C _1-6 Alkylamino). Representative examples include 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxypropyl, 1-hydroxymethylethyl, 3-hydroxybutyl, 2,3-dihydroxybutyl, 2-hydroxy-1-methylpropyl, 2-aminoethyl, 3-aminopropyl, 2-methylsulfonylethyl, aminosulfonylmethyl, aminosulfonylethyl, aminosulfonylpropyl , Methylaminosulfonylmethyl, methylaminosulfonylethyl, methylaminosulfonylpropyl, and the like, but are not limited thereto.

As used herein, the term “acyl” refers to a group of the formula —C (═O) R, wherein R is hydrogen or lower alkyl as defined herein. As used herein, the term “alkylcarbonyl” refers to a group of formula C (═O) R, wherein R is alkyl as defined herein. As used herein, the term “arylcarbonyl” refers to a group of the formula C (═O) R, wherein R is an aryl group; The term "benzoyl" as used herein refers to an "arylcarbonyl" group, where R is phenyl.

As used herein, "acylamino" refers to a group of -NHC (= 0) R, wherein R refers to hydrogen or lower alkyl as defined herein.

The term "acyloxy" as used herein refers to the radical -OC (O) R, wherein R refers to a lower alkyl radical as defined herein. Examples of acyloxy radicals include, but are not limited to, acetoxy, propionyloxy.

The term "alkoxy" as used herein includes isomers thereof, including -O-alkyl groups, where alkyl is methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyl as defined above. Oxy, i-butyloxy, t-butyloxy, pentyloxy, hexyloxy “lower alkoxy” as used herein refers to an alkoxy group having a “lower alkyl” group as previously defined. "C _1-10 alkoxy" as used refers to -O-alkyl, wherein alkyl is C _1-10 .

The term "alkylthio" or "thioalkyl" includes isomers thereof, including -S-alkyl groups, wherein alkyl is methylthio, ethylthio, n-propylthio, i-propylthio, n-butyl as defined above. Thio, hexylthio). "Lower alkylthio" or "lower thioalkyl" as used herein refers to an alkylthio group having a "lower alkyl" group as already defined. "C _1-10 alkylthio" as used herein refers to -S-alkyl, wherein alkyl is C _1-10 .

The prefix "carbamoyl" as used herein means the radical -CONH ₂ . The prefixes "N-alkylcarbamoyl" and "N, N-dialkylcarbamoyl" each represent a radical CONHR 'or CONR'R "group wherein the R' and R" groups are independently alkyl as defined herein. ). The prefix "N-arylcarbamoyl" refers to the radical CONHR ', wherein R' is an aryl radical as defined herein.

As used herein, the terms "amino", "alkylamino" and "dialkylamino" refer to -NH ₂ , -NHR and -NR ₂ , where R is alkyl as defined above. The two alkyl groups bonded to the nitrogen in the dialkyl moiety may be the same or different. The terms "aminoalkyl", "alkylaminoalkyl" and "dialkylaminoalkyl" as used herein refer to NH ₂ (CH ₂ ) n-, RHN (CH ₂ ) n-, and R ₂ N (CH _{2), respectively.} n-, where n is 1 to 6 and R is alkyl as defined above. "C _1-10 alkylamino" as used herein refers to _-aminoalkyl , wherein alkyl is C _1-10 . The term "phenylamino" as used herein refers to -NHPh, where Ph represents an optionally substituted phenyl group.

The term "halogen" or "halo" as used herein means fluorine, chlorine, bromine or iodine.

The term "aryl" as used herein, unless otherwise indicated, refers to hydroxy, thio, cyano, alkyl, alkoxy, lower haloalkoxy, alkylthio, halogen, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl , Amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, and dialkylaminoalkyl, alkylsulfonyl, arylsulfinyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino , Optionally substituted with one or more, preferably 1 or 3 substituents independently selected from carbamoyl, alkylcarbamoyl and dialkylcarbamoyl, arylcarbamoyl, alkylcarbonylamino, arylcarbonylamino Monovalent aromatic carbocyclic radicals having 5 to 15 carbon atoms, which may consist of one individual ring, or one or more fused rings, wherein one or more rings are originally aromatic He says. Alternatively, two adjacent atoms of the aryl ring may be substituted with methylenedioxy or ethylenedioxy groups. Thus, bicyclic aryl substituents can be fused to heterocyclyl or heteroaryl rings; The point of attachment of the bicyclic aryl substituent is on the carbocyclic aromatic ring. Examples of aryl radicals include phenyl, naphthyl, indanyl, anthraquinolyl, tetrahydronaphthyl, 3,4-methylenedioxyphenyl, 1,2,3,4-tetrahydroquinolin-7-yl, 1, 2,3,4-tetrahydroisoquinolin-7-yl and the like.

The term "arylalkyl" or "aralkyl" as used herein is a radical R'R "-where R 'is an aryl radical as defined herein and R" is an alkylene as defined herein. Radical, and the point of attachment of the arylalkyl moiety is thought to be on the alkylene radical). R "is an alkylene chain comprising 1 to 6 methylenes. The term" phenyl C _1-6 alkyl "is a radical R'R" where R 'is a phenyl group and R "comprises 1 to 6 methylenes Alkylene chains) Examples of arylalkyl radicals include, but are not limited to, benzyl, phenylethyl, 3-phenylpropyl.

The term "aryloxy" as used herein refers to an O-aryl group, where aryl is as defined above. The aryloxy group can be unsubstituted or substituted with 1 or 2 suitable substituents. The term "phenoxy" refers to an aryloxy group in which the aryl moiety is a phenyl ring.

As used herein, the term “heteroaryl” or “heteroaromatic” means one or more aromatics containing 4 to 8 atoms per ring, incorporating one or more N, 0, or S heteroatoms, and wherein the remaining ring atoms are carbon By a monocyclic or bicyclic radical of 5 to 12 ring atoms having a ring, the point of attachment of the heteroaryl radical is believed to be on the heteroaryl ring. As is well known to those skilled in the art, heteroaryl rings have the feature of being less aromatic than their all-carbon counterparts. Thus, for the purposes of the present invention, heteroaryl groups need only have some aromatic character. Examples of heteroaryl moieties include monocyclic aromatic heterocycles having 5 to 6 ring atoms and comprising 1 to 3 heteroatoms, and hydroxy, cyano, alkyl, alkoxy, thio, lower haloalkoxy, alkyl Thio, halo, haloalkyl, alkylsulfinyl, alkylsulfonyl, halogen, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, and dialkylaminoalkyl, nitro, alkoxycarbonyl and carbamoyl, alkyl Pyridinyl, pyrimidinyl, which may be optionally substituted with one or more substituents selected from carbamoyl, dialkylcarbamoyl, arylcarbamoyl, alkylcarbonylamino and arylcarbonylamino , Pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolinyl, thiadiazolyl and oxadiazolinyl This is not restrictive. Examples of bicyclic moieties include, but are not limited to, quinolinyl, isoquininolinyl, benzofuryl, benzothiophenyl, benzoxazole, benzisoxazole, benzothiazole and benzisothiazole. The bicyclic moiety can be optionally substituted on either ring; The point of attachment is on a ring containing heteroatoms.

The term “heteroaryl alkyl” or “heteroaralkyl” is of the formula R′R ”wherein R ′ is an optionally substituted heteroaryl radical as defined herein and R” is an alkylene radical as defined herein. , The bond point of the heteroaryl radical is believed to be on the alkylene radical. Examples of heteroarylalkyl radicals include, but are not limited to, 2-imidazolylmethyl, 3-pyrrolylethyl.

As used herein, the term “heterocyclyl” or “heterocycle” incorporates one or more ring heteroatoms (selected from N, O or S (O) 0-2) and is selected from 3 to 8 atoms per ring. Monovalent saturated cyclic radicals consisting of one or more rings, preferably one to two rings, unless otherwise indicated, hydroxy, oxo, cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio , Halo, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkyl Optionally substituted with one or more, preferably one or two substituents independently selected from aminocarbonyl, arylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino have. Bicyclic heterocycles can be fused to aryl or heteroaryl rings; The point of attachment is on a heterocyclic ring. Examples of heterocyclic radicals include azetidinyl, pyrrolidinyl, hexahydroazinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, oxazolidinyl, thiazolidinyl, isoxazolidinyl, mor Polyyl, piperazinyl, piperidinyl, tetrahydropyranyl, thiomorpholinyl, quinuclidinyl and imidazolinyl.

The term "heterocycloalkyl" (or "heterocyclylalkyl") is of the formula R'R "where R 'is a heterocyclic radical as defined herein and R" is alkylene as defined herein. Radical), and the point of attachment of the heterocycloalkyl radical will be on the alkylene radical. Examples of heterocycloalkyl radicals include, but are not limited to, 1-piperazinylmethyl, 2-morpholinomethyl, and the like.

The term “cycloalkyl” as used herein refers to a saturated carbocyclic ring containing 3 to 8 carbon atoms, ie cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. "C _3-7 cycloalkyl" as used herein refers to cycloalkyl consisting of 3 to 7 carbons in a carbocyclic ring.

As used herein, the term "cycloalkylalkyl" is a radical R'R "-where R 'is a cycloalkyl radical as defined herein and R" is an alkylene radical as defined herein. It is believed that the point of attachment of the cycloalkylalkyl moiety will be on the alkylene radical. Examples of cycloalkylalkyl radicals include, but are not limited to, cyclopropylmethyl, cyclohexylmethyl, cyclopentylethyl. C _3-7 cycloalkyl-C _1-3 alkyl refers to the radical R′R ″ wherein R ′ is C _3-7 cycloalkyl and R ″ is C _1-3 alkylene as defined herein. .

The term "cycloalkyl" as used herein refers to a saturated carbocyclic ring having 3 to 8 carbon atoms, ie cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. "C _3-7 cycloalkyl" as used herein refers to cycloalkyl consisting of 3 to 7 carbon atoms in the carbocyclic ring.

As used herein, the term "cycloalkylalkyl" is a radical R'R "-where R 'is a cycloalkyl radical as defined herein and R" is an alkylene radical as defined herein. It is believed that the point of attachment of the cycloalkylalkyl moiety will be on the alkylene radical. Examples of cycloalkylalkyl radicals include, but are not limited to, cyclopropylmethyl, cyclohexylmethyl, cyclopentylethyl. C _3-7 cycloalkyl-C _1-3 alkyl refers to the radical R′R ″ wherein R ′ is C _3-7 cycloalkyl and R ″ is C _1-3 alkylene as defined herein. .

As used herein, the terms "hydroxyalkyl" and "alkoxyalkyl" refer to the radical R'R ", where R 'is each a hydroxy radical or alkoxy radical and R" is alkylene as defined herein. Wherein the point of attachment of the hydroxyalkyl or alkoxyalkyl radical will be on the alkylene radical.

The term "alkylene" as used herein refers to a divalent saturated linear hydrocarbon radical having 1 to 8 carbon atoms or a branched saturated divalent hydrocarbon radical having 3 to 8 carbon atoms unless otherwise indicated. Examples of alkylene radicals include, but are not limited to, methylene, ethylene, propylene, 2-methyl-propylene, butylene, 2-ethylbutylene.

As used herein, the terms "alkylsulfinyl" and "arylsulfinyl" refer to the formula -S (= 0) R, wherein R is alkyl or aryl, respectively, and alkyl and aryl are as defined herein. Say the flag.

As used herein, the terms “alkylsulfonyl” and “arylsulfonyl” are of the formula —S (═O) ₂ R, wherein R is alkyl or aryl, respectively, and alkyl and aryl are as defined herein. Says the flag.

The term “sulfamoyl” as used herein refers to the radical —S (O) ₂ NH ₂ . As used herein, the terms "N-alkylsulfamoyl" and "N, N-dialkylsulfamoyl" refer to the radical -S (O) ₂ NR'R "where R 'and R" are hydrogen and lower alkyl And R 'and R "are each independently lower alkyl. Examples of N-alkylsulfamoyl substituents include, but are not limited to, methylaminosulfonyl, iso-propylaminosulfonyl. Examples of N-dialkylsulfamoyl substituents include, but are not limited to, dimethylaminosulfonyl, iso-propyl-methylaminosulfonyl, where the prefix N-alkyl or N, N-dialkyl is aryl, heteroaryl, Substituted with heterocyclyl or other radicals to indicate when the amine is substituted with a group other than alkyl.

The term "alkylsulfonamido" refers to the radical -NH-S (O) ₂ -alkyl. The term alkyl may be substituted by other chemically corresponding radicals such as aryl or heteroaryl, for example, to indicate phenylsulfonamido-NH-S (O) ₂ -Ph. "N-alkylalkylsulfonamido" refers to the radical -NR-S (O) ₂ -alkyl, wherein R is a lower alkyl group.

As used herein, the term “ureido” means a —N ¹ RC (═O) N ³ R′R ”radical, where R, R ′ and R” are independently hydrogen or lower alkyl. If the nitrogen atom is substituted with a group other than hydrogen or lower alkyl, then N or N 'or 1 and 3 are used to define the substituted nitrogen atom, respectively. The point of attachment of the ureido radical refers to N or 1. For example, using this nomenclature, N'-phenylureido refers to -NRC (= 0) NPhR ', where R and R' are as previously defined. The position of certain alkyl substituents may optionally be specified using the same nomenclature.

The term "carbamate" or "urethane" as used herein refers to a ROC (= 0) N ³ R'R "radical, wherein one of R or R 'is a core structure and R, R' and R" Others as defined in the specification and claims. The term "urea" as used herein refers to the group RR'NC (= 0) NR "R"'wherein R is a core structure and R', R "and R"'are as defined in the specification and claims. Equals)

As used herein, the term “aminocarbonylpyridyl” refers to a radical —NHCOR where R is 2-pyridinyl (picolinoyl), 3-pyridinyl (nicotinoyl) or 4-pyridinyl (isonico Thinoyl)) and N-oxides derived therefrom.

Compounds of formula I exhibit tautomerism. Tautomeric compounds may be present in two or more interconverting species. Tautomers of independent nutrition are due to the migration of covalently bonded hydrogen atoms between two atoms. Tautomers generally exist in equilibrium and usually isolate individual tautomers, resulting in a mixture in which the chemical and physical properties are consistent with the mixture of compounds. The position of the equilibrium depends on the chemical properties in the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form dominates; In phenol, the enol form is dominant. Common independent nutritional tautomers are keto / enol (-C (= O) -CH- □ -C (-OH) = CH-), amide / imide acid (-C (= O) -NH- □ -C (-OH) = N-) and amidine (-C (= NR) -NH- □ -C (-NHR) = N-) tautomers. The latter two are particularly common in heteroaryl and heterocyclic rings, and the present invention includes all tautomeric forms of the compounds.

Those skilled in the art will appreciate that a compound of Formula ( I ) may contain one or more chiral centers, so that it may exist in two or more structural isomeric forms. Where two are chiral centers, not only diastereomers, but also mixtures rich in the racemates of the isomers, the individual isomers and one enantiomer, and mixtures partially enriched in the particular diastereomers are within the scope of the invention. . In addition, those skilled in the art will appreciate that the substitution of the tropan ring may be in either an inner or an outer arrangement, and the present invention encompasses two modes of configuration. The present invention includes all individual structural isomers (eg, enantiomers), racemic mixtures or partially dissolved mixtures of the compounds of formula ( I ), and, where appropriate, the individual tautomers form them.

Racemates can be used on their own or can be broken down into their individual isomers. Degradation makes it possible to obtain structurally pure compounds or compounds rich in one or more isomers. Methods for isomer separation are well known (cf. Allinger N. L. and Eliel E. L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971), and physical methods such as chromatography using chiral adsorbents. Individual isomers may be prepared in chiral form from chiral precursors. Alternatively, the individual isomers are like individual enantiomers such as 10-camphorsulfonic acid, camphoric acid, alpha-bromocamphoric acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, Chiral acid can form a mixture of diastereomeric salts, fractionally crystallize the salts, and then freely separate one or two degraded bases, optionally repeating the above method, so that they can be chemically separated from the mixture, substantially free of the remainder. One or two can be obtained; That is, it can be obtained in a form having an optical purity of> 95%. Alternatively, the racemates can be covalently attached to the chiral compound (adjuvant) such that the chiral adjuvant is chemically removed to produce diastereomers which can be separated by chromatography or fractional crystallization after the pure enantiomer is obtained. have.

Compounds of formula ( I ) contain one or more basic centers and suitable acid addition salts are formed from acids which form non-toxic salts. Examples of inorganic acid salts include hydrogen chloride, hydrogen bromide, hydrogen iodide, chloride, bromide, iodide, sulfate, bisulfate, nitrate, phosphate, hydrogen phosphate. Examples of organic acid salts include acetate, fumarate, pamoate, aspartate, besylate, carbonate, bicarbonate, chamlate, D and L-lactate, D and L-tartrate, ecylate, mesylate , Malonate, orotate, gluceptate, methylsulfate, stearate, glucuronate, 2-lead silicate, tosylate, hibenzate, nicotinate, isethionate, maleate, maleate, sheet Late, gluconate, succinate, saccharide, benzoate, acrylate, and pamoate salts. As a review of suitable salts, see Berge et. al . , J. Pharm . Sci . , 66, 1-19, 1977.

As used herein, the term "solvate" means a compound of the present invention or a salt thereof that further comprises a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent internal molecular forces. Preferred solvents are acceptable even when administered to humans in volatile, non-toxic, and / or trace amounts.

As used herein, the term “hydrate” means a compound of the present invention or a salt thereof and further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent internal molecular forces.

As used herein, the term “inclusion compound” refers to a compound of the present invention in the form of a crystal ladder containing a space (eg, a channel) with a guest molecule (eg, a solvent or water) confined therein, or Means its salt.

The term “nucleoside and nucleotide reverse transcriptase inhibitor” (“NRTI”) as used herein refers to HIV-1 reverse transcriptase, an enzyme that catalyzes the conversion of viral genomic HIV-1 RNA into postviral HIV-1 DNA. Nucleosides and nucleotides and their analogs that inhibit the activity of enzymes. Typical suitable NRTIs are Glaxo-Wellcome Inc. Zidovudine (AZT) sold as RETROVIR ^{® by the} company; Bristol-Myers Squibb Co. Of didanosine (ddl) is sold as VIDEX ^®; Zalcitabine (ddC) sold as HIVID ^® from Roche Pharmaceuticals; Bristol-Myers Squibb Co. Stavudine (d4T) sold as ZERIT ^® from; Lamivudine (3TC) sold as EPIVIR ^{® by} Glaxo-Wellcome; It is disclosed in W096 / 30025 & F Kabir (1592U89) and sold as ^® Glaxo-Wellcome's ZIAGEN; Adefovir difficile [bis (POM) -PMEA] sold as PREVON ^® from Gilead Sciences; Lobucavir (BMS-180194), a nucleoside reverse transcriptase inhibitor disclosed in EP-0358154 and EP-0736533 and developed by Bristol-Myers Squibb; BCH-10652, a reverse transcriptase inhibitor (in the form of a racemic mixture of BCH-10618 and BCH-10619) developed by Biochem Pharma; US Pat. No. Emitteritabine [(-)-FTC], licensed from Emory University under 5,814,639 and developed by Triangle Pharmaceuticals; Beta-L-FD4 (also known as beta-L-D4C, also known as beta-L-2 ', 3'-dicleoxy-5-fluoro-cytidene) licensed by Yale University to Vion Pharmaceuticals; DAPD, a purine nucleoside, (-)-bD-2,6-diamino-purine dioxolane, disclosed in EP-0656778 and licensed to Triangle Pharmaceuticals by Emory University and University of Georgia; And by NIH and US Bioscience Inc. Acid developed by Rhodesin (FddA) which is 9- (2,3-dideoxy-2-fluoro-bD-threo-pentofuranosyl) adenine which is a suitable purine-based reverse transcriptase inhibitor.

The term "non-nucleoside reverse transcriptase inhibitor"("NNRTI") as used herein refers to a non-nucleoside that inhibits the activity of HIV-1 reverse transcriptase. Typical suitable NNRTIs include nevirapine (BI-RG-587) sold as VIRAMUNE ^® from Roxane Laboratories; Delaviraradin (BHAP, U-90152) sold as RESCRIPTOR ^® from Pfizer; Disclosed in WO 94/03440 and described in Bristol-Myers Squibb Co. Efabilens (DMP-266) which is benzoxazine-2-one usable as SUSTIVA ^® from the company; PNU-142721, puropyridine-thio-pyrimidine developed by Pfizer 08807; AG-1549 (formerly Shionogi # S-1153); Agouron Pharmaceuticals, Inc., disclosed in WO 96/10019. 5- (3,5-dichlorophenyl) -thio-4-isopropyl-1- (4-pyridyl) methyl-1H-imidazol-2-ylmethyl carbonate developed by; Mitsubishi Chemical Co. MKC-442 (1- (ethoxy-methyl) -5- (1-methylethyl) -6- (phenylmethyl)-(2,4 (1H, 3H) -pyri), discovered by and developed by Triangle Pharmaceuticals Midinedione) and (+)-carnolide A (NSC-675451) and B (Vita- as oral administration products), a courine derivative disclosed by NIH US Pat.No. 5,489,697 and licensed to Med Chem Research. co-expression of (+) colorolide A with invest).

The term “protease inhibitor” (“PI”) as used herein refers to the viral polyprotein precursors (eg, viral GAG and GAG Pol polyproteins) as individual functional proteins found in infectious HIV-1. An inhibitor of HIV-1 protease, an enzyme required for proteolytic cleavage. HIV protease inhibitors include compounds having peptide like structure, high molecular weight (7600 Daltons) and substantial peptide characteristics. Typical suitable PI is Roche Pharmaceuticals, Nutley, NJ INVIRASE ^® as a rigid gel that is available within the capsule and FORTOVASE ^® of saquinavir (Ro 31-8959) as a soft gel capsules that are available as from 07110-1199; Ritonavir (ABT-538) sold as NORVIR ^® from Abbott Laboratories; Merck & Co., Inc. Indinavir (MK-639), sold as CRIXIVAN ^® from; Agouron Pharmaceuticals, Inc. Nelpeu butterfly LE (AG-1343) sold as VIRACEPT ^® from; Vertex Pharmaceuticals, Inc. Amprenavir (141W94), AGENERASE ^® , which is a non-peptide protease inhibitor developed by and marketed by Glaxo-Wellcome under the Extended Performance Program; Racinavir (BMS-234475) sold from Bristol-Myers Squibb; DMP-450, a cyclic urea found by Dupont and developed by Triangle Pharmaceuticals; BMS-2322623, an azapeptide developed by Bristol-Myers Squibb as a second generation HIV-1 PI; ABT-378 developed by Abbott; And Shionogi, and Agouron Pharmaceuticals, Inc. AG-1549, an imidazole carbamate active upon oral administration developed by

Other antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12, pentafuside. Hydroxyurea (Droxia), ribonucleoside triphosphate reductase inhibitors, enzymes involved in T-cell activation were found in NCI, and preclinical studies have shown synergistic effects on the activity of didanosine, star Studyed with Budine. IL-2 is described in Ajinomoto EP-0142268, Takeda EP-0176299, and Chiron US Pat. Nos. RE 33,653, 4,530,787, 4,569,790, 4,604,377 , 4,748,234, 4,752,585, and are disclosed in 4,949,314, is sold as a water reconstruction and dilution a lyophilized powder for or subcutaneous administration for IV injection with PROLEUKIN ^® (aldehyde through Kin) and available ; At a dosage of about 1 to about 20 million 1 U / day, it is preferred to be administered subcutaneously; More preferably, it is administered subcutaneously at a dosage of about 15 million 1 U / day. IL-12 is disclosed in WO 96/25171 and is administered at a dosage of about 0.5 μg / kg / day to about 10 μg / kg / day, preferably subcutaneously. Pentafuside (FUZEON ^® ), a 36-amino acid synthetic peptide, is described in US Pat. No. 5,464,933, which acts by inhibiting the fusion of HIV-1 to the target membrane. Pentafuside (3-100 mg / day) is administered as a continuous subcutaneous infusion or injection with efavirens and 2 PI in HIV-1 positive patients refractory to triple combination therapy; Preference is given to using at 100 mg / day. Ribavirin, 1-.beta.-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide, is described in ICN Pharmaceuticals, Inc. , Costa Mesa, Calif. Available from; Its preparations and formulations are described in US Pat. No. 4,211,771.

The term “virus fusion inhibitor” as used herein refers to a compound that inhibits the fusion of free viral particles and the introduction of viral RNA into host cells, regardless of the molecular locus of the inhibitor binding. Thus, viral fusion inhibitors include T-20; CD-4 binding ligands including BMS-378806, BMS-488043; SCH-351125, Sch-350634, Sch-417690 (Scheroing Plough), UK-4278957 (Pfizer), TAK-779 (Takeda), ONO-4128 (Ono), AK-602 (Ono, GlaxoSmithKline), Compound 1-3 CCR5 binding ligands including (Merck); KRH-1636 (K. Ichiyama et al . , Proc . Nat . Acad . Sci USA 2003 100 (7): 4185-4190), T-22 (T. Murakami et al . , J. Virol . 1999 73 (9): 7489-7496), T-134 (R. Arakaki et. al . , J. Virol. 1999 73 (2): 1719-1723), including but not limited to CXCR4 binding ligands. Virus fusion inhibitors as used herein also include peptide and protein soluble receptors, antibodies, chimeric antibodies, humanized antibodies.

Abbreviations used in the present application are: acetyl (Ac), acetic acid (HOAc), azo-bis-isobutyrylnitrile (AIBN), 1-N-hydroxybenzotriazole (HOBT), atmospheric pressure (Atm), high pressure liquid Chromatography (HPLC), 9-vorabicyclo [3.3.1] nonane (9-BBN or BBN), methyl (Me), tert-butoxycarbonyl (Boc), acetonitrile (MeCN), di-tert- Butyl pyrocarbonate or boc anhydride (BOC ₂ O), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), benzyl (Bn), m-chloroperbenzoic acid (MCPBA), Butyl (Bu), methanol (MeOH), benzyloxycarbonyl (cbz or Z), melting point (mp), carbonyl diimidazole (CDI), MeSO _2- (mesyl or Ms), 1,4-diazabicyclo [2.2.2] octane (DABCO), mass spectrum (ms), diethylaminosulfur trifluoride (DAST), methyl t-butyl ether (MTBE), dibenzylideneacetone (Dba), N-carboxy anhydride (NCA ), 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), N -Bromosuccinimide (NBS), 1,8-diazabicyclo [5.4.0] undes-7-ene (DBU), N-methylpyrrolidone (NMP), 1,2-dichloroethane (DCE ), Pyridium chlorochromate (PCC), N, N'-dicyclohexylcarbodiimide (DCC), pyridinium dichromate (PDC), dichloromethane (DCM), propyl (Pr), diethyl azodicarboxyl Rate (DEAD), phenyl (Ph), di-iso-propylazodicarboxylate (DIAD), pounds per square inch (psi), di-iso-propyl-ethylamine (DIPEA), pyridine (pyr), di Iso-butylaluminum hydride (DIBAL-H), room temperature (rt or RT), N, N-dimethyl acetamide (DMA), tert-butyldimethylsilyl or t-BuMe ₂ Si, (TBDMS), 4- N, N-dimethylaminopyridine (DMAP), triethylamine (Et ₃ N or TEA), N, N-dimethylformamide (DMF), triflate or CF ₃ SO _2- (Tf), dimethyl sulfoxide (DMSO ), Trifluoroacetic acid (TFA), 1,1'-bis- (diphenylphosphino) ethane (dppe), 2,2,6,6-te Tramethylheptan-2,6-dione (TMHD), 1,1'-bis- (diphenylphosphino) ferrocene (dppf), thin layer chromatography (TLC), ethyl acetate (EtOAc), tetrahydrofuran (THF) , Diethyl ether (Et ₂ O), trimethylsilyl or Me ₃ Si (TMS), ethyl (Et), p-toluenesulfonic acid monohydrate (TsOH or pTsOH), lithium hexamethyl disilazane (LiHMDS), 4- Me-C ₆ H ₄ SO ₂ -or tosyl (Ts), iso-propyl (i-Pr), N-urethane-N-carboxy anhydride (UNCA), ethanol (EtOH). Common names, including the prefix normal (n), iso (i-), secondary (sec-), tertiary (tert-) and neo, have their customary meaning when used with alkyl moieties (J. Rigaudy and DP Klesney, Nomenclature in Organic Chemistry , IUPAC 1979 Pergamon Press, Oxford.

Compounds of the present invention can be prepared by various methods described in the synthetic schemes of the schemes shown and described below. Starting materials and reagents used in the preparation of the compounds are generally described in Aldrich Chemical Co. Commercially available from conventional suppliers, such as Fieser and Fieser's Reagents for Organic Synthesis ; Wiley & Sons: New York, Volumes 1-21; RC LaRock, Comprehensive Organic Transformations , 2 ^nd edition Wiley-VCH, New York 1999; Comprehensive Organic Synthesis , B. Trost and I. Fleming (Eds.) Vol. 1-9 Pergamon, Oxford, 1991; Comprehensive Heterocyclic Chemistry , AR Katritzky and CW Rees (Eds) Pergamon, Oxford 1984, vol. 1-9; C omprehensive Heterocyclic Chemistry II , AR Katritzky and CW Rees (Eds) Pergamon, Oxford 1996, vol. 1-11; And Organic Reactions , Wiley & Sons: New York, 1991 , Volumes 1-40. The following synthetic reaction schemes are merely illustrative of some methods by which the compounds of the present invention can be synthesized, and various modifications may be made to the synthetic reaction schemes and will be suggested to those skilled in the art with reference to the disclosure contained in this application.

Starting materials and intermediates in the synthetic reaction schemes can be isolated or purified using conventional techniques, including, but not limited to, filtration, distillation, crystallization, chromatography, and the like, if desired. The material can be characterized using conventional means, including physical constants and spectral data.

Unless stated to the contrary, the reactions described herein are preferably about -78 ° C to 150 ° C, more preferably about 0 ° C to about 125 ° C, and most preferably and conveniently about room temperature (or ambient temperature), For example, it is carried out in an inert atmosphere at atmospheric pressure in the reaction temperature range of about 20 ° C.

2-benzyl-octahydro-pyrrolo [3,4-c] pyrrole ( 4a ) was added to the [2,3] -bipolar cycloaddition of imine illi using N-benzylmaleimide as previously described. Prepared by (R. Colon-Cruz et al . , WO 02/070523 and M.Bjorsne et al . , WO 02/060902). Reduction of the imide, and selective debenzylation, is accomplished as described therein.

The preparation of some compounds of the invention, wherein R ² is phenyl, is depicted in Scheme 1. The procedure of Scheme 1 is particularly suitable for the preparation of a series of compounds in which amides (or urea or sulfonamides) linked to hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] scaffolds. The totally assimilated 1-phenyl-1-amino-propyl side chain is introduced prior to deprotection of the secondary amine. Debenzylation of amines allows for elaboration of secondary nitrogen atoms.

Alternatively, the amide (or urea or sulfonamide) is first selected from 4a , for example 2,6-dimethylbenzoyl chloride, 2,4-dimethyl-nicotinoyl chloride or 4,6-dimethyl-pyrimidine-5- Introduced by acylation with carbonyl chloride and subsequent debenzylation yields 66 , 54 and 44 , respectively. Introduction of the Boc group and subsequent debenzylation yields 74 . The accompanying examples illustrate the utility of these compounds for the preparation of the compounds of the present invention.

Scheme 1

β-aminoacylcarboxaldehyde 15b is β-acylamino carboxylic acid or carboxylic acid derivative ( 15a : X = OH, OR ^b or NR ^b R ^c , where R ^a is an acyl radical or protecting group and R ^b And R ^c is typically lower alkyl, as a typical synthetic intermediate which may be carried out by reduction, see eg Example 15. Acylation of □ -amino esters ( 14 : X is O-alkyl) is typically carried out at temperatures between -20 ° C and 200 ° C, but preferably between -10 ° C and 100 ° C, optionally in the presence of an inorganic or organic base. To a corresponding acyl halide, anhydrous carboxylic acid or chloroformate in a solvent such as DCM, chloroform, carbon tetrachloride, ether, THF, dioxane, benzene, toluene, MeCN, DMF, sodium hydroxide solution or sulfolane Is performed.

Scheme 2

Acylation is also carried out in the presence of an activator or dehydrating agent, for example at a temperature of -20 ° C to 200 ° C, preferably at -10 ° C to 100 ° C, for example isobutyl chloroformate, thionyl chloride Trimethylchlorosilane, HCl, H ₂ SO ₄ , methanesulfonic acid, p-toluenesulfonic acid, phosphorus trichloride, P ₂ O ₅ , N, N'-dicyclohexylcarbodiimide, N, N'-dicyclohexyl-carbox Bodyimide / N-hydroxysuccinimide or HOBt, N, N'-carbonyldiimidazole, O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyl-uro Tetrafluoroborate / N-methylmorpholine, O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyl-uroniumtetrafluoroborate / N-ethyldiisopropyl In the presence of an amine, N, N'-thionyldiimidazole or triphenylphosphine / CCl ₄ , it can be carried out using a carboxylic acid.

Aldehyde 15b is reacted with a hydride reducing agent in a suitable solvent to the corresponding acid ( 15a : X = OH), ester ( 15a : X = OR ^b ) or amide ( 15a : X = NR ^b R ^c ), where R ^b and R ^c is lower alkyl). Alternatively, the reduction of acyl halides can be carried out using a suitable transition metal catalyst, hydrogen source, in a suitable solvent. Typical hydride reducing agents are aluminum hydrides or boron hydrides such as DIBAL-H, LiAl (O-tert-Bu) ₃ H, or Me ₂ CHCH (Me) ₂ BH. Suitable solvents are inert solvents such as THF, DCM or toluene. Acid chloride ( 15a : X = Cl) can be reduced using a transition metal catalyst such as Pd / C or Pd / BaSO ₄ in a solvent such as THF or toluene under a hydrogen atmosphere with a modifier such as 2,4-dimethylpyridine have. Another route to □ -acylamino-carboxyaldehyde 15b includes oxidation of □ -acylaminoalcohol 14b , which may be performed by various oxidizing agents, for example pyridine.SO ₃ .TEA. Preferably the N-acylated acid or ester is selected from DR Armor et al . Aldehyde is reduced using DIBAL-H in DCM at −78 ° C. as described by (WO 00/38680).

Aldehyde 15b (R ^a is an acyl radical or nitrogen protecting group) is incorporated into a 2-octahydro-pyrrolo [3,4-c] pyrrole scaffold by reductive amination to give diamine 11 . Reductive amination usually involves complexing metal hydrides such as sodium borohydride, lithium borohydride, sodium cyanoborohydride, zinc borohydride, sodium triacetoxyborohydride or borane / pyridine. It is preferably carried out by combining amines and aldehydes in the presence of. The reaction mixture optionally comprises a molecular network or a dehydrating agent such as Ti (IV) (Oi-Pr) ₄ , for example in the presence of Pd / C at a hydrogen pressure of 1 to 5 bar, preferably from 20 ° C. to The use of hydrogen at temperatures between the boiling points of the solvents used, or the formation of intermediate imines at ambient temperatures, is useful. It may also be advantageous during the reaction if the reactor is protected during the reaction by conventional protecting groups which are cut back by conventional methods after the reaction. Reductive amination processes are described in RM Hutchings and MK Hutchings Reduction of C = N to CHNH by Metal Hydrides in Comprehensive Organic Synthesis col. 8, I. Fleming (Ed) Pergamon, Oxford 1991 pp. 47-54.

Removal of the remaining benzyl protecting group affords amine 12 . Removal of the benzyl protecting group can be easily carried out by catalytic hydrogenolysis using Pd, Pt, Ni or Rh catalysts. Acids are often added to promote hydrocracking. Acylation of the free secondary amine yields 13 . Alternatively, the nitrogen atom is alkylated with an aralkyl halide to yield I (X ² is aralkyl) or sulfonylated to yield sulfonamide I (X ² is SO ₂ R ⁴ ). Sulfonylation of amines is typically carried out by treating the amine with alkyl or aryl sulfonyl chlorides in an inert solvent, in the presence of an organic base such as pyridine or TEA.

While the preparation of 13 illustrates the synthesis of the compounds of the present invention using cyclopentylcarboxamides, one skilled in the art will recognize that a wide variety of amides, ureas or sulfonamides can be introduced using analogs.

Scheme 3

Amino protecting groups such as Boc derivative 25b can be used at the position of the acyl radical during the reductive amination process (Scheme 3). Numerous reactions for the formation and removal of such amine protecting groups are described, for example, in the inserted disclosures disclosed herein in their entirety ["Protective Groups in Organic Chemistry", Plenum Press, London and New York, 1973; Greene, Th. and Wutts, PGM Protective Groups in Organic Synthesis , Wiley, New York , 1999; The Peptides, Vol. I, Schroder and Lubke, Academic Press, London and New York, 1965; Methoden der Organischen Chemie , Houben-Weyl , 4th Edition, Vol 15/1, Georg Thieme Verlag, Stuttgart 1974]. The protecting group can be chosen to be cleaved under various conditions selected to be compatible with the other functional groups in the molecule. Subsequent introduction of the acyl group is followed by deprotection of the primary amine and acylation with the carboxylic acid as described above after the reductive amination step. Urea, carbamate and sulfonamide can be performed by reaction of 26b with isocyanates, chloroformates and sulfonyl chlorides, respectively. Scheme 3 illustrates the introduction of the carboxamido group into the diazabicyclooctane ring before reductive alkylation and the assimilation of the aminopropyl side chain after reductive alkylation.

Embodiments of the invention provide alkyl ( 30 : R '= Me), alkoxyalkyl ( 30 : R' = CH ₂ OMe or CH ₂ OCH ₂ Ph) or hydroxymethyl ( 30 : R '= CH ₂ OH on propylene linkages. ) May have a substituent. One route to the compound is described in Scheme 4. □ -acylaminocarboxylic acid to N-methoxy-N-methyl amide, reacted with methyl lithium, and pyrrolo [3,4-c] pyrrole-2-yl by reductive alkylation as previously described Butanone 29a was obtained which could be incorporated into the scaffold. Methoxymethyl- and benzyloxymethyl compounds were prepared by similar methods starting from stan organometallics as described in Examples 27 and 28. Debenzylation of 29d afforded the corresponding hydroxylmethyl compound 29c . Compounds with methyl or dimethyl substituents on the linker carbon adjacent to the aminomethine carbons were prepared as described in Examples 24 and 26. An example of the preparation of the compound having hydroxyl substituents on the propylene linkage is Example 35.

Examples of representative compounds included in the present invention and within the claims are provided in the table below. The examples and preparations are provided to enable those skilled in the art to more clearly understand and to practice the present invention. They should not be construed as limiting the scope of the invention, but should be understood to be illustrative and representative thereof. Reagents used to introduce X ¹ and X ² may be prepared from commercially available or commercially available materials. Test and working examples of the compounds included in the present invention illustrate the generality of the reaction sequence and the nature of the protecting groups that can be optimized for specific targets without the general procedures discussed herein.

Generally, the nomenclature used in the present application is AUTONOM ™ v. Beilstein Institute computerized system for generations of IUPAC system nomenclature. Based on 4.0. If there is a contradiction between the depicted structure and the name given to that structure, the depicted structure is given more weight. Also, unless the stereochemistry of the structure or proportion of the structure is indicated, for example, by bold or dashed lines, the structure or proportion of the structure includes both isomers. While the compounds of the present invention are often depicted by (S) structural chemistry, both structural isomers are included in the present invention and both can be prepared by the same process from suitable starting materials.

Representative compounds of the present invention, wherein R ² is an aryl or heteroaryl group, are summarized in Table 1.

designation MS Mp I-1 Tetrahydro-furan-3-carboxylic acid {(S) -1-phenyl-3- [5- (quinoxaline-2-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2- General] -propyl} -amide; Compound with trifluoro-acetic acid 500.3 I-2 Cyclopentanecarboxylic acid {(S) -3- [5- (3,4-dichloro-benzyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -amides; Compound with trifluoro-acetic acid 500 I-3 Cyclopentanecarboxylic acid {(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -amides 474 60.9-63.9 I-4 Cyclopentanecarboxylic acid {(S) -1-phenyl-3- [5- (pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -propyl}- amides; Compound with trifluoro-acetic acid 447 I-5 Cyclopentanecarboxylic acid [(S) -1-phenyl-3- (5-phenylacetyl-hexahydro-pyrrolo [3,4-c] pyrrol-2-yl) -propyl] -amide; Compound with trifluoro-acetic acid 460 I-6 5-[(S) -3- (Cyclopentanecarbonyl-amino) -3-phenyl-propyl] -hexahydro-pyrrolo [3,4-c] pyrrole-2-carboxylic acid benzyl ester 476 I-7 Cyclopentanecarboxylic acid {(R) -2- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-ethyl} -amides; Compound with trifluoro-acetic acid 460 I-8 Cyclopentanecarboxylic acid {(S) -3- [5- (2,5-dimethyl-2H-pyrazol-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl ] -1-phenyl-propyl} -amide 464 70.1-72.5 I-9 Cyclopentanecarboxylic acid {(S) -3- [5- (1-oxy-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl -Propyl} -amide 463 62.0-64.3 I-10 Cyclopentanecarboxylic acid {(S) -1-phenyl-3- [5- (1H- [1,2,4] triazole-3-carbonyl) -hexahydro-pyrrolo [3,4-c] Pyrrole-2-yl] -propyl} -amide 437 107.0-108.0 I-11 Cyclopentanecarboxylic acid {(S) -3- [5- (4-methoxy-2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -1 -Phenyl-propyl} -amide; Compound with trifluoro-acetic acid 504.8 I-12 Cyclopentanecarboxylic acid {(S) -3- [5- (2,6-dichloro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -amides; Compound with trifluoro-acetic acid 514.7 I-13 Cyclopentanecarboxylic acid {(S) -3- [5- (2-chloro-6-methyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl- Propyl} -amide; Compound with trifluoro-acetic acid 494.8 I-14 Cyclopentanecarboxylic acid {(S) -3- [5- (2,6-dichloro-4-methyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1- Phenyl-propyl} -amide; Compound with trifluoro-acetic acid 528.7 I-15 Cyclopentanecarboxylic acid {(S) -3- [5- (4-butoxy-2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -1 -Phenyl-propyl} -amide; Compound with trifluoro-acetic acid 546.9 I-16 Cyclopentanecarboxylic acid {(S) -3- [5- (4-ethoxy-2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -1 -Phenyl-propyl} -amide; Compound with trifluoro-acetic acid 518.8

I-17 Cyclopentanecarboxylic acid {(S) -3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl -Propyl} -amide; Compound with hydrochloric acid 498.7 I-18 Cyclopentanecarboxylic acid {(S) -1-phenyl-3- [5- (2,4,6-trimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl]- Propyl} -amide; Compound with trifluoro-acetic acid 488.8 I-19 Cyclopentanecarboxylic acid {(S) -3- [5- (2-bromo-6-methyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl -Propyl} -amide; Compound with trifluoro-acetic acid 540.7 I-20 Cyclopentanecarboxylic acid {(S) -3- [5- (2,6-difluoro-4-methoxy-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 512.8 I-21 Cyclopentanecarboxylic acid {(S) -1-phenyl-3- [5- (2,4,6-trimethoxy-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl ] -Propyl} -amide; Compound with trifluoro-acetic acid 536.8 I-22 Cyclopentanecarboxylic acid {(S) -3- [5- (4-chloro-2-methoxy-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl -Propyl} -amide; Compound with trifluoro-acetic acid 510.8 I-23 Cyclopentanecarboxylic acid {(S) -3- [5- (2,3-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -amides; Compound with trifluoro-acetic acid 474.8 I-24 Cyclopentanecarboxylic acid {(S) -3- [5- (2,4-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -amides; Compound with trifluoro-acetic acid 474.8 I-25 Cyclopentanecarboxylic acid {(S) -3- [5- (2-methoxy-4-methylsulfanyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -1 -Phenyl-propyl} -amide; Compound with trifluoro-acetic acid 522.8 I-26 Cyclopentanecarboxylic acid {(S) -3- [5- (2-dimethylamino-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -1-phenyl-propyl}- amides; Compound with trifluoro-acetic acid 489.8 I-27 Cyclopentanecarboxylic acid {(S) -1-phenyl-3- [5- (1H-pyrrole-2-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl }-amides; Compound with trifluoro-acetic acid 435.8 I-28 Cyclopentanecarboxylic acid {(S) -3- [5- (3,5-dimethyl-isoxazole-4-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl]- 1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 465.8 I-29 Cyclopentanecarboxylic acid {(S) -3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl]- 1-phenyl-propyl} -amide 476 48.0-49.0 I-30 Cyclopentanecarboxylic acid [(S) -3- (5-acetyl-hexahydro-pyrrolo [3,4-c] pyrrol-2-yl) -1-phenyl-propyl] -amide; Compound with trifluoro-acetic acid 384 I-31 Cyclopentanecarboxylic acid {(S) -3- [5- (2,2-dimethyl-propionyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl }-amides; Compound with trifluoro-acetic acid 426 I-32 N-{(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -benzenesulphone amides; Compound with trifluoro-acetic acid 518.8 I-33 Cyclopropanecarboxylic acid {(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -amides; Compound with trifluoro-acetic acid 446.8

I-34 Furan-2-carboxylic acid {(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -1-phenyl- Propyl} -amide; Compound with trifluoro-acetic acid 472.8 I-35 N-{(S) -3- [5- (2,6-Dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -isobutyr amides; Compound with trifluoro-acetic acid 448.8 I-36 N-{(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -3- Methyl-butyramide; Compound with trifluoro-acetic acid 462.8 I-37 Thiophene-2-carboxylic acid {(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl -Propyl} -amide; Compound with trifluoro-acetic acid 488.8 I-38 N-{(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -2, 2-dimethyl-propionamide; Compound with trifluoro-acetic acid 462.8 I-39 Cyclohexanecarboxylic acid {(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -amides; Compound with trifluoro-acetic acid 488.9 I-40 Morpholine-4-carboxylic acid {(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl -Propyl} -amide; Compound with trifluoro-acetic acid 491.8 I-41 N-{(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -2- Hydroxy-2-methyl-propionamide; Compound with trifluoro-acetic acid 464.8 I-42 Cyclobutanecarboxylic acid {(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -amides; Compound with trifluoro-acetic acid 460.8 I-43 Pyrrolidine-1-carboxylic acid {(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -1- Phenyl-propyl} -amide; Compound with trifluoro-acetic acid 475.8 I-44 N-{(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -acetamide ; Compound with trifluoro-acetic acid 420.8 I-45 N-{(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -2- Methoxy-acetamide; Compound with trifluoro-acetic acid 450.8 I-46 N-{(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -2- Hydroxy-2-phenyl-acetamide; Compound with trifluoro-acetic acid 512.8 I-47 2-cyclopentyl-N-{(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl- Propyl} -acetamide; Compound with trifluoro-acetic acid 488.8 I-48 N-{(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -4- Methanesulfonyl-benzamide; Compound with trifluoro-acetic acid 560.8 I-49 N-((S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -1-phenyl-propyl} -benzamide Trifluoro-acetic acid 482.8 I-50 Furan-3-carboxylic acid {(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -1-phenyl- Propyl} -amide; Compound with trifluoro-acetic acid 472.8

I-51 1H-Pyrrole-2-carboxylic acid {(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -1- Phenyl-propyl} -amide; Compound with trifluoro-acetic acid 471.8 I-52 5-Methyl-thiophene-2-carboxylic acid {(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 502.8 I-53 1-Methyl-1H-pyrrole-2-carboxylic acid {(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl ] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 485.8 I-54 2-acetylamino-N-{(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl- Propyl} -acetamide; Compound with trifluoro-acetic acid 477.9 I-55 N-{(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -4- Sulfamoyl-benzamide; Compound with trifluoro-acetic acid 561.8 I-56 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -1 -Phenyl-propyl} -amide; Compound with trifluoro-acetic acid 476.9 I-57 2-oxo-thiazolidine-4-carboxylic acid {(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl ] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 507.8 I-58 Pyrazine-2-carboxylic acid {(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -1-phenyl- Propyl} -amide; Compound with trifluoro-acetic acid 484.8 I-59 N-{(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -2- Hydroxy-acetamide; Compound with trifluoro-acetic acid 436.8 I-60 N-{(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -2- Methyl-butyramide; Compound with trifluoro-acetic acid 462.8 I-61 Tetrahydro-furan-2-carboxylic acid {(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -1 -Phenyl-propyl} -amide; Compound with trifluoro-acetic acid 476.8 I-62 2-dimethylamino-N-{(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl- Propyl} -acetamide; Compound with trifluoro-acetic acid 463.8 I-63 1-{(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -3- Phenyl-urea; Compound with trifluoro-acetic acid 497.8 I-64 1-{(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -3- Isopropyl-urea; Compound with trifluoro-acetic acid 463.8 I-65 1-acetyl-piperidine-4-carboxylic acid {(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl ] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 531.9 I-66 4,4-Difluoro-cyclohexanecarboxylic acid {(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl ] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 524.8

I-67 Cyclopentanecarboxylic acid [(S) -3- (5-isobutyryl-hexahydro-pyrrolo [3,4-c] pyrrol-2-yl) -1-phenyl-propyl] -amide; Compound with trifluoro-acetic acid 412 I-68 Cyclopentanecarboxylic acid {(S) -3- [5- (3-methyl-butyryl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl}- amides; Compound with trifluoro-acetic acid 426 I-69 Cyclopentanecarboxylic acid [(S) -3- (5-butyryl-hexahydro-pyrrolo [3,4-c] pyrrol-2-yl) -1-phenyl-propyl] -amide; Compound with trifluoro-acetic acid 412 I-70 Cyclopentanecarboxylic acid [(S) -3- (5-cyclopropanecarbonyl-hexahydro-pyrrolo [3,4-c] pyrrol-2-yl) -1-phenyl-propyl] -amide; Compound with trifluoro-acetic acid 410 I-71 Cyclopentanecarboxylic acid [(S) -3- (5-cyclobutanecarbonyl-hexahydro-pyrrolo [3,4-c] pyrrol-2-yl) -1-phenyl-propyl] -amide; Compound with trifluoro-acetic acid 424 I-72 Cyclopentanecarboxylic acid {(S) -3- [5- (2-methyl-butyryl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl}- amides; Compound with trifluoro-acetic acid 426 I-73 Cyclopentanecarboxylic acid {(S) -3- [5- (2-ethyl-butyryl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl}- amides; Compound with trifluoro-acetic acid 440 I-74 {(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-pyridin-3-yl-propyl}- Carbamic acid tert-butyl ester 479 I-75 Cyclopentanecarboxylic acid {(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-butyl} -amides 488 I-76 Cyclopentanecarboxylic acid {(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-pyridine-3- Yl-propyl} -amide 475 I-77 Cyclopentanecarboxylic acid {3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-butyl} -amide 488 I-78 Cyclopentanecarboxylic acid {(S) -3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1 -Phenyl-propyl} -amide 475 68.8-73.6 I-79 Cyclopentanecarboxylic acid {(S) -3- [5- (2,4-dimethyl-1-oxy-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2- Il] -1-phenyl-propyl} -amide 491 93.3-95.5 I-80 Cyclopentanecarboxylic acid {(S) -3- [5- (1-acetyl-piperidine-4-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -1 -Phenyl-propyl} -amide; Compound with trifluoro-acetic acid 495 I-81 Cyclopentanecarboxylic acid [(S) -3- (5-benzyl-hexahydro-pyrrolo [3,4-c] pyrrol-2-yl) -1-phenyl-propyl] -amide; Compound with trifluoro-acetic acid 432 I-82 Cyclopentanecarboxylic acid {(S) -1-phenyl-3- [5- (2,4,6-trifluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl ] -Propyl} -amide; Compound with trifluoro-acetic acid 499 I-83 Cyclopentanecarboxylic acid {(S) -3- [5- (1-benzyl-5-oxo-pyrrolidine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2- Il] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 543

I-84 Cyclopentanecarboxylic acid {(S) -3- [5- (2,6-dimethyl-benzyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -amides; Compound with trifluoro-acetic acid 460 I-85 (1S, 5R) -Bicyclo [3.1.0] hexane-3-carboxylic acid {(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4- c] pyrrole-2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 486 I-86 4,4-Difluoro-cyclohexanecarboxylic acid [(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl ] -1- (3-fluoro-phenyl) -propyl] -amide; Compound with trifluoro-acetic acid 542 I-87 N-[(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1- (3-fluoro-phenyl ) -Propyl] -acetamide; Compound with trifluoro-acetic acid 438 I-88 (2S, 3S) -1-Methyl-5-oxo-2-pyridin-3-yl-pyrrolidine-3-carboxylic acid {(S) -3- [5- (2,6-dimethyl-benzoyl) -Hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 580.8 I-89 4-dimethylamino-N-{(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl- Propyl} -butyramide; Compound with trifluoro-acetic acid 491.9 I-90 1-Methyl-pyrrolidin-3-carboxylic acid {(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl ] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 489.8 I-91 N-{(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -2- Morpholin-4-yl-propionamide; Compound with trifluoro-acetic acid 519.9 I-92 2- (2-Aza-bicyclo [2.2.1] hept-2-yl) -N-{(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3 , 4-c] pyrrole-2-yl] -1-phenyl-propyl} -acetamide; Compound with trifluoro-acetic acid 515.9 I-93 1- (Furan-2-carbonyl) -4-hydroxy-pyrrolidine-2-carboxylic acid {(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 585.8 I-94 N-{(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -2- (5-morpholin-4-yl-tetrazol-2-yl) -acetamide; Compound with trifluoro-acetic acid 573.8 I-95 1-Methyl-piperidine-2-carboxylic acid {(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl ] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 503.8 I-96 1-Methyl-azepane-2-carboxylic acid {(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 517.9 I-97 2-Methyl-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid {(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3 , 4-c] pyrrole-2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 551.8 I-98 3- (2-Aza-bicyclo [2.2,1] hept-2-yl) -N-{(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3 , 4-c] pyrrole-2-yl] -1-phenyl-propyl} -propionamide; Compound with trifluoro-acetic acid 529.9 I-99 N-{(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -2- Piperidin-1-yl-acetamide; Compound with trifluoro-acetic acid 503.9 I-100 1-isopropyl-5-oxo-pyrrolidine-3-carboxylic acid {(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] Pyrrole-2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 531.9

I-101 1-Ethyl-piperidine-4-carboxylic acid {(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl ] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 517.9 I-102 1-isobutyl-5-oxo-pyrrolidine-3-carboxylic acid {(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] Pyrrole-2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 545.9 I-103 N-{(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -2- Pyrrolidin-1-yl-acetamide; Compound with trifluoro-acetic acid 489.8 I-104 1-Methyl-5-sulfamoyl-1H-pyrrole-2-carboxylic acid {(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] Pyrrole-2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 564.8 I-105 (S) -1-acetyl-pyrrolidine-2-carboxylic acid {(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole -2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 517.8 I-106 Cyclopentanecarboxylic acid {(S) -3- [5- (2-methyl-1,2,3,4-tetrahydro-isoquinoline-3-carbonyl) -hexahydro-pyrrolo [3,4- c] pyrrole-2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 515.9 I-107 Cyclopentanecarboxylic acid {(S) -1-phenyl-3- [5- (1-pyrimidin-2-yl-piperidine-4-carbonyl) -hexahydro-pyrrolo [3,4-c ] Pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 531.9 I-108 Cyclopentanecarboxylic acid {(S) -3- [5- (1-isobutyl-5-oxo-pyrrolidine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2 -Yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 509.9 I-109 Cyclopentanecarboxylic acid {(S) -3- [5- (1-methyl-5-sulfamoyl-1H-pyrrole-2-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2 -Yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 528.8 I-110 Cyclopentanecarboxylic acid ((S) -3- {5- [1- (furan-2-carbonyl) -4-hydroxy-pyrrolidine-2-carbonyl] -hexahydro-pyrrolo [3, 4-c] pyrrole-2-yl} -1-phenyl-propyl) -amide; Compound with trifluoro-acetic acid 549.8 I-111 Cyclopentanecarboxylic acid {(S) -3- [5- (4-benzyl-morpholine-2-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -1- Phenyl-propyl} -amide; Compound with trifluoro-acetic acid 545.9 I-112 Cyclopentanecarboxylic acid {(S) -3- [5- (6-chloro-imidazo [2,1-b] thiazole-5-sulfonyl) -hexahydro-pyrrolo [3,4-c] Pyrrole-2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 562.7 I-113 Cyclopentanecarboxylic acid {(S) -3- [5- (5-methyl-1-phenyl-1 H-pyrazole-4-sulfonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2 -Yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 562.8 I-114 Cyclopentanecarboxylic acid {(S) -3- [5- (5-methyl-2-phenyl-2H- [1,2,3] triazole-4-carbonyl) -hexahydro-pyrrolo [3, 4-c] pyrrole-2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 527.8 I-115 Cyclopentanecarboxylic acid ((S) -3- {5- [3- (2-chloro-phenyl) -5-methyl-isoxazole-4-carbonyl] -hexahydro-pyrrolo [3,4-c ] Pyrrole-2-yl} -1-phenyl-propyl) -amide; Compound with trifluoro-acetic acid 561.8 I-116 Cyclopentanecarboxylic acid {(S) -1-phenyl-3- [5- (4,5,6,7-tetrahydro-2H-indazole-3-carbonyl) -hexahydro-pyrrolo [3, 4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 490.8

I-117 Cyclopentanecarboxylic acid {(S) -1-phenyl-3- [5- (1,4,5,6-tetrahydro-cyclopentapyrazole-3-carbonyl) -hexahydro-pyrrolo [3, 4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 476.8 I-118 Cyclopentanecarboxylic acid {(S) -3- [5- (5-ethyl-2-methyl-2H-pyrazole-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2 -Yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 478.8 I-119 [(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1- (3-fluoro-phenyl)- Propyl] -carbamic acid tert-butyl ester 496 I-120 Cyclopentanecarboxylic acid {(S) -3- [5- (4-fluoro-2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -1 -Phenyl-propyl} -amide 492 61.6-66.3 I-121 2-Chloro-N-{(S) -3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -1- Phenyl-propyl} -4-fluoro-benzamide; Compound with trifluoro-acetic acid 558.5 I-122 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -2-trifluoromethyl-benzamide; Compound with trifluoro-acetic acid 574.6 I-123 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -2-methoxy-benzamide; Compound with trifluoro-acetic acid 536.6 I-124 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -4-methoxy-benzamide; Compound with trifluoro-acetic acid 536.6 I-125 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} Benzamide; Compound with trifluoro-acetic acid 506.6 I-126 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -3,3-dimethyl-butyramide; Compound with trifluoro-acetic acid 500.7 I-127 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} Succinic acid methyl ester; Compound with trifluoro-acetic acid 516.6 I-128 2-Chloro-N-{(S) -3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1- Phenyl-propyl} -benzamide; Compound with trifluoro-acetic acid 540.6 I-129 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} 3-cyano-benzamide; Compound with trifluoro-acetic acid 531.6 I-130 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo (3,4-c) pyrrol-2-yl] -1-phenyl-propyl} -2,4-difluoro-benzamide; Compound with trifluoro-acetic acid 542.6 I-131 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -2,6-difluoro-benzamide; Compound with trifluoro-acetic acid 542.6 I-132 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -3,4-difluoro-benzamide; Compound with trifluoro-acetic acid 542.5 I-133 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -2-fluoro-benzamide; Compound with trifluoro-acetic acid 524.6

I-134 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -4-fluoro-benzamide; Compound with trifluoro-acetic acid 524.5 I-135 Furan-2-carboxylic acid {(S) -3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -1 -Phenyl-propyl} -amide; Compound with trifluoro-acetic acid 496.5 I-136 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} Isobutyramide; Compound with trifluoro-acetic acid 472.6 I-137 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -3-methyl-butyramide; Compound with trifluoro-acetic acid 486.6 I-138 3-chloro-N-{(S) -3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1- Phenyl-propyl} -4-fluoro-benzamide; Compound with trifluoro-acetic acid 558.5 I-139 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -2-thiophen-2-yl-acetamide; Compound with trifluoro-acetic acid 526.5 I-140 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} 3-trifluoromethyl-benzamide; Compound with trifluoro-acetic acid 574.5 I-141 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -4-cyano-benzamide; Compound with trifluoro-acetic acid 531.5 I-142 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} 4-ethoxy-benzamide; Compound with trifluoro-acetic acid 550.5 I-143 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -3,5-difluoro-benzamide; Compound with trifluoro-acetic acid 542.5 I-144 Thiophene-2-carboxylic acid {(S) -3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl]- 1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 512.5 I-145 4-chloro-N-{(S) -3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1- Phenyl-propyl} -benzamide; Compound with trifluoro-acetic acid 540.5 I-146 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} 3-methoxy-benzamide; Compound with trifluoro-acetic acid 536.5 I-147 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -3-fluoro-benzamide; Compound with trifluoro-acetic acid 524.5 I-148 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -3,4-dimethoxy-benzamide; Compound with trifluoro-acetic acid 566.5

I-149 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -2,2-dimethyl-propionamide; Compound with trifluoro-acetic acid 586.5 I-150 Cyclohexanecarboxylic acid {(S) -3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl -Propyl} -amide; Compound with trifluoro-acetic acid 512.5 I-151 Morpholine-4-carboxylic acid {(S) -3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl]- 1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 515.5 I-152 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} Oxalamic acid ethyl ester; Compound with trifluoro-acetic acid 502.5 I-153 Acetic acid 1-{(S) -3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl Carbamoyl} -1-methyl-ethyl ester; Compound with trifluoro-acetic acid 530.5 I-154 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} 2-phenyl-acetamide; Compound with trifluoro-acetic acid 520.5 I-155 (1R, 2R) -2-phenyl-cyclopropanecarboxylic acid {(S) -3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] Pyrrole-2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 546.6 I-156 Cyclobutanecarboxylic acid {(S) -3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl -Propyl} -amide; Compound with trifluoro-acetic acid 484.6 I-157 Isoxazole-5-carboxylic acid {(S) -3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl]- 1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 497.5 I-158 5-Chloro-4-methoxy-thiophene-3-carboxylic acid {(S) -3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4- c] pyrrole-2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 576.5 I-159 4-Methyl- [1,2,3] thiadiazole-5-carboxylic acid {(S) -3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3 , 4-c] pyrrole-2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 528.5 I-160 3-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -1,1-diethyl-urea; Compound with trifluoro-acetic acid 501.6 I-161 3-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -1,1-diisopropyl-urea; Compound with trifluoro-acetic acid 529.6 I-162 3-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -1,1-dimethyl-urea; Compound with trifluoro-acetic acid 473.6 I-163 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} Acetamide; Compound with trifluoro-acetic acid 444.6 I-164 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} 2-methoxy-acetamide; Compound with trifluoro-acetic acid 474.6

I-165 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} 3-cyclopentyl-propionamide; Compound with trifluoro-acetic acid 526.6 I-166 Acetic acid {(S) -3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propylcarba Moyl} -methyl ester; Compound with trifluoro-acetic acid 502.6 I-167 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -2- (4-methoxy-phenyl) -acetamide; Compound with trifluoro-acetic acid 550.6 I-168 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} 2-cyclopentyl-acetamide; Compound with trifluoro-acetic acid 512.6 I-169 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -4-dimethylamino-benzamide; Compound with trifluoro-acetic acid 549.6 I-170 3,5-Dimethyl-isoxazole-4-carboxylic acid {(S) -3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole -2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 525.6 I-171 3-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -1-methyl-1-phenyl-urea; Compound with trifluoro-acetic acid 535.6 I-172 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -2-methylsulfanyl-acetamide; Compound with trifluoro-acetic acid 490.6 I-173 3-Chloro-thiophene-2-carboxylic acid {(S) -3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2 -Yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 546.5 I-174 {(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -carr Chest acid methyl ester; Compound with trifluoro-acetic acid 460.5 I-175 1-benzyl-3-{(S) -3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1- Phenyl-propyl} -1-methyl-urea; Compound with trifluoro-acetic acid 549.6 I-176 Cyclopentanecarboxylic acid {(S) -3- [5- (2,6-dichloro-4-methanesulfonyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl]- 1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 592 I-177 3-acetylamino-N-{(S) -3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -1 -Phenyl-propyl} -benzamide; Compound with trifluoro-acetic acid 563.6 I-178 4-acetylamino-N-{(S) -3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1 -Phenyl-propyl} -benzamide; Compound with trifluoro-acetic acid 563.6 I-179 1-acetyl-piperidine-4-carboxylic acid {(S) -3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole- 2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 555.6 I-180 3-amino-N-{(S) -3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1- Phenyl-propyl} -propionamide; Compound with trifluoro-acetic acid 473.6

I-181 2-amino-N-{(S) -3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1- Phenyl-propyl} -acetamide; Compound with trifluoro-acetic acid 459.6 I-182 (S) -pyrrolidine-2-carboxylic acid {(S) -3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole- 2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 499.6 I-183 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} 2-cyano-acetamide; Compound with trifluoro-acetic acid 469.6 I-184 Cycloheptancarboxylic Acid {(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl -Propyl} -amide; Compound with trifluoro-acetic acid 526.6 I-185 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} 2-cyclohexyl-acetamide; Compound with trifluoro-acetic acid 526.6 I-186 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -2-cyclopropyl-acetamide; Compound with trifluoro-acetic acid 484.6 I-187 Furan-3-carboxylic acid {(S) -3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1 -Phenyl-propyl} -amide; Compound with trifluoro-acetic acid 496.5 I-188 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} Isnicotinamide; Compound with trifluoro-acetic acid 507.6 I-189 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} Terephthalic acid methyl ester; Compound with trifluoro-acetic acid 564.5 I-190 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -3-piperidin-1-yl-propionamide; Compound with trifluoro-acetic acid 541.6 I-191 1H-Pyrrole-2-carboxylic acid {(S) -3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 495.6 I-192 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} Succinamides; Compound with trifluoro-acetic acid 501.6 I-193 1H-indole-2-carboxylic acid {(S) -3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 545.6 I-194 5-Methyl-thiophene-2-carboxylic acid {(S) -3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2 -Yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 526.6 I-195 1-Methyl-1H-pyrrole-2-carboxylic acid {(S) -3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole- 2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 509.6 I-196 2-acetylamino-N-{(S) -3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1 -Phenyl-propyl} -acetamide; Compound with trifluoro-acetic acid 501.6

I-197 Pyridine-2-carboxylic acid {(S) -3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -1 -Phenyl-propyl} -amide; Compound with trifluoro-acetic acid 507.6 I-198 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -4-methylamino-benzamide; Compound with trifluoro-acetic acid 535.7 I-199 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -2-methylamino-benzamide; Compound with trifluoro-acetic acid 535.7 I-200 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} 2-dimethylamino-benzamide; Compound with trifluoro-acetic acid 549.7 I-201 5-Amino-1-phenyl-1 H-pyrazole-4-carboxylic acid {(S) -3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4 -c] pyrrole-2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 587.7 I-202 2,2,3,3-tetramethyl-cyclopropanecarboxylic acid {(S) -3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c ] Pyrrole-2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 526.7 I-203 2-acetylamino-N-{(S) -3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1 -Phenyl-propyl} -4-methylsulfanyl-butyramide; Compound with trifluoro-acetic acid 575.7 I-204 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid {(S) -3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4 -c] pyrrole-2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 538.7 I-205 5-Amino-2H- [1,2,4] triazole-3-carboxylic acid {(S) -3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [ 3,4-c] pyrrole-2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 512.6 I-206 5-Chloro-thiophene-2-carboxylic acid {(S) -3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2 -Yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 546.5 I-207 (S) -2-acetylamino-N-{(S) -3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2- Yl] -1-phenyl-propyl} -4-methylsulfanyl-butyramide; Compound with trifluoro-acetic acid 575.6 I-208 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} 3-diethylamino-propionamide; Compound with trifluoro-acetic acid 529.7 I-209 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -2-methyl-nicotinamide; Compound with trifluoro-acetic acid 521.6 I-210 3-Methyl-furan-2-carboxylic acid {(S) -3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2- Il] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 510.6 I-211 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} Nicotinamide; Compound with trifluoro-acetic acid 507.5

I-212 Pyrazine-2-carboxylic acid {(S) -3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -1 -Phenyl-propyl} -amide; Compound with trifluoro-acetic acid 508.5 I-213 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -2- (1-methyl-1H-imidazol-4-yl) -acetamide; Compound with trifluoro-acetic acid 524.7 I-214 3H-imidazole-4-carboxylic acid {(S) -3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl ] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 496.6 I-215 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} 2-methanesulfonyl-acetamide; Compound with trifluoro-acetic acid 522.6 I-216 2-Methyl-thiazole-4-carboxylic acid {(S) -3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2 -Yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 527.6 I-217 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} 2-imidazol-1-yl-acetamide; Compound with trifluoro-acetic acid 510.7 I-218 1-Methyl-1H-pyrazole-3-carboxylic acid {(S) -3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole -2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 510.7 I-219 1-Methyl-1H-imidazole-2-carboxylic acid {(S) -3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole -2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 510.7 I-220 Cyclopentanecarboxylic acid {(S) -3- [5- (2,6-dichloro-4-methylsulfanyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl]- 1-phenyl-propyl} -amide MH + 560 67.2-72.6 I-221 5-{(S) -3-phenyl-3-[(tetrahydro-furan-3-carbonyl) -amino] -propyl} -hexahydro-pyrrolo [3,4-c] pyrrole-2-carboxyl Acid phenylamides; Compound with trifluoro-acetic acid 463.3 I-222 5-{(S) -3-phenyl-3-[(tetrahydro-furan-3-carbonyl) -amino) -propyl} -hexahydro-pyrrolo [3,4-c] pyrrole-2-carboxyl Acid (2,6-dimethyl-phenyl) -amide; Compound with trifluoro-acetic acid 491.3 I-223 Tetrahydro-furan-3-carboxylic acid [(S) -3- (5-benzenesulfonyl-hexahydro-pyrrolo [3,4-c] pyrrol-2-yl) -1-phenyl-propyl]- amides; Compound with trifluoro-acetic acid 484.2 I-224 Tetrahydro-furan-3-carboxylic acid {(S) -1-phenyl-3- [5- (thiophen-2-sulfonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2- General] -propyl} -amide; Compound with trifluoro-acetic acid 490.2 I-225 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (3,5-dimethyl-isoxazole-4-sulfonyl) -hexahydro-pyrrolo [3,4-c] pyrrole- 2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 503.2 I-226 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl) -hexahydro-pyrrolo [3, 4-c] pyrrole-2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 536.3 I-227 2,5-dimethyl-4- (5-{(S) -3-phenyl-3-[(tetrahydro-furan-3-carbonyl) -amino] -propyl} -hexahydro-pyrrolo [3,4 -c] pyrrole-2-sulfonyl) -furan-3-carboxylic acid methyl ester; Compound with trifluoro-acetic acid 560.3

I-228 Tetrahydro-furan-3-carboxylic acid {(S) -1-phenyl-3- [5- (1,3,5-trimethyl-1H-pyrazole-4-sulfonyl) -hexahydro-pyrrolo [ 3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 516.3 I-229 1-Methyl-5- (5-{(S) -3-phenyl-3-[(tetrahydro-furan-3-carbonyl) -amino] -propyl} -hexahydro-pyrrolo [3,4-c ] Pyrrole-2-sulfonyl) -1H-pyrrole-2-carboxylic acid methyl ester; Compound with trifluoro-acetic acid 545.3 I-230 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (4-cyano-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1- Phenyl-propyl} -amide; Compound with trifluoro-acetic acid 473.3 I-231 Tetrahydro-furan-3-carboxylic acid {(S) -1-phenyl-3- [5- (1H-pyrrole-2-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2 -Yl] -propyl} -amide; Compound with trifluoro-acetic acid 437.4 I-232 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (5-methoxy-1 H-indole-2-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole- 2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 517.4 I-233 Tetrahydro-furan-3-carboxylic acid {(S) -1-phenyl-3- [5- (pyridine-2-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl ] -Propyl} -amide; Compound with trifluoro-acetic acid 449.3 I-234 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (2-methylamino-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1- Phenyl-propyl} -amide; Compound with trifluoro-acetic acid 477.7 I-235 Tetrahydro-furan-3-carboxylic acid {(S) -1-phenyl-3- [5- (pyrazine-2-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl ] -Propyl} -amide; Compound with trifluoro-acetic acid 450.3 I-236 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (5-methyl-isoxazole-4-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2- Il] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 453.3 I-237 Tetrahydro-furan-3-carboxylic acid {(S) -1-phenyl-3- [5- (tetrahydro-furan-2-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole- 2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 442.4 I-238 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (4-acetylamino-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1- Phenyl-propyl} -amide; Compound with trifluoro-acetic acid 505.4 I-239 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (isoquinolin-7-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -1 -Phenyl-propyl} -amide; Compound with trifluoro-acetic acid 499.4 I-240 Tetrahydro-furan-3-carboxylic acid {(S) -1-phenyl-3- [5- (quinolin-4-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl ] -Propyl} -amide; Compound with trifluoro-acetic acid 499.4 I-241 Cyclopentanecarboxylic acid {(S) -3- [5- (3,5-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -amides 474 I-242 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (1H-indole-2-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl]- 1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 487.4 I-243 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (benzofuran-2-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -1 -Phenyl-propyl} -amide; Compound with trifluoro-acetic acid 488.4

I-244 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (benzo [b] thiophene-2-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2- Il] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 504.4 I-245 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (1-methyl-1H-indole-2-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2 -Yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 501.4 I-246 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (2-chloro-6-methyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 496.4 I-247 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (2-methoxy-3-methyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl ] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 492.4 I-248 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (4-methylamino-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1- Phenyl-propyl} -amide; Compound with trifluoro-acetic acid 477.4 I-249 Tetrahydro-furan-3-carboxylic acid ((S) -3- {5- [4- (3-methyl-5-oxo-4,5-dihydro-pyrazol-1-yl) -benzoyl]- Hexahydro-pyrrolo [3,4-c] pyrrole-2-yl} -1-phenyl-propyl) -amide; Compound with trifluoro-acetic acid 544.5 I-250 Tetrahydro-furan-3-carboxylic acid {(S) -1-phenyl-3- [5- (tetrahydro-furan-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole- 2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 442.4 I-251 Tetrahydro-furan-3-carboxylic acid {(S) -1-phenyl-3- [5- (thiophen-2-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2- General] -propyl} -amide; Compound with trifluoro-acetic acid 454.4 I-252 Tetrahydro-furan-3-carboxylic acid {(S) -1-phenyl-3- [5- (2-thiophen-2-yl-acetyl) -hexahydro-pyrrolo [3,4-c] pyrrole -2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 468.4 I-253 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (3-chloro-thiophene-2-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2- Il] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 488.3 I-254 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (2-methyl-5-phenyl-furan-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole -2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 528.4 I-255 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (5-fluoro-2-methyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl ] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 480.4 I-256 Tetrahydro-furan-3-carboxylic acid ((S) -3- {5- [3- (2-oxo-pyrrolidin-1-yl) -benzoyl] -hexahydro-pyrrolo [3,4- c] pyrrole-2-yl} -1-phenyl-propyl) -amide; Compound with trifluoro-acetic acid 531.4 I-257 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (benzo [b] thiophene-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2- Il] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 504.4 I-258 4- (5-{(S) -3-phenyl-3-[(tetrahydro-furan-3-carbonyl) amino] -propyl} -hexahydro-pyrrolo [3,4-c] pyrrole-2- Carbonyl) -benzoic acid tert-butyl ester; Compound with trifluoro-acetic acid 548.5

I-259 3- (5-{(S) -3-phenyl-3-[(tetrahydro-furan-3-carbonyl) -amino] -propyl} -hexahydro-pyrrolo [3,4-c] pyrrole-2 -Carbonyl) -benzoic acid tert-butyl ester; Compound with trifluoro-acetic acid 548.5 I-260 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (3,5-dimethyl-isoxazole-4-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole- 2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 467.4 I-261 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (1H-indole-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl]- 1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 487.4 I-262 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (benzofuran-4-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1 -Phenyl-propyl} -amide; Compound with trifluoro-acetic acid 488.4 I-263 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (2,3-dihydro-benzofuran-4-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole -2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 490.4 I-264 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (2-methoxy-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1- Phenyl-propyl} -amide; Compound with trifluoro-acetic acid 478.4 I-265 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (3-methoxy-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1- Phenyl-propyl} -amide; Compound with trifluoro-acetic acid 478.4 I-266 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (3,3-dimethyl-butyryl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl]- 1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 442.4 I-267 Tetrahydro-furan-3-carboxylic acid [(S) -3- (5-cyclobutanecarbonyl-hexahydro-pyrrolo [3,4-c] pyrrol-2-yl) -1-phenyl-propyl] -amides; Compound with trifluoro-acetic acid 426.4 I-268 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (2-cyclohexyl-acetyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1- Phenyl-propyl} -amide; Compound with trifluoro-acetic acid 468.4 I-269 Tetrahydro-furan-3-carboxylic acid [(S) -3- (5-cyclopentanecarbonyl-hexahydro-pyrrolo [3,4-c] pyrrol-2-yl) -1-phenyl-propyl] -amides; Compound with trifluoro-acetic acid 440.4 I-270 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (2-cyclopentyl-acetyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1- Phenyl-propyl} -amide; Compound with trifluoro-acetic acid 454.4 I-271 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (2,6-dichloro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1 -Phenyl-propyl} -amide; Compound with trifluoro-acetic acid 516.3 I-272 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (4-dimethylamino-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1- Phenyl-propyl} -amide; Compound with trifluoro-acetic acid 491.4 I-273 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (3-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1- Phenyl-propyl} -amide; Compound with trifluoro-acetic acid 466.4 I-274 Tetrahydro-furan-3-carboxylic acid [(S) -3- (5-isobutyryl-hexahydro-pyrrolo [3,4-c] pyrrol-2-yl) -1-phenyl-propyl]- amides; Compound with trifluoro-acetic acid 414.4

I-275 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (3-methyl-butyryl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1- Phenyl-propyl} -amide; Compound with trifluoro-acetic acid 428.4 I-276 Tetrahydro-furan-3-carboxylic acid [(S) -1-phenyl-3- (5-propionyl-hexahydro-pyrrolo [3,4-c] pyrrol-2-yl) -propyl] -amide ; Compound with trifluoro-acetic acid 400.4 I-277 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (3-methyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl -Propyl} -amide; Compound with trifluoro-acetic acid 462.4 I-278 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (4-methyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl -Propyl} -amide; Compound with trifluoro-acetic acid 462.4 I-279 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (3-cyano-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1- Phenyl-propyl} -amide; Compound with trifluoro-acetic acid 473.3 I-280 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (4-chloro-2-ethyl-2H-pyrazole-3-carbonyl) -hexahydro-pyrrolo [3,4- c] pyrrole-2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 500.3 I-281 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (4-chloro-2-methyl-2H-pyrazole-3-carbonyl) -hexahydro-pyrrolo [3,4- c] pyrrole-2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 486.3 I-282 Tetrahydro-furan-3-carboxylic acid {(S) -1-phenyl-3- [5- (2,4,5-trimethyl-thiophene-3-carbonyl) -hexahydro-pyrrolo [3, 4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 496.4 I-283 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (4-fluoro-2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2 -Yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 494.4 I-284 Tetrahydro-furan-3-carboxylic acid [(S) -3- (5-benzoyl-hexahydro-pyrrolo [3,4-c] pyrrol-2-yl) -1-phenyl-propyl] -amide; Compound with trifluoro-acetic acid 448.4 I-285 1-Methyl-cyclohexanecarboxylic acid {(S) -3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 526.6 I-286 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl) -3-morpholin-4-yl-propionamide; Compound with trifluoro-acetic acid 543.7 I-287 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -3- (4-methyl-piperazin-1-yl) -propionamide; Compound with trifluoro-acetic acid 556.7 I-288 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -3- (1H- [1,2,4] triazol-3-yl) -propionamide; Compound with trifluoro-acetic acid 525.7 I-289 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -2- (1H-tetrazol-5-yl) -acetamide; Compound with trifluoro-acetic acid 512.7 I-290 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -3-furan-2-yl-propionamide; Compound with trifluoro-acetic acid 524.7

I-291 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} 3-thiophen-2-yl-propionamide; Compound with trifluoro-acetic acid 540.7 I-292 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -3-pyridin-3-yl-propionamide; Compound with trifluoro-acetic acid 535.7 I-293 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -3- (3H-imidazol-4-yl) -propionamide; Compound with trifluoro-acetic acid 524.7 I-294 Tetrahydro-furan-2-carboxylic acid {(S) -3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl ] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 500.7 I-295 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -2- (methanesulfonyl-methyl-amino) -acetamide; Compound with trifluoro-acetic acid 551.7 I-296 4-Methoxy-thiophene-3-carboxylic acid {(S) -3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole- 2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 542.6 I-297 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -3,3,3-trifluoro-propionamide; Compound with trifluoro-acetic acid 512.6 I-298 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} 2-dimethylamino-acetamide; Compound with trifluoro-acetic acid 487.7 I-299 2-Methyl-cyclopropanecarboxylic acid {(S) -3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 484.6 I-300 1-cyano-cyclopropanecarboxylic acid {(S) -3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl ] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 495.6 I-301 5-acetyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid {(S) -3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3, 4-c] pyrrole-2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 565.6 I-302 2,4-Dimethyl-6-oxo-6H-pyran-3-carboxylic acid {(S) -3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3, 4-c] pyrrole-2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 552.6 I-303 4,6-Dimethyl-pyrimidine-5-carboxylic acid {(S) -3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole -2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 536.6 I-304 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -2,4-dimethyl-nicotinamide; Compound with trifluoro-acetic acid 535.6 I-305 (S) -2-amino-N-{(S) -3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl ] -1-phenyl-propyl) -propionamide; Compound with trifluoro-acetic acid 473.6 I-306 (S) -2-Amino-4-methyl-pentanoic acid {(S) -3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole -2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 515.6

I-307 (S) -2-amino-N-{(S) -3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl ] -1-phenyl-propyl} -3-methyl-butyrylamide; Compound with trifluoro-acetic acid 501.6 I-308 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} Butyramide; Compound with trifluoro-acetic acid 472.5 I-309 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -2,3-dimethyl-benzamide; Compound with trifluoro-acetic acid 534.5 I-310 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -2,6-dimethyl-benzamide; Compound with trifluoro-acetic acid 534.5 I-311 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl} -1-phenyl-propyl} -2- (4-fluoro-phenyl) -acetamide; Compound with trifluoro-acetic acid 538.6 I-312 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -2-phenyl-propionamide; Compound with trifluoro-acetic acid 534.6 I-313 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -4-methanesulfonyl-benzamide; Compound with trifluoro-acetic acid 584.6 I-314 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl} -1-phenyl-propyl} -2-methyl-benzamide; Compound with trifluoro-acetic acid 520.6 I-315 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -3-methyl-benzamide; Compound with trifluoro-acetic acid 520.7 I-316 N-{(S) -3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -4-methyl-benzamide; Compound with trifluoro-acetic acid 520.7 I-317 Cyclopentanecarboxylic acid {(S) -3- [5- (3,4-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -amides; Compound with trifluoro-acetic acid 474 I-318 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (4-amino-2,6-difluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole- 2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 499.3 I-319 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (2,4-dimethyl-6-oxo-6H-pyran-3-carbonyl) -hexahydro-pyrrolo [3,4 -c] pyrrole-2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 494.3 I-320 Tetrahydro-furan-3-carboxylic acid {(S) -1-phenyl-3- [5- (2,4,6-trimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3, 4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 492.4 I-321 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (1-acetyl-piperidine-4-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2 -Yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 497.3 I-322 Tetrahydro-furan-3-carboxylic acid [(S) -3- (5-cyclohexanecarbonyl-hexahydro-pyrrolo [3,4-c] pyrrol-2-yl) -1-phenyl-propyl] -amides; Compound with trifluoro-acetic acid 454.4

I-323 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (furan-2-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1- Phenyl-propyl} -amide; Compound with trifluoro-acetic acid 438.3 I-324 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (furan-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1- Phenyl-propyl} -amide; Compound with trifluoro-acetic acid 438.3 I-325 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (4-methanesulfonyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1 -Phenyl-propyl} -amide; Compound with trifluoro-acetic acid 526.3 I-326 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (2-methyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl -Propyl} -amide; Compound with trifluoro-acetic acid 462.3 I-327 Tetrahydro-furan-3-carboxylic acid {(S) -1-phenyl-3- [5- (2-trifluoromethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2 -Yl] -propyl} -amide; Compound with trifluoro-acetic acid 516.3 I-328 Tetrahydro-furan-3-carboxylic acid {(S) -1-phenyl-3- [5- (thiophen-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2- General] -propyl} -amide; Compound with trifluoro-acetic acid 454.2 I-329 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (2-dimethylamino-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1- Phenyl-propyl} -amide; Compound with trifluoro-acetic acid 491.3 I-330 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (2-ethyl-5-methyl-2H-pyrazole-3-carbonyl) -hexahydro-pyrrolo [3,4- c] pyrrole-2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 480.3 I-331 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (2-methyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl ] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 463.3 I-332 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (3-methyl-furan-2-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl ] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 452.3 I-333 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (3-fluoro-2-methyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl ] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 480.3 I-334 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (2,6-difluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 484.3 I-335 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (2-chloro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl -Propyl} -amide; Compound with trifluoro-acetic acid 482.3 I-336 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (2-methyl-thiazole-4-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2- Il] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 469.3 I-337 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (1-methyl-1H-pyrazole-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole- 2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 452.3 I-338 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (4-methoxy-thiophene-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2 -Yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 484.2

I-339 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (3-acetylamino-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1- Phenyl-propyl} -amide; Compound with trifluoro-acetic acid 505.3 I-340 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (2-acetylamino-2-phenyl-acetyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl ] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 519.3 I-341 Tetrahydro-furan-3-carboxylic acid {(S) -1-phenyl-3- [5-((S) -pyrrolidine-2-carbonyl) -hexahydro-pyrrolo [3,4-c ] Pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 441.3 I-342 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (4-chloro-2-methoxy-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl ] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 512.2 I-343 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (isoquinoline-1-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -1 -Phenyl-propyl} -amide; Compound with trifluoro-acetic acid 499.3 I-344 Tetrahydro-furan-3-carboxylic acid {(S) -1-phenyl-3- [5- (quinolin-2-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl ] -Propyl} -amide; Compound with trifluoro-acetic acid 499.3 I-345 Tetrahydro-furan-3-carboxylic acid {(S) -1-phenyl-3- [5- (quinolin-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl ] -Propyl} -amide; Compound with trifluoro-acetic acid 499.3 I-346 Tetrahydro-furan-3-carboxylic acid {(S) -1-phenyl-3- [5- (quinolin-6-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl ] -Propyl} -amide; Compound with trifluoro-acetic acid 499.3 I-347 Tetrahydro-furan-3-carboxylic acid {(S) -1-phenyl-3- [5- (quinolin-8-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl ] -Propyl} -amide; Compound with trifluoro-acetic acid 499.3 I-348 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (3-carbamoyl-propionyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl]- 1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 443.3 I-349 Tetrahydro-furan-3-carboxylic acid [(S) -3- (5-cyclopropanecarbonyl-hexahydro-pyrrolo [3,4-c] pyrrol-2-yl) -1-phenyl-propyl] -amides; Compound with trifluoro-acetic acid 412.3 I-350 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (2-methyl-butyryl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1- Phenyl-propyl} -amide; Compound with trifluoro-acetic acid 428.4 I-351 Tetrahydro-furan-3-carboxylic acid ((S) -3- {5- [2- (methanesulfonyl-methyl-amino) -acetyl] -hexahydro-pyrrolo [3,4-c] pyrrole- 2-yl} -1-phenyl-propyl) -amide; Compound with trifluoro-acetic acid 493.4 I-352 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (2,6-difluoro-4-methoxy-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole -2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 514.4 I-353 Tetrahydro-furan-3-carboxylic acid {(S) -1-phenyl-3- [5- (2,4,6-trifluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] Pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 502.4 I-354 Cyclopentanecarboxylic acid {(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -4-methoxy-1 -Phenyl-butyl} -amide 518 61.1-84.5

I-355 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5-((R) -2-acetylamino-3-methyl-butyryl) -hexahydro-pyrrolo [3,4-c] Pyrrole-2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 485.3 I-356 Cyclopentanecarboxylic acid {(S) -3- [5- (1-methyl-5-oxo-pyrrolidine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2- Il] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 467 I-357 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole- 2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 478.2 I-358 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (2,4-dimethyl-1-oxy-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c ] Pyrrole-2-yl] -1-phenyl-propyl} -amidetrifluoro-acetic acid; 493.2 I-359 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (4,6-dimethyl-2-methylsulfanyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3, 4-c] pyrrole-2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 524.3 I-360 Cyclopentanecarboxylic acid {(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -4-hydroxy-1 -Phenyl-butyl} -amide 504 78.9-84.9 I-361 Tetrahydro-furan-3-carboxylic acid {(S) -1-phenyl-3- [5- (2,4,6-trimethoxy-benzoyl) -hexahydro-pyrrolo [3,4-c] Pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 538.5 I-362 Tetrahydro-furan-3-carboxylic acid {(S) -1-phenyl-3- [5- (2,3,6-trichloro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole -2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 550.3 I-363 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (5-methyl-2-phenyl-2H- [1,2,3] triazole-4-carbonyl) -hexahydro- Pyrrolo [3,4-c] pyrrole-2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 529.5 I-364 2-oxo-imidazolidine-4-carboxylic acid {(S) -3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole -2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 514.4 I-365 5-Methyl-thiophene-2-carboxylic acid {(S) -3- [5- (2,4-dimethyl-1-oxy-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4 -c] pyrrole-2-yl] -1-phenyl-propyl} -amidetrifluoro-acetic acid; 519.5 I-366 2-cyclohexyl-N-{(S) -3- [5- (2,4-dimethyl-1-oxy-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole- 2-yl] -1-phenyl-propyl} -acetamidetrifluoro-acetic acid; 519.5 I-367 N-{(S) -3- [5- (2,4-Dimethyl-1-oxy-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl]- 1-phenyl-propyl} -2- (4-fluoro-phenyl) -acetamidetrifluoro-acetic acid; 531.5 I-368 N-{(S) -3- [5- (2,4-Dimethyl-1-oxy-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl]- 1-phenyl-propyl} -2- (4-methoxy-phenyl) -acetamidetrifluoro-acetic acid; 543.5 I-369 1-{(S) -3- [5- (2,4-Dimethyl-1-oxy-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl]- 1-phenyl-propyl} -3-isopropyl-ureatrifluoro-acetic acid; 480.5 I-370 2-oxo-thiazolidine-4-carboxylic acid {(S) -3- [5- (2,4-dimethyl-l-oxy-pyridine-3-carbonyl) -hexahydro-pyrrolo [3, 4-c] pyrrole-2-yl] -1-phenyl-propyl} -amidetrifluoro-acetic acid; 524.4

I-371 Furan-3-carboxylic acid {(S) -3- [5- (2,4-dimethyl-1-oxy-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole- 2-yl] -1-phenyl-propyl} -amidetrifluoro-acetic acid; 489.4 I-372 N-{(S) -3- [5- (2,4-Dimethyl-1-oxy-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl]- 1-phenyl-propyl} -3,4-difluoro-benzamidetrifluoro-acetic acid; 535.4 I-373 1-{(S) -3- [5- (2,4-Dimethyl-1-oxy-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl]- 1-phenyl-propyl} -3-phenyl-ureatrifluoro-acetic acid; 514.5 I-374 4,4-Difluoro-cyclohexanecarboxylic acid {(S) -3- [5- (2,4-dimethyl-1-oxy-pyridine-3-carbonyl) -hexahydro-pyrrolo [3, 4-c] pyrrole-2-yl] -1-phenyl-propyl} -amidetrifluoro-acetic acid; 541.5 I-375 Tetrahydro-pyran-4-carboxylic acid {(S) -3- [5- (2,4-dimethyl-1-oxy-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c ] Pyrrole-2-yl] -1-phenyl-propyl} -amidetrifluoro-acetic acid; 507.5 I-376 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2 -Yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 477.5 I-377 5-Methyl-thiophene-2-carboxylic acid {(S) -3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole -2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 503.4 I-378 2-cyclohexyl-N-{(S) -3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -1-phenyl-propyl} -acetamide; Compound with trifluoro-acetic acid 503.5 I-379 N-{(S) -3- [5- (2,4-Dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl- Propyl} -2- (4-fluoro-phenyl) -acetamide; Compound with trifluoro-acetic acid 515.5 I-380 N-{(S) -3- [5- (2,4-Dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl- Propyl} -2- (4-methoxy-phenyl) -acetamide; Compound with trifluoro-acetic acid 527.5 I-381 Cyclohexanecarboxylic acid {(S) -3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1 -Phenyl-propyl} -amide; Compound with trifluoro-acetic acid 489.5 I-382 Furan-3-carboxylic acid {(S) -3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 473.4 I-383 N-{(S) -3- [5- (2,4-Dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl- Propyl} -acetamide; Compound with trifluoro-acetic acid 421.4 I-384 N-{(S) -3- [5- (2,4-Dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl- Propyl} -3,4-difluoro-benzamide; Compound with trifluoro-acetic acid 519.4 I-385 1-{(S) -3- [5- (2,4-Dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl- Propyl} -3-phenyl-urea; Compound with trifluoro-acetic acid 498.4 I-386 4,4-Difluoro-cyclohexanecarboxylic acid {(S) -3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrole [3,4-c] pyrrole -2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 525.5

I-387 Tetrahydro-pyran-4-carboxylic acid {(S) -3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2 -Yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 491.4 I-388 Tetrahydro-pyran-4-carboxylic acid {(S) -3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl ] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 514.4 I-389 (R) -Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2- Il] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 476.5 I-390 (R) -Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4- c] pyrrole-2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 478.4 I-391 (R) -Tetrahydro-furan-3-carboxylic acid {(S) -1-phenyl-3- [5- (2,4,5-trimethyl-thiophene-3-carbonyl) -hexahydro-pi Rolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 496.4 I-392 (S) -Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2- Il] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 476.5 I-393 (S) -Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c ] Pyrrole-2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 477.5 I-394 (S) -Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4- c] pyrrole-2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 478.5 I-395 (S) -Tetrahydro-furan-3-carboxylic acid {(S) -1-phenyl-3- [5- (2,4,5-trimethyl-thiophene-3-carbonyl) -hexahydro-pi Rolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 496.4 I-396 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (5-methyl-3-phenyl-isoxazole-4-carbonyl) -hexahydro-pyrrolo [3,4-c] Pyrrole-2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 529.4 I-397 Tetrahydro-furan-3-carboxylic acid {(S) -1-phenyl-3- [5- (quinolin-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl ] -Propyl} -amide; Compound with trifluoro-acetic acid 499.4 I-398 Tetrahydro-furan-3-carboxylic acid {(S) -1-phenyl-3- [5- (quinolin-4-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl ] -Propyl} -amide; Compound with trifluoro-acetic acid 499.4 I-399 Tetrahydro-furan-3-carboxylic acid {(S) -1-phenyl-3- [5- (quinolin-6-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl ] -Propyl} -amide; Compound with trifluoro-acetic acid 499.4 I-400 Tetrahydro-furan-3-carboxylic acid {(S) -1-phenyl-3- [5- (quinolin-8-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl ] -Propyl} -amide; Compound with trifluoro-acetic acid 499.5 I-401 (R) -Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c ] Pyrrole-2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 477.7 I-402 Cyclopentanecarboxylic acid {(S) -3- [5- (2,6-dimethyl-4-pyridin-4-yl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl ] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 551.3

I-403 Cyclopentanecarboxylic acid {(S) -3- [5- (4-cyano-2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -1 -Phenyl-propyl} -amide; Compound with trifluoro-acetic acid 499.2 I-404 Cyclopentanecarboxylic acid {(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -1-pyridine-2- Yl-propyl} -amide; Compound with trifluoro-acetic acid 475 I-405 Cyclopropanecarboxylic acid {(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-pyridine-2- Yl-propyl} -amide; Compound with trifluoro-acetic acid 447 I-406 5-Methyl-thiophene-2-carboxylic acid {(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -1-pyridin-2-yl-propyl} -amide; Compound with trifluoro-acetic acid 503 I-407 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -1 -Pyridin-2-yl-propyl} -amide; Compound with trifluoro-acetic acid 477 I-408 4,4-Difluoro-cyclohexanecarboxylic acid {(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl ] -1-pyridin-2-yl-propyl} -amide; Compound with trifluoro-acetic acid 525 I-409 1,1-Dioxo-hexahydro-1λ ⁶ -thiopyran-4-carboxylic acid {(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4 -c] pyrrole-2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 538 I-410 Tetrahydro-furan-3-carboxylic acid ((S) -3- {5- [5-amino-1- (4-methoxy-phenyl) -1 H-pyrazole-4-carbonyl] -hexahydro- Pyrrolo [3,4-c] pyrrole-2-yl} -1-phenyl-propyl) -amide; Compound with trifluoro-acetic acid 559.4 I-411 Tetrahydro-furan-3-carboxylic acid {(S) -1-phenyl-3- [5- (1-phenyl-5-trifluoromethyl-1 H-pyrazole-4-carbonyl) -hexahydro- Pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 582.3 I-412 Tetrahydro-furan-3-carboxylic acid ((S) -3- {5- [1- (4-methoxy-phenyl) -5-trifluoromethyl-1H-pyrazole-4-carbonyl]- Hexahydro-pyrrolo [3,4-c] pyrrole-2-yl} -1-phenyl-propyl) -amide; Compound with trifluoro-acetic acid 612.3 I-413 Tetrahydro-furan-3-carboxylic acid ((S) -3- {5- [1- (2-methoxy-phenyl) -5-trifluoromethyl-1H-pyrazole-4-carbonyl]- Hexahydro-pyrrolo [3,4-c] pyrrole-2-yl} -1-phenyl-propyl) -amide; Compound with trifluoro-acetic acid 612.3 I-414 Tetrahydro-furan-3-carboxylic acid ((S) -3- {5- [1- (4-chloro-phenyl) -5-trifluoromethyl-1H-pyrazole-4-carbonyl] -hexa Hydro-pyrrolo [3,4-c] pyrrole-2-yl} -1-phenyl-propyl) -amide; Compound with trifluoro-acetic acid 616.3 I-415 Tetrahydro-furan-3-carboxylic acid {(S) -1-phenyl-3- [5- (1-p-tolyl-5-trifluoromethyl-1H-pyrazole-4-carbonyl) -hexa Hydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 596.3 I-416 Tetrahydro-furan-3-carboxylic acid ((S) -3- {5- [1- (4-fluoro-phenyl) -5-trifluoromethyl-1H-pyrazole-4-carbonyl]- Hexahydro-pyrrolo [3,4-c] pyrrole-2-yl} -1-phenyl-propyl) -amide; Compound with trifluoro-acetic acid 600.3 I-417 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (5-methyl-1-phenyl-1 H-pyrazole-4-carbonyl) -hexahydro-pyrrolo [3,4- c] pyrrole-2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 528.3

I-418 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (5-methyl-1-p-tolyl-1H-pyrazole-4-carbonyl) -hexahydro-pyrrolo [3, 4-c] pyrrole-2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 542.4 I-419 Tetrahydro-furan-3-carboxylic acid ((S) -3- {5- [2- (4-methoxy-phenyl) -5-methyl-2H-pyrazole-3-carbonyl] -hexahydro- Pyrrolo [3,4-c] pyrrole-2-yl} -1-phenyl-propyl) -amide; Compound with trifluoro-acetic acid 558.4 I-420 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (4,6-dimethyl-2-phenyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4- c] pyrrole-2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 554.4 I-421 Tetrahydro-furan-3-carboxylic acid ((S) -3- {5- [4,6-dimethyl-2- (2-methyl-thiazol-4-yl) -pyrimidine-5-carbonyl] -Hexahydro-pyrrolo [3,4-c] pyrrole-2-yl} -1-phenyl-propyl) -amide; Compound with trifluoro-acetic acid 575.3 I-422 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (4,6-dimethyl-2-pyridin-4-yl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [ 3,4-c] pyrrole-2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 555.4 I-423 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (2-bromo-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2- Il] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 529.2 I-424 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (2-fluoro-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2- Il] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 467.3 I-425 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (3-chloro-pyridine-4-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl ] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 483.3 I-426 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (2-methoxy-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2- Il] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 479.3 I-427 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (2-methanesulfonyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1 -Phenyl-propyl} -amide; Compound with trifluoro-acetic acid 526.3 I-428 Tetrahydro-furan-3-carboxylic acid {(S) -1-phenyl-3- [5- (2-trifluoromethoxy-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2 -Yl] -propyl} -amide; Compound with trifluoro-acetic acid 532.3 I-429 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (5-amino-1-phenyl-1 H-pyrazole-4-carbonyl) -hexahydro-pyrrolo [3,4- c] pyrrole-2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 529.2 I-430 Tetrahydro-furan-3-carboxylic acid ((S) -3- {5- [5-amino-1- (4-fluoro-phenyl) -1 H-pyrazole-4-carbonyl] -hexahydro- Pyrrolo [3,4-c] pyrrole-2-yl} -1-phenyl-propyl) -amide; Compound with trifluoro-acetic acid 547.2 I-431 Tetrahydro-furan-3-carboxylic acid ((S) -3- {5- [5-amino-1- (2-methoxy-phenyl) -1 H-pyrazole-4-carbonyl] -hexahydro- Pyrrolo [3,4-c] pyrrole-2-yl} -1-phenyl-propyl) -amide; Compound with trifluoro-acetic acid 559.2 I-432 Tetrahydro-furan-3-carboxylic acid ((S) -3- {5- [1- (4-chloro-phenyl) -5-methyl-1H-pyrazole-4-carbonyl] -hexahydro-py Rolo [3,4-c] pyrrole-2-yl} -1-phenyl-propyl) -amide; Compound with trifluoro-acetic acid 562.2 I-433 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (3-bromo-2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2 -Yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 556.2

I-434 Cyclopentanecarboxylic acid {(S) -3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl]- 1-phenyl-butyl} -amide 540 71.3-72.9 I-435 4,4-Difluoro-cyclohexanecarboxylic acid {(S) -3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4-c ] Pyrrole-2-yl] -1-phenyl-propyl} -amide 526 131.8-133.2 I-436 Pentanoic acid {(S) -3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl- Propyl} -amide; Compound with trifluoro-acetic acid 463.3 I-437 Cyclobutanecarboxylic acid {(S) -3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -1 -Phenyl-propyl} -amide; Compound with trifluoro-acetic acid 461.3 I-438 2-cyclopentyl-N-{(S) -3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -1-phenyl-propyl} -acetamide; Compound with trifluoro-acetic acid 489.3 I-439 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (2-methyl-5-trifluoromethyl-oxazole-4-carbonyl) -hexahydro-pyrrolo [3,4 -c] pyrrole-2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 521.2 I-440 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (2-amino-6-trifluoromethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2 -Yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 531.3 I-441 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (2,6-dimethyl-4-nitro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2- Il] -1-phenyl-propyl} -amidetrifluoro-acetic acid; 521.3 I-442 N-{(S) -3- [5- (2,4-Dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl- Propyl} -propionamide; Compound with trifluoro-acetic acid 435.3 I-443 N-{(S) -3- [5- (2,4-Dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl- Propyl} -butyramide; Compound with trifluoro-acetic acid 449.3 I-444 Cyclopropanecarboxylic acid {(S) -3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1 -Phenyl-propyl} -amide; Compound with trifluoro-acetic acid 447.3 I-445 {(S) -3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -2-methyl-1- Phenyl-propyl} -carbamic acid tert-butyl ester 493 I-446 Cyclopentanecarboxylic acid {(S) -3- [5- (2,6-dimethyl-benzoyl) -3a, 6a-dimethyl-hexahydro-pyrrolo [3,4-c] pyrrole-2-yl]- 1-phenyl-propyl} -amide 502 (M + Na) 524 I-447 5-Oxo-1- (2,2,2-trifluoro-ethyl) -pyrrolidine-3-carboxylic acid {(S) -3- [5- (2,6-dimethyl-benzoyl) -hexa Hydro-pyrrolo [3,4-c] pyrrole-2-yl] -1-phenyl-propyl} -amide 571 93.3-94.5 I-448 4,4-Difluoro-cyclohexanecarboxylic acid {(S) -3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4-c ] Pyrrole-2-yl] -1-phenyl-butyl} -amide 540 71.3-72.9 I-449 4,4-Difluoro-cyclohexanecarboxylic acid {(S) -3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4-c ] Pyrrole-2-yl] -1-phenyl-butyl} -amide 540 86.4-87.0 I-450 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (6-chloro-2-dimethylamino-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] Pyrrole-2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 526.1

I-451 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (4-cyano-2,5-dimethyl-thiophen-3-carbonyl) -hexahydro-pyrrolo [3,4 -c] pyrrole-2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 507.1 I-452 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (4-iodo-2,5-dimethyl-thiophene-3-carbonyl) -hexahydro-pyrrolo [3,4 -c] pyrrole-2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 608 I-453 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (2,5-dimethyl-thiophene-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole- 2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 482.1 I-454 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (2,5-di-tert-butyl-4-cyano-thiophene-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 591.2 I-455 4-oxo-cyclohexanecarboxylic acid {(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1- Phenyl-propyl} -amide 502 94.3-95.7 I-456 Cyclopentanecarboxylic acid {(S) -3- [5- (2-ethoxy-4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole- 2-yl] -1-phenyl-propyl} -amide 520 I-457 Cyclopentanecarboxylic acid {(S) -3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -2 -Methyl-1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 489 I-458 Cyclopropanecarboxylic acid {(S) -3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -2 -Methyl-1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 461 I-459 5-Methyl-thiophene-2-carboxylic acid {(S) -3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole -2-yl] -2-methyl-1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 517 I-460 4,4-Difluoro-cyclohexanecarboxylic acid {(S) -3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] Pyrrole-2-yl] -2-methyl-1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 539 I-461 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (4-bromo-2,5-di-tert-butyl-thiophene-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 646.1 I-462 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (3,5-diethyl-isoxazole-4-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole -2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 495.2 I-463 Cyclopentanecarboxylic acid {(S) -3- [5- (2-methanesulfonyl-4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole -2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 554 I-464 (5- {5-[(S) -3- (Cyclopentanecarbonyl-amino) -3-phenyl-propyl] -hexahydro-pyrrolo [3,4-c] pyrrole-2-carbonyl} -4 , 6-dimethyl-pyrimidin-2-yloxy) -acetic acid methyl ester 564 I-465 Cyclopentanecarboxylic acid {(S) -3- [5- (2-benzylamino-4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole- 2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 581 I-466 (5- {5-[(S) -3- (Cyclopentanecarbonyl-amino) -3-phenyl-propyl] -hexahydro-pyrrolo [3,4-c] pyrrole-2-carbonyl} -4 , 6-dimethyl-pyrimidin-2-yloxy) -acetic acid; Compound with trifluoro-acetic acid 550 I-467 Cyclopentanecarboxylic acid {(S) -3- [5- (2,4-dimethyl-6-oxo-6H-pyran-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole- 2-yl] -1-phenyl-propyl} -amide 492 113.0-113.7

I-468 Cyclopentanecarboxylic acid {(S) -1-phenyl-3- [5- (2,4,6-trimethyl-benzenesulfonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl ] -Propyl} -amide 524.6 I-469 Cyclopentanecarboxylic acid {(R) -3- [5- (2-dimethylamino-4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole- 2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 519 I-470 N-{(S) -3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl -Propyl} -3,4-difluoro-benzamide; Compound with trifluoro-acetic acid 520 I-471 Cyclobutanecarboxylic acid {(S) -3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl]- 1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 462 I-472 2-cyclopentyl-N-{(S) -3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl ] -1-phenyl-propyl} -acetamide; Compound with trifluoro-acetic acid 490 I-473 5-Methyl-thiophene-2-carboxylic acid {(S) -3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4-c] Pyrrole-2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 504 I-474 2-oxo-thiazolidine-4-carboxylic acid {(S) -3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4-c ] Pyrrole-2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 509 I-475 2-cyclohexyl-N-{(S) -3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl ] -1-phenyl-propyl} -acetamide; Compound with trifluoro-acetic acid 504 I-476 3,3-Difluoro-cyclobutanecarboxylic acid {(S) -3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4-c ] Pyrrole-2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 498 I-477 3-oxo-cyclobutanecarboxylic acid {(S) -3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2 -Yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 476 I-478 N-{(S) -3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl -Propyl} -3,4-difluoro-benzenesulfonamide; Compound with trifluoro-acetic acid 556 I-479 Cyclopropanecarboxylic acid {(S) -3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl]- 1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 448 I-480 Thiophene-2-carboxylic acid {(S) -3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2- Il] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 490 I-481 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (3-methyl-benzofuran-2-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2- Il] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 502 I-482 Tetrahydro-furan-3-carboxylic acid {(S) -3- [5- (7-methoxy-3-methyl-1H-indole-2-carbonyl) -hexahydro-pyrrolo [3,4- c] pyrrole-2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 531 I-483 Tetrahydro-pyran-3-carboxylic acid {(S) -3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole- 2-yl] -1-phenyl-propyl} -amide; Compound with trifluoro-acetic acid 492

I-484 Cyclopentanecarboxylic acid [(S) -3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl]- 1- (3-Fluoro-phenyl) -propyl] -amide 494 I-485 4,4-Difluoro-cyclohexanecarboxylic acid [(S) -3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4-c ] Pyrrole-2-yl] -1- (3-fluoro-phenyl) -propyl] -amide 544 I-486 4-hydroxycyclohexanecarboxylic acid {(S) -3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole- 2-yl] -1-phenyl-propyl} -amide 506.3 I-487 4-hydroxycyclohexanecarboxylic acid {(S) -3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole- 2-yl] -1-phenyl-propyl} -amide 506.3 I-488 3,3-Difluoro-cyclobutanecarboxylic acid {(S) -3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] Pyrrole-2-yl] -1-phenyl-propyl} -amide 498

Compounds of formula (I) in which R ¹ is aryl can be prepared by a series of alkylations usually depicted in Scheme 5. 2-benzyl-octahydro-pyrrolo [3,4-c] pyrrole ( 4a ) is acylated prior to debenzylation as depicted in Scheme 1. Acylation can be performed by the standard techniques described above. The hydrolysis process (step 2) of the benzyl protecting group to yield 66 is well known in the art. In another embodiment of the present invention, 4a may be alkylated or sulfonylated prior to hydrolysis of the benzyl group as described above.

Scheme 5

[S. Imamura et al . (WO 01/25200) 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-(3-chloro-propyl) -amide by the conventional methodology described in ( 18 ) was prepared (Scheme 5). Those skilled in the art will appreciate that 18 consists of fragments derived from aryl amines, carboxylic acids and difunctional alkylene chains. Substitution of other aryl or heteroaryl amines and other carboxylic acids readily yields homology of 18 with other substitutions on the ring along with the aryl heteroaryl amines and other acyl radicals.

Alkylation of aryl amine 17 (or optionally heteroaryl amine) with 1-bromo-3-chloropropane yields 20 . Typically in the presence of a base such as TEA, DIPEA or DBU, or an inorganic base such as Na ₂ CO ₃ , NaHCO ₃ , K ₂ CO ₃ or Cs ₂ CO ₃ : optionally in the presence of a phase transfer catalyst, acetonitrile, DMF, DMSO, The reaction can be carried out in a solvent such as 1,4-dioxane, THF or toluene. Other difunctional propylene compounds can also be used, taking bromo-chloro-propane as an example here. Alternatively, the metal salt of the amine (ie, deprotonated type) may be nucleophilic in a suitable solvent such as THF, DMF or 1,4-dioxane. Preferably, the reaction is carried out with amine 17 and bromo-chloro-propane dissolved in DMF or MeCN, K ₂ CO ₃ or CS ₂ CO ₃ , DBU in MeCN, or K ₂ CO ₃ and 18-crown-6 (1 , 4,7,10,13,16-hexaoxacyclooctadecane). Potassium iodide is frequently added to generate alkyl iodide in situ. Optimum conditions for alkylation can vary depending on the nature of the reactants, and those skilled in the art can optimize certain reaction conditions without unnecessary experimentation.

Acylation of the obtained secondary amine 20 with 1-acetyl-piperidine-4-carboxylic acid or the corresponding chlorinated carboxylic acid, or other carboxylic acid is carried out by standard protocol as described above. Urea and sulfonamide homology is prepared by substituting isocyanate or sulfonyl chloride for carboxylic acid.

Scheme 6

Alternative aryl amines are sufficiently capable of performing alkylation of 74 or other octahydro-pyrrolo [3,4-c] pyrrole derivatives directly to 20 without further modification of the aryl amine functionality to yield 31 which can be further acylated. Inactivated. The reaction is illustrated in Scheme 6 using a Boc protecting group that can be removed under acidic conditions for the final completion of the compounds of the present invention (conversion from 42a to 42c ).

Scheme 7

Methylation of propylene linkages can be achieved from readily available butanone derivatives by reacting aryl or heteroaryl amines with methyl vinyl ketone (Scheme 7). Reductive alkylation of 32 and 66 (or other amides described herein) and acylation of 33 proceed as described above.

The synthesis of compounds where R ⁶ is not hydrogen is illustrated in Examples 37, 38, 40 and 41.

Representative compounds of the invention wherein R ¹ is an aryl or heteroaryl group are shown in Table 2.

II-1 designation Ms ¹ mp II-2 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4 -c] pyrrole-2-yl] -propyl} -amide 579 58.1-65.2 II-3 N- {3- [5- (2,6-Dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -propyl} -N- (4-fluoro-phenyl) Benzenesulfonamide; Compound with trifluoro-acetic acid 536.6 II-4 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pipe Rolo [3,4-c] pyrrol-2-yl] -propyl} -amide 580 91.8-96.9 II-5 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,4-dimethyl-1-oxy-pyridine-3-carbonyl)- Hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide 596 67.2-72.6 II-6 4,4-difluoro-cyclohexanecarboxylic acid {3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -Propyl}-(3-chloro-4-methyl-phenyl) -amide; Compound with trifluoro-acetic acid 596 II-7 1-acetyl-piperidine-4-carboxylic acid [3- (5-benzyl-hexahydro-pyrrolo [3,4-c] pyrrol-2-yl) -propyl]-(3-chloro-4- Methyl-phenyl) -amide 537 II-8 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,4,5-trimethyl-thiophene-3-carbonyl) -hexa Hydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 599.3 II-9 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro- Pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 581.4 II-10 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,6-difluoro-4-methoxy-benzoyl) -hexahydro -Pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 617.4 II-11 1-acetyl-piperidine-4-carboxylic acid {3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -Propyl}-(3-chloro-4-methyl-phenyl) -amide; Compound with trifluoro-acetic acid 603.3 II-12 1-acetyl-piperidine-4-carboxylic acid {3- [5- (2-chloro-6-methyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl]- Propyl}-(3-chloro-4-methyl-phenyl) -amide; Compound with trifluoro-acetic acid 599.4 II-13 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,6-dichloro-4-methyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 633.3 II-14 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,4,6-trimethyl-benzoyl) -hexahydro-pyrrolo [3 , 4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 593.4 II-15 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (3,5-dimethyl-isoxazole-4-carbonyl) -hexahydro- Pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 570.4

II-16 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2-dimethylamino-benzoyl) -hexahydro-pyrrolo [3,4- c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 594.4 II-17 1-acetyl-piperidine-4-carboxylic acid {3- [5- (4-chloro-2-methoxy-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -Propyl}-(3-chloro-4-methyl-phenyl) -amide; Compound with trifluoro-acetic acid 615.4 II-18 1-acetyl-piperidine-4-carboxylic acid {3- [5- (5-acetyl-2,4-dimethyl-1H-pyrrole-3-carbonyl) -hexahydro-pyrrolo [3,4- c] pyrrole-2-yl] -propyl}-(3-chloro-4-methyl-phenyl) -amide; Compound with trifluoro-acetic acid 610.5 II-19 4,4-Difluoro-cyclohexanecarboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,4-dimethyl-1-oxy-pyridine-3-carbonyl)- Hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide 589 67.0-74.1 II-20 4,4-Difluoro-cyclohexanecarboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pi Rolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with hydrochloric acid 573 152.4-161.3 II-21 Furan-2-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4- c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 521.4 II-22 N- (3-Chloro-4-methyl-phenyl) -N- {3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole -2-yl] -propyl} -isobutyramide; Compound with trifluoro-acetic acid 497.5 II-23 Thiophene-2-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4 -c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 537.4 II-24 Cyclohexanecarboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] Pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 537.5 II-25 Morpholine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4 -c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 540.5 II-26 Isoxazole-5-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4 -c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 522.4 II-27 4-Methyl- [1,2,3] thiadiazole-5-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,4-dimethyl-pyridine-3-carbox Carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 553.4 II-28 Pyrrolidine-1-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3, 4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 524.5 II-29 1- (3-Chloro-4-methyl-phenyl) -1- {3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole -2-yl] -propyl} -3,3-dimethyl-urea; Compound with trifluoro-acetic acid 498.5 II-30 N- (3-Chloro-4-methyl-phenyl) -N- {3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole -2-yl] -propyl} -acetamide; Compound with trifluoro-acetic acid 496.4

II-31 N- (3-Chloro-4-methyl-phenyl) -2-cyclopentyl-N- {3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3, 4-c] pyrrole-2-yl] -propyl} -acetamide; Compound with trifluoro-acetic acid 537.5 II-32 3,5-Dimethyl-isoxazole-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro- Pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 550.5 II-33 N- (3-Chloro-4-methyl-phenyl) -N- {3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole -2-yl] -propyl} -4-methanesulfonyl-benzamide; Compound with trifluoro-acetic acid 609.5 II-34 Piperidine-1-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3, 4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 538.5 II-35 1-Methyl-1H-pyrrole-2-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-py Rolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 534.5 II-36 1- (3-Chloro-4-methyl-phenyl) -3- (4-chloro-phenyl) -1- {3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro- Pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -urea; Compound with trifluoro-acetic acid 580.4 II-37 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pipe Rolo [3,4-c] pyrrole-2-yl] -butyl} -amide 594 60.9-62.4 II-38 1-acetyl-piperidine-4-carboxylic acid {3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2- General] -propyl} -p-tolyl-amide 546 60.9-61.1 II-39 1-acetyl-piperidine-4-carboxylic acid (3- {5- [5-chloro-2- (2,5-dimethyl-pyrrole-1-yl) -benzoyl] -hexahydro-pyrrolo [3 , 4-c] pyrrole-2-yl} -propyl)-(3-chloro-4-methyl-phenyl) -amide; Compound with trifluoro-acetic acid 678.3 II-40 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2-methyl-quinoline-3-carbonyl) -hexahydro-pyrrolo [ 3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 616.3 II-41 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2-chloro-4-methyl-6-pyrrolidin-1-yl- Benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 668.4 II-42 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-(3- {5- [2- (1,1-dioxo-1λ ⁶ -thiomorpholine-4 -Yl) -benzoyl] -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl} -propyl) -amide; Compound with trifluoro-acetic acid 684.4 II-43 1-acetyl-piperidine-4-carboxylic acid {3- [5- (3-bromo-2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2- Il] -propyl}-(3-chloro-4-methyl-phenyl) -amide; Compound with trifluoro-acetic acid 657.4 II-44 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (4,6-dimethyl-2-pyridin-4-yl-pyrimidine-5 -Carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 658.5 II-45 5- {3-[(1-acetyl-piperidine-4-carbonyl)-(3-chloro-4-methyl-phenyl) -amino] -propyl} -hexahydro-pyrrolo [3,4-c ] Pyrrole-2-carboxylic acid (2-isopropyl-phenyl) -amide; Compound with trifluoro-acetic acid 608.5

II-46 5- {3-[(1-acetyl-piperidine-4-carbonyl)-(3-chloro-4-methyl-phenyl) -amino] -propyl} -hexahydro-pyrrolo [3,4-c ] Pyrrole-2-carboxylic acid (2,6-dimethyl-phenyl) -amide; Compound with trifluoro-acetic acid 594.5 II-47 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,4,6-trimethyl-benzenesulfonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 629.5 II-48 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (thiophen-2-sulfonyl) -hexahydro-pyrrolo [3,4 -c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 593.4 II-49 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (3,5-dimethyl-isoxazole-4-sulfonyl) -hexahydro- Pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 606.5 II-50 1-acetyl-piperidine-4-carboxylic acid {3- [5- (5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl) -hexahydro-pyrrolo [3,4 -c] pyrrole-2-yl] -propyl}-(3-chloro-4-methyl-phenyl) -amide; Compound with trifluoro-acetic acid 639.5 II-51 4- (5- {3-[(1-acetyl-piperidine-4-carbonyl)-(3-chloro-4-methyl-phenyl) -amino] -propyl} -hexahydro-pyrrolo [3, 4-c] pyrrole-2-sulfonyl) -2,5-dimethyl-furan-3-carboxylic acid methyl ester; Compound with trifluoro-acetic acid 663.6 II-52 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (1,3,5-trimethyl-1H-pyrazole-4-sulfonyl) -Hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 619.6 II-53 1-acetyl-piperidine-4-carboxylic acid {3- [5- (1-acetyl-piperidine-4-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2- Il] -propyl}-(3-chloro-4-methyl-phenyl) -amide; Compound with trifluoro-acetic acid 600.6 II-54 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (4-cyano-benzoyl) -hexahydro-pyrrolo [3,4- c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 576.5 II-55 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,6-dimethoxy-benzoyl) -hexahydro-pyrrolo [3, 4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 611.6 II-56 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,4-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4 -c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 579.6 II-57 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (furan-2-carbonyl) -hexahydro-pyrrolo [3,4- c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 541.5 II-58 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (furan-3-carbonyl) -hexahydro-pyrrolo [3,4- c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 541.5 II-59 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (pyridine-4-carbonyl) -hexahydro-pyrrolo [3,4- c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 552.5

II-60 3- (5- {3-[(1-acetyl-piperidine-4-carbonyl)-(3-chloro-4-methyl-phenyl) -amino] -propyl} -hexahydro-pyrrolo [3, 4-c] pyrrole-2-carbonyl) -benzoic acid methyl ester; Compound with trifluoro-acetic acid 609.6 II-61 4-((3-Chloro-4-methyl-phenyl)-{3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl]- Propyl} -carbamoyl) -piperidine-1-carboxylic acid tert-butyl ester 637.6 II-62 Piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole -2-yl] -propyl} -amide 537.5 II-63 1-acetyl-piperidine-4-carboxylic acid {3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2- General] -propyl} -phenyl-amide 532 60.1-61.1 II-64 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (4-methanesulfonyl-benzoyl) -hexahydro-pyrrolo [3,4 -c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 629.2 II-65 4- (5- {3-[(1-acetyl-piperidine-4-carbonyl)-(3-chloro-4-methyl-phenyl) -amino] -propyl} -hexahydro-pyrrolo [3, 4-c] pyrrole-2-carbonyl) -benzoic acid methyl ester; Compound with trifluoro-acetic acid 609.3 II-66 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (1H-pyrrole-2-carbonyl) -hexahydro-pyrrolo [3, 4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 540.4 II-67 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2-methyl-benzoyl) -hexahydro-pyrrolo [3,4-c ] Pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 565.4 II-68 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2-trifluoromethyl-benzoyl) -hexahydro-pyrrolo [3, 4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 619.5 II-69 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (5-methyl-thiophene-2-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 571.5 II-70 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (1-methyl-1H-pyrrole-2-carbonyl) -hexahydro-pi Rolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 554.5 II-71 1-Acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (thiophene-3-carbonyl) -hexahydro-pyrrolo [3,4 -c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 557.5 II-72 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-(3- [5- (pyridine-2-carbonyl) -hexahydro-pyrrolo [3,4- c] pyrrole-2-yl] -propyl} -amide; a compound with trifluoro-acetic acid 552.5 II-73 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2-methylamino-benzoyl) -hexahydro-pyrrolo [3,4- c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 580.6 II-74 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (4-methoxy-2,6-dimethyl-benzoyl) -hexahydro-pipe Rolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 609.6

II-75 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2-ethyl-5-methyl-2H-pyrazole-3-carbonyl) -Hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 583.6 II-76 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2-methyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [ 3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 566.5 II-77 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (3-methyl-furan-2-carbonyl) -hexahydro-pyrrolo [ 3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 555.5 II-78 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4- c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 552.5 II-79 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (3-fluoro-2-methyl-benzoyl) -hexahydro-pyrrolo [ 3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 583.6 II-80 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,6-difluoro-benzoyl) -hexahydro-pyrrolo [3 , 4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 587.6 II-81 1-acetyl-piperidine-4-carboxylic acid {3- [5- (2-chloro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -propyl}-( 3-chloro-4-methyl-phenyl) -amide; Compound with trifluoro-acetic acid 585.5 II-82 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (3H-imidazole-4-carbonyl) -hexahydro-pyrrolo [3 , 4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 541.5 II-83 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (5-methyl-isoxazole-4-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 556.5 II-84 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2-methyl-thiazole-4-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 572.5 II-85 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (1-methyl-1H-pyrazole-3-carbonyl) -hexahydro- Pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 555.6 II-86 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (tetrahydro-furan-2-carbonyl) -hexahydro-pyrrolo [3 , 4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 545.5 II-87 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (4-methoxy-thiophene-3-carbonyl) -hexahydro-pipe Rolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 587.5 II-88 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2-methoxy-benzoyl) -hexahydro-pyrrolo [3,4- c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 581.5 II-89 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (4-dimethylamino-benzoyl) -hexahydro-pyrrolo [3,4- c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 594.6

II-90 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (isoquinoline-1-carbonyl) -hexahydro-pyrrolo [3,4 -c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 602.5 II-91 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2-methyl-cyclohexanecarbonyl) -hexahydro-pyrrolo [3, 4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 571.6 II-92 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (quinoline-2-carbonyl) -hexahydro-pyrrolo [3,4- c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 602.5 II-93 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (1H-indole-2-carbonyl) -hexahydro-pyrrolo [3, 4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 590.5 II-94 1-acetyl-piperidine-4-carboxylic acid {3- [5- (benzofuran-2-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -propyl} -(3-chloro-4-methyl-phenyl) -amide; Compound with trifluoro-acetic acid 591.3 II-95 1-acetyl-piperidine-4-carboxylic acid {3- [5- (benzo [b] thiophen-2-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl ] -Propyl}-(3-chloro-4-methyl-phenyl) -amide; Compound with trifluoro-acetic acid 607.4 II-96 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (1-methyl-1H-indole-2-carbonyl) -hexahydro-pipe Rolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 604.4 II-97 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2-methoxy-3-methyl-benzoyl) -hexahydro-pyrrolo [ 3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 595.5 II-98 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (1H-indole-5-carbonyl) -hexahydro-pyrrolo [3, 4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 590.5 II-99 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (3-chloro-thiophene-2-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 591.5 II-100 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2-methyl-5-phenyl-furan-3-carbonyl) -hexahydro -Pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 631.6 II-101 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (5-fluoro-2-methyl-benzoyl) -hexahydro-pyrrolo [ 3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 583.6 II-102 1-acetyl-piperidine-4-carboxylic acid {3- [5- (1-benzyl-3,5-dimethyl-1H-pyrazole-4-carbonyl) -hexahydro-pyrrolo [3,4 -c] pyrrole-2-yl] -propyl}-(3-chloro-4-methyl-phenyl) -amide; Compound with trifluoro-acetic acid 659.7 II-103 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,4,6-trimethoxy-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 641.6 II-104 1-acetyl-piperidine-4-carboxylic acid {3- [5- (3-chloro-2,6-dimethoxy-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2- Il] -propyl}-(3-chloro-4-methyl-phenyl) -amide; Compound with trifluoro-acetic acid 645.6

II-105 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (3,5-dimethyl-1-phenyl-1H-pyrazole-4-carbox Carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 645.6 II-106 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,6-difluoro-3-methyl-benzoyl) -hexahydro- Pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 601.6 II-107 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2-fluoro-6-trifluoromethyl-benzoyl) -hexahydro- Pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 637.6 II-108 1-acetyl-piperidine-4-carboxylic acid {3- [5- (6-chloro-2-fluoro-3-methyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole- 2-yl] -propyl}-(3-chloro-4-methyl-phenyl) -amide; Compound with trifluoro-acetic acid 617.6 II-109 1-acetyl-piperidine-4-carboxylic acid {3- [5- (2-chloro-6-fluoro-3-methyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole- 2-yl] -propyl}-(3-chloro-4-methyl-phenyl) -amide; Compound with trifluoro-acetic acid 617.5 II-110 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,4,6-trifluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl) -amide; Compound with trifluoro-acetic acid 605.5 II-111 1-acetyl-piperidine-4-carboxylic acid {3- [5- (3-chloro-2-fluoro-6-trifluoromethyl-benzoyl) -hexahydro-pyrrolo [3,4-c ] Pyrrole-2-yl] -propyl}-(3-chloro-4-methyl-phenyl) -amide; Compound with trifluoro-acetic acid 671.6 II-112 1-Methanesulfonyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3 , 4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 615.6 II-113 1-cyclopropanecarbonyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [ 3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 605.6 II-114 Piperidine-1,4-dicarboxylic acid 4-((3-chloro-4-methyl-phenyl)-{3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3 , 4-c] pyrrole-2-yl] -propyl} -amide) 1-dimethylamide; Compound with trifluoro-acetic acid 608.6 II-115 Piperidine-1,4-dicarboxylic acid 4-((3-chloro-4-methyl-phenyl)-{3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3 , 4-c] pyrrole-2-yl] -propyl} -amide) 1-ethylamide; Compound with trifluoro-acetic acid 608.6 II-116 1-dimethylsulfamoyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3 , 4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 644.6 II-117 1- (2,2,2-Trifluoro-acetyl) -piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,6-dimethyl- Benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 633.5 II-118 1-acetyl-piperidine-4-carboxylic acid {3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -propyl} -Pyridin-2-yl-amide 532.5 II-119 1-acetyl-piperidine-4-carboxylic acid (3,4-dichloro-phenyl)-{3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [ 3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 600

II-120 1-acetyl-piperidine-4-carboxylic acid {3- [5- (5-amino-1-phenyl-1 H-pyrazole-4-carbonyl) -hexahydro-pyrrolo [3,4-c ] Pyrrole-2-yl] -propyl}-(3-chloro-4-methyl-phenyl) -amide; Compound with trifluoro-acetic acid 632.5 II-121 1-acetyl-piperidine-4-carboxylic acid (3- {5- [5-amino-1- (4-methoxy-phenyl) -1H-pyrazole-4-carbonyl] -hexahydro-pi Rolo [3,4-c] pyrrol-2-yl} -propyl)-(3-chloro-4-methyl-phenyl) -amide; Compound with trifluoro-acetic acid 662.5 II-122 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (1-phenyl-5-trifluoromethyl-1 H-pyrazole-4- Carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 685.5 II-123 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-(3- {5- [1- (4-methoxy-phenyl) -5-trifluoromethyl- 1H-pyrazole-4-carbonyl] -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl} -propyl) -amide; Compound with trifluoro-acetic acid 715.5 II-124 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-(3- {5- [1- (2-methoxy-phenyl) -5-trifluoromethyl- 1H-pyrazole-4-carbonyl] -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl} -propyl) -amide; Compound with trifluoro-acetic acid 715.5 II-125 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-(3- {5- [1- (4-chloro-phenyl) -5-trifluoromethyl-1H -Pyrazole-4-carbonyl] -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl} -propyl) -amide; Compound with trifluoro-acetic acid 719.5 II-126 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (1-p-tolyl-5-trifluoromethyl-1H-pyrazole- 4-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 699.5 II-127 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-(3- {5- [1- (4-fluoro-phenyl) -5-trifluoromethyl- 1H-pyrazole-4-carbonyl] -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl} -propyl) -amide; Compound with trifluoro-acetic acid 703.5 II-128 1-acetyl-piperidine-4-carboxylic acid {3- [5- (5-amino-1-p-tolyl-1H-pyrazole-4-carbonyl) -hexahydro-pyrrolo [3,4 -c] pyrrole-2-yl] -propyl}-(3-chloro-4-methyl-phenyl) -amide; Compound with trifluoro-acetic acid 646.5 II-129 1-acetyl-piperidine-4-carboxylic acid (3- {5- [5-amino-1- (4-fluoro-phenyl) -1H-pyrazole-4-carbonyl] -hexahydro-pi Rolo [3,4-c] pyrrol-2-yl} -propyl)-(3-chloro-4-methyl-phenyl) -amide; Compound with trifluoro-acetic acid 650.5 II-130 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (5-methyl-1-phenyl-1 H-pyrazole-4-carbonyl) -Hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 631.5 II-131 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (5-methyl-2-p-tolyl-1H-pyrazole-4-car Carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 645.5

II-132 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (5-methyl-2-p-tolyl-2H-pyrazole-3-carr Carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 645.5 II-133 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-(3- {5- [2- (4-methoxy-phenyl) -5-methyl-2H-pyra Sol-3-carbonyl] -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl} -propyl) -amide; Compound with trifluoro-acetic acid 661.5 II-134 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2-methyl-4,5,6,7-tetrahydro-benzofuran- 3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 609.5 II-135 1-acetyl-piperidine-4-carboxylic acid {3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -propyl} -Phenyl-amide 531 II-136 1-acetyl-piperidine-4-carboxylic acid {3- [5- (2-bromo-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl ] -Propyl}-(3-chloro-4-methyl-phenyl) -amide; Compound with trifluoro-acetic acid 632.3 II-137 1-acetyl-piperidine-4-carboxylic acid {3- [5- (2-acetylamino-4-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl ] -Propyl}-(3-chloro-4-methyl-phenyl) -amide; Compound with trifluoro-acetic acid 626.4 II-138 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2-fluoro-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 570.3 II-139 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (3-chloro-pyridine-4-carbonyl) -hexahydro-pyrrolo [ 3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 586.3 II-140 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2-methoxy-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 582.3 II-141 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2-methanesulfonyl-benzoyl) -hexahydro-pyrrolo [3,4 -c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 629.3 II-142 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2-methanesulfonylamino-benzoyl) -hexahydro-pyrrolo [3, 4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 644.3 II-143 1- (3-chloro-4-methyl-phenyl) -3- (2,6-dichloro-pyridin-4-yl) -1- {3- [5- (2,4-dimethyl-pyridine-3-car Carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -urea; Compound with trifluoro-acetic acid 617.2 II-144 1- (3-Chloro-4-methyl-phenyl) -3- (3,5-dimethyl-isoxazol-4-yl) -1- {3- [5- (2,4-dimethyl-pyridine-3- Carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -propyl} -urea; Compound with trifluoro-acetic acid 565.3 II-145 1- (3-Chloro-4-methyl-phenyl) -3-cyclopentyl-1- {3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3, 4-c] pyrrole-2-yl] -propyl} -urea; Compound with trifluoro-acetic acid 538.3 II-146 1- (3-Chloro-4-methyl-phenyl) -1- {3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole -2-yl] -propyl} -3-thiophen-3-yl-urea; Compound with trifluoro-acetic acid 552.3

II-147 1- (3-Chloro-4-methyl-phenyl) -1- {3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole -2-yl] -propyl} -3-furan-2-ylmethyl-urea; Compound with trifluoro-acetic acid 550.3 II-148 1- (3-Chloro-4-methyl-phenyl) -1- {3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole -2-yl] -propyl} -3- [1- (2,2,2-trifluoro-acetyl) -piperidin-3-yl] -urea; Compound with trifluoro-acetic acid 650.3 II-149 1- (3-Chloro-4-methyl-phenyl) -1- {3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole -2-yl] -propyl} -3- [1- (2,2,2-trifluoro-acetyl) -piperidin-4-yl] -urea; Compound with trifluoro-acetic acid 650.3 II-150 1- (3-Chloro-4-methyl-phenyl) -3-cyclohexylmethyl-1- {3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3 , 4-c] pyrrole-2-yl] -propyl} -urea; Compound with trifluoro-acetic acid 566.4 II-151 1- (3-Chloro-4-methyl-phenyl) -1- {3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole -2-yl] -propyl} -3- (5-methyl-2-trifluoromethyl-furan-3-yl) -urea; Compound with trifluoro-acetic acid 618.3 II-152 1- (3-Chloro-4-methyl-phenyl) -1- {3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole -2-yl] -propyl} -3-phenyl-urea; Compound with trifluoro-acetic acid 546.3 II-153 1- (3-Chloro-4-methyl-phenyl) -3- (3-chloro-phenyl) -1- {3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro- Pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -urea; Compound with trifluoro-acetic acid 580.2 II-154 1- (3-Chloro-4-methyl-phenyl) -1- {3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole -2-yl] -propyl} -3- (4-fluoro-phenyl) -urea; Compound with trifluoro-acetic acid 564.3 II-155 1- (3-Chloro-4-methyl-phenyl) -1- {3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole -2-yl] -propyl} -3-p-tolyl-urea; Compound with trifluoro-acetic acid 560.3 II-156 1- (3-Chloro-4-methyl-phenyl) -1- {3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole -2-yl] -propyl} -3- (4-trifluoromethoxy-phenyl) -urea; Compound with trifluoro-acetic acid 630.3 II-157 (3- (3-Chloro-4-methyl-phenyl) -3- {3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] Pyrrole-2-yl] -propyl} -ureido) -acetic acid ethyl ester; Compound with trifluoro-acetic acid 556.3 II-158 1- (3-Chloro-4-methyl-phenyl) -1- {3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole -2-yl] -propyl} -3- (4-fluoro-benzyl) -urea; Compound with trifluoro-acetic acid 578.3 II-159 1- (3-Chloro-4-methyl-phenyl) -1- {3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole -2-yl] -propyl} -3- (4-methoxy-benzyl) -urea; Compound with trifluoro-acetic acid 590.3 II-160 1- (3-Chloro-4-methyl-phenyl) -1- {3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole -2-yl] -propyl} -3- (4-trifluoromethyl-phenyl) -urea; Compound with trifluoro-acetic acid 614.2 II-161 3- (4-acetyl-phenyl) -1- (3-chloro-4-methyl-phenyl) -1- {3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro- Pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -urea; Compound with trifluoro-acetic acid 588.3

II-162 1- (3-chloro-4-methyl-phenyl) -3- (3,4-difluoro-phenyl) -1- {3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -Hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -urea; Compound with trifluoro-acetic acid 582.2 II-163 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,4-dimethyl-6-oxo-6H-pyran-3-carbonyl ) -Hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 598 II-164 1- (3-Chloro-4-methyl-phenyl) -3- (4-dimethylamino-phenyl) -1- {3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro -Pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -urea; Compound with trifluoro-acetic acid 589.3 II-165 4- (3- (3-Chloro-4-methyl-phenyl) -3- {3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4- c] pyrrole-2-yl] -propyl} -ureido) -piperidine-1-carboxylic acid benzyl ester; Compound with trifluoro-acetic acid 687.3 II-166 1- (3-Chloro-4-methyl-phenyl) -1- {3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole -2-yl] -propyl} -3- (4-methoxy-phenyl) -urea; Compound with trifluoro-acetic acid 576.3 II-167 1- (3-Chloro-4-methyl-phenyl) -3-cyclohexyl-1- {3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3, 4-c] pyrrole-2-yl] -propyl} -urea; Compound with trifluoro-acetic acid 552.4 II-168 1- (3-Chloro-4-methyl-phenyl) -1- {3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole -2-yl] -propyl} -3- (4-methylsulfanyl-phenyl) -urea; Compound with trifluoro-acetic acid 592.3 II-169 1- (3-Chloro-4-methyl-phenyl) -3- (2,4-dichloro-phenyl) -1- {3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexa Hydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -urea; Compound with trifluoro-acetic acid 616.2 II-170 1- (3-chloro-4-methyl-phenyl) -3- (4-chloro-2-trifluoromethyl-phenyl) -1- {3- [5- (2,4-dimethyl-pyridine-3- Carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -propyl} -urea; Compound with trifluoro-acetic acid 648.3 II-171 1- (3-Chloro-4-methyl-phenyl) -1- {3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole -2-yl] -propyl} -3- (4-methyl-benzyl) -urea; Compound with trifluoro-acetic acid 574.4 II-172 1- (3-Chloro-4-methyl-phenyl) -3- (3,4-dichloro-benzyl) -1- {3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexa Hydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -urea; Compound with trifluoro-acetic acid 630.3 II-173 1- (3-Chloro-4-methyl-phenyl) -3- (4-cyano-phenyl) -1- {3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro -Pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -urea; Compound with trifluoro-acetic acid 571.4 II-174 1-acetyl-piperidine-4-carboxylic acid {3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -propyl} -(3,4-dimethyl-phenyl) -amide 559 II-175 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -3a, 6a- Dimethyl-hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 608, 610 II-176 4,4-Difluoro-cyclohexanecarboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,4-dimethyl-6-oxo-6H-pyran-3-carbonyl ) -Hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 590

II-177 4,4-Difluoro-cyclohexanecarboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (3,5-dimethyl-isoxazole-4-carbonyl) -hexahydro- Pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 563 II-178 4,4-Difluoro-cyclohexanecarboxylic acid {3- [5- (5-acetyl-2,4-dimethyl-1H-pyrrole-3-carbonyl) -hexahydro-pyrrolo [3,4- c] pyrrole-2-yl] -propyl}-(3-chloro-4-methyl-phenyl) -amide; Compound with trifluoro-acetic acid 603.1 II-179 4,4-Difluoro-cyclohexanecarboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro- Pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 574.1 II-180 4,4-Difluoro-cyclohexanecarboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,4,5-trimethyl-thiophene-3-carbonyl) -hexa Hydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 592.1 II-181 4,4-Difluoro-cyclohexanecarboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4 -c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 572.1 II-182 4,4-Difluoro-cyclohexanecarboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (3,5-dimethyl-1-phenyl-1 H-pyrazole-4-carbox Carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 638.2 II-183 4,4-Difluoro-cyclohexanecarboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,6-dichloro-4-methanesulfonyl-benzoyl) -hexahydro- Pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 692 II-184 4,4-Difluoro-cyclohexanecarboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (4,6-dimethyl-2-pyridin-4-yl-pyrimidine-5 -Carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 651.2 II-185 4,4-Difluoro-cyclohexanecarboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (4,6-dimethyl-2-phenyl-pyrimidine-5-carbonyl) -Hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 650.2 II-186 4,4-Difluoro-cyclohexanecarboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (5-methyl-3-phenyl-isoxazole-4-carbonyl) -hexa Hydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 625.2 II-187 Cyclobutanecarboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] Pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 509.3 II-188 Cyclopentanecarboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] Pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 523.3 II-189 1- (3-Chloro-4-methyl-phenyl) -1- {3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole -2-yl] -propyl} -3- [1- (2,2,2-trifluoro-acetyl) -piperidin-3-yl] -urea; Compound with trifluoro-acetic acid 649.3

II-190 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4 -c] pyrrole-2-yl] -2-hydroxy propyl} -amide 595 107.9-409.8 II-191 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -bis-hydroxy Methyl-hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide 640 II-192 4,4-Difluoro-cyclohexanecarboxylic acid {3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2- General] -propyl} -p-tolyl-amide 538 II-193 4,4-Difluoro-cyclohexanecarboxylic acid {3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2- General] -propyl} -phenyl-amide 525 II-194 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2-methyl-5-trifluoromethyl-oxazole-4-carbonyl ) -Hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 624.1 II-195 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl ) -Hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 686.1 II-196 1-acetyl-piperidine-4-carboxylic acid {3- [5- (2-amino-6-trifluoromethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2- Il] -propyl}-(3-chloro-4-methyl-phenyl) -amide; Compound with trifluoro-acetic acid 634.1 II-197 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,6-dimethyl-4-nitro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -propyl} -amidetrifluoro-acetic acid; 624.3 II-198 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (1,3,5-trimethyl-1H-pyrazole-4-carbonyl) -Hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 583.4 II-199 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (3,5-dimethyl-1H-pyrazole-4-carbonyl) -hexa Hydro-pyrrolo [3,4c] pyrrol-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 569.3 II-200 N- (3-Chloro-4-methyl-phenyl) -N- {3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole -2-yl] -propyl} -propionamide; Compound with trifluoro-acetic acid 483.3 II-201 N- (3-Chloro-4-methyl-phenyl) -N- {3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole -2-yl] -propyl} -butyramide; Compound with trifluoro-acetic acid 497.3 II-202 Pentanoic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2 -Yl] -propyl} -amide; Compound with trifluoro-acetic acid 511.3 II-203 Cyclopropanecarboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] Pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 495.3 II-204 3- (4-Chloro-phenyl) -1- {3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl ] -Propyl} -1-p-tolyl-urea 546 60.5-62.5

II-205 1-acetyl-piperidine-4-carboxylic acid {3- [5- (5-chloro-2-methoxy-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -Propyl}-(3-chloro-4-methyl-phenyl) -amide; Compound with trifluoro-acetic acid 615.1 II-206 1-acetyl-piperidine-4-carboxylic acid [3- (5-benzoyl-hexahydro-pyrrolo [3,4-c] pyrrol-2-yl) -propyl]-(3-chloro-4- Methyl-phenyl) -amide; Compound with trifluoro-acetic acid 551.2 II-207 1-acetyl-piperidine-4-carboxylic acid {3- [5- (2,4-bis-trifluoromethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2- Il] -propyl}-(3-chloro-4-methyl-phenyl) -amide; Compound with trifluoro-acetic acid 687.1 II-208 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,4-dimethoxy-benzoyl) -hexahydro-pyrrolo [3, 4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 611.2 II-209 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,3-dihydro-benzofuran-7-carbonyl) -hexahydro -Pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 593.2 II-210 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,3-dimethoxy-benzoyl) -hexahydro-pyrrolo [3, 4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 611.3 II-211 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2-chloro-5-methylsulfanyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 631.2 II-212 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (4-fluoro-3-trifluoromethyl-benzoyl) -hexahydro- Pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 637.2 II-213 1-acetyl-piperidine-4-carboxylic acid {3- (5- (3-chloro-2-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -Propyl}-(3-chloro-4-methyl-phenyl) -amide; compound with trifluoro-acetic acid 603.2 II-214 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,3-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4 -c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 579.3 II-215 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2-ethoxy-benzoyl) -hexahydro-pyrrolo [3,4- c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 595.3 II-216 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,3-difluoro-benzoyl) -hexahydro-pyrrolo [3 , 4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 587.2 II-217 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2-fluoro-5-methyl-benzoyl) -hexahydro-pyrrolo [ 3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 583.3 II-218 1-acetyl-piperidine-4-carboxylic acid {3- [5- (2-chloro-4,5-difluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2 -Yl] -propyl}-(3-chloro-4-methyl-phenyl) -amide; Compound with trifluoro-acetic acid 621.2 II-219 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,4,5-trifluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 605.2

II-220 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,4-difluoro-benzoyl) -hexahydro-pyrrolo [3 , 4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 587.2 II-221 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,4-dichloro-benzoyl) -hexahydro-pyrrolo [3,4 -c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 621.2 II-222 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,5-dichloro-benzoyl) -hexahydro-pyrrolo [3,4 -c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 621.2 II-223 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,3-dichloro-benzoyl) -hexahydro-pyrrolo [3,4 -c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 621.2 II-224 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,5-difluoro-benzoyl) -hexahydro-pyrrolo [3 , 4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 587.2 II-225 1-acetyl-piperidine-4-carboxylic acid {3- [5- (2-chloro-4-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -Propyl}-(3-chloro-4-methyl-phenyl) -amide; Compound with trifluoro-acetic acid 603.2 II-226 1-acetyl-piperidine-4-carboxylic acid {3- [5- (4-chloro-2-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -Propyl}-(3-chloro-4-methyl-phenyl) -amide; Compound with trifluoro-acetic acid 603.2 II-227 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (4-methoxy-benzoyl) -hexahydro-pyrrolo [3,4- c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 581.3 II-228 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2-trifluoromethoxy-benzoyl) -hexahydro-pyrrolo [3, 4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 635.3 II-229 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (3-trifluoromethyl-benzoyl) -hexahydro-pyrrolo [3, 4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 619.3 II-230 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (3-methoxy-benzoyl) -hexahydro-pyrrolo [3,4- c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 581.3 II-231 Acetic acid 2- (5- {3-[(1-acetyl-piperidine-4-carbonyl)-(3-chloro-4-methyl-phenyl) -amino] -propyl} -hexahydro-pyrrolo [3 , 4-c] pyrrole-2-carbonyl) -phenyl ester; Compound with trifluoro-acetic acid 609.3 II-232 1-acetyl-piperidine-4-carboxylic acid {3- [5- (2-bromo-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -propyl}- (3-chloro-4-methyl-phenyl) -amide; Compound with trifluoro-acetic acid 631.2 II-233 1-acetyl-piperidine-4-carboxylic acid {3- [5- (5-bromo-2-chloro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -Propyl}-(3-chloro-4-methyl-phenyl) -amide; Compound with trifluoro-acetic acid 665.2 II-234 1-acetyl-piperidine-4-carboxylic acid {3- [5- (4-acetyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -propyl}-( 3-chloro-4-methyl-phenyl) -amide; Compound with trifluoro-acetic acid 593.3

II-235 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,5-dimethoxy-benzoyl) -hexahydro-pyrrolo [3, 4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 611.3 II-236 2- (5- {3-[(1-acetyl-piperidine-4-carbonyl)-(3-chloro-4-methyl-phenyl) -amino] -propyl} -hexahydro-pyrrolo [3, 4-c] pyrrole-2-carbonyl) -benzoic acid methyl ester; Compound with trifluoro-acetic acid 609.3 II-237 1-acetyl-piperidine-4-carboxylic acid {3- [5- (2,5-bis-trifluoromethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2- Il] -propyl}-(3-chloro-4-methyl-phenyl) -amide; Compound with trifluoro-acetic acid 687.3 II-238 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,3,4-trifluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 605.3 II-239 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2-fluoro-3-trifluoromethyl-benzoyl) -hexahydro- Pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 637.3 II-240 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,4-dichloro-5-fluoro-benzoyl) -hexahydro-pipe Rolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 639.2 II-241 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (4-fluoro-2-trifluoromethyl-benzoyl) -hexahydro- Pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 637.3 II-242 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (3-fluoro-5-trifluoromethyl-benzoyl) -hexahydro- Pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 637.3 II-243 1-acetyl-piperidine-4-carboxylic acid {3- [5- (2-acetyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl}-( 3-chloro-4-methyl-phenyl) -amide; Compound with trifluoro-acetic acid 593.3 II-244 1-acetyl-piperidine-4-carboxylic acid {3- [5- (4-bromo-2-methyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -Propyl}-(3-chloro-4-methyl-phenyl) -amide; Compound with trifluoro-acetic acid 645.2 II-245 1-acetyl-piperidine-4-carboxylic acid {3- [5- (2-bromo-3-methyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -Propyl}-(3-chloro-4-methyl-phenyl) -amide; Compound with trifluoro-acetic acid 645.2 II-246 1-acetyl-piperidine-4-carboxylic acid {3- [5- (2-bromo-5-methyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -Propyl}-(3-chloro-4-methyl-phenyl) -amide; Compound with trifluoro-acetic acid 645.2 II-247 1-acetyl-piperidine-4-carboxylic acid {3- [5- (3-bromo-2-methyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -Propyl}-(3-chloro-4-methyl-phenyl) -amide; Compound with trifluoro-acetic acid 645.2 II-248 1-acetyl-piperidine-4-carboxylic acid {3- [5- (3,5-bis-trifluoromethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2- Il] -propyl}-(3-chloro-4-methyl-phenyl) -amide; Compound with trifluoro-acetic acid 687.2 II-249 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2-fluoro-benzoyl) -hexahydro-pyrrolo [3,4- c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 569.3

II-250 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (3-fluoro-4-trifluoromethyl-benzoyl) -hexahydro- Pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 637.3 II-251 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,5-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4 -c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 579.3 II-252 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (4-trifluoromethyl-benzoyl) -hexahydro-pyrrolo [3, 4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 619.3 II-253 1-acetyl-piperidine-4-carboxylic acid {3- [5- (2-bromo-5-methoxy-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl ] -Propyl}-(3-chloro-4-methyl-phenyl) -amide; Compound with trifluoro-acetic acid 661.2 II-254 1-acetyl-piperidine-4-carboxylic acid {3- [5- (2-chloro-3-methyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl]- Propyl}-(3-chloro-4-methyl-phenyl) -amide; Compound with trifluoro-acetic acid 599.3 II-255 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (3-dimethylamino-benzoyl) -hexahydro-pyrrolo [3,4- c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 594.3 II-256 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2-iodo-benzoyl) -hexahydro-pyrrolo [3,4- c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 677.2 II-257 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2-ethyl-benzoyl) -hexahydro-pyrrolo [3,4-c ] Pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 579.3 II-258 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-[3- (5- {4-[(2-hydroxy-ethyl) -methyl-amino] -benzoyl } -Hexahydro-pyrrolo [3,4-c] pyrrole-2-yl) -propyl] -amide; Compound with trifluoro-acetic acid 624.3 II-259 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (6-fluoro-4H-benzo [1,3] dioxine-8- Carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 627.2 II-260 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,5-dibromo-benzoyl) -hexahydro-pyrrolo [3 , 4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 709 II-261 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (4-methoxy-2-methyl-benzoyl) -hexahydro-pyrrolo [ 3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 595.3 II-262 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (5-fluoro-2-methoxy-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 599.2 II-263 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (3-methoxy-2-methyl-benzoyl) -hexahydro-pyrrolo [ 3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 595.2 II-264 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (5-fluoro-2-trifluoromethyl-benzoyl) -hexahydro- Pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 637.2

II-265 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (cinnoline-4-carbonyl) -hexahydro-pyrrolo [3,4 -c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 603.2 II-266 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,6-dimethoxy-pyridine-3-carbonyl) -hexahydro- Pyrrolo [3,4-c] pyrrole-2-yl] -propyl) -amide; Compound with trifluoro-acetic acid 612.2 II-267 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (4-trifluoromethyl-pyridine-3-carbonyl) -hexahydro- Pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 620.2 II-268 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (4-methyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [ 3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 566.2 II-269 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- (5- (3-methyl-pyridine-2-carbonyl) -hexahydro-pyrrolo [ 3,4-c] pyrrole-2-yl] -propyl} -amide; a compound with trifluoro-acetic acid 566.2 II-270 1-acetyl-piperidine-4-carboxylic acid {3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -propyl} -Pyrimidin-2-yl-amide; Compound with trifluoro-acetic acid 533 II-271 5-Oxo-1- (2,2,2-trifluoro-ethyl) -pyrrolidine-3-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2, 6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -propyl} -amide 619 68.8-72.9 II-272 1-acetyl-piperidine-4-carboxylic acid {3- [5- (6-chloro-2-dimethylamino-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole -2-yl] -propyl}-(3-chloro-4-methyl-phenyl) -amide; Compound with trifluoro-acetic acid 629.1 II-273 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (4-cyano-2,5-dimethyl-thiophene-3-carbonyl ) -Hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 610.1 II-274 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (4-iodo-2,5-dimethyl-thiophene-3-carbonyl ) -Hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 711 II-275 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,5-dimethyl-thiophen-3-carbonyl) -hexahydro- Pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 585.1 II-276 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (3,6-dimethoxy-pyridazine-4-carbonyl) -hexahydro -Pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 613.1 II-277 1-acetyl-piperidine-4-carboxylic acid {3- [5- (4-bromo-2,5-di-tert-butyl-thiophene-3-carbonyl) -hexahydro-pyrrolo [ 3,4-c] pyrrole-2-yl] -propyl}-(3-chloro-4-methyl-phenyl) -amide; Compound with trifluoro-acetic acid 749.1 II-278 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,5-di-tert-butyl-4-cyano-thiophene- 3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 694.2

II-279 3- (4-Chloro-phenyl) -1- {3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl ] -Propyl} -1-phenyl-urea; Compound with trifluoro-acetic acid 532 II-280 1,1-Dioxo-hexahydro-1λ ⁶ -thiopyran-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,6-dimethyl-benzoyl) -hexa Hydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide 586 101.3-102.7 II-281 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pipe Rolo [3,4-c] pyrrol-2-yl] -2-hydroxy-propyl} -amide 596 97.3-98.1 II-282 Cyclopentanecarboxylic acid {3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -cyclohexyl} -phenyl -amides 515 108.7-109.3 II-283 Cyclopentanecarboxylic acid {3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -propyl} -phenyl- amides; Compound with trifluoro-acetic acid 130.3 475-130.7 II-284 1-acetyl-piperidine-4-carboxylic acid {3- [5- (4-chloro-2-methyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl]- Propyl}-(3-chloro-4-methyl-phenyl) -amide; Compound with trifluoro-acetic acid 599.1 II-285 1-acetyl-piperidine-4-carboxylic acid {3- [5- (3-chloro-2-methyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl]- Propyl}-(3-chloro-4-methyl-phenyl) -amide; Compound with trifluoro-acetic acid 599.1 II-286 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2-chloro-3-trifluoromethyl-benzoyl) -hexahydro-pipe Rolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 653.1 II-287 1-acetyl-piperidine-4-carboxylic acid {3- [5- (3-bromo-2-methoxy-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl ] -Propyl}-(3-chloro-4-methyl-phenyl) -amide; Compound with trifluoro-acetic acid 661 II-288 1-acetyl-piperidine-4-carboxylic acid {3- [5- (5-chloro-2-methyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl]- Propyl}-(3-chloro-4-methyl-phenyl) -amide; Compound with trifluoro-acetic acid 599.1 II-289 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (3-chloro-pyridine-2-carbonyl) -hexahydro-pyrrolo [ 3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 586.1 II-290 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (4-methyl-2-methylsulfanyl-pyrimidine-5-carbonyl) -Hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 613.1 II-291 1-acetyl-piperidine-4-carboxylic acid {3- [5- (2-chloro-4-methanesulfonyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl ] -Propyl}-(3-chloro-4-methyl-phenyl) -amide; Compound with trifluoro-acetic acid 663.1 II-292 1-acetyl-piperidine-4-carboxylic acid {3- [5- (2-chloro-3-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -Propyl}-(3-chloro-4-methyl-phenyl) -amide; Compound with trifluoro-acetic acid 603.1

II-293 1-acetyl-piperidine-4-carboxylic acid {3- [5- (4-bromo-2-chloro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -Propyl}-(3-chloro-4-methyl-phenyl) -amide; Compound with trifluoro-acetic acid 665 II-294 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2-cyano-benzoyl) -hexahydro-pyrrolo [3,4- c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 576.1 II-295 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,2,3,3-tetramethyl-cyclopropanecarbonyl) -hexa Hydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 571.2 II-296 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2-ethyl-butyryl) -hexahydro-pyrrolo [3,4- c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 545.2 II-297 1-acetyl-piperidine-4-carboxylic acid {3- [5- (2-chloro-4-fluoro-benzenesulfonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2- Il] -propyl}-(3-chloro-4-methyl-phenyl) -amide; Compound with trifluoro-acetic acid 639 II-298 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (4-cyano-benzenesulfonyl) -hexahydro-pyrrolo [3, 4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 612.1 II-299 {1- [4-((3-Chloro-4-methyl-phenyl)-{3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4 -c] pyrrole-2-yl] -propyl} -carbamoyl) -piperidine-1-carbonyl] -2-methyl-propyl} carbamic acid tert-butyl ester; Compound with trifluoro-acetic acid 738.2 II-300 [4-((3-Chloro-4-methyl-phenyl)-{3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4-c] Pyrrole-2-yl] -propyl} -carbamoyl) -piperidin-1-yl] -oxo-acetic acid methyl ester; Compound with trifluoro-acetic acid 625.1 II-301 4-((3-Chloro-4-methyl-phenyl)-{3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole -2-yl] -propyl} -carbamoyl) -piperidine-1-carboxylic acid methyl ester; Compound with trifluoro-acetic acid 597.1 II-302 1- (2-Amino-3-methyl-butyryl) -piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (4,6-dimethyl-pyri Midin-5-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 638.2 II-303 1- (2-Methoxy-ethyl) -piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (4,6-dimethyl-pyrimidine-5- Carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 597.2 II-304 [4-((3-Chloro-4-methyl-phenyl)-{3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4-c] Pyrrole-2-yl] -propyl} -carbamoyl) -piperidin-1-yl] -oxo-acetic acid; Compound with trifluoro-acetic acid 611.1 II-305 1-acetyl-piperidine-4-carboxylic acid {3- [5- (6-chloro-2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] Pyrrole-2-yl] -propyl}-(3-chloro-4-methyl-phenyl) -amide; Compound with trifluoro-acetic acid 614 oil

II-306 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,4-dimethyl-6-methylsulfanyl-pyridine-3-carbonyl ) -Hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 626 oil II-307 Cyclopentanecarboxylic acid {3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl}-(4-trifluoromethyl -Pyrimidin-2-yl) -amide 544 II-308 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (4-cyano-2-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 594 II-309 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2-dimethylamino-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 595 II-310 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (4-dimethylamino-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 595.1 II-311 Cyclopentanecarboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl ] -2-methyl-propyl} -amide 536 II-312 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -3a, 6a -Dimethyl-hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide 609; 611 II-313 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,4-dimethyl-1-oxy-pyridine-3-carbonyl)- 3a, 6a-dimethyl-hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide 624; 626 (M + Na) 646; 648 II-314 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (4-dimethylamino-pyrimidine-5-carbonyl) -hexahydro-pipe Rolo [3,4-c] pyrrol-2-yl] -propyl} -amide 569 II-315 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (4-dimethylamino-2-methylsulfanyl-pyrimidine-5-carbonyl ) -Hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide 642 II-316 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (4-dimethylamino-pyridine-3-sulfonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 630.8 II-317 [4- (5- {3-[(1-acetyl-piperidine-4-carbonyl)-(3-chloro-4-methyl-phenyl) -amino] -propyl} -hexahydro-pyrrolo [3 , 4-c] pyrrole-2-carbonyl) -3-chloro-phenoxy] -acetic acid; Compound with trifluoro-acetic acid 658.8 II-318 1-acetyl-piperidine-4-carboxylic acid {3- [5- (5-bromo-2-methylsulfanyl-pyrimidine-4-carbonyl) -hexahydro-pyrrolo [3,4- c] pyrrole-2-yl] -propyl}-(3-chloro-4-methyl-phenyl) -amide; Compound with trifluoro-acetic acid 678 II-319 1-dimethylsulfamoyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexa Hydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 646.3 II-320 1- (2,2,2-Trifluoro-acetyl) -piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (4,6-dimethyl- Pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 635

II-321 1-dimethylsulfamoyl-azetidine-3-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro -Pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 618 II-322 1- (2,2,2-Trifluoro-acetyl) -azetidine-3-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (4,6-dimethyl-pyri Midin-5-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 607 II-323 1-Methanesulfonyl-azetidine-3-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro -Pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 589 II-324 Cyclopentanecarboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl ] -2-hydroxy-propyl} -amide; Compound with trifluoro-acetic acid 538 II-325 4-Oxo-cyclohexanecarboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole -2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 550 II-326 [5- (5- {3-[(1-acetyl-piperidine-4-carbonyl)-(3-chloro-4-methyl-phenyl) -amino] -propyl} -hexahydro-pyrrolo [3 , 4-c] pyrrole-2-carbonyl) -4,6-dimethyl-pyridin-2-ylsulfanyl] -acetic acid; Compound with trifluoro-acetic acid 670 II-327 Cyclopentanecarboxylic acid {3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -propyl}-( 3-fluoro-phenyl) -amide; Compound with trifluoro-acetic acid 494 II-328 4,4-Difluoro-cyclohexanecarboxylic acid {3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2 -Yl] -propyl}-(3-fluoro-phenyl) -amide 544 II-329 3-((3-Chloro-4-methyl-phenyl)-{3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole -2-yl] -propyl} -carbamoyl) -pyrrolidine-1-carboxylic acid tert-butyl ester 625 II-330 1-acetyl-piperidine-4-carboxylic acid {2- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2 -Yl] -ethyl}-(3-fluoro-phenyl) -amide 537 II-331 2-cyclopentyl-N- {2- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -ethyl} -N- (3-fluoro-phenyl) -acetamide 494 II-332 N- {2- [5- (4,6-Dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -ethyl} -N- (3 -Fluoro-phenyl) -propionamide 440 II-333 N- {2- [5- (4,6-Dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -ethyl} -N- (3 -Fluoro-phenyl) -3-methyl-butyrylamide 468 II-334 1-acetyl-piperidine-4-carboxylic acid {3- (5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2 -Yl] -propyl} -p-tolyl-amide 547 II-335 1-acetyl-piperidine-4-carboxylic acid {3- [5- (2,4-dimethyl-1-oxy-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] Pyrrole-2-yl] -propyl} -p-tolyl-amide 562

II-336 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (6-dimethylamino-2-ethoxy-pyridine-3-carbonyl)- Hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide 639 II-337 1,1-dioxo-hexahydro-1λ ⁶ -thiopyran-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,4-dimethyl-pyridine-3- Carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide 587 II-338 5- (5- {3-[(1-acetyl-piperidine-4-carbonyl)-(3-chloro-4-methyl-phenyl) -amino] -propyl} -hexahydro-pyrrolo [3, 4-c] pyrrole-2-carbonyl) -3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester 706 II-339 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (1,2,3,4-tetrahydro-isoquinoline-5-carbonyl ) -Hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide 606 II-340 1-acetyl-piperidine-4-carboxylic acid {3- [5- (2-acetyl-1,2,3,4-tetrahydro-isoquinoline-5-carbonyl) -hexahydro-pyrrolo [ 3,4-c] pyrrole-2-yl] -propyl}-(3-chloro-4-methyl-phenyl) -amide 648 II-341 4- (5- {3-[(1-acetyl-piperidine-4-carbonyl)-(3-chloro-4-methyl-phenyl) -amino] -propyl} -hexahydro-pyrrolo [3, 4-c] pyrrole-2-carbonyl) -3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester 640 II-342 [3-((3-Chloro-4-methyl-phenyl)-{3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4-c] Pyrrole-2-yl] -propyl} -carbamoyl) -pyrrolidin-1-yl] -oxo-acetic acid methyl ester 611 II-343 5- {3-[(1-acetyl-piperidine-4-carbonyl)-(3-chloro-4-methyl-phenyl) -amino] -propyl} -hexahydro-pyrrolo [3,4-c ] Pyrrole-2-carboxylic acid methyl-phenyl-amide; Compound with trifluoro-acetic acid 580 II-344 5- (3-[(1-acetyl-piperidine-4-carbonyl)-(3-chloro-4-methyl-phenyl) -amino] -propyl} -hexahydro-pyrrolo [3,4-c ] Pyrrole-2-carboxylic acid benzylamide; compound with trifluoro-acetic acid 580 II-345 1- (3-Chloro-4-methyl-phenyl) -1- (3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4-c] Pyrrole-2-yl] -propyl} -3-methyl-3-phenyl-urea; compound with trifluoro-acetic acid 561 II-346 1-acetyl-azetidine-3-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pi Rolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 553 II-347 1-propionyl-azetidine-3-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro- Pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 567 II-348 {2- [3-((3-Chloro-4-methyl-phenyl)-{3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4 -c] pyrrole-2-yl] -propyl} -carbamoyl) -azetidin-1-yl] -2-oxo-ethoxy} -acetic acid; Compound with trifluoro-acetic acid 627 II-349 4- [3-((3-Chloro-4-methyl-phenyl)-{3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4- c] pyrrole-2-yl] -propyl} -carbamoyl) -azetidin-1-yl] -4-oxo-butyric acid; Compound with trifluoro-acetic acid 611 II-350 3-((3-Chloro-4-methyl-phenyl)-{3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole -2-yl] -propyl} -carbamoyl) -azetidine-1-carboxylic acid methyl ester; Compound with trifluoro-acetic acid 569

II-351 [3-((3-Chloro-4-methyl-phenyl)-{3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4-c] Pyrrole-2-yl] -propyl} -carbamoyl) -azetidin-1-yl] -oxo-acetic acid methyl ester; Compound with trifluoro-acetic acid 597 II-352 1-Cyclopropanecarbonyl-azetidine-3-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexa Hydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 579 II-353 1-Butylyl-azetidine-3-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro- Pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 581 II-354 1- (2-Methoxy-acetyl) -azetidine-3-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (4,6-dimethyl-pyrimidine-5-carbox Carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 583 II-355 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro- Pyrrolo [3,4-c] pyrrole-2-yl] -2,2-dimethyl-propyl} -amide 609 II-356 4- (5- {3-[(1-acetyl-piperidine-4-carbonyl)-(3-chloro-4-methyl-phenyl) -amino] -propyl} -hexahydro-pyrrolo [3, 4-c] pyrrole-2-sulfonyl) -3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester 676 II-357 1-acetyl-piperidine-4-carboxylic acid {3- [5- (2-azetidin-1-yl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole -2-yl] -propyl}-(3-chloro-4-methyl-phenyl) -amide 607 II-358 4- (5- {3-[(1-acetyl-piperidine-4-carbonyl)-(3-chloro-4-methyl-phenyl) -amino] -propyl} -hexahydro-pyrrolo [3, 4-c] pyrrole-2-carbonyl) -1,3,5-trimethyl-1H-pyrrole-2-carboxylic acid ethyl ester 654 II-359 5- (5- {3-[(1-acetyl-piperidine-4-carbonyl)-(3-chloro-4-methyl-phenyl) -amino] -propyl} -hexahydro-pyrrolo [3, 4-c] pyrrole-2-carbonyl) -1,2,4-trimethyl-1H-pyrrole-3-carboxylic acid ethyl ester 654 II-360 4- (5- {3-[(1-acetyl-piperidine-4-carbonyl)-(3-chloro-4-methyl-phenyl) -amino-propyl} -hexahydro-pyrrolo [3,4 -c] pyrrole-2-carbonyl) -3,5-dimethyl-1H-pyrrole-2-carboxylic acid 612 II-361 1-acetyl-piperidine-4-carboxylic acid {3- [5- (2,6-bis-dimethylamino-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole -2-yl] -propyl}-(3-chloro-4-methyl-phenyl) -amide 638 II-362 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (5-methyl-1-phenyl-1 H-pyrazole-4-sulfonyl) -Hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide 667 II-363 4-Oxo-cyclohexanecarboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3 , 4-c] pyrrole-2-yl] -propyl} -amide 552 II-364 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2-methyl-pyridine-3-sulfonyl) -hexahydro-pyrrolo [ 3,4-c] pyrrole-2-yl] -propyl} -amide 602 II-365 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (3-methyl-benzofuran-2-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 605

II-366 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (7-methoxy-3-methyl-1H-indole-2-carbonyl) -Hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 634 II-367 Tetrahydro-pyran-3-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [ 3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 540 II-368 N- (3-Chloro-4-methyl-phenyl) -N- {3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4-c] Pyrrole-2-yl] -propyl} -acetamide; Compound with trifluoro-acetic acid 470 II-369 Cyclopropanecarboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4-c ] Pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 496 II-370 1-acetyl-pyrrolidine-3-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro- Pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 567 II-371 1- (2,2,2-Trifluoro-acetyl) -pyrrolidine-3-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (4,6-dimethyl- Pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 621 II-372 1-Methanesulfonyl-pyrrolidine-3-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexa Hydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 603 II-373 1-cyclopropanecarbonyl-pyrrolidine-3-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl)- Hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 593 II-374 3-((3-Chloro-4-methyl-phenyl)-{3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole -2-yl] -propyl} -carbamoyl) -pyrrolidine-1-carboxylic acid methyl ester; Compound with trifluoro-acetic acid 583 II-375 1-dimethylsulfamoyl-pyrrolidine-3-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexa Hydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 632 II-376 [3-((3-Chloro-4-methyl-phenyl)-{3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4-c] Pyrrole-2-yl] -propyl} -carbamoyl) -pyrrolidin-1-yl] -oxo-acetic acid; Compound with trifluoro-acetic acid 597 II-377 2- (5- {3-[(1-acetyl-piperidine-4-carbonyl)-(3-chloro-4-methyl-phenyl) -amino] -propyl} -hexahydro-pyrrolo [3, 4-c] pyrrole-2-sulfonyl) -benzoic acid methyl ester; Compound with trifluoro-acetic acid 645 II-378 2- (5- {3-[(1-acetyl-piperidine-4-carbonyl)-(3-chloro-4-methyl-phenyl) -amino] -propyl} -hexahydro-pyrrolo [3, 4-c] pyrrole-2-sulfonyl) -benzoic acid; Compound with trifluoro-acetic acid 631 II-379 1-Methanesulfonyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexa Hydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 617

II-380 Pyrrolidine-1,3-dicarboxylic acid 3-((3-chloro-4-methyl-phenyl)-{3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexa Hydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide) 1-dimethylamide; Compound with trifluoro-acetic acid 596 II-381 1-cyclopropanesulfonyl-pyrrolidine-3-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl)- Hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 629 II-382 1-Isobutyryl-pyrrolidine-3-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexa Hydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 595 II-383 1-propionyl-pyrrolidine-3-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro -Pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 581 II-384 1- (2,2,2-Trifluoro-ethyl) -pyrrolidine-3-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (4,6-dimethyl- Pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 607 II-385 4- (5- {3-[(1-acetyl-piperidine-4-carbonyl)-(3-chloro-4-methyl-phenyl) -amino] -propyl} -hexahydro-pyrrolo [3, 4-c] pyrrole-2-sulfonyl) -3,5-dimethyl-1H-pyrrole-2-carboxylic acid 648.3 II-386 8- (5- {3-[(1-acetyl-piperidine-4-carbonyl)-(3-chloro-4-methyl-phenyl) -amino] -propyl} -hexahydro-pyrrolo [3, 4-c] pyrrole-2-carbonyl) -3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester 706 II-387 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (1-methyl-1 H-imidazole-2-carbonyl) -hexahydro- Pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide 555 II-388 4-hydroxycyclohexanecarboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [ 3,4-c] pyrrole-2-yl] -propyl} -amide 554 II-389 1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (1,2,3,4-tetrahydro-isoquinoline-8-carbonyl ) -Hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide 606 II-390 1-acetyl-piperidine-4-carboxylic acid (5-chloro-thiazol-2-yl)-{3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3, 4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 572 II-391 3- [4- (5- {3-[(1-acetyl-piperidine-4-carbonyl)-(3-chloro-4-methyl-phenyl) -amino] -propyl} -hexahydro-pyrrolo [3,4-c] pyrrole-2-carbonyl) -3,5-dimethyl-pyrazol-1-yl] -benzoic acid methyl ester 703 II-392 1-acetyl-piperidine-4-carboxylic acid (5-chloro-thiazol-2-yl)-{3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3, 4-c] pyrrole-2-yl] -propyl} -amide; Compound with trifluoro-acetic acid 572 II-393 3- (3- (3-Chloro-4-methyl-phenyl) -3- {3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4 -c] pyrrole-2-yl] -propyl} -ureido) -benzoic acid; Compound with trifluoro-acetic acid 591 II-394 3- (3- (3-Chloro-4-methyl-phenyl) -3- {3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4 -c] pyrrole-2-yl] -propyl} -ureido) -benzoic acid ethyl ester; Compound with trifluoro-acetic acid 619 II-395 1. The observed mass spectrum is (M) + or (M + H) + and is consistent with the compound

Dosage and Administration

The compounds of the present invention can be formulated in a wide variety of oral dosage concentration forms and carriers. Oral administration can be in the form of tablets, coated tablets, hard and soft gelatin capsules, solutions, emulsions, syrups or suspensions. The compounds of the present invention can be used in other dosage forms, including continuous (intravenous dropping) topical parenteral, intramuscular, intravenous, subcutaneous, transdermal (may include penetration enhancers), buccal, nasal, inhalation and suppository administration. Effective when administered in a dosage form. Preferred modes of administration are generally oral administration using conventional daily dosing regimens which can be adjusted according to the extent of pain and the patient's response to the active ingredient.

The compound or compounds of the present invention, as well as their pharmaceutically usable salts, may be incorporated in pharmaceutical compositions and unit dosage forms with one or more excipients, carriers, or diluents. The pharmaceutical compositions and unit dosage forms can be comprised of conventional ingredients in conventional proportions, with or without additional active compounds or active ingredients, and the unit dosage form is intended to be used with any suitable effective amount of the active ingredient. It may contain to suit the daily dosage range. The pharmaceutical compositions can be applied as solids, semisolids, powders, sustained release preparations, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, or oral filled capsules; Or in the form of suppositories for rectal or vaginal administration; Or in the form of sterile injectable solutions for parenteral use. A typical preparation will contain about 5% to about 95% active compound or compounds (w / w). The term "preparation" or "dose form" includes both solid and liquid formulations of the active compound, and those skilled in the art will appreciate that the active ingredient may be present as a different preparation depending on the target organ or tissue and upon the desired administration and pharmacokinetic parameters. You will know.

The term “excipient” as used herein refers to a compound that is generally useful for the preparation of pharmaceutical compositions that are stable, non-toxic, and are not biologically or otherwise unnecessary. The term “excipient” as used herein includes both such excipients and those other than the excipients.

The phrase "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include: (1) formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; Acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, Mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4- Methylbicyclo [2.2.2] -oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaph Acid addition salts formed with organic acids such as tomic acid, salicylic acid, stearic acid, muconic acid and the like; Or (2) replacing acidic protons present in the parent compound with metal ions, such as alkali metal ions, alkaline earth metal ions, or ammonium ions; Salts formed upon coordination with organic bases such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like.

Preferred pharmaceutically acceptable salts are salts formed from acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, maleic acid, phosphoric acid, tartaric acid, citric acid, sodium, potassium, calcium, zinc, and magnesium. It is to be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystalline forms (polymorphs) of the same acid addition salt, as defined herein.

Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. The solid carrier can be one or more substances that can also act as diluents, flavors, solubilizers, lubricants, suspensions, binders, preservatives, tablet disintegrants, or encapsulating materials. In powders, the carrier is generally a finely divided solid which is a mixture with the finely divided active component. In tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugars, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melt wax, cocoa butter, and the like. It doesn't happen. Solid form preparations may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, and the like.

Liquid formulations are also suitable for oral administration, including liquid formulations including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions. This includes solid form preparations which are converted to liquid form preparations immediately before use. Emulsions may be prepared in solution, for example in aqueous propylene glycol, or may contain emulsifiers such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavors, stabilizers, and thickeners. Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous materials such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well known suspending agents.

The compounds of the present invention may be formulated for parenteral administration (eg, by injection such as bolus injection or continuous infusion), and may be used in ampoules, pre-filled syringes, It may be provided in a single dosage form or in a duplicate dosage container with an added preservative. The composition may take the form of a suspension, solution, or emulsion in an oily or aqueous vehicle, for example a solution in aqueous polyethylene glycol. Examples of oily or non-aqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils (eg olive oil), and injectable organic esters (eg ethyl oleate), It may contain formulating agents such as preservatives, wetting agents, emulsifiers or suspending agents, stabilizers and / or dispersants. Alternatively, the active ingredient may be in powder form obtained by aseptic isolation of sterile solids or by lyophilization from solution, consisting of a suitable vehicle, eg pyrogen-free sterile water, before use.

The compounds of the present invention may be formulated for topical administration to the epidermis as an ointment, cream or lotion, or as a transdermal patch. Ointments and creams may be formulated using aqueous or oily bases, for example, by the addition of suitable thickening and / or gelling agents. Lotions may be formulated with an aqueous or oily base and will generally also contain one or more emulsifiers, stabilizers, dispersants, suspending agents, thickeners, or colorants. Formulations suitable for topical administration in the oral cavity include, but are not limited to, flavoring bases, typically troches comprising sucrose and an active agent in acacia or tragacanth; Pastilles comprising the active substance in an inert base such as gelatin and glycerin or sucrose and acacia; And mouthwashes comprising the active ingredient in a suitable liquid carrier.

The compounds of the present invention may be formulated for administration as suppositories. Low melt waxes such as mixtures of fatty acid glycerides or cocoa butter are first melted and the active ingredient is homogeneously dispersed, for example by stirring. The molten homogeneous mixture is then poured into a mold of convenient size, cooled and solidified.

The compounds of the present invention may be formulated for vaginal administration. Suitable are pessaries, tampons, creams, gels, pastes, foams or sprays containing carriers such as those known in the art in addition to the active ingredient.

The compounds of the present invention may be formulated for nasal administration. The solution or suspension is applied directly to the nasal cavity by conventional means such as a dropper, pipette or spray. The formulations may be provided in single or duplicate dosage forms. In the latter case of a dropper or pipette, this can be achieved by the patient administering a suitable predetermined amount of solution or suspension. In the case of a spray, this can be achieved for example by means of a metering atomizing spray pump.

The compounds of the present invention may be formulated for aerosol administration, including intranasal administration, especially to the airways. The compound will generally have a small particle size, for example on the order of 5 microns or less. Such particle size can be obtained by means known in the art, for example by micronization. The active ingredient is a compressed compressed inert gas such as chlorofluorocarbon (CFC), for example compressed with dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, or carbon dioxide or other suitable gas. Comes in a pack. Aerosols may also conveniently contain surfactants such as lecithin. The dose of drug can be controlled by a metered valve. Alternatively, the active ingredient may be provided in the form of a dry powder, for example a powder mixture of compounds in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP). Can be. The powder carrier will form a gel in the nasal cavity. The powder composition may be provided in unit dosage form, such as a capsule or cartridge of gelatin, or a blister pack into which the powder may be administered by inhaler.

If desired, the formulations may be prepared using an enteric coating suitable for sustained or controlled release administration of the active ingredient. For example, the compounds of the present invention can be formulated in a transdermal or subcutaneous drug delivery device. These delivery systems are advantageous when sustained release of the compound is required and where patient compliance with the treatment plan is essential. Compounds in transdermal delivery systems are frequently attached to skin-adhesive solid supports. The compound may also be combined with a penetration enhancer, for example Azone (1-dodecylaza-cycloheptan-2-one). Sustained release delivery systems are injected subcutaneously into the subdermal layer by surgery or injection. Subcutaneous implants encapsulate the polymer in liquid soluble membranes such as silicone rubber, or biodegradable polymers such as polyacetic acid.

Suitable formulations with pharmaceutical carriers, diluents and excipients are described in Remington: The Science and Practice of Pharmacy 1995 , edited by EW Martin, Mack Publishing Company, 19th edition, Easton, Pennsylvania. The skilled formulation scientist can modify the formulation within the teachings of the specification to provide multiple formulations for a particular route of administration without destabilizing or degrading its therapeutic activity.

Modifications that make the compound more soluble in water or other vehicles can be readily accomplished, for example, with small modifications (salt formulations, esterifications, etc.) that perform well within conventional techniques in the art. It is also well within the ordinary skill in the art to modify the route of administration and dosing schedule of a particular compound in order to manage the pharmacokinetics of the compound for the maximally beneficial effect in the patient.

As used herein, the term "therapeutically effective amount" refers to an amount necessary to reduce the symptoms of a disease in a subject. The dosage will be adjusted to the individual requirements in each particular case. The dosage will vary within wide limits depending on a number of factors, such as the severity of the disease to be treated, the age and general health of the patient, other medications the patient has been treated, the route and form of administration, and the preferences and experience of the physician involved. Can be. For oral administration, a daily dose of about 0.01 to about 100 mg / kg body weight per day will be suitable for monotherapy and / or combination therapy. Preferred daily dosages are about 0.1 to about 500 mg / kg body weight, more preferably 0.1 to about 100 mg / kg body weight, most preferably 1.0 to about 10 mg / kg body weight. Thus, for administration to 70 kg of human, the dosage range will be about 7 mg to 0.7 g per day. The daily dose may be administered in a single dose or in divided doses, typically 1-5 times a day. In general, treatment begins with a lower dose that is less than the optimal dose of the compound. Thereafter, the dosage is increased in small increments until the optimum effect for the individual patient is reached. Those skilled in the art of treating the diseases described herein will be able to ascertain the therapeutically effective amount of a compound of the invention for a given disease and patient, based on personal knowledge, experience and the disclosure of this application, without unnecessary experimentation.

In an embodiment of the invention, the active compound or salt is administered in parallel with another antiviral agent, such as a nucleoside reverse transcriptase inhibitor, another non-nucleoside reverse transcriptase inhibitor, an HIV protease inhibitor and / or a viral fusion inhibitor. can do. When the active compound or derivative or salt thereof is administered in parallel with another antiviral agent, the activity may be increased over the parent compound. If the treatment is a combination therapy, such administration may be simultaneous or sequential with the administration of the nucleoside derivatives. As used herein, "simultaneous administration" includes administration at the same time point or at different times of the agent. Administering two or more agents at the same time can be accomplished by a single formulation containing two or more active ingredients or by substantially simultaneous administration of two or more dosage forms with a single active agent.

In addition, the treatment of HIV infection as used herein also includes the treatment or prevention of a disease or condition associated with or mediated by HIV infection, or a clinical symptom thereof.

The pharmaceutical preparation is preferably in unit dosage form. In this form, the formulation is subdivided into unit doses containing appropriate amounts of the active ingredient. The unit dosage form can be a packaged preparation, such as a packeted tablet, capsule, and powder in a vial or ampoule, which is a package containing discrete amounts of the preparation. In addition, the unit dosage form may be a capsule, tablet, cachet, or the troche itself, or may be any of a suitable number of these in the form of a package.

Example  One

Cyclopentanecarboxylic acid {3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -amide ( I -3 ; Scheme 1)

Step 1 -A solution of 2-benzyl-octahydro-pyrrolo [3,4-c] pyrrole ( 4a , 1.22 g, 4.97 mmol) in DCM (20 mL) was dissolved in toluene (8 mL) with HOAc (0.34 mL). ) To a solution of cyclopentanecarboxylic acid (3-oxo-1-phenyl-propyl) -amide ( 10 , 1.0 g, 4.97 mmol). Sodium triacetoxyborohydride (1.26 g, 5.96 mmol) was added in 2 parts at 0.5 hour intervals and the reaction was stirred for 18 hours at room temperature. The reaction was quenched by the addition of 0.5M solution of KOH (30 mL) and the product was extracted with DCM (3 x 50 mL). The combined organic extracts were dried (MgSO ₄ ) and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with 4% in DCM (10% ammonium hydroxide in methanol) to give 11 as a viscous liquid (0.62 g, theoretical 29%): ¹ H NMR ( CDCl ₃ ) δ 1.46-1.64 (m, 2H), 1.65-1.94 (m, 7H), 1.96-2.11 (m, 1H), 2.23-2.44 (m, 4H), 2.45-2.83 (m, 9H), 3.59 (q, 2H, J = 18.2, 12.8 Hz), 5.11 (q, 1H, J = 6.2, 5.8 Hz), 7.07-7.39 (m, 10H), 7.93 (d, 1H, J = 7.1 Hz); MS (ES +) m / z 432 (M + H) ⁺ .

Step 2 -Palladium hydroxide (0.2 g) and ammonium formate (2.92 g, 0.046 mol) were added to cyclopentanecarboxylic acid in EtOH (50 mL) [3- (5-benzyl-hexahydro-pyrrolo [3, 4-c] pyrrole-2-yl) -1-phenyl-propyl] -amide ( 11 , 2.0 g, 0.004 mol) was added to the solution. The solution was heated to reflux for 2 hours and filtered through a CELITE ^® pad. The resulting solution was concentrated in vacuo and the crude product was purified by flash column chromatography on silica gel (CH ₂ Cl ₂ : MeOH: NH ₄ OH = 60: 10: 1) to give 12 : ¹ H NMR (DMSO- d ₆ ) δ 1.4-1.8 (m, 11H), 2.15-2.42 (m, 6H), 2.55-2.65 (m, 2H), 2.75-2.85 (m, 2H), 4.33 (q, 1H), 7.15-7.35 (m, 5H), 8.2 (dd, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 25.96, 26.00, 30.15, 30.45, 35.60, 39.07, 39.35, 39.62, 39.90, 40.18, 40.46, 40.74, 41.37, 43.43, 44.61, 51.02, 52.14, 54.02, 60.20, 60.30, 126.64, 126.82, 128.51, 144.46, 174.81; MS (ES +) m / z 341 (M + H) ⁺ .

Step 3 -Cyclopentanecarboxylic acid [3- (hexahydro-pyrrolo [3,4-c] pyrrole-2-yl) -1-phenyl-propyl] -amide ( 12 , 0.20 g, 0.585 mmol in dichloromethane) 2,6-dimethylbenzoic acid was added to the solution at To the resulting solution was added EDCI (0.14 g, 0.760 mmol), HOBt (0.10 g, 0.760 mmol) and diisopropylethylamine (0.3 mL, 1.755 mmol) sequentially to the mixture. The mixture was stirred at rt overnight. The reaction mixture was washed with 5% NaHCO ₃ solution, dried (MgSO ₄ ) and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (5% MeOH / CH ₂ Cl ₂ ) to give 13 : mp 60.9-63.9 ° C; ¹ H NMR (DMSO-d ₆ ) δ 1.4-1.9 (m, 10H), 2.1 (s, 3H), 2.2 (s, 3H), 2.3-2.5 (m, 5H), 3.35 (m, 1H), 3.5 (dd, 1H), 3.75 (m, 1H), 4.88 (m, 1H), 7.05 (d, 2H), 7.15-7.35 (m, 6H), 8.0 (d, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 18.85, 18.98, 25.96, 26.00, 30.12, 30.42, 35.73, 39.05, 39.33, 39.60, 39.88, 41.69, 44.56, 50.49, 51.05, 52.37, 53.11, 60.37, 126.64, 126.67, 126.89, 127.53, 127.61, 128.31, 128.52, 133.05, 138.25, 144.39, 167.72, 174.81; MS (ES +) m / z 473 (M + H) ⁺ ; Assay (C ₃₀ H ₃₉ N ₃ O ₃ .0.15M CH ₂ Cl ₂ ) C; Calculated, 74.45; Found, 74.55; H; Calculated value, 8.14; Found, 7.74; N; Calculated value, 8.64; Found, 8.95.

Example 2

1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4 -c] pyrrole-2-yl] -propyl} ( II-1 )

Step 1-1 -Chloro-3-iodopropane (3.0 mL, 28.49 mmol) and cesium carbonate (18.0 g, 56.49 mol) were added 2-chloro-4-aminotoluene (4 g, 28.49 mmol) in DMF (8 mL). ) To the solution. The mixture was stirred at rt overnight. Water (15 mL) was added to the mixture and the resulting solution was extracted with hexanes. The organic layer was washed again with water and dried (MgSO ₄ ). The crude product was purified by flash column chromatography on silica gel (5% EtOAc / hexanes) to give 20 : ¹ H NMR (CHCl ₃ ) δ 1.5 (s, 1H), 2.05 (m, 2H), 2.25 ( s, 3H), 3.3 (t, 2H), 3.65 (t, 2H), 6.4 (dd, 1H), 6.65 (d, 1H), 7.0 (d, 1H).

Step 2 -A solution of (3-chloro-4-methyl-phenyl)-(3-chloro-propyl) -amine ( 20 , 3.20 g, 14.70 mmol) in CH ₂ Cl ₂ (100 mL) was cooled to 0 ° C. . The mixture was treated with triethylamine (4.9 mL, 35.28 mmol) and 1-acetyl-piperidine-4-carbonyl chloride (5.57 g, 29.40 mmol), which was then stirred for 5 hours at 0 ° C. Saturated NaHCO ₃ was added to the mixture and the mixture was stirred for 20 minutes. The solvent was evaporated and the mixture extracted with EtOAc. The organic layer was washed with 2N HCl and brine, dried (MgSO ₄ ) and purified by flash column chromatography on silica gel (5% MeOH / EtOAc) to give 18 :

¹ H NMR (CHCl ₃ ) δ 1.55-1.8 (br, 4H), 2.0 (m, 3H), 2.05 (s, 3H), 2.3-2.4 (m, 2H), 2.45 (s, 3H), 3.52 (t , 2H), 3.3 (t, 2H), 6.97 (dd, 1H), 7.18 (t, 1H), 7.32 (d, 1H); ¹³ C NMR (CHCl ₃ ) δ 20.19, 21.68, 28.94, 31.17, 39.64, 42.64, 48.03, 126.63, 128.79, 132.47, 135.79, 137.12, 141.27, 169.27, 174.58; ms (ES +) m / z 370 (M + H).

Step 3 -A solution of 2-benzyl-octahydro-pyrrolo [3,4-c] pyrrole ( 4b , 1.03 g, 5.11 mmol) in DCM (30 mL) at room temperature was added 2,6-dimethylbenzoic acid (1.53 g, 10.22 mmol), BOP-Cl (2.60 g, 10.22 mmol), DMAP (1.24 g, 10.22 mmol) and Et ₃ N (1.5 mL, 10.22 mmol) were added. The reaction mixture was stirred overnight at room temperature and washed with 5% NaHCO ₃ and brine. The resulting was dried (MgSO ₄ ), filtered and evaporated in vacuo. The crude product was purified by flash chromatography on silica gel (CH ₂ Cl ₂ : MeOH: NH ₄ OH / 4000: 10: 1) to afford 16 : ms (ES +) m / z = 235 (M + H) ⁺ .

Step 4 -Palladium hydroxide (0.13 g) and ammonium formate (2.45 g, 0.038 mol) were dissolved in EtOH (30 mL) (5-benzyl-hexahydro-pyrrolo [3,4-c] pyrrole-2- To a solution of yl)-(2,6-dimethyl-phenyl) -methanone ( 16 , 1.30 g, 3.88 mmol). The solution was heated to reflux for 2 hours and filtered through a CELITE ^® pad. The volatile solvents were removed by vacuum evaporation and the crude reaction product was purified by flash column chromatography on silica gel (CH ₂ Cl ₂ : MeOH: NH ₄ OH / 120: 10: 1) to give 66: ¹ H NMR ( CHCl ₃ ) δ 2.13 (s, 1H), 2.25 (s, 3H), 2.28 (s, 3H), 2.65 (dd, 1H), 2.2-2.95 (m, 3H), 3.08-3.25 (m, 2H), 3.35 (dd, 1H), 3.65 (dd, 1H), 3.85-3.95 (m, 1H), 7.0 (m, 2H), 7.15 (q, 1H); ms (ES +) m / z 245 (M + H).

Step 5-1 -Acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-(3-chloro-propyl) -amide ( 17 , 0.22 g, 0.61 mmol) and (2, 6-Dimethyl-phenyl)-(hexahydro-pyrrolo [3,4-c] pyrrole-2-yl) -methanone ( 18 , 0.15 g, 0.61 mmol) was dissolved in MeCN (15 mL). K ₂ CO ₃ (0.25 g, 1.84 mmol) and potassium iodide (0.11 g, 0.67 mmol) were added to the mixture and the resulting solution was heated to reflux overnight. The mixture was cooled down, diluted with water and extracted with EtOAc. The combined EtOAc extracts were washed with brine, dried (MgSO ₄ ) and evaporated. The crude product was purified by flash column chromatography on silica gel (5% MeOH / CH ₂ Cl ₂ ) to give 19: mp 58.1-65.2 ° C .; ¹ H NMR (DMSO-d ₆ ) δ 1.5-1.65 (m, 6H), 1.95 (s, 3H), 2.12 (d, 6H), 2.23-2.52 (m, 12H), 2.68-2.85 (m, 4H) , 3.2-3.25 (m, 1H), 3.45 (dd, 1H), 3.6-3.7 (m, 3H), 7.05 (d, 2H), 7.1-7.2 (m, 2H), 7.35 (d, 1H), 7.43 (d, 1H); ¹³ C NMR (DMSO-d ₆ ) δ 18.84, 18.93, 19.60, 21.53, 26.64, 28.37, 29.04, 39.05, 39.33, 39.61, 39.88, 41.63, 45.23, 47.46, 50.62, 52.37, 53.13, 60.18, 60.60, 127.42, 127.52, 127.57, 128.29, 128.62, 132.43, 132.96, 133.05, 134.13, 135.64, 138.24, 141.63, 167.65, 168.18, 173.47; ms (ES +) m / z 578 (M + H); Assay (C ₃₃ H ₄₃ ClN ₄ O ₃ -0.2M CH ₂ Cl ₂ ) C; Calculated 66.89; Found, 66.70; H; Calculated value, 7.34; Found, 7.10; N; Calculated value, 9.40; Found, 9.50.

Example 3

2-acetylamino-N- {3- [5- (2-chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl } -Acetamide ( I-196 )

Step 1 -A solution of 4a (6.25 g, 31 mmol) in DCM (200 mL) was added to 35 (1.0 g, 4.97 mmol). To the resulting mixture was added NaBH (OAc) ₃ (9.86 g, 47 mmol) in 2 parts and the reaction was stirred at rt for 18 h. The reaction was washed with 5% NaHCO ₃ solution (100 mL). The organic phase was dried (Na ₂ SO ₄ ) and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with DCM / 3.5% MeOH (containing 10% NH ₄ OH) to give 6.8 g (46%) of 36a as a viscous liquid: MS (ES +) m / z 436 (M + H) ⁺ .

Step 2 -Palladium hydroxide (0.2 g) and ammonium formate (6.3 g, 0.100 mol) were added to a solution of 36a (4.36 g, 0.010 mol) in EtOH (200 mL). The solution was heated to reflux for 2 hours and filtered through a CELITE ^® pad. The resulting solution was concentrated in vacuo to give 3.5 g (100%) of 36b : ms (ES +) m / z 346 (M + H) ⁺ .

Step 3 -To a solution of 36b (3.5 g, 10.0 mmol) in DMF (100 ml) was added 2-chloro-6-fluorobenzoic acid (1.75 g, 10.0 mmol) at room temperature. To the resulting solution was added EDCI (2.0 g, 10.0 mmol), HOBt (1.35 g, 10.0 mmol) and NaHCO ₃ (3.4 g, 40.0 mmol) sequentially and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure and the residue was dissolved in DCM (100 ml). The organics were washed with 2% HCl, water, saturated NaHCO ₃ solution, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (3.5% MeOH / DCM) to give 3.3 g (66%) of 37a : MS (ES +) m / z 502 (M + H) ⁺ .

Step 4 -To a solution of 37a (3.3 g, 6.6 mmol) in DCM (50 ml) was added a solution of HCl on ether (100 mL, 1 N in ether). The reaction was stirred for 18 hours. The solution was evaporated under reduced pressure to give 3.6 g (110%) of 37b HCl as a white solid: MS (ES +) m / z 401 (M + H) ⁺ .

Step 5 -The weight of acetylamino-acetic acid (6.1 mg, 52.5 μmol) was measured in the reaction vessel and resin-bound carbodiimide (78 mg, 2.0 equiv) was added. HOBt (60 μmol, 1.7 equivalents in 10% DMF in DCM, 1.0 ml) was added and the reaction was shaken for 1 hour. A solution of 37b HCl in DCM (35 μmol, 500 μl, 30 μl DIEA) was added. The reaction was shaken for 72 hours. The resin was filtered off, washed with DCM (3 × 1.0 mL) and the solvent was evaporated under reduced pressure. The residue was purified by reverse phase preparative HPLC to give I-196 : ms (ES +) m / z 501 (M + H) ⁺ .

Example 4

N- {3- [5- (2-Chloro-6-fluoro-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -2-phenyl Propionamide ( I-312 )

I-312 was synthesized in the same manner as in Example 3, except that in step 5, acetylamino-acetic acid was replaced with 2-methylphenyl acetic acid to obtain I-312 isolated as a TFA salt: ms (ES + ) m / z 534 (M + H) ⁺ .

Example 5

1- {3- [5- (2,4-Dimethyl-1-oxy-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl- Propyl} -3-phenyl-urea ( I-373 )

Step 1 -To a solution of 36b (0.456 g, 1.1 mmol) in DMF (10 ml) was added 2,4-dimethyl-3-pyridine carboxylic acid N-oxide (0.184 g, 1.1 mmol) at room temperature. To the resulting solution was added sequentially EDCI (0.221 g, 1.2 mmol), HOBt (0.149 g, 1.1 mmol) and NaHCO ₃ (0.370 g, 4.4 mmol). The mixture was stirred overnight at room temperature and then evaporated under reduced pressure. The residue was dissolved in DCM (25 ml). The organics were washed with 2% HCl, water, saturated NaHCO ₃ solution, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (3.5% MeOH / CH ₂ Cl ₂ ) to give 0.360 g (66%) of 38a : ms (ES +) m / z 495 (M + H) ⁺ .

Step 2 -To a solution of 38a (0.36 g, 0.73 mmol) in DCM (20 ml) was added a solution of HCl (1N in ether, 20 ml). The reaction was stirred for 18 hours. The solution was evaporated under reduced pressure to give 0.31 g (100%) of 38b HCl as a white solid: ms (ES +) m / z 395 (M + H) ⁺ .

Step 3 -The weight of phenyl isocyanate (8.1 mg, 75 μmol) was measured in the reaction vessel and 38b HCl (50 μmol) in DCM (500 μl with 60 μl DIEA) was added. The reaction was shaken for 18 hours. The solvent was evaporated under reduced pressure. The residue was purified by reverse phase preparative HPLC to give I-373 : ms (ES +) m / z 514 (M + H) ⁺ .

Example 6

2-cyclohexyl-N- {3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl -Propyl} -acetamide, TFA salt ( I-378 )

Step 1-2,4-dimethyl-3-pyridine carboxylic acid N-oxide was replaced with 2,4-dimethyl-3-pyridine carboxylic acid, except that 0.643 g (61%) of 39a was obtained. Was prepared as described in step 1 of Example 5: ms (ES +) m / z 479 (M + H) ⁺ .

Step 2 -Prepared as described in Step 2 of Example 5, except that 0.790 g (100%) of 39b HCl salt was obtained using 39a from Step 1: ms (ES +) m / z 379 (M + H) ⁺ .

Step 3 -The weight of cyclohexyl acetic acid (10.6 mg, 75 μmol) was measured in the reaction vessel and 39b 2HCl (50 μmol) in DCM (500 μl with 60 μl DIPEA) was added. The reaction was shaken for 18 hours and the solvent was evaporated under reduced pressure. The residue was purified by reverse phase preparative HPLC to give I-378 as TFA salt: ms (ES +) m / z 503 (M + H) ⁺ .

Example 7

Tetrahydro-furan-3-carboxylic acid {3- [5- (4,6-dimethyl-2-pyridin-4-yl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4- c] pyrrole-2-yl] -1-phenyl-propyl} -amide, TFA salt ( I-422 )

Step 1 -To a solution of 40a (5.85 g, 13.4 mmol) in DCM (50 ml) was added a solution of HCl (1N in ether, 50 ml) and the reaction was stirred for 18 hours. The solution was evaporated under reduced pressure to give 6.3 g (100%) of 40b HCl as a white solid: ms (ES +) m / z 336 (M + H) ⁺ .

Step 2 -To a solution of 40b HCl (6.3 g, 13.4 mmol) in DMF (50 ml) was added tetrahydro-3-furoic acid (1.29 ml, 13.4 mmol) at room temperature. To the resulting solution was added sequentially EDCI (2.7 g, 14.1 mmol), HOBt (1.81 g, 13.4 mmol) and NaHCO ₃ (4.5 g, 53.6 mmol). The mixture was stirred at rt overnight. The solvent was evaporated under reduced pressure and the residue was dissolved in DCM (25 ml). The organic phase was washed with 2% HCl, water, saturated NaHCO ₃ solution, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (3.5% MeOH / DCM) to give 5.23 g (90% of theory) of 41a : ms (ES +) m / z 434 (M + H) ⁺ .

Step 3 -Palladium hydroxide (0.2 g) and ammonium formate (3.0 g, 46 mmol) were added to a solution of 41a (2.0 g, 4.6 mmol) in EtOH (100 mL). The solution was heated to reflux for 5 hours and filtered through a CELITE ^® pad. The resulting solution was concentrated in vacuo to give 1.40 g (89%) of 41b : ms (ES +) m / z 344 (M + H) ⁺ .

Step 3-4,6-Dimethyl-2-pyridin-4-yl-pyrimidine-5-carboxylic acid (18.7 mg, 75 μmol, T. Gebhard et al. J. Med. Chem. 2004 47 (8): 1939-1955 and prepared as described in WO 2002081449 A1) were weighed in a reaction vessel and resin-bound carbodiimide (120 mg, 2.0 equiv) was added. HOBt (85 μmol, 1.0 ml in 10% DMF in DCM) was added. The reaction was shaken for 18 hours. A solution of 41b (50 μmol) in DCM (500 μl with 60 μl DIEA) was added. The reaction was shaken continuously for 18 hours. The resin was filtered off and washed with DMF (1.0 ml) and DCM (2 × 1.0 mL). The residue was purified by reverse phase preparative HPLC to give I-422 : ms (ES +) m / z 555 (M + H) ⁺ .

Example 8

1- (3-Chloro-4-methyl-phenyl) -3-cyclohexylmethyl-1- {3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3 , 4-c] pyrrole-2-yl] -propyl} -urea, TFA salt ( II-149 )

Step 1 -To a solution of 44 (0.90 g, 3.7 mmol) in MeCN (80 ml) was added sequentially 20 (0.887 mg, 4.1 mmol), KI (0.681 g, 4.1 mmol) and DIPEA (1.3 mL, 7.4 mmol). It was. The reaction mixture was heated at 80 ° C for 18 h. The reaction was quenched with water and extracted three times with EtOAc. The organic phase was dried (Na ₂ SO ₄ ), filtered and evaporated. The crude product was purified by flash column chromatography on silica gel eluting with 3.5% MeOH / DCM (containing 0.4% ammonia) to give 1.06 g (67%) of 45 : ms (ES +) m / z 426 (M + H) ⁺ .

Step 2 -The flask was charged with cyclohexaneaminemethyl isocyanate (7.5 mg, 52.5 μmol) and 45 (35 μmol) in DCM (500 μL) was added. The reaction was shaken for 18 hours. The residue was purified by reverse phase preparative HPLC to give II-149 : ms (ES +) m / z 566 (M + H) ⁺ .

Example 9

1-acetyl-piperidine-4-carboxylic acid {3- [5- (2-acetyl-1,2,3,4-tetrahydroisoquinoline-5-carbonyl) hexahydro-pyrrolo [3, 4-c] pyrrole-2-yl] -propyl}-(3-chloro-4-methyl-phenyl) -amide ( II-339 )

1-acetyl-piperidine- by the procedure described in Example 2, except that 4a was first alkylated with 18 as described in step 4 and the benzyl protecting group was removed by catalytic hydrolysis as described in step 3 4-carboxylic acid (3-chloro-4-methyl-phenyl)-[3- (hexahydro-pyrrolo [3,4-c] pyrrol-2-yl) -propyl] -amide ( 42b ) was prepared. .

Step 1 - DMF (2 mL) of 42b (0.1 g, 0.224 mmol) , boc-5- hydroxy-carbonyl-1,2,3,4-tetrahydroisoquinoline (62 mg, 0.224 mmol, Arch Corp. catalog # AR02230), DIPEA (80 □ L, 0.336 mmol) was added to a solution of EDCI (51 mg, 0.268 mmol) and HOBT (41 mg, 0.268 mmol) at room temperature. The resulting mixture was stirred at rt for 16 h and then partitioned between EtOAc and water. The aqueous layer was back extracted twice with EtOAc. Layers were dried (Na ₂ SO ₄ ), filtered and evaporated. The residue is transferred from 100% DCM (2 minutes constant solvent composition run time) to a 1: 1 mixture DCM of a solution of DCM / MeOH / NH ₄ OH (80/10/1) at a flow rate of 25 mL / min for 20 minutes. Purification by SiO ₂ chromatography eluting with a gradient of 0.142 g (90%) of 46a was obtained as a light pink foam: ¹³ C NMR (CDCl ₃ ) δ 20.19, 21.77, 26.62, 27.20, 28.74, 28.89, 29.56, 39.78, 41.09, 41.28, 42.47, 45.93, 48.47, 50.99, 53.00, 54.34, 60.27, 60.75, 80.31, 124.34, 126.71, 128.88, 131.62, 132.39, 135.64, 136.88, 141.53, 155.20,69. MS (ES +) m / z 706 (M + H) ⁺ .

Step 2 -To a solution of 46a (0.11 g, 0.156 mmol) in DCM (2.5 mL) was added TFA (0.5 mL) at room temperature. The resulting solution was stirred at rt for 2 h and then evaporated. The residue is eluted by a gradient of 100% DCM to 100% of a solution of DCM / MeOH / NH ₄ OH (80/10/1) at a flow rate of 25 mL / min, followed by a 20 minute gradient followed by maintaining this composition for an additional 10 minutes. Purification by SiO ₂ chromatography gave 0.060 g (64%) of 46b : ¹ H NMR (CD ₃ OD) δ ¹ 1.51-1.78 (m, 6H), 2.30-2.56 (m, 11H), 2.61 (dd, 1H, J = 9, 8 Hz), 2.69-2.98 (m, 6H), 3.00-3.14 (m, 3H), 3.42 (dd, 1H, J = 12, 6 Hz), 3.58 (dd, 1H , J = 15, 3 Hz), 3.63-3.93 (m, 5H), 4.02 (m, 2H), 4.43 (bd, 1H, J = 12 Hz), 7.03-7.26 (m, 4H), 7.37-7.47 ( m, 2H); ¹³ C NMR (CD ₃ OD) δ 20.19, 21.54, 26.90, 28.05, 29.78, 30.37, 41.28, 42.34, 42.54, 43.52, 44.29, 47.16, 50.27, 52.30, 54.21, 55.72, 61.91, 125.38, 127.75, 128.40, 128.93 , 130.11, 132.08, 133.77, 137.16, 138.32, 138.85, 171.40, 171.83; MS (ES +) m / z 606 (M + H) ⁺ .

Steps 3-46b (30 mg, 49.5 □ mol), a solution of pyridine (0.5 mL) and Ac ₂ O (0.5 mL) were stirred at rt for 16 h and then diluted with MeOH (2 mL). The resulting mixture was stirred at rt for 1 h, then evaporated and co-evaporated with toluene. The residue was purified by SiO ₂ chromatography, eluting with a gradient from 100% DCM to a 1: 1 solution of DCM and DCM / MeOH / NH ₄ OH (80/10/1) at a flow rate of 25 mL / min for 20 minutes. Purification gave 22 mg (66%) of II-339 ; ¹ H NMR (CD ₃ OD) δ 1.51-1.78 (m, 6H), 2.05 (s, 3H), 2.19 and 2.16 (2s, 3H), 2.28-2.55 (m, 8H), 2.60 (m, 1H), 2.73-2.96 (m, 5H), 3.04 (m, 1H), 3.43 (m, 1H), 3.55-3.90 (m, 7H), 4.43 (bd, 1H, J = 12 Hz), 4.71 (d, 2H, J = 15 Hz), 7.16 (m, 2H), 7.29 (m, 2H), 7.42 (m, 2H), two quantum signals were masked by the deuterated methanol signal; ¹³ C NMR (CD ₃ OD) δ 19.77, 21.12, 21.42, 21.66, 26.81, 27.59, 29.37, 29.95, 40.62, 40.85, 41.92, 42.08, 43.13, 44.82, 45.16, 46.74, 52.00, 53.78, 55.42, 61.05, 61.51 , 125.37, 125.52, 127.90, 128.00, 128.46, 128.71, 129.71, 133.35, 135.46, 135.81, 136.21, 138.01, 142.38, 170.66, 171.42, 172.21, 176.17; MS (ES +) m / z 648 (M + H) ⁺ .

Example 10

3- [4- (5- {3-[(1-acetyl-piperidine-4-carbonyl)-(3-chloro-4-methyl-phenyl) -amino] -propyl} hexahydro-pyrrolo [ 3,4-c] pyrrole-2-carbonyl) -3,5-dimethyl-pyrazol-1-yl] -benzoic acid methyl ester ( II-390 )

Step 1 -A suspension of 3-hydrazinobenzoic acid (1.52 g, 9.99 mmol) (CAS # 38235-71-1) in water (20 mL) and HOAc (20 mL) at room temperature 50 (2 g, 9.99 mmol, Org Prep. Proc. Int. 2001 34 (4): prepared according to the procedure described in 357-409). The resulting mixture was stirred at room temperature for 30 minutes before pouring into a 400 mL of ice cold water and a 1: 1 mixture of EtOAc. The aqueous layer was extracted once with EtOAc. The combined organic layers were washed with saturated aqueous NaHCO ₃ until the aqueous extract remained basic. The organic layer was dried (Na ₂ SO ₄ ), filtered and evaporated. The residue was used directly without further purification or characterization. To the residue dissolved in DCM (100 mL) was added trimethylsilyldiazomethane (5 mL of 2M in hexane solution, 10 mmol) at room temperature. The resulting mixture was stirred for 30 min at room temperature and then quenched by the addition of methanol. The mixture was stirred at rt for 30 min and then evaporated. The residue was subjected to SiO ₂ chromatography eluting with a hexane / EtOAc gradient (gradient to 100% hexanes for 2 minutes, followed by 20% EtOAc for 20 minutes, maintained for an additional 10 minutes) at a flow rate of 55 mL / min. Purification by means of 1.09 g (33%) of 52a : ¹ H NMR (CDCl ₃ ) δ 1.59 (s, 9H), 2.48 (s, 3H), 2.52 (s, 3H), 3.94 (s, 3H ), 7.54-7.64 (m, 1 H), 8.07 (m, 1 H), 8.09 (m, 1 H); MS (ES +) m / z 331 (M + H).

Step 2 -TFA (5 mL) was added to a solution of 52a (1.088 g, 3.293 mmol) in DCM (50 mL) and triethylsilane (5 mL). The resulting mixture was stirred for 48 hours at room temperature and then evaporated to give 0.9 g (99% of theory) of 52b : ¹ H NMR (DMSO-d ₆ ) δ 2.27 (s, 3H), 2.39 (s, 3H ), 3.78 (s, 3 H), 7.58 (m, 1 H), 7.71 (m, 1 H), 7.87-7.95 (m, 2 H); MS (ES +) m / z 502 (M + H) ⁺ .

Step 3 -Diisopropylethylamine was added at room temperature. DIPEA (0.15 mL, 0.839) in a solution of 42b (75 mg, 0.168 mmol), 52b (51 mg, 0.185 mmol), EDCI (39 mg, 0.201 mmol), HOBT (31 mg, 0.201 mmol) and DMF (1.5 mL) mmol) was added. The resulting mixture was stirred at rt for 16 h and then partitioned between EtOAc and water. The aqueous layer was extracted twice with EtOAc. The combined extracts were dried (Na ₂ SO ₄ ), filtered and evaporated. Residue was passed 20 min from 100% DCM (1 min isocratic composition) to a 1: 1 solution of DCM and DCM / MeOH / NH ₄ OH (80/10/1) at a flow rate of 25 mL / min, followed by 2: Purification by SiO ₂ chromatography eluting with a gradient of 10 minutes at 8 gave 66 mg (% of theory) of II-390 : ¹ H NMR (CD ₃ OD) δ 1.45-1.78 (m, 6H) , 2.04 (s, 3H), 2.27 (s, 3H), 2.30 (s, 3H), 2.31-2.53 (m, 9H), 2.53-2.73 (m, 2H), 2.77-2.97 (m, 3H), 3.58 -3.78 (m, 6H), 3.84 (bd, 1H, J = 10 Hz), 3.94 (s, 3H), 4.42 (bd, 1H, J = 12 Hz), 7.16 (dd, 1H, J = 6, 2 Hz), 7.38 (1H, J = 2 Hz), 7.41 (d, 1H, J = 6 Hz), 7.67 (m, 1H), 7.75 (m, 1H), 8.11 (m, 2H); ¹³ C NMR (CD ₃ OD) δ 12.26, 12.99, 20.18, 24.54, 28.02, 29.76, 30.35, 41.25, 42.32, 43.54, 47.14, 50.28, 52.22, 53.43, 54.22, 55.24, 61.41, 61.90, 118.72, 127.55, 128.39 , 130.09, 130.69, 131.13, 131.30, 133.24, 133.75, 136.62, 138.31, 140.79, 140.93, 142.75, 149.05, 166.81, 167.77, 171.82, 176.56; MS (ES +) m / z 703 (M + H) ⁺ .

Example 11

4,4-Difluoro-cyclohexanecarboxylic acid {3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole- 2-yl] -1-phenyl-propyl} -amide ( I-435 )

Step 1 -Sodium triacetoxyborohydride (0.24 g, 1.12 mmol) in a mixture of 35 (0.20 g, 0.82 mmol, CAS 135865-78-0) and 44 (0.18 g, 0.75 mmol) in DCM (10 mL) Was added and the resulting solution was stirred at room temperature for 3 hours. The mixture was diluted with DCM and washed with saturated NaHCO ₃ . The organic layer was dried (MgSO ₄ ), filtered and evaporated. The crude product was purified by SiO ₂ column chromatography eluting with DCM: MeOH: NH ₄ OH (140: 10: 1) to afford 0.29 g (80%) of 53a : ms (ES +) m / z 480 ( M + H).

Step 2 -Methanolic HCl (10 mL, 1.25M) was added to 53a (0.29 g, 0.60 mmol) and the mixture was heated at 50 ° C for 2 h. The mixture was concentrated in vacuo to give 53b , which was used in the next step without further purification.

Step 3 -Thionyl chloride (66 μL, 0.90 mmol) was added to a solution of 4,4-difluoro-cyclohexanecarboxylic acid (0.13 g, 0.78 mmol) in toluene (5 mL). It was heated to reflux for 2 hours. Solvent and excess thionyl chloride were evaporated and residual acid chloride was diluted with DCM (4 mL) and toluene (2 mL). The acid chloride solution was added to a mixture of 53b in saturated Na ₂ CO ₃ (5 mL) and H ₂ O (3 mL) and stirred at rt for 4 h. The reaction mixture was diluted with H ₂ O and extracted with DCM. The organic layer was dried (MgSO ₄ ), filtered and evaporated. The crude product was purified by SiO ₂ column chromatography eluting with DCM: MeOH: NH ₄ OH (120: 10: 1) to give 0.16 g (50%) of I-435 : mp 131.8-133.2 ° C .; ms (ES +) m / z 526 (M + H);

Example 12

1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pipe Rolo [3,4-c] pyrrol-2-yl] -propyl} -amide ( II-3 )

To a solution of 18 (0.35 g, 1.15 mmol), 54 (0.18 g, 0.76 mmol) and MeCN (10 mL) add K ₂ CO ₃ (0.31 g, 2.30 mmol) and KI (0.25 g, 1.53 mmol), The resulting solution was heated to reflux overnight. The mixture was cooled down, diluted with water and extracted with EtOAc. The combined EtOAc extracts were washed with brine, dried (MgSO ₄ ) and evaporated. The crude product was purified by SiO ₂ column chromatography eluting with DCM: MeOH: NH ₄ OH (150: 10: 1) to afford 0.25 g (57%) of II-3 : mp 81.5-83.6 ° C .; ¹ H NMR (DMSO-d ₆ ) δ 1.3-1.6 (m, 8H), 1.95 (s, 3H), 2.15 (s, 3H), 2.3 (s, 3H), 2.35 (s, 3H), 2.65-2.85 (m, 5H), 3.2-3.3 (m, 1H), 3.4-3.8 (m, 6H), 4.2-4.3 (d, 1H), 7.1 (m, 1H), 7.15-7.25 (d, 1H), 7.45 (d, 1H), 8.3 (d, 1H); ms (ES +) m / z 580 (M + H); Assay (C ₃₂ H ₄₂ ClN ₅ O _3. 0.3M CH ₂ Cl ₂ ) C; Calculated, 65.78; Found, 65.74; H; Calculated, 7.38; Found, 7.30; N; Calculated 12.07; Found, 11.58.

Example 13

Cyclopentanecarboxylic acid {3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl- Propyl} -amide (I-29)

To a solution of 12 (0.24 g, 0.70 mmol) in DCM (10 mL) 4,6-dimethyl-pyrimidine-5-carboxylic acid ( 55 , 0.12 g, 0.84 mmol), EDCI (0.17 g, 0.91 mmol), HOBt (0.12 g, 0.91 mmol) and DIPEA (0.36 mL, 2.10 mmol) were added. The mixture was stirred at rt for 3 h. The reaction mixture was washed with saturated NaHCO ₃ and the organic layer was dried (Na ₂ SO ₄ ). The crude product was purified by SiO ₂ column chromatography eluting with DCM: MeOH: NH ₄ OH (150: 10: 1) to afford 0.27 g (81%) of I-29 : mp 48.0-49.0 ° C .; ms (ES +) m / z 476 (M + H); Assay (C ₂₈ H ₃₇ N ₅ O ₂ , 0.2M CH ₂ Cl ₂ ) C; Calculated, 68.76; Found, 68.61; H; Calculated, 7.65; Found, 7.51; N; Calculated, 14.22; Found, 14.28

Example 14

(S) -4,4-difluoro-cyclohexanecarboxylic acid [3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4-c ] Pyrrole-2-yl] -1- (3-fluoro-phenyl) -propyl] -amide ( I-485 )

Step 1 -NaBH in a solution of 56 (562 mg, 2.1 mmol, prepared as described in WO 2004/018425) and 44 (518 mg, 2.1 mmol) in DCM (20 mL) with HOAc (0.31 mL) (OAc) ₃ (579 mg, 2.73 mmol) was added in 1 portion and the reaction mixture was stirred for 18 hours at room temperature. The reaction was quenched by addition of 10% K ₂ CO ₃ (20 mL) and stirred continuously for 30 minutes. The product was extracted twice with DCM (25 mL). The combined extracts were dried (MgSO ₄ ) and concentrated in vacuo. The crude product was purified by flash chromatography on silica eluting with DCM / 5% MeOH (containing 2% NH ₄ OH) to give 821 mg (79% on theory) of 57a as a white foam: ms (ES +) m / z 498 (M + H) ⁺ .

Step 2 -A solution of 57a (821 mg, 1.65 mmol) dissolved in 10M HCl in MeOH (40 mL) was heated at 65 ° C. for 2 hours. MeOH was evaporated under reduced pressure and the residue was carefully partitioned between DCM (35 mL) and 20% K ₂ CO ₃ solution. The aqueous layer was extracted with DCM (2 x 35 mL). The combined organic extracts were dried (Na ₂ SO ₄ ) and concentrated in vacuo to give 641 mg (98%) of 57b as a viscous liquid: ms (ES +) m / z 398 (M + H) ⁺ .

Step 3 -To a solution of 57b (98 mg, 0.25 mmol) in DCM (4 mL) was added 4,4-difluorocyclohexanecarboxylic acid (49 mg, 0.30 mmol) at room temperature. To the resulting solution was added sequentially EDCI (61.4 mg, 0.32 mmol), HOBt (43 mg, 0.32 mmol) and DIPEA (0.13 mL, 0.74 mmol). The mixture was stirred for 4 hours. The reaction mixture was washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The crude product was purified by flash chromatography on silica eluting with DCM / 7.5% MeOH (containing 2% NH ₄ OH) to give 113 mg (84%) of I-485 as a white foam: ms (ES +) m / z 544 (M + H) ⁺ .

Example 15

5-Methyl-thiophene-2-carboxylic acid {(S) -3- [5- (2,6-dimethyl-benzoyl) hexahydro-pyrrolo [3,4-c] pyrrole-2-yl]- 1-pyridin-2-yl-propyl} -amide; Compound with trifluoro-acetic acid ( I-406 )

Step 1- (S) -3-amino-3-pyridin-2-yl in 1 part to a cold (0 ° C.) mixture of Na ₂ CO ₃ (418 mg, 3.95 mmol) in THF: H ₂ O (2: 1). Propionic acid methyl ester dihydrochloride ( 58a , 200 mg, 0.79 mmol; prepared as described for the isomer 3-pyridyl analog in J. Org. Chem. 2002 67: 7819). A solution of (BOC) ₂ O (189 mg, 0.86 mmol) in THF (2 mL) was added in 1 part and the reaction was stirred at 0 ° C. for 1 hour and then at room temperature for 2 hours. The product was extracted with EtOAc (2 x 25 mL). The combined organic extracts were dried (MgSO ₄ ) and concentrated in vacuo. The crude product was purified by flash chromatography on silica eluting with DCM / 5.0% MeOH (containing 2% NH ₄ OH) to give 157 mg (71%) of 58b as a viscous liquid: ms (ES +) m / z 281 (M + H) ⁺ .

Step 2 -To a solution of 58b (561 mg, 2.0 mmol) in DCM (20 mL) cooled to -70 ° C, DIBAL-H (4.0 mL of 1.0M DCM solution, 4.0 mmol) was kept at -70 ° C. It was added dropwise at a rate to. After 1 hour the reaction was quenched by addition of MeOH (5 mL) and H ₂ O (1 mL) at -78 ° C, then warmed to room temperature. The mixture was filtered through a CELITE ^® pad. The filtrate was dried (Na ₂ SO ₄ ) and concentrated in vacuo. The crude product was purified by flash chromatography on silica eluting with DCM / 6.0% MeOH (containing 2% NH ₄ OH) to give 416 mg (83%) of 59 as a viscous liquid; ms (ES +) m / z 251 (M + H) ⁺ .

Step 3 -NaBH (OAc) ₃ (224 mg, 1.05 mmol) was added to a solution of 59 (220 mg, 0.88 mmol) and 44 (215 mg, 0.88 mmol) in DCM (10 mL) containing HOAc (0.13 mL). Add in 1 part and stir the reaction for 5 hours. The reaction was quenched by the addition of 10% K ₂ CO ₃ solution (10 mL) and stirred for an additional 30 minutes. The product was extracted with DCM (2 x 20 mL). The combined extracts were dried (Na ₂ SO ₄ ) and concentrated in vacuo. The crude product was purified by flash chromatography on silica eluting with DCM / 7.5% MeOH (containing 2% NH ₄ OH) to give 304 mg (72%) of 60a as a viscous liquid: ms (ES +) m / z 479 (M + H) ⁺ .

Step 4-10 A solution of 60a (304 mg, 0.64 mmol) in 10M HCl and MeOH (10 mL) was heated at 65 ° C. for 2 hours. MeOH was evaporated under reduced pressure and the residue was carefully partitioned between DCM (35 mL) and 20% K ₂ CO ₃ solution (20 mL). The aqueous layer was extracted with DCM (2 x 35 mL). The combined organic extracts were dried (Na ₂ SO ₄ ) and concentrated in vacuo to give 60b as a viscous liquid (254 mg), which was used without further purification in the next step: ms (ES +) m / z 379 (M + H) ⁺ .

Step 5 -Resin bond-carbodiimide (81 mg) in 5 -methyl-2-thiophencarboxylic acid (10.7 mg, 0.075 mmol) and HOBt (DCM: DMF, 1.0 mL 0.06M solution in 9: 1) Was added and the mixture was stirred for 18 hours. 60b of solution (500 μL of 0.1M solution in DCM) was added and stirring continued for 18 hours. The reaction mixture was concentrated in vacuo and purified by reverse phase HPLC to give I-406 : ms (ES +) m / z 503 (M + H) ⁺ .

Example 16

(3S, 3'S) -Tetrahydro-furan-3-carboxylic acid {3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -amide ( I-390 )

Steps 1-50 of tetrahydro-3-furoic acid (1.55 g, 13.34 mmol) and (S) -3-amino-3-phenylpropanoic acid ethyl ester hydrochloride ( 63 , 3.06 g, 13.34 mmol) in 50 mL of DCM To the mixture was added EDCI (3.42 g, 16.01 mmol), HOBt (2.16 g, 16.01 mmol) and DIPEA (11.62 mL, 66.74 mmol) sequentially at room temperature. The mixture was stirred at rt overnight. The reaction mixture was washed with 5% NaHCO ₃ solution, dried (MgSO ₄ ) and concentrated in vacuo. The crude product was purified by preparative HPLC using a Chiralcel OD-H column eluting with 20% 2-propanol / hexanes to give 1.5 g of (3S, 3'S) -3-phenyl-3-[(tetrahydro-furan- 3-carbonyl) -amino] -propionic acid ethyl ester ( 64a ) was obtained: retention time: 14.71 min, mp 84.6-85.9 ° C, ms (ES +) m / z = 291 M ⁺ .

Step 2 -A solution of 64a (1.1 g, 3.7 mmol) and DCM (20 mL) cooled to DIBAL-H (1M solution in DCM, 7.5 mL, 7.5 mmol) to -78 ° C and with stirring Dropped in After stirring for 2 hours at -78 ° C, 2N hydrochloric acid (1 mL) was added dropwise at -78 ° C, and the mixture was allowed to warm to room temperature. Additional 2N HCl (20 mL) was added, the layers were separated and the aqueous layer was extracted three times with DCM (3 ×). Layers were dried (MgSO ₄ ) and concentrated. The crude product was purified by SiO ₂ chromatography eluting with EtOAc / DCM (0-100% EtOAc) to give 0.33 g of 65 : MS (ES +) m / z = 248 (M + H) ⁺ .

Step 3 was performed as described in Step 3 of Example 14 to obtain I-390 : MS (ES +) m / z = 476 (M + H) ⁺ .

Example 17

1-dimethylsulfamoyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3 , 4-c] pyrrole-2-yl] -propyl} -amide ( I-115 )

Step 1 -A stirred mixture of Boc-isonipeptic acid ( 67 , 2.12 g, 9.22 mmol), pyridine (1.9 mL, 23.6 mmol), and DCM (13 mL) was placed under a nitrogen atmosphere and at room temperature under SOCl ₂ (0.8 mL, 11 mmol) was added. After 25 minutes, a solution of 20 (2.21 g, 10.16 mmol), TEA (4.5 mL, 32.33 mmol), and DMAP (0.12 g, 0.92 mmol) in DCM (16 mL) was added dropwise and stirred continuously for 72 hours. 5% HCl (20 mL) was added dropwise, the layers were separated and the aqueous layer was extracted three times with DCM. Layers were dried (MgSO ₄ ) and concentrated. The crude product was purified by SiO ₂ chromatography eluting with an EtOAc / hexane gradient (0 to 30%) to give 2.2 g of 68 : ms (ES +) m / z = 451 (M + Na) ⁺ .

Step 2 -K ₂ CO ₃ (0.33 g, 2.4 mmol) and potassium iodide (0.22 g, 1.32) in a solution of 68 (0.52 g, 1.2 mmol) and 66 (0.3 g, 1.2 mmol) dissolved in MeCN (30 mL) mmol) was added and the resulting mixture was heated to reflux overnight. Additional 68 (0.2 g, 0.46 mmol) was added and heating continued for 6 hours. A third aliquot of 68 (0.2 g, 0.46 mmol) was added and the reaction continued for an additional 18 hours. The mixture was cooled to rt, diluted with water and extracted with EtOAc. The combined EtOAc extracts were washed with brine, dried (MgSO ₄ ) and evaporated. The crude product was purified by flash chromatography on silica gel eluting with MeOH / DCM (from 0 to 4%) containing 10% NH ₄ OH to give 0.244 g of 69a : ms (ES +) m / z 637 (M + H) ⁺ .

Step 3 -TFA (1 mL) was added to 69a (0.24 g, 0.37 mmol) dissolved in DCM (9 mL) and the mixture was stirred at rt overnight. The solvent was evaporated and the residue suspended in toluene and re-evaporated (2 x). The residue was purified by flash chromatography on silica gel eluting with MeOH / DCM (from 0 to 7%) containing 10% NH ₄ OH to give 0.194 g of 69b : MS (ES +) 537 (M + H) ⁺ .

Step 4 -To a room temperature solution of 69b (0.019 g, 0.035 mmol) and DIPEA (0.02 mL, 0.105 mmol) in 1 mL of DCM is added dimethylsulfamoyl chloride (0.01 g, 0.07 mmol) and the mixture is allowed to stand at room temperature overnight. Stirred. The reaction mixture was concentrated in vacuo and purified by reverse phase HPLC to give II-115 : ms (ES +) m / z 644 (M + H) ⁺ .

Example 18

3- (4-Chloro-phenyl) -1- {3-[[(3aS, 6aR) -5- (2,4-dimethyl-pyridine-3-carbonyl) hexahydro-pyrrolo [3,4-c ] Pyrrole-2-yl] -propyl} -1-p-tolyl-urea ( II-203 )

Step 1 -K ₂ CO ₃ (0.20 g, 1.51 mmol) and potassium iodide (0.18 g, 1.13) in a solution of 61 (0.20 g, 1.13 mmol) and 54 (0.18 g, 0.75 mmol) dissolved in MeCN (10 mL) mmol) was added and the resulting solution was heated to reflux overnight. The mixture was cooled down, diluted with water and extracted with EtOAc. The combined EtOAc extracts were washed with brine, dried (MgSO ₄ ) and evaporated. The crude product was purified by flash column chromatography on silica gel (DCM: MeOH: NH ₄ OH / 130: 10: 1) to give 0.16 g (54%) of 71: ms (ES +) m / z 393 ( M + H).

Step 2 -To a solution of 71 (0.16 g, 0.41 mmol) in DCM (5 mL) was added 1-chloro-4-isocyanato-benzene (0.09 g, 0.62 mmol) and TEA (0.13 mL, 0.91 mmol). . The mixture was stirred at rt for 2 h, then diluted with DCM and washed with water. The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product was purified by flash column chromatography on silica gel (CH ₂ Cl ₂ : MeOH: NH ₄ OH / 200: 10: 1) to give 0.19 g (83% yield) of II-203 : mp 60.5- 62.5 ° C., ms (ES +) m / z 546 (M + H).

Example 19

3- (3- (3-Chloro-4-methyl-phenyl) -3- {3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4 -c] pyrrole-2-yl] -propyl} -ureido) -benzoic acid ethyl ester; Compound with trifluoro-acetic acid ( II-393 ) and 3- (3- (3-chloro-4-methyl-phenyl) -3- {3- [5- (4,6-dimethyl-pyrimidine-5 -Carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -propyl} -ureido) -benzoic acid ( II-392 )

Step 1 -NaHCO ₃ (1.36 g, 16.24 mmol) and KI (1.34 g, 8.12 mmol) were dissolved in a solution of 20 (1.77 g, 8.12 mmol) and 44 (2.0 g, 8.12 mmol) dissolved in MeCN (10 mL). Added. The resulting mixture was heated to reflux overnight. The mixture was cooled down, diluted with water and extracted with EtOAc. The combined EtOAc extracts were washed with brine, dried (MgSO ₄ ) and evaporated. The crude product was purified by flash chromatography on silica gel eluting with MeOH (containing 10% NH ₄ OH) / DCM (from 0 to 4%) to give 2.7 g of 70 : ms (ES +) m / z 428 (M + H) ⁺ .

Steps 2 and 3 -A solution of ethyl 3-isocyanatobenzoate and 70 and THF was shaken overnight at room temperature. The solvent was evaporated to afford II-393 , which could be purified by SiO ₂ chromatography. The crude product was dissolved in MeOH (1 mL) and treated with a 10% solution (excess) of NaOH. The reaction mixture was shaken at room temperature overnight. The reaction mixture was acidified with TFA, the solvent was evaporated and the crude product was dissolved in 5% MeOH / DCM, filtered and concentrated to give carboxylic acid II-392 : ms (ES +) m / z 591 (M + H) ⁺ .

Example 20

1-acetyl-piperidine-4-carboxylic acid {3- [5- (2-bromo-3-methyl-benzoyl) hexahydro-pyrrolo [3,4-c] pyrrole-2-yl]- Propyl}-(3-chloro-4-methyl-phenyl) -amide ( II-244 )

2-bromo-3-methyl-benzoic acid ( 62 , 0.016 g, 0.075 mmol) in DCM: DMF (1 mL, 10: 1), resin-bound carbodiimide (0.078 g, 0.15 mmol) and HOBT (0.012 g , 0.085 mmol) was shaken for 18 hours. A solution of 42b (0.022 g, 0.05 mmol) and DIPEA (0.03 mL, 0.17 mmol) and DCM (1 mL) was added. Continuous shaking for 24 hours, the resin was filtered off, washed with DMF (1 mL) and twice DCM (1 mL). The reaction mixture was concentrated in vacuo and purified by reverse phase HPLC to give II-244 : ms (ES +) m / z 644 (M + H) ⁺ .

Example 21

[4-((3-Chloro-4-methyl-phenyl)-{3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4-c] Pyrrole-2-yl] -propyl} -carbamoyl) -piperidin-1-yl] -oxo-acetic acid, hydrochloride salt ( II-303 )

Step 1-4,6-Dimethyl-pyrimidine-5-carboxylic acid (0.85 g, 5.58 mmol, TJ Kress et. Al. Heterocycles 1994 38: 1375) and 4a (1.13 g, 5.58 mmol) in DCM (25 mL) , CJ Ohnmacht et al. J. Heterocycl. Chem. 1983 20: 321), sequentially added EDCI (1.43 g, 6.7 mmol), HOBt (0.9 g, 6.7 mmol) and DIPEA (3.9 mL, 22.34 mmol) at room temperature. And the mixture was stirred overnight at room temperature. The reaction mixture was washed with 5% NaHCO ₃ solution, dried (MgSO ₄ ) and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with MeOH (containing 10% NH ₄ OH) / DCM (from 0 to 4%) to give 1.5 g of (5-benzyl-hexahydro-pyrrolo [3, 4-c] pyrrole-2-yl)-(4,6-dimethyl-pyrimidin-5-yl) -methanone was obtained: ms (ES +) m / z 337 (M + H) ⁺ . To a solution of amide (1.5 g, 4.45 mmol) from the previous step in MeOH (50 mL) was added ammonium formate (2.81 g, 44.58 mmol). Palladium on charcoal previously wetted with MeOH was added slowly and the mixture was heated to reflux for 18 hours. The catalyst was filtered off and the solvent was evaporated. The residue was purified by flash chromatography on silica gel eluting with MeOH (containing 10% NH ₄ OH) / DCM (from 0 to 4%) to give 0.941 g of 44b : ms (ES +) m / z 247 (M + H) ⁺ .

Step 2 - the addition of 18 (0.6 g, 1.39 mmol) and 44 (0.31 g, 1.27 mmol) and MeCN (20 mL) DIPEA (0.44 mL, 2.54 mmol) to a solution of and KI (0.23 g, 1.39 mmol) and The resulting mixture was heated to reflux overnight. The mixture was cooled down, diluted with water and extracted with EtOAc. The combined EtOAc extracts were washed with brine, dried (MgSO ₄ ) and evaporated. The crude product was purified by flash chromatography on silica gel eluting with MeOH (containing 10% NH ₄ OH) / DCM (from 0 to 4%) to give 0.347 g of 72a: ms (ES +) m / z 639 (M + H) ⁺ .

Step 3 -TFA (1 mL) was added to a solution of 72a dissolved in DCM (9 mL) and the mixture was stirred at rt overnight. The solvent was evaporated and the residue suspended in toluene and evaporated again (2 ×). The residue was purified by flash chromatography on silica gel eluting with a DCM / MeOH (containing 10% NH ₄ OH) (MeOH from 0 to 4%) gradient to give 0.347 g of 72b : ms (ES +) m / z 539 (M + H) ⁺ .

Step 4 -To a mixture of 72b (0.3 g, 0.55 mmol) and methyl oxalyl chloride (0.057 mL, 0.61 mmol) in DCM (5 mL) was added DIPEA (0.145 mL, 0.83 mmol) at room temperature. The reaction mixture was stirred at rt overnight, then washed with 5% NaHCO ₃ solution, back extracted with DCM (5 ×), dried (MgSO ₄ ) and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with MeOH (containing 10% NH ₄ OH) / DCM (from 0 to 4%) to afford 0.304 g of II-299 : mp, 60.3-62 ° C. ; Analysis, calculated for C ₃₂ H ₄₁ ClN ₆ O ₅ (containing 0.15 mol of CH ₂ Cl ₂ ): C, 60.53; H, 6.53; N, 13.17. Found: C, 60.59; H, 6. 49; N, 12.99; MS (ES +) 625 (M + H) ⁺ .

Step 5 -To a solution of II-299 (0.194 g, 0.31 mmol) in MeOH (3 mL) was added a solution of NaOH (0.019 g, 0.47 mmol) in water (1 mL). The mixture was stirred at rt overnight. The solvent was evaporated into a stream of nitrogen, redissolved in MeOH, acidified with HCl (1M solution in ethyl ether), stirred at room temperature for 15 minutes and then concentrated in vacuo. The residue was dissolved in DCM, stirred for 15 minutes and filtered to remove NaCl. Cyclohexane was added and the oily phase was separated. The solvent was poured off and the product dried in vacuo to give 0.12 g of II-303 : mp 172.4-175.2 ° C; Analysis, calculated for C ₃₁ H ₃₉ ClN ₆ O ₅ (containing 1 mol of HCl and 0.55 mol of CH ₂ Cl ₂ ): C, 54.58; H, 5.97; N, 12.10. Found: C, 54.66; H, 5.88; N, 12.03; MS (ES +) 611 (M + H) ⁺ .

Example 22

1-acetyl-piperidine-4-carboxylic acid {3- [5- (2-azetidin-1-yl-pyridine-3-carbonyl) hexahydro-pyrrolo [3,4-c] pyrrole- 2-yl] -propyl}-(3-chloro-4-methyl-phenyl) -amide ( II-356 )

To a mixture of 42b (0.063 g, 0.138 mmol) and 2-chloronicotinoyl chloride ( 73 , 0.027 g, 0.15 mmol) in DCM (3 mL) was added DIPEA (0.05 mL, 0.27 mmol) at room temperature. The mixture was stirred overnight at room temperature and the solvent was evaporated. The residue contained 74a when obtained, which was treated with a solution of azetidine (0.1 mL, excess) in THF (2 mL). The reaction mixture was heated at 80 ° C. with stirring for 4 hours. The reaction mixture was cooled to rt and the solvent was evaporated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with MeOH (containing 10% NH ₄ OH) / DCM (from 0 to 4%). The recovered material was dissolved in DCM and cyclohexane was added to separate the oil. The solvent was poured off and the product dried in vacuo to afford 0.045 g of II-356 : mp 72.9-74 ° C .; Analysis, calculated for C ₃₃ H ₄₃ ClN ₆ O ₃ (containing 0.5 mol of C ₆ H ₁₂ and 0.5 mol of H ₂ O): C, 65.69; H, 7. 66; N, 12.77. Found: C, 65.99; H, 7.47; N, 12.61; ms (ES +) m / z 607 (M + H) ⁺ .

Example 23

(5-{(5-[(S) -3- (Cyclopentanecarbonyl-amino) -3-phenyl-propyl] -hexahydropyrrolo [3,4-c] pyrrole-2-carbonyl} -4 , 6-Dimethyl-pyrimidin-2-yloxy) -acetic acid; compound with trifluoro-acetic acid ( I-466 )

Step 1 -A solution of (BOC) ₂ 0 (15.7 g, 72 mmol) in THF (20 mL) was added to a solution of 4a (12 g, 59.3 mmol) in THF (100 mL) at room temperature and the resulting solution was 18 h. Stirred and concentrated in vacuo. The residue was dissolved in EtOAc (100 mL) and the organic phase was washed with saturated NaHCO ₃ (25 mL), 1M citric acid (25 mL) and brine (1 × 25 mL), dried (MgSO ₄ ) and concentrated in vacuo. . The crude product was purified by flash chromatography on SiO ₂ eluting with 10% EtOAc / DCM to give 11.7 g (65%) of 74 : ¹ H NMR (CDCl ₃ ) δ 1.46 (s, 9H), 2.37- 2.40 (m, 2H), 2.62-2.68 (m, 2H), 2.76-2.79 (m, 2H), 3.25 (m, 2H), 3.51-3.57 (m, 2H), 3.58 (s, 2H), 7.23- 7.31 (m, 5 H); MS (ES +) m / z 303 (M + H) ⁺ .

Step 2 -Palladium hydroxide (0.1 g) was added to a solution of 74 (1.0 g, 3.3 mmol) in EtOH (50 mL). The solution was hydrogenated overnight under atmospheric pressure and filtered through a CELITE ^® pad. The resulting solution was concentrated in vacuo to give 0.6 g (85%) of 75 : MS (ES +) m / z 213 (M + H) ⁺ .

Step 3 - DMF (5 mL) of 75 (0.6 g, 2.82 mmol) , dimethylsulfamoyl chloride (0.3 mL, 2.82 mmol), 4,6- dimethyl-2-methylsulfanyl-pyrimidine-5-carboxylic acid (0.56 g, 2.82 mmol), N, N-dimethylbutyl amine (1.16 mL, 8.4 mmol) and DMAP (34 mg, 0.000282 mol) solution were stirred at 65 ° C. overnight. DMF was removed under vacuum. The residue was dissolved in EtOAc (30 mL), washed with saturated NaHCO ₃ (25 mL), 1M citric acid (25 mL), brine (25 mL), dried (MgSO ₄ ) and concentrated in vacuo. The crude product was purified by flash chromatography on SiO ₂ eluting with 20% MeOH / DCM to give 0.6 g (54%) of 76a : MS (ES +) m / z 393 (M + H) ⁺ .

Step 4 -A solution of 76a (1 g, 2.54 mmol) in DCM (15 mL) was cooled to 0 ° C. and MCPBA (1.3 g, 7.6 mmol) was added in portions. Stirring was continued for 2 hours. The reaction mixture was diluted with DCM (15 mL), washed with saturated NaHCO ₃ (25 mL), brine (25 mL), dried (MgSO ₄ ) and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with 10% MeOH / CH ₂ Cl ₂ to afford 0.34 g (31%) of 76b : MS (ES +) m / z 425 (M + H) ⁺ .

Step 5 -Carbamate 76b (0.12 g, 0.00028 mol) was dissolved in 50% TFA / DCM (5 mL) and stirred at rt for 1 h. The solvent was removed under vacuum and the residue was dried in vacuo at 40 ° C. for 5 hours, giving 0.12 g of 77 : MS (ES +) m / z 325 (M + H) ⁺ .

Step 6 -Add cyclopentanecarboxylic acid (3-oxo-1-phenyl-propyl) -amide ( 12 , 0.41 g, 1.68 mmol) to a solution of 77 TFA salt (0.51 g, 1.18 mmol) in DCM (5 mL) And NaBH (OAc) ₃ (0.35 g, 1.65 mmol) was added. The reaction was stirred at rt for 18 h, diluted with EtOAc (25 mL), washed with saturated NaHCO ₃ (25 mL), brine (25 mL), dried (MgSO ₄ ) and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with 10% MeOH / DCM to give 0.4 g (61%) of 78 : MS (ES +) m / z 554 (M + H) ⁺ .

Step 7 -Benzyl glycolate (0.05 g, 3 mmol) is added to a mixture of 78 (0.14 g, 2.51 mmol) and CS ₂ CO ₃ (0.16 g, 5.0 mmol) in DMF (2 mL) and the resulting mixture is Stir at 70 ° C. for 8 hours. The DMF was removed under vacuum and the residue was purified by flash chromatography on silica gel eluting with 10% MeOH / DCM to give 0.1 g (62%) of 79 : MS (ES +) m / z 640 (M + H) ⁺ .

Step 8 -Palladium on carbon (20 mg) was added to a solution of 79 (0.1 g, 0.15 mmol) in EtOH (20 mL). The solution was hydrogenated overnight under atmospheric pressure and filtered through a CELITE ^® pad. The resulting solution was concentrated in vacuo to afford 78 mg (91%) of I-466 : mp 117.3-119.0 ° C., ms (ES +) m / z 550 (M + H) ⁺ .

Example 24

Cyclopentanecarboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl ] -2-methyl-propyl} -amide ( II-310 )

Step 1-1 -Bromo-3-chloro-2-methyl-propane (0.17 mL, 1.45 mmol) and TEA (0.24 mL, 1.71 mmol) were dissolved in DMF (6 mL) (2,6-dimethyl-phenyl)- To a solution of (hexahydro-pyrrolo [3,4-c] pyrrole-2-yl) -methanone ( 66 , 358 mg, 1.47 mmol) was added. The mixture was stirred at rt overnight. Water was added and the mixture was extracted with DCM. The organic layer was dried (Na ₂ SO ₄ ) and concentrated. The crude product was purified by SiO ₂ column chromatography on silica gel eluting with a DCM: MeOH: NH ₄ OH gradient (98: 1.4: 0.14 to 96: 3.5: 0.35 for 40 minutes) to give 82 (224 mg, 46%): ms (LCMS) m / z 335 (M + H).

Step 2 -KI (120 mg, 0.72 mmol), 3-chloro-4-methyl-phenylamine (105 mg, 0.74 mmol) and DIPEA ( 82 mg, 0.67 mmol) dissolved in DMF (3 mL) solution 0.12 mL, 0.69 mmol) was added and the reaction mixture was stirred at 80 ° C. for 4 h. The mixture was cooled to rt, diluted with water and extracted with DCM. The combined DCM extracts were dried (Na ₂ SO ₄ ) and concentrated. The crude product was purified by SiO ₂ column chromatography eluting with CH ₂ Cl ₂ : MeOH: NH ₄ OH (99: 0.7: 0.07) to give 83 as an off-white solid (146 mg, 49%): ms (LCMS ) m / z 440 (M + H).

Step 3 -Cyclopentanecarbonyl chloride (0.07 mL, 0.06 mmol) and DIPEA (0.02 mL, 0.11 mmol) were added to a solution of 83 (28.5 mg, 0.06 mmol) in toluene (1 mL). The resulting solution was stirred at 50 ° C. for 1 hour. The mixture was cooled to rt, diluted with water and extracted with DCM. The combined DCM extracts were dried (Na ₂ SO ₄ ) and concentrated. The crude product was purified by SiO ₂ column chromatography eluting with a DCM: MeOH: NH ₄ OH gradient (99: 0.7: 0.07 to 96: 3.5: 0.35 for 50 min) to give II-310 (14 mg, 40 %): ¹ H NMR (CDCl ₃ ) δ 0.9 (d, 3H), 1.35- 1.45 (m, 2H), 1.55 (s, 3H), 1.6-1.85 (m, 5), 2.1-2.5 (m, 15H ), 2.65-2.9 (m, 3H), 3.22-3.3 (m, IH), 3.4-3.9 (m, 4H), 6.95-7.4 (m, 3H), 7.1-7.3 (m, 3H); ms (ES +) m / z 536 (M + H).

Example 25

Cyclopentanecarboxylic acid {(S) -3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-butyl} -Amides ( I-75 )

Steps 1 and 2- (S) -3-amino-3-phenylpropanoic acid ethyl ester in H ₂ O (50 mL), saturated Na ₂ CO ₃ (50 mL), DCM (50 mL) and toluene (20 mL) To the solution of hydrochloride ( 84 , 5.0 g, 21.76 mmol) was added cyclopentylcarboxylic acid chloride (2.9 mL, 23.93 mmol). The reaction was stirred at rt overnight. The mixture was extracted with DCM and the organic layer was dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue containing 85a was redissolved in H ₂ O (50 mL) and THF (50 mL) and LiOH.H ₂ O (2.73 g, 65.06 mmol) was added. After 3 hours, the mixture was washed with ether. The aqueous layer was acidified with 2N HCl and extracted with EtOAc. The organic layer was dried (MgSO ₄ ), filtered and evaporated to give 5.56 g (97%) of 85b : ¹ H NMR (CDCl ₃ ) δ 1.5-1.65 (m, 2H), 1.65-1.95 (m, 6H), 2.55 (t, 1H), 2.8-3.0 (qd, 2H), 5.4-5.5 (m, 1H), 6.4-6.45 (d, 1H), 7.2-7.45 (m, 5H).

Step 3 -N, O-dimethylhydroxylamine hydrochloride (0.92 g, 9.50 mmol), O- (7-azabenzotriazol-1-yl) N, N, N ', N'-tetramethyluronium hexa Fluorophosphate (3.61 g, 9.50 mmol) and DIPEA (5.5 mL, 31.68 mmol) were added to a solution of 85b (2.07 g, 7.92 mmol) in DCM (80 mL). The reaction mixture was stirred at rt overnight, poured into 2N NaOH solution and stirred for 10 min. The organic layer was washed with H ₂ O, 2N HCl and brine, dried (MgSO ₄ ) and concentrated in vacuo. The crude product was purified by SiO ₂ column chromatography eluting with n-hexane: EtOAc (1: 2) to afford 1.24 g of 85c (yield 51%): ¹ H NMR (CDCl ₃ ) δ 1.55-1.65 ( m, 2H), 1.65-1.95 (m, 6H), 2.65 (q, 1H), 2.8 (dd, 1H), 3.1 (s, 3H), 3.1-3.2 (dd, 1H), 3.45 (s, 3H) , 5.43 (m, 1 H), 7.15-7.45 (m, 5 H), 7.4 (d 1 H).

Step 4 -MeMgCl (3.7 mL, 3M in THF) was added dropwise at -78 ° C to a solution of 85c (1.06 g, 3.50 mmol) in THF (15 mL). The mixture was warmed to rt over 3 h and stirred at rt for a further 1 h. The reaction was quenched with 1N K ₂ HPO ₄ and extracted with Et ₂ O. The organic layer was washed with saturated NaHCO ₃ and brine, dried (MgSO ₄ ), filtered and concentrated in vacuo. The crude product was purified by SiO ₂ column chromatography eluting with n-hexane: EtOAc (1: 1) to give 0.89 g (98%) of 85d .

Step 5- (2,6-Dimethyl-phenyl)-(hexahydro-pyrrolo [3,4-c] pyrrol-2-yl) -methanone in DCM (7 mL) and THF (7 mL) ( 66 , 0.12 g, 0.52 mmol) was added cyclopentanecarboxylic acid (3-oxo-1-phenyl-butyl) -amide ( 85d , 0.15 g, 0.57 mmol). Titanium tetraisopropoxide (0.34 mL, 1.15 mmol) was added to the mixture. After 30 minutes NaBH (OAc) ₃ (0.16 g, 0.78 mmol) was added and the mixture was stirred at rt for 4 h. Saturated NaHCO ₃ was added to the mixture, which was stirred for 10 minutes. The mixture was extracted with DCM and the organic layer was dried (MgSO ₄ ), filtered and evaporated. The crude product was purified by SiO ₂ chromatography on silica gel eluting with DCM: MeOH: NH ₄ OH (150: 10: 1) to give I-75 : ms (ES +) m / z 488 (M + H ); (C ₃₁ H ₄₁ N ₃ O ₂ .0.3MH ₂ O) Analytical C; Calc. 75.51; Observation, 75.53; H; Calculated 8.50; Observation, 8.29; N; Calculated, 8.52; Observation, 8.53.

Example 26

1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro- Pyrrolo [3,4-c] pyrrole-2-yl] -2,2-dimethyl-propyl} -amide ( II-354 )

Step 1-3 -Bromo-2,2-dimethyl-propan-1-ol in DCM (20 mL) with Dess-Martin reagent (1.12 g, 2.64 mmol) maintained at 0 ° C. ( 87 , 0.37 mL, 3.00 mmol) was added to the solution. The reaction mixture was stirred at 0 ° C. for 1 hour. The ice bath was removed and the reaction mixture was stirred for an additional 30 minutes at room temperature. Et ₂ O (40 mL) was added and the mixture was poured onto 20 ml of a 9: 1 mixture of aqueous saturated NaHCO ₃ and aqueous saturated Na ₂ S ₂ O ₃ . The mixture was stirred until a clear solution was obtained (10 minutes). The layers were separated and the Et ₂ 0 layer was washed with saturated aqueous NaHCO ₃ (2 ×) and water (2 ×). The organic layer was dried (Na ₂ SO ₄ ) and concentrated to give 88 (393 mg). The crude product was used for next step without further purification.

Step 2 -A solution of 3-bromo-2,2-dimethyl-propionaldehyde ( 88 , 393 mg, 23.8 mmol) and 44 (620 mg, 25.2 mmol) in DCM (6 mL) was added with HOAc (0.2 mL, 34.9 mmol). ) And NaBH (OAc) ₃ (530 mg, 25.0 mmol). The reaction mixture was stirred at rt for 2 h and then quenched by addition of aqueous NaOH (2 M, 2.4 mL, 0.48 mmol). The mixture was extracted with DCM. The combined DCM extracts were dried (Na ₂ SO ₄ ) and concentrated. The crude product was purified by SiO ₂ column chromatography eluting with a CH ₂ Cl ₂ : MeOH: NH ₄ OH gradient (99: 0.7: 0.07 to 96: 3.5: 0.35 for 50 minutes), 89 (95 mg, 10%) Obtained: ms (LCMS) m / z 397 (M + H).

Step 3 -A 89 (95 mg, 0.24 mmol) solution in MeCN (1 mL) was treated with 3-chloro-4-methyl-phenylamine (76 mg, 0.53 mmol) and TEA (0.035 mL, 0.25 mmol). The reaction mixture was stirred at 50 ° C. overnight. The mixture was cooled to rt, diluted with water and extracted with DCM. The combined CH ₂ Cl ₂ extracts were dried (Na ₂ SO ₄ ) and concentrated. The crude product was purified by SiO ₂ column chromatography eluting with a CH ₂ Cl ₂ : MeOH: NH ₄ OH gradient (99: 0.7: 0.07 to 96: 3.5: 0.35 for 50 min), 90 (25 mg, 23%) Obtained: ms (LCMS) m / z 456 (M + H).

Step 4-1 -acetyl-piperidine-4-carbonyl chloride (24 mg, 0.13 mmol) and TEA (0.02 mL, 0.14 mmol) were added to a solution of 90 (25 mg, 0.054 mmol) in DCM (2 mL). Added. The resulting solution was stirred overnight. The mixture was diluted with water and extracted with DCM. The combined DCM extracts were dried (Na ₂ SO ₄ ) and concentrated. The crude product was purified by SiO ₂ column chromatography eluting with a CH ₂ Cl ₂ : MeOH: NH ₄ OH gradient (98: 1.4: 0.14 to 93: 6: 0.6 for 50 minutes), II-354 (9 mg, 27 %) Were obtained: ¹ H NMR (DMSO-d ₆ ) δ 0.75 (s, 6H), 1.2-1.6 (m, 4H), 1.95 (s, 3H), 2.1 (s, 2H), 2.2-2.5 ( m, 16H), 2.65-2.85 (m, 4H), 3.25-3.35 (m, 1H), 3.6-3.8 (m, 4H), 4.2-4.3 (m, 1H), 7.25-7.5 (m, 3H), 8.95 (s, 1 H); ms (ES +) m / z 609 (M + H).

Example 27

Cyclopentanecarboxylic acid {3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -4-methoxy-1-phenyl-butyl }-amides. ( I-354 )

Step 1 -n-BuLi (1.4 mL, 1.5 in hexanes) in a solution of tributyl-methoxymethyl-stannan (0.71 g, 2.14 mmol, TS Kaufman Syn. Lett. 1997 12: 1377-1378) in THF (5 mL) M) was added dropwise at -78 ° C, and the reaction was stirred at -78 ° C for 10 minutes. A 92a (0.22 g, 0.71 mmol) solution in THF (3 mL) was added slowly to the mixture, after which the reaction mixture was stirred at -78 ° C for 30 minutes. Saturated NH ₄ Cl was added to the mixture, which was warmed to room temperature. The mixture was extracted with EtOAc and the organic layer was washed with brine, dried (MgSO ₄ ), filtered and concentrated in vacuo. The crude product was purified by SiO ₂ column chromatography eluting with n-hexane: EtOAc (2: 1) to give 0.13 g (62%) of 92b : ¹ H NMR (CDCl ₃ ) δ 1.42 (s, 9H ), 2.85-3.1 (dd, 2H), 3.35 (s, 3H), 3.85 (s, 2H), 5.1 (br, 1H), 5.38 (br, 1H), 7.2-7.4 (m, 5H).

Step 2 -Methanolic HCl (17 mL, 1.25 M) was added to 92b (0.31 g, 1.05 mmol) and the mixture was heated to 50 ° C. for 2 h. The mixture was concentrated in vacuo and dried in vacuo. The crude product is dissolved in a mixture of saturated Na ₂ CO ₃ (4 mL), H ₂ O (2 mL), DCM (2 mL) and toluene (1 mL), and the resulting mixture is cyclopentylcarboxylic acid chloride (0.18 mL, 1.48 mmol). After stirring overnight, the solution was extracted with DCM and the organic layer was washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The crude product was purified by SiO ₂ column chromatography eluting with n-hexane: EtOAc (1: 1) to give 0.23 g (76%) of 93 . mp 89.5-92.2 ° C; ms (ES +) m / z 290 (M + H).

Step 3 - the DCE 93 66 (0.18 g, 0.63 mmol) in (0.15 g, 0.63 mmol) solution of (7 mL) and THF (7 mL) was added. Titanium tetraisopropoxide (0.41 mL, 1.39 mmol) was added to the mixture and after 30 minutes, NaBH (OAc) ₃ (0.20 g, 0.95 mmol) was added and the reaction stirred at rt overnight. Saturated NaHCO ₃ was added to the mixture and stirring was continued for 10 minutes. The mixture was filtered through a CELITE ^® pad and extracted with DCM. The organic layer was dried (MgSO ₄ ), filtered and concentrated in vacuo. The crude product was purified by SiO ₂ column chromatography eluting with 5% MeOH / EtOAc to give 0.32 g (50%) of II-354 : ms (ES +) m / z 517 (M + H); (C ₃₂ H ₄₃ N ₃ O ₃ .0.15M DCM) Analytical C; Calc. 72.80; Observation, 72.55; H; Calculated, 8.23; Observation, 8.22; N; Calc. 7.92; Observation, 7.93.

Example 28

Cyclopentanecarboxylic acid {3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -4-hydroxy-1-phenyl-butyl } -Amide ( I-360 )

Steps 1 to 3 were carried out as described in Example 27, except that benzyloxymethyl-tributyl-stannan was used instead of methoxymethyl-tributyl-stannan in step 1.

Step 4 - the 96 (0.21g, 0.35 mmol) and EtOH (6 mL) 2N HCl ( 2 mL) and Pd / C (0.02 g) was added to a solution of. The mixture was stirred overnight at room temperature under H ₂ atmosphere. The catalyst was filtered through a CELITE ^® pad and the filtrate was concentrated in vacuo. The crude product was purified by SiO ₂ column chromatography eluting with CH ₂ Cl ₂ : MeOH: NH ₄ OH (120: 10: 1) to afford 0.10 g (56%) of I-360 : mp 78.9-84.9 ℃; ms (ES +) m / z 504 (M + H).

Example 29

4,4-Difluoro-cyclohexanecarboxylic acid {3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2 -Yl] -1-phenyl-butyl} -amide ( I-448 )

N-Boc derivatives of 84 were formed using standard protocols. Steps 2 and 3 were carried out as described in steps 4 and 5 of Example 25, except that the N-protecting groups in this example were Boc and benzyl. Silica chromatography on 98a eluting with DCM: MeOH: NH ₄ OH (150: 10: 1) gave 0.72 g (57%): ¹ H NMR (DMSO-d ₆ ) δ 0.9-0.95 (m, 3H), 1.35 (s, 9H), 1.45-1.7 (m 1H), 1.8-2.2 (m, 1H), 2.25-2.38 (m, 4H), 2.45-2.7 (m, 6H), 3.55 ( q, 2H), 4.6-4.75 (1H), 7.25-7.32 (m, 10H).

Step 4 -Palladium on carbon (0.07 g) and ammonium formate (1.01 g, 16.01 mmol) were added to a solution of 98a (0.72 g, 1.60 mmol) in MeOH (30 mL). The solution was heated to reflux for 2 hours and filtered through a CELITE ^® pad. The resulting solution was concentrated in vacuo and the crude product was purified by SiO ₂ column chromatography eluting with DCM: MeOH: NH ₄ OH (90: 10: 1) to give 98b .

Step 5- [3- (hexahydro-pyrrolo [3,4-c] pyrrol-2-yl) -1-phenyl-butyl] -carbamic acid tert-butyl ester 98b (0.22 g, in DCM (10 mL) 0.63 mmol) 4,6-dimethyl-pyrimidine-5-carboxylic acid (0.11 g, 0.76 mmol), EDCI (0.16 g, 0.82 mmol), HOBt (0.11 g, 0.82 mmol) and DIPEA (0.33 mL, 1.90 mmol) was added. The mixture was stirred at rt overnight. The mixture was washed with saturated NaHCO ₃ and the organic layer was dried (Na ₂ SO ₄ ). The crude product was purified by SiO ₂ column chromatography eluting with CH ₂ Cl ₂ : MeOH: NH ₄ OH (160: 10: 1) to afford 0.30 g (95%) of 99a .

Step 6 -Methanolic HCl (5 mL, 1.25 M) was added to 99a (0.30 g, 0.61 mmol) and the mixture was heated at 50 ° C. for 2 h. The mixture was concentrated in vacuo and purified by SiO ₂ column chromatography eluting with CH ₂ Cl ₂ : MeOH: NH ₄ OH (120: 10: 1) to afford 0.17 g (70%) of 99b .

Step 7-4,4-difluoro-cyclohexanecarboxylic acid (0.08 g, 0.51 mmol), EDCI (0.10 g, 0.56 mmol) in a solution of 99b (0.17 g, 0.43 mmol) in DCM (10 mL), HOBt (0.07 g, 0.56 mmol) and DIPEA (0.22 mL, 1.29 mmol) were added. The mixture was stirred at rt overnight. The mixture was washed with saturated NaHCO ₃ and the organic layer was dried (Na ₂ SO ₄ ). The crude product was purified by SiO ₂ column chromatography eluting with DCM: MeOH: NH ₄ OH (150: 10: 1) to afford 0.22 g (95%) of I-448 : mp 86.4-87.0 ° C .; ms (ES +) m / z 540 (M + H).

Example 30

Cyclopentanecarboxylic acid {3- [5- (5-methyl-1-phenyl-1 H-pyrazole-4-sulfonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl]- 1-phenyl-propyl} -amide ( I-113 )

In a solution of 12 (0.012 g, 0.035 mmol), DIPEA (0.02 mL, 0.105 mmol) and DCM (1 mL) at room temperature, 5-methyl-1-phenyl-1H-pyrazole-4-sulfonyl chloride ( 100 , 0.018 g, 0.07 mmol) was added and the mixture was stirred at rt overnight. The reaction mixture was concentrated in vacuo and purified by reverse phase HPLC to give I-113 : MS (ES +) m / z 562 (M + H) ⁺ .

Example 31

4-acetyl-piperidine-1-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2-methyl-pyridine-3-sulfonyl) -hexahydro-pyrrolo [ 3,4-c] pyrrole-2-yl] -propyl} -amide ( II-363 )

Step 1 -Benzylmercaptan (664 mg, 0.63 mL, 5.34 mmol) was dissolved in 8.5 mL DMF under N ₂ atmosphere. NaH (214 mg 60% as an oil dispersion, 5.34 mmol) was added in portions with stirring, followed by stirring for further 15 minutes. 3-bromo-2-methyl-pyridine ( 102a , 707 mg, 4.11 mmol) was added to the solution at once, and the mixture was heated to 130 ° C. for 4 hours in an oil bath. The reaction mixture was cooled to rt and partitioned between H ₂ O (50 mL) and hexane (50 mL). The hexane layer was separated, washed with H ₂ O (50 mL), dried over MgSO ₄ and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with EtOAc: hexane (1: 2) to give 522 mg (44%) of 102b as a viscous liquid: ms (ES +) m / z 216 (M + H) ⁺ .

Step 2 -A solution of 102b (414 mg, 1.92 mmol) in ice HOAc (8.3 mL) and H ₂ O (0.83 mL) was cooled to 0 ° C. Chlorine gas was bubbled into the mixture for 15 minutes and then stirred for a further 20 minutes. The mixture was diluted with DCM (50 mL), washed with brine, saturated NaHCO ₃ solution, brine, dried (MgSO ₄ ), and concentrated in vacuo. The crude product was purified by flash chromatography on silica eluting with EtOAc: hexane (1: 2) to give 285 mg (76%) of 102c as a pale yellow liquid: ms (ES +) m / z 191 (M ⁺ ) .

Step 3 -A solution of 102c (47 mg, 0.25 mmol), DIPEA (35 mg, 0.05 mL, 0.27 mmol) and 42b (100 mg, 0.22 mmol) in DCM (3.5 mL) was stirred for 2 hours and then concentrated in vacuo . The crude product was purified by flash chromatography on silica eluting with DCM / 8% MeOH (containing 2% NH ₄ OH) to give 133 mg (99%) of II-363 as a viscous liquid.

Example 32

N- {3- [5- (2,6-Dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -propyl} -N- (4-fluoro-phenyl) -Benzenesulfonamide ( II-2 )

At room temperature, in a 66 (0.012 g, 0.05 mmol) solution in MeCN (1 mL) N- (4-fluoro-phenyl) -N- (3-iodo-propyl) -benzenesulfonamide ( 102 , 0.025 g, 0.06 mmol) and K ₂ CO ₃ (0.01 g, 0.075 mmol) were added. The reaction mixture was shaken at 80 ° C. for 48 hours. After cooling to rt, the mixture was diluted with DCM (5 mL), filtered and evaporated in vacuo. The crude product was purified by reverse phase HPLC to give II-2 : MS (ES +) m / z = 536 (M + H) ⁺ .

Example 33

N- {3- [5- (2,6-Dimethyl-benzoyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl-propyl} -benzenesulfonamide ( I- 32 )

A 103 (35 μmol) solution in DCM was added to benzenesulfonyl chloride (9.3 mg, 53 μmol) and DIPEA (30 μl). The reaction was shaken for 18 hours. The solution was evaporated under reduced pressure and purified by preparative HPLC to give II-32 : ms (ES +) m / z 518 (M + H) ⁺ .

Example 34

1-acetyl-piperidine-4-carboxylic acid {3- [5- (2-chloro-4-fluoro-benzenesulfonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2- Ill-propyl}-(3-chloro-4-methyl-phenyl) -amide ( II-296 )

At room temperature, 2-chloro-4-fluorobenzenesulfonyl chloride ( 104 , 0.016 g, 0.07 mmol) was added to a solution of 42b (0.016 g, 0.035 mmol) and DIPEA (0.02 mL, 0.105 mmol) in DCM (1 mL). Add and shake the mixture overnight at room temperature. The reaction mixture was concentrated in vacuo and purified by reverse phase HPLC to give II-296 : ms (ES +) m / z 639 (M + H) ⁺ .

Example 35

1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3,4 -c] pyrrole-2-yl] -2-hydroxy-propyl} -amide ( II-189 )

Step 1-3 -chloro-4-methyl-phenylamine (3.0 g, 21.18 mmol) and 2-chloromethyl-oxirane (0.83 mL, 10.59 mmol) and EtOH (30 mL) solution were heated to reflux overnight. The mixture was concentrated in vacuo and purified by SiO ₂ column chromatography eluting with n-hexane: EtOAc (5: 1) to give 2.23 g (90%) of 105 : ¹ H NMR (CDCl ₃ ) δ 2.25 ( s, 3H), 3.18 (dd, 1H), 3.35 (dd, 1H), 3.6-3.75 (m, 2H), 4.0-4.15 (m, 1H), 6.45 (dd, 1H), 6.65 (dd, 1H) , 7.0 (d, 1H)

Stage 2 - 105 (0.12 g, 0.52 mmol) and 66 (0.11 g, 0.47 mmol) and _{K 2 CO 3 (0.13 g,} 0.94 mmol) and KI (0.09 g, 0.56 mmol) in a solution of MeCN (10 mL) to The resulting solution was heated to reflux overnight. The mixture was cooled down, diluted with water and extracted with EtOAc. The combined EtOAc extracts were washed with brine, dried (MgSO ₄ ), filtered and evaporated. The crude product was purified by SiO ₂ column chromatography eluting with DCM: MeOH: NH ₄ OH (120: 10: 1) to give 0.13 g (62%) of 106 .

Step 3 -Add 1-acetyl-piperidine-4-carbonyl chloride (0.16 g, 0.82 mmol) and pyridine (0.94 mL, 1.17 mL) to a solution of 106 (0.13 g, 0.29 mmol) in DCE (5 mL). It was. The solution was heated to 50 ° C. overnight. The mixture was cooled down, diluted with DCM and washed with saturated NaHCO ₃ . The organic layer was dried (Na ₂ SO ₄ ), filtered and evaporated. The crude product was purified by SiO ₂ column chromatography eluting with CH ₂ Cl ₂ : MeOH: NH ₄ OH (150: 10: 1) to give 0.12 g (68%) of II-189 : mp 107.9-109.8 ℃; ms (ES +) m / z 595 (M + H).

Example 36

1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pipe Rolo [3,4-c] pyrrol-2-yl] -butyl} -amide ( II-36 )

Step 1 -Methyl vinyl ketone in a mixture of 3-chloro-4-methyl-phenylamine (2.5 g, 17.65 mmol) and trifluoromethanesulfonimide (0.33 g, 1.20 mmol) in MeCN (20 mL) (1 mL, 12.05 mmol) was added. After 1 hour, silica gel and Na ₂ CO ₃ (200 mg) were added to the mixture, which was concentrated in vacuo. The crude product was purified by SiO ₂ column chromatography eluting with n-hexane: EtOAc (4: 1) to give 1.3 g (51%) of 107 : NMR (CDCl ₃ ) δ 2.15 (s, 3H), 2.25 (s, 3H), 2.73 (t, 2H), 3.35 (t, 2H), 3.93 (br, 1H), 6.4 (dd, 1H), 6.6 (d, 1H), 6.98 (d, 1H).

Step 2-1 -acetyl-piperidine-4-carbonyl chloride (3.49 g, 18.42 mmol) and TEA (3 mL, 22.09 mmol) in 107 (1.3 g, 6.14 mmol) solution in DCM (30 mL) were 0 It was added at ℃. After 20 minutes, the solution was heated to 40 ° C. overnight. The mixture was diluted with DCM and washed successively with H ₂ O, 2N HCl, saturated NaHCO ₃ and brine. The organic layer was dried (Na ₂ SO ₄ ), filtered and evaporated. The crude product was purified by SiO ₂ column chromatography eluting with 5% MeOH / EtOAc to give 1.28 g (57%) of 108 : ¹ H NMR (CDCl ₃ ) δ 1.6-1.85 (m, 4H), 2.05 (s, 3H), 2.45 (s, 3H), 2.68 (t, 2H), 2.85 (t, 1H), 3.28 (d, 1H), 3.85-3.95 (m. 2H), 4.5 (d, 1H), 6.98 (dd, 1 H), 7.2 (d, 1 H), 7.33 (d, 1 H).

Step 3 -A solution of 54 (0.10 g, 0.40 mmol) in DCM (7 mL) was added to a solution of 108 (0.17 g, 0.48 mmol) in THF (7 mL). Titanium tetra-isopropoxide (0.26 mL, 0.89 mmol) was added to the mixture. After stirring for 40 minutes, NaBH (OAc) ₃ (0.13 g, 0.61 mmol) was added to the mixture and stirring continued at room temperature overnight. Saturated NaHCO ₃ was added to the mixture, which was stirred for 10 minutes. The mixture was filtered through a CELITE ^® pad and the filtrate was extracted with DCM. The organic layer was dried (MgSO ₄ ) and purified by SiO ₂ column chromatography eluting with DCM: MeOH: NH ₄ OH (150: 10: 1) to afford 0.15 g (64%) of II-36 : mp 60.9-62.4 ° C .; ms (ES +) m / z 594 (M + H).

Example 37

Cyclopentanecarboxylic acid {3- [5- (2,6-dimethyl-benzoyl) -3a, 6a-dimethyl-hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1-phenyl- Propyl} -amide ( I-446 )

Step 1-0 2.5 M of butyllithium in hexane (2 mL, 5 mmol) to 110 (0.35 g, 3 mmol, J. Org. Chem. 1996, 61: 8897-8903] in THF (8 mL) . Prepared as described) into the suspension. The resulting mixture was stirred at 0 ° C. for 15 min, then 2,6-dimethyl-benzoyl chloride (0.421 g, 3 mmol) in THF (2 mL) was added. The reaction mixture was stirred at 0 ° C. for 15 min, then quenched by addition of MeOH (7 mL) and evaporated. The residue was partitioned between EtOAc and water. The organic layer was dried (MgSO ₄ ), filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with a 1: 1 solution gradient of 100% DCM to DCM and DCM / MeOH / NH ₄ OH 80/10/1 to give 52 mg (8%) of 111 . Obtained: ¹ H NMR (CDCl ₃ ) δ 1.01 (s, 3H), 1.11 (s, 3H), 2.26 (s, 6H), 2.83 (d, 1H, J = 12 Hz), 2.90 (d, 1H, J = 12 Hz), 2.95 (d, 1H, J = 12 Hz), 2.96 (d, 1H, J = 12 Hz), 3.09 (d, 1H, J = 12 Hz), 3.15 (d, 1H, J = 12 Hz), 3.54 (d, 1H, J = 12 Hz), 3.84 (d, 1H, J = 12 Hz), 7.03 (bd, 2H, J = 9 Hz), 7.15 (dd, 1H, J = 9; 8 Hz); MS (ES +) m / z 273 (M + H) ⁺ .

Step 2 - DCM (5 mL) of 11 (52 mg, 0.191 mmol) , aldehyde 10 (56 mg, 0.228 mmol) , hydride (81 mg, 0.382 mmol) and HOAc (30 with sodium triacetoxyborohydride □ l, 0.524 mmol) was stirred at room temperature for 48 h and then partitioned between DCM and 5% aqueous NaHCO ₃ solution. The aqueous layer was back extracted three times with DCM. The combined organic layers were dried over magnesium sulphate, filtered and evaporated. The residue was purified by SiO ₂ flash chromatography on silica gel eluting with a 6: 4 solution gradient of DCM (100%) to DCM and DCM / MeOH / NH ₄ OH (80/10/1) ( I -446 ) (50 mg, theoretical 54%) were obtained. ¹ H NMR (DMSO-d ₆ ) δ will be added; ¹³ C NMR (DMSO-d ₆ ) δ 18.86, 18.99, 25.96, 26.01, 30.13, 30.43, 35.74, 41.69, 44.57, 50.50, 51.06, 52.37, 53.12, 60.37, 126.64, 126.68, 126.89, 127.54, 127.61, 128.32, 128.32 128.53, 133.06, 138.25, 144.40, 167.72, 174.81; MS (ES +) m / z 502 (M + H) ⁺ .

Example 38

1-acetyl-piperidine-4-carboxylic acid (5-chloro-thiazol-2-yl)-{3- [5- (2,6-dimethyl-benzoyl) -hexahydro-pyrrolo [3, 4-c] pyrrole-2-yl] -propyl} -amide ( II-389 )

Step 1-1 -acetyl-piperidine-4-carbonyl chloride ( 43 , 282 in a solution of 5-chloro-thiazol-2-ylamine hydrochloride ( 115 , 216 mg, 1.26 mmol) in DCM (3 mL) mg, 1.49 mmol) and TEA (0.41 mL, 2.92 mmol) were added. The mixture was stirred at rt for 12 h. The reaction was quenched with water and the mixture was extracted with DCM. The organic layer was dried (Na ₂ SO ₄ ), concentrated and purified by SiO ₂ chromatography on (100% EtOAc) to give 93 mg (26%) of 114 : ¹ H NMR (CDCl ₃ , 1 H was Not observed) δ 1.66-2.04 (m, 4H), 2.12 (s, 3H), 2.54-2.71 (m, 1H), 2.72-2.84 (m, 1H), 3.10-3.25 (m, 1H), 3.85- 3.99 (m, 1 H), 4.54-4.65 (m, 1 H), 7.23 (s, 1 H).

Step 2- (2,6-dimethyl-phenyl)-(hexahydro-pyrrolo [3,4-c] pyrrole-2-yl) -methanone (111, 964 mg, 3.95 mmol) in DMF (7 mL) To the solution was added 1-chloro-3-iodo-propane (0.6 mL, 5.58 mmol) and Cs ₂ CO ₃ (1.7 g, 5.21 mol). The mixture was stirred at rt overnight. Water was added to the mixture and the resulting solution was extracted with EtOAc. The organic layer was dried (Na ₂ SO ₄ ) and concentrated. The crude product was purified by flash column chromatography on silica gel eluting with a DCM: MeOH: NH ₄ OH gradient (99: 0.7: 0.07 to 96: 3.5: 0.35 for 50 minutes) to afford 0.828 g (65%) of 113 . Obtained: ms (LCMS) m / z 321 (M + H).

Step 3-1-acetyl-piperidine-4-carboxylic acid (5-chloro-thiazol-2-yl) -amide ( 114 , 79 mg, 0.28 mmol) is dissolved in DMF (3 mL) and the result is The prepared solution was cooled to 0 ° C. NaH (29 mg, 60% dispersion in mineral oil) was added and the mixture was heated to 50 ° C. for 2 hours. A solution of 113 (88 mg, 0.28 mmol) and DMF (0.6 mL) was added dropwise and the reaction mixture was stirred at 90 ° C. for 9 hours. The mixture was cooled down, diluted with water and extracted with DCM. The combined DCM extracts were dried (MgSO ₄ ) and concentrated. The crude product was purified by preparative HPLC to give 20.5 mg (13%) of II-389 as TFA salt: ¹ H NMR (DMSO-d ₆ ) δ 1.4-1.6 (m, 2H), 1.85-1.95 (m , 2H), 2.0 (s, 3H), 2.05-2.22 (m, 9H), 2.55-2.65 (m, 1H), 2.9-3.0 (m, 1H), 3.2-3.3 (m, 7H), 3.5-3.9 (m, 7H), 4.15-4.2 (m, 2H), 7.05-7.2 (m, 3H), 7.6 (s, 1H); ms (ES +) m / z 572 (M + H).

Example 39

(S) -cyclopropanecarboxylic acid {3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -2 -Methyl-1-phenyl-propyl} -amide ( I-458 )

Step 1- (2R, 3S, αR) 3-[benzyl- (1-phenyl-ethyl) -amino] -2-methyl-3-phenyl-propionic acid methyl ester ( 116 , 1.00 g, 2.58 mmol, [ J. Chem Soc.Perkin Trans. 1 1994 1129) and a solution of MeOH: EtOAc: 1O% HCl solution (25 mL) containing Pd (OH) ₂ -C (0.50 g) for hydrogenation for 24 hours. (1 atm). The reaction mixture was filtered through a CELITE ^® pad to remove the catalyst. The filtrate was concentrated in vacuo and the residue partitioned between Et ₂ O (40 mL) and saturated NaHCO ₃ solution (25 mL). The organic layer was dried (MgSO ₄ ) and concentrated in vacuo to give 408 mg (80%) of 117a as a pale yellow liquid: ms (ES +) m / z 194 (M + H) ⁺ .

Step 2 -A solution of (2R, 3S) -3-amino-2-methyl-3-phenyl-propionic acid methyl ester ( 117a , 400 mg, 2.06 mmol) in THF (5 mL) was cooled to 0 ° C. A cold solution of NaOH (166 mg, 4.14 mmol) in H ₂ O (3.75 mL) was added to the above solution, then a (BOC) ₂ O solution in THF (2.5 mL) was added and the mixture was allowed to stand at room temperature for 5 hours. Was stirred. The reaction mixture was extracted with EtOAc (2 × 50 mL) and the combined organic extracts were dried (MgSO ₄ ) and concentrated in vacuo to give 117b as a waxy solid: ms (ES +) m / z 237 (MC ₄ H ₈ ) ⁺ .

Step 3 -DIBAL-H (2.42 mL, 2.42 mmol) of 1M DCM solution in 117b (355 mg, 1.21 mmol) in DCM (20 mL) cooled to -78 ° C was maintained at a temperature below -70 ° C. Dropwise at speed. After 2 hours, the reaction was quenched by the slow addition of MeOH (2 mL) and then warmed to room temperature. The reaction mixture was filtered through a CELITE ^® pad. The filtrate was dried (Na ₂ SO ₄ ) and concentrated in vacuo. The crude product was purified by flash chromatography on silica eluting with EtOAc: hexanes (1: 3) to give 118 as a white solid: ¹ H-NMR showed the material to be a diastereomer in a 1: 1.38 ratio.

Step 4 -NaBH (OAc) ₃ (191 mg, 0.90 mmol) at a time in a solution of 118 (197 mg, 0.75 mmol) and 54 (184 mg, 0.75 mmol) in DCM (16 mL) with HOAc (0.11 mL) Joined and the reaction was stirred at rt for 18 h. The reaction was quenched by addition of 10% K ₂ CO ₃ solution (10 mL) and stirred for 20 minutes. The product was extracted with DCM (2 × 20 mL) and the combined extracts were dried (Na ₂ SO ₄ ) and concentrated in vacuo. The crude product was purified by flash chromatography on silica eluting with DCM / 7.5% MeOH (containing 2% NH ₄ OH) to give 290 mg (79%) of 119a as an off-white foam: ms (ES +) m / z 493 (M + H) ⁺ .

Step 5 -A solution of 119a (258 mg, 0.52 mmol) dissolved in 10 M HCl in MeOH (8 mL) was heated to 65 ° C. for 2 hours. MeOH was evaporated under reduced pressure, and the residue was partitioned successively into DCM (25 mL) and 20% K ₂ CO ₃ solution (15 mL). The aqueous layer was reextracted with DCM (2 x 20 mL). The combined extracts were dried (Na ₂ SO ₄ ) and concentrated in vacuo to give 194 mg (95%) of 119b as a viscous liquid: MS (ES +) m / z 393 (M + H) ⁺ .

Step 6-119b (500 μl of 0.1 M DCM solution, 0.050 mmol) and cyclopropanecarbonyl chloride (6.8 μl, 7.8 mg, 0.075 mmol) were added to a solution of DIPEA (0.03 mL), and the resulting mixture was stirred for 18 hours at room temperature. Was stirred. The reaction mixture was concentrated in an N ₂ stream and purified by reverse phase HPLC to give I-458 : ms (ES +) m / z 461 (M + H) ⁺ .

Example 40

1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -3a, 6a- Dimethyl-hexahydro-pyrrolo [3,4-c] pyrrole-2-yl] -propyl} -amide ( II-174 )

Step 1 -A mixture of 110 (1.2 g, 8 mmol), 18 (0.75 g, 2 mmol), KI (0.55 g, 3 mmol) and K ₂ CO ₃ (0.825 g, 6 mmol) in DMF (30 mL) was added to 80 After stirring for 16 h at C, it was partitioned into water and EtOAc. The aqueous layer was extracted twice with EtOAc. The combined organic layers were dried (MgSO ₄ ), filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with a 1: 9 solution gradient of 100% DCM to DCM and DCM / MeOH / NH ₄ OH 60/10/1 to give 0.100 g (3%) of 126 . ¹ H NMR (CDCl ₃ ) δ 1.53-2.46 (m, 15H), 2.56 (d, 2H, J = 9 Hz), 2.67 (d, 2H, J = 9 Hz), 2.78-2.95 (m, 3H ), 3.48 (s, 6H), 4.52 (db, 1H, J = 15 Hz), 6.97 (dd, 1H, J = 9; 3 Hz), 7.18 (d, 1H, J = 3 Hz), 7.31 (d , 1H, J = 3 Hz); MS (ES +) m / z 608 (M + H) ⁺ .

Step 2 -DIPEA (73 □ l, 0.42 mmol) was added 126 (100 mg, 0.21 mmol), 2,4-dimethyl-3-pyridyl carboxylic acid (32 mg, 0.21 mmol) in DMF (1 mL) at room temperature, Add to EDCI (48 mg, 0.25 mmol) and HOBT (34 mg, 0.25 mmol) solution. The resulting mixture was stirred at rt for 16 h and then partitioned between EtOAc and water. The aqueous layer was extracted twice with EtOAc. The combined organic layers were dried (Na ₂ SO ₄ ), filtered and evaporated. The residue is eluted with a 1: 1 mixture DCM gradient of 100% DCM to DCM / MeOH / NH ₄ OH (80/10/1) solution for 20 minutes and then eluted with 8/2 DCM / MeOH solution for 10 minutes. (15 mL / min), purified by SiO ₂ flash chromatography to yield 87 mg (64%) of II-174 : ¹ H NMR (CD ₃ OD) δδ 0.90-3.34 (m, 35H), 3.39-3.84 (m, 4H), 3.92 (m, 1H), 4.52 (bd, 1H, J = 12 Hz), 6.97 (m, 2H), 7.17 (bs, 1H), 7.31 (d, 1H, 1 = 6 Hz), 8.36 (d, 1 H, 1 = 3 Hz); ¹³ C NMR (CDCl ₃ ) δ 19.10, 19.18, 20.19, 20.82, 21.14, 21.77, 22.52, 22.62, 27.05, 28.71, 29.22, 39.76, 41.07, 45.91, 48.41, 49.35, 49.38, 50.12, 50.69, 53.36, 58.30, 60.95, 67.41, 67.72, 123.02, 123.10, 126.69, 128.83, 132.40, 133.10, 135.64, 136.91, 141.50, 143.49, 143.58, 149.17, 149.22, 153.88, 154.06, 167.45, 169.19, 174

Example 41

1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3-[(5- (2,4-dimethyl-pyridine-3-carbonyl) -3a, 6a -Bis-hydroxymethyl-hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -propyl} -amide ( II-190 )

Step 1 -Formaldehyde (37% by weight in water) was added to a reflux suspension of N-benzylglycine (10 g, 60.37 mmol) and dimethylacetylenedicarboxylate (3.7 mL, 30.19 mmol) in 200 mL of toluene for 3 hours. Added dropwise. The resulting mixture was stirred and reflux heated for 14 hours while water was removed continuously with Dean Stark trap. The reaction mixture was cooled to rt and evaporated. The residue was purified by SiO ₂ chromatography eluting with a hexane / EtOAc gradient (100% EtOAc to 75/25) for 40 minutes at a flow rate of 80 mL / min to give 3.4 g (28%) of 122a : ¹ H NMR (CDCl ₃ ) δ 2.71 (d, 2H, J = 9 Hz), 3.08 (d, 2H, J = 9 Hz), 3.66 (s, 5H), 7.17-7.42 (m, 5H); MS (ES +) m / z 409 (M + H) ⁺ .

Step 2 -LAH solution (33 mL, 33 mmol, 1M solution in THF) was added to a solution of 122a (3.4 g, 8.323 mmol) and THF (100 mL) cooled to 0 ° C. and maintained under nitrogen. The resulting reaction mixture was stirred at 0 ° C. for 2 hours and then quenched by addition of saturated NaHCO ₃ . The aqueous layer was extracted twice with EtOAc and the combined organic layers were dried (Na ₂ SO ₄ ), filtered and evaporated to give 2.9 g (99%) of 122b : ¹ H NMR (CDCl ₃ ) δ 2.56 (s, 4H), 3.58 (s, 2H), 3.63 (s, 2H), 7.18-7.38 (m, 5H); MS (ES +) m / z 353 (M + H) ⁺ .

Step 3 -Trimethyl acetyl chloride (1.7 mL, 13.8 mmol) was added to a solution of 122b (1.9 g, 5.39 mmol) in DCM (25 mL) and pyridine (2 mL). The resulting mixture was stirred at rt for 24 h before 5 mL of MeOH was added. After stirring for 1 h at rt, the reaction mixture was diluted with DCM and washed with 1M aqueous HCl, aqueous saturated NaHCO ₃ and water. The organic layer was dried (Na ₂ SO ₄ ), filtered and evaporated. The residue was purified by SiO ₂ chromatography eluting with a hexane / EtOAc gradient (100% hexanes to 10% EtOAc) to give 1.14 g (41% theory) of 122c : ¹ H NMR (CDCl ₃ ) δ 1.15 ( s, 9H), 2.53 (d, 2H, J = 9 Hz), 2.57 (d, 2H, J = 9 Hz), 3.58 (s, 2H), 4.12 (s, 2H), 7.18-7.34 (m, 5H ); MS (ES +) m / z 521 (M + H) ⁺ .

Step 4 -Mixing a mixture of 122c (1.14 g, 2.189 mmol) and Pd (OH) ₂ / C (0.5 g; 20 wt% to carbon) in EtOH (40 mL) and 10 mL of cyclohexane with stirring for 24 hours Heated to reflux. The reaction mixture was cooled to rt, filtered and evaporated. The residue was dissolved in DCM and 5 mL of 1M HCl in Et ₂ O was added. The precipitate was filtered off and washed with DCM to give 0.365 g (40%) of 123 as a light brown solid: ¹ H NMR (DMSO-d ₆ ) δ 1.18 (s, 9H), 3.37 (d, 2H, J = 9 Hz), 3.60 (d, 2H, J = 9 Hz), 4.26 (s, 2H), 10.01 (bs, 1H); MS (ES +) m / z 341 (M + H) ⁺ .

Step 5 -A mixture of 123 (90 mg, 0.242 mmol) and KI (44 mg, 0.266 mmol) in DMF (1 mL) was stirred at 80 ° C. for 8 hours, then chloride 18 (0.1 g, in DMF (1 mL), 0.242 mmol) and DIPEA (110 □ l, 0.605 mmol). The resulting hazy mixture was stirred at 40 ° C. for 15 hours and then at 80 ° C. for 2 hours, then cooled to room temperature and diluted with EtOAc. The organic layer was washed with water and the aqueous layer was back extracted once with EtOAc. The combined organic layers were dried (Na ₂ SO ₄ ), filtered and evaporated. The residue was purified on a SiO ₂ chromatography gel eluting with a 1: 1 solution gradient of 100% DCM to DCM and DCM / MeOH / NH ₄ OH 60/10/1 for 20 minutes at a flow rate of 25 mL / min, 0.064 g (39%) of 124 was obtained: MS (ES +) m / z 341 (M + H) ⁺ .

Step 6-2,4-dimethyl-nicotinoyl chloride hydrochloride (39 mg / 188.7 □ mol) prepared from 2,4-dimethyl-nicotinic acid was charged with 124 (64 mg / 94.33 □ mol) and DIPEA in 0.5 mL of DCM. (30 □ L / 188.7 □ mol) to the mixture. The resulting reaction mixture was stirred at rt for 5 h, then diluted with DCM and washed with water. The aqueous layer was extracted once with DCM. The combined organic layers were dried over sodium sulphate, filtered and evaporated. The residue was purified by SiO ₂ chromatography, eluting with a 1: 1 solution gradient of 100% DCM to DCM and DCM / MeOH / NH ₄ OH 60/10/1 for 20 minutes at a flow rate of 25 mL / min, 0.062 g (81%) of 125 were obtained: ¹ H NMR (CDCl ₃ ) δ, mixture of rotamers, selected data: 4.51 (bd, 1H, J = 12 Hz), 6.93-7.04 (m, 2H), 7.16 ( m, 1H), 7.32 (d, 1H, J = 9 Hz), 8.37 (dd, 1H, J = 3, 1 Hz); MS (ES +) m / z 808 (M + H) ⁺ .

Step 7 -Sodium methoxide (0.5 mL, 25 wt.% In MeOH) was added to a solution of 125 (0.060 g, 74.21 □ mol) in MeOH (4 mL) at room temperature. The resulting mixture was stirred at rt overnight, then neutralized by addition of Dowex 50WX8-200. The resin was filtered off and washed with MeOH. The filtrate was evaporated and the residue was subjected to SiO ₂ chromatography (13 g RediSep column, DCM / [DCM / MeOH / NH ₄ OH 60/10/1] 10/0 to 1/1, 25 mL / min for 20 min. Purification to give 23 mg (48%) of II-190 as a white foam: ¹ H NMR (CDCl ₃ ) δ 1.51-1.85 (m, 6H), 2.05 (s, 3H), 2.22-2.56 ( m, 16H), 2.61 (m, 1H), 2.84 (m, 1H), 3.07 (m, 1H), 3.39 (m, 1H), 3.51 (m, 1H), 3.38-3.57 (m, 8H), 4.51 (bd, 1H, J = 12 Hz), 6.96 (dd, 1H, J = 9, 1 Hz), 6.99 (dd, 1H, J = 3, 1 Hz), 7.17 (m, 1H), 7.32 (d, 1H, J = 9 Hz), 8.34 (t, 1H, 1 = 3 Hz); C NMR (CDCl ₃ ) δ 19.09, 19.31, 20.20, 21.76, 22.41, 22.68, 26.87, 28.72, 29.22, 30.08, 39.73, 41.07, 45.91, 48.16, 52.60, 53.82, 55.07, 55.13, 55.97, 56.05, 56.48, 63.91 , 64.16, 123.16, 123.24, 126.61, 128.73, 132.48, 135.72, 137.07, 141.35, 149.09, 149.24, 153.73, 167.70,167.92, 169.24, 174.37; MS (ES +) m / z 640 (M + H) ⁺ .

Example 42

Human CCR5 Receptor-ligand Binding Assay Protocol

Human CCR5 receptor (GenBank ID: 29169292) was cloned into pTarget (Promega), a mammalian expression vector. Using the Fugene reagent (Roche), the constructs were transfected into CHO-G _α16 cells. Clones were selected under antibiotic pressure (G418 and hygromycin) and separated four times with fluorescently labeled cell separators and monoclonal antibodies specific to the CCR5 receptor (BD Biosciences Pharmigen, Mab 2D7, Cat. 555993). The most expressed clones (100,000 copies per cell) were selected for binding assays.

Adhesion cells (˜90% fusion) in 225 mL tissue culture flasks were harvested using 1 mM EDTA in PBS (phosphate-buffered saline) free of Ca ²⁺ and Mg ²⁺ . Cells were washed twice with PBS without Ca ²⁺ and Mg ²⁺ . Subsequently, CHO-G _α16 -hCCR5 cells, freshly prepared 0.5% BSA and 0.05% NaN ₃ supplemented with, ice-cold binding buffer (50 mM HEPES, 1 mM CaCl _2, 5 mM MgCl _2, 0.5% BSA, 0.05% NaN ₃ , pH 7.24) pH 7.4) (1 × 10 ⁶ / ml).

_{80 ㎕ CHO-G α16 -hCCR5 (} 1 x 10 6 / ml) cells were added to 96 well (well) plates. All diluted with binding buffer (50 mM HEPES, 1 mM CaCl ₂ , 5 mM MgCl ₂ , 0.5% BSA, 0.05% NaN ₃ , pH 7.24).

The plates were incubated on a cell shaker at room temperature for 2 hours at a final concentration of 0.1 nM ¹²⁵ I RANTES or ¹²⁵ I MIP-1α or ¹²⁵ I MIP-1β. The compound was diluted with PBS, 1% BSA. The total reaction volume was 100 μl per well. Test compounds were added to the cells prior to radioligand addition.

After incubation, the cells were harvested onto GF / C filter plates using a Packard cell harvester. The filter was pretreated with 0.3% PEI / 0.2% BSA for 30 minutes. The filter plate was washed five times rapidly with 25 mM HEPES, 500 mM NaCl, 1 mM CaCl ₂ and 5 mM MgCl ₂ adjusted to pH 7.1. The plate was dried in an oven (70 ° C.) for 20 minutes, 40 μl of scintillation fluid was added and sealed with Packard TopSeal-A. Packard Top Count was used to measure radioactivity for 1 minute per well.

Total binding was measured using control wells with radioisotopes and buffer added, and nonspecific binding was measured with excess cold RANTES in some control wells. Specific binding was measured by subtracting nonspecific binding from total binding. The results are expressed as a percentage of specific ¹²⁵ I RANTES binding. IC ₅₀ values were measured using three test ligands of varying concentrations, and the data was analyzed using GraphPad Prism (GraphPad, San Diego, Calif.).

Compound number Coupled IC ₅₀ (M) Compound number Coupled IC ₅₀ (M) RANTES RANTES II-303 0.1019 II-279 0.0015 I-466 0.011 I-39 0.0032 I-449 0.001 II-152 0.0022 II-3 0.0184 II-355 0.0027 I-78 0.037 II-182 0.0028 II-1 0.0042 I-52 0.0028 I-29 0.016 II-175 0.0029 I-4 0.0191 I-47 0.0037 I-14 0.0019

Example 43

Pharmaceutical compositions of the subject compounds for administration by various routes were prepared as described in this example.

Compositions for Oral Administration (A)

ingredient % Weight / weight Active Ingredients Lactose Magnesium Stearate 20.0% 79.5% 0.5%

The ingredients were mixed and dispensed into capsules containing about 100 mg each (one capsule is approximately the total daily dose).

Composition for Oral Administration (B)

ingredient % Weight / weight Active Ingredient Magnesium Stearate Croscarmellose Sodium Lactose PVP (Polyvinylpyrrolidine) 20.0% 0.5% 2.0% 76.5% 1.0%

The components were combined and granulated using a solvent such as methanol. The formulation is then dried and formulated into tablets (containing about 20 mg of active compound) using an appropriate tablet machine.

Compositions for Oral Administration (C)

ingredient % Weight / weight Active ingredient Sodium fumarate Methyl paraben Propyl paraben Granulated sugar Sorbitol (70% solution) Veegum K (Vanderbilt Co.) Perfume colorant Distilled water 1.0 g 0.5 g 2.0 g 0.15 g 0.05 g 25.5 g 12.85 g 1.0 g 0.035 ml 0.5 mg Sufficient to be 100 ml

The components were mixed to formulate a suspension for oral administration.

Parenteral Formulations (D)

ingredient % Weight / weight Active ingredient sodium chloride water for injection 100 ml sufficient to produce 0.25 g isotonic solution

The active ingredient was dissolved in some water for injection. Subsequently, a sufficient amount of sodium chloride was added with stirring to cause the solution to isotonic. The solution was weighted up with the remaining water for injection, filtered through a 0.2 micron membrane filter and packaged under sterile conditions.

Suppository Formulations (E)

ingredient % Weight / weight Active ingredient Polyethylene glycol 1000 Polyethylene glycol 4000 1.0% 74.5% 24.5%

The components were melted and mixed together on a steam bath and poured into a mold containing 2.5 g total weight.

Topical Formulations (F)

ingredient gram Active Ingredient Span 60 Tween 60 Mineral Oil Petrolactum Methyl Paraben Propyl Paraben BHA (Butylated Hydroxy Anisole) Water 0.2-2 2 2 5 10 0.15 0.05 0.01 100 Sufficient to be

All components except water were combined and heated to about 60 ° C. with stirring. Subsequently, a sufficient amount of water of about 60 ° C. was added with vigorous stirring to emulsify the components, followed by addition of a sufficient amount of water to be about 100 g.

Nasal Spray Formulations (G)

Several aqueous suspensions containing about 0.025-0.5% of active compound were prepared as nasal spray formulations. The formulation optionally contains inert ingredients such as, for example, microcrystalline cellulose, sodium carboxymethylcellulose, textose and the like. Hydrochloric acid can be added to adjust the pH. Nasal spray formulations can be delivered via a nasal spray metering pump, which delivers about 50-100 μl of the formulation per launch. A typical dosing schedule is 2-4 sprays every 4-12 hours.

Reference Example

(2,4-Dimethyl-pyridin-3-yl)-(hexahydro-pyrrolo [3,4-c] pyrrole-2-yl) -methanone ( 54 )

Step 1 -add 4a (1.0 g, 4.94 mmol) and (dry) toluene (4 mL) to a 25 mL three-neck flask equipped with a stir bar, an addition funnel, an N ₂ inlet tube and a reflux condenser, It cooled to 0 degreeC. Trimethylaluminum (2.5 mL of 2.0 M toluene solution, 5.0 mmol) was added dropwise and then warmed to room temperature. 2,4-dimethyl-nicotinic acid ethyl ester ( 80 , 0.93 g, 5.2 mmol) in toluene (1 mL) was added dropwise and then heated at 120 ° C. for 18 hours. The reaction mixture was cooled in an ice bath and MeOH (2 mL) was added. The mixture was brought to room temperature, heated to reflux for 10 minutes and then recooled to room temperature. The mixture was filtered through a CELITE ^® pad. The filtrate was washed with brine, dried (MgSO ₄ ) and then concentrated in vacuo. The crude product was purified by flash chromatography on silica eluting with 7.5% MeOH (containing 2% NH ₄ OH) / DCM to give 1.17 g (71%) of 81 as a pale yellow liquid: ms (ES +) m / z 336 (M + H) ⁺ .

Step 2 -A solution of 81 (5.55 g, 16.5 mmol) in EtOH (250 mL) containing 20% Pd (OH) ₂ (2.75 g) was hydrogenated at 55 psi to 60 psi for 18 hours. The mixture was filtered through a CELITE ^® pad to remove the catalyst and the filtrate was concentrated in vacuo to give 3.88 g (95%) of 54 as a dark viscous liquid: ms (ES +) m / z 246 (M + H ) ⁺ .

Features, as indicated in the foregoing descriptions or in the claims below, represented in a particular form or means for achieving the functions disclosed, or as a method or process for obtaining the disclosed results, where appropriate, individually or in any combination thereof The present invention can be realized in various forms.

The foregoing invention has been described in more detail by way of illustration and example, for clarity and understanding. It will be apparent to those skilled in the art that changes and modifications can be made within the scope of the appended claims. Accordingly, the foregoing description is to be understood as illustrative and not restrictive. Accordingly, the scope of the invention should not be determined with reference to the foregoing description, but instead should be determined with reference to the appended claims, along with the full scope of equivalents to which such claims are entitled.

All patents, patent applications and publications mentioned in this application are incorporated herein by reference in their entirety for all purposes to the same extent as the individual patents, patent applications or publications individually represent.

Claims (35)

A compound of formula I, and pharmaceutically acceptable salts, hydrates and stereoisomers thereof, as follows:

[here: X ¹ is —C (═O) R ³ or —S (═O) ₂ R ³ ; X ² is -C (= 0) R ⁴ or -S (= 0) ₂ R ⁴ ; One of R ¹ and R ² is phenyl optionally substituted with 1 to 4 substituents independently selected at each occurrence from the group consisting of halogen, C _1-6 alkyl and C _1-6 alkoxy; The rest of R ¹ and R ² are hydrogen; R ³ is selected from the group consisting of: (i) phenyl optionally substituted with 1 to 4 substituents independently selected at each occurrence from the group consisting of: (a) C _1-10 alkyl, (b) C _1-10 heteroalkyl, wherein the carbon atom may be replaced by one or more atoms selected from the group consisting of oxygen, sulfur and nitrogen atoms, (c) C _1-6 haloalkyl, (d) C _1-6 alkoxy, (e) C _1-6 thioalkyl, (f) amino, (g) C _1-6 alkyl amino, (h) C _1-6 dialkylamino, (g) C _1-6 acylamino, (i) carbamoyl, NC _1-6 alkylcarbamoyl or N, NC _1-6 dialkylcarbamoyl, (j) ureido, (k) nitro, (l) cyano, (m) halogen, (n) C _1-6 alkylsulfonyl, (o) sulfamoyl, NC _1-6 alkylsulfamoyl or N, NC _1-6 dialkylsulfamoyl, (p) C _1-6 alkylsulfonamido or optionally substituted phenylsulfonamido, (q) optionally substituted phenoxy, (r) -Y (CH ₂ ) _n R ¹¹ where R ¹¹ is cyano, -CO ₂ R ¹² , -CONR ¹² R ¹³ , -SO ₂ N ¹² R ¹³ , -NHSO ₂ R ¹² and -NHSO ₂ NR ¹² R ¹³ ), (s) CO ₂ R ¹² , (t) C _1-6 acyloxy, (u) C _1-6 alkylcarbonyl, and (v) C _1-6 haloalkoxy; (Ii) phenyl C _1-6 alkyl, wherein phenyl is as described in (i) above; (iii) C _3-7 cycloalkyl or bicyclohexyl, 4-oxo-cyclohexyl or 3-oxo-cyclobutyl (the cycloalkyl being 1 to 4 fluorine, cyano, hydroxyl, C _1-3 alkyl or Optionally substituted with phenyl); (iv) C _1-3 alkyl-C _3-7 cycloalkyl, wherein said cycloalkyl is optionally substituted with _1-4 fluorine, C _1-3 alkyl or phenyl; (v) NR ^14a R ^14b ; R ⁴ is heteroaryl selected from the group consisting of pyridinyl, pyridinyl N-oxide, pyrimidinyl, pyrazinyl, pyridazinyl and cinnaolin-4-yl, wherein said heteroaryl is (a) C _1-10 Alkyl, (b) phenyl optionally substituted with 1 to 4 substituents independently selected in each case from the group consisting of substituents (i) (a) to (i) (v) described for R ³ above, (c ) Benzyl, (d) acetyl, (e) amino, (f) C _1-6 alkylamino, (g) C _1-6 dialkylamino, (h) aminobenzyl, (i) C _1-6 haloalkyl, (j) C _1-6 alkoxy, (k) C _1-6 thioalkyl, (l) C _1-6 alkylsulfonyl, (m) C _1-6 alkoxycarbonyl, (n) carboxyl, (o) Group consisting of carbamoyl, (p) nitro, (q) cyano, (r) sulfamoyl, (s) -OCH ₂ CO ₂ R ^14c , (t) -SCH ₂ CO ₂ R ^14c and (u) halogen Optionally substituted with 1 to 3 substituents independently selected at each occurrence from; R ⁵ and R ^5a are hydrogen or C _1-6 alkyl; R ⁶ is hydrogen; R ¹² and R ¹³ are (i) independently hydrogen, C _1-6 alkyl or C _1-6 heteroalkyl, wherein the carbon atoms may be replaced with one or more atoms selected from the group consisting of oxygen, sulfur and nitrogen atoms ego; R ^14a and R ^14b are independently hydrogen, R ³ (i), R ³ (ii), R ³ (iii), R ³ (iv), C (═O) OR ^14c , or (a) hydroxy, (b) halogen, (c) C _1-6 alkoxy, (d) C _1-6 thioalkyl, (e) acyloxy, (f) C _1-6 alkoxycarbonyl, (g) C _1-6 acylamino , (h) N (R ^14c ) ₂ , wherein R ^14c is independently selected, (i) cyano, (j) C _1-6 alkylsulfonyl, (k) N-methyl-methyl-sulfonamido , (l) carbamoyl, (m) C _1-6 alkoxycarbonyl, and (n) 1 independently selected in each case from the group consisting of optionally substituted phenyl as defined in R ³ (i) above Phenyl optionally substituted at each occurrence independently with from 3 to 3 substituents; R ^14c is hydrogen or C _1-6 alkyl; Y is a direct bond, -0-, -S- or -NR ^12- ; n is an integer from 1 to 6; delete delete delete delete delete delete delete delete delete delete delete delete delete delete The compound of claim 1 selected from the group consisting of: Cyclopentanecarboxylic acid {(S) -1-phenyl-3- [5- (pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -propyl}- amides; Compound with trifluoro-acetic acid, Cyclopentanecarboxylic acid {(S) -3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrole-2-yl]- 1-phenyl-propyl} -amide, Cyclopentanecarboxylic acid {(S) -3- [5- (2,4-dimethyl-pyridine-3-carbonyl) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -1 -Phenyl-propyl} -amide, 3- (3- (3-Chloro-4-methyl-phenyl) -3- {3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4 -c] pyrrole-2-yl] -propyl} -ureido) -benzoic acid; Compound with trifluoro-acetic acid, 4,4-Difluoro-cyclohexanecarboxylic acid {(S) -3- [5- (4,6-dimethyl-pyrimidine-5-carbonyl) -hexahydro-pyrrolo [3,4-c ] Pyrrole-2-yl] -1-phenyl-butyl} -amide, or (5- {5-[(S) -3- (Cyclopentanecarbonyl-amino) -3-phenyl-propyl] -hexahydro-pyrrolo [3,4-c] pyrrole-2-carbonyl} -4 , 6-dimethyl-pyrimidin-2-yloxy) -acetic acid; Compound with trifluoro-acetic acid. delete delete delete delete Formula I according to claim 1, wherein R ¹ is hydrogen and R ² is independently selected in each case from the group consisting of halogen, C _1-6 alkyl and C _1-6 alkoxy Phenyl optionally substituted with 1 to 4 substituents, X ¹ is —C (═O) R ³ , X ² is —C (═O) R ⁴ , and R ⁵ , R ^5a and R ⁶ are independently hydrogen; , R ³ and R ⁴ are as defined in claim 1)

(a) V , wherein R 'is benzyl, a benzoyl or tert-butoxycarbonyl protecting group optionally substituted with a methyl group, under acidic conditions sufficient to promote the formation of imine and the reduction of the corresponding iminium salt. Contacting with β-acylaminoaldehyde of IV , wherein R is a R ³ group according to claim 1 and sodium triacetoxyborohydride to yield VI ;

(b) if R 'is a protecting group, optionally exposing VI to a condition sufficient to effect deprotection to yield VII ;

(c) contacting VII with a carboxylic acid, R "CO ₂ H, or an oxide or halide of an activated carboxylic acid under conditions sufficient to promote acylation, wherein VIII (where R" is defined in claim 1 R ⁴ term according to the above). Formula I according to claim 1, wherein R ¹ is 1 to 4 substituents independently selected in each case from the group consisting of halogen, C _1-6 alkyl and C _1-6 alkoxy Optionally substituted phenyl, R ² is hydrogen, X ¹ is —C (═O) R ³ , X ² is —C (═O) R ⁴ , and R ⁵ , R ^5a and R ⁶ are independently hydrogen; , R ³ and R ⁴ are as defined in claim 1)

(a) V (wherein, R 'is benzyl, optionally substituted with a methyl group benzoyl or tert- butoxycarbonyl protecting group), under conditions sufficient to calculate the X, β- acylamino aldehyde of formula (IX) (wherein R is a group R ³ according to claim 1 and (het) Ar is 1 to 4 independently selected in each case from the group consisting of halogen, C _1-6 alkyl and C _1-6 alkoxy according to claim 1 Contacting a phenyl group optionally substituted with a substituent) to yield X ;

(b) when R 'is a protecting group, optionally exposing X to a reagent sufficient to effect deprotection to yield XI ;

(c) XI is contacted with a carboxylic acid, R "CO ₂ H, or an oxide or halide of an activated carboxylic acid, under the conditions under which acylation occurs so that XII (where R" is R ⁴ according to claim ¹ Step). delete The method of claim 1, R ¹ is optionally substituted phenyl, X ¹ is —C (═O) R ³ or —S (═O) ₂ R ³ , X ² is —C (═O) R ⁴ , and R ² , R ⁵ , R ^5a and R ⁶ are hydrogen. The compound of claim 24, wherein R ³ is NR ^14a R ^14b . The compound of claim 25, wherein R ^14a is optionally substituted phenyl and R ^14b is hydrogen. The compound of claim 26, wherein R ¹ is 4-methyl-3-chloro-phenyl, R ^14a is phenyl substituted with carboxyl or C _1-6 alkoxycarbonyl, and R ^14b is hydrogen. The method of claim 1, R ² is optionally substituted phenyl, X ¹ is —C (═O) R ³ or —S (═O) ₂ R ³ , X ² is —C (═O) R ⁴ , and R ¹ , R ⁵ , R ^5a and R ⁶ are hydrogen. The compound of claim 28, wherein X ¹ is —C (═O) R ³ , R ³ is optionally substituted phenyl, optionally substituted cycloalkyl, 4-oxo-cyclohexyl, or 3-oxo-cyclobutyl, and R ⁴ is One or more atoms adjacent to the atom bonded to X ² is a heteroaryl which is a substituted carbon atom 30. The compound of claim 29, wherein X ¹ is -C (= 0) R ³ and R ³ is cycloalkyl optionally substituted with 1 to 4 fluorine atoms. 31. The compound of claim 30, wherein R ³ is cyclopentyl, 4,4-difluorocyclohexyl or 3,3-difluorocyclobutyl, and R ⁴ is 2,6-dimethyl-pyrimidin-5-yl, 2 , 6-dimethyl-pyridin-3-yl and a compound selected from the group consisting of

. 32. The compound of claim 31, wherein R ² is phenyl. 33. A compound of formula I according to any one of claims 1, 16 or 24 to 32 for use as a medicament. 33. A method of using the compound of formula I according to any one of claims 1, 16 or 24 to 32 for the manufacture of a medicament for the treatment of a disease mediated by human immunodeficiency virus (HIV). Human immunodeficiency virus comprising a pharmaceutically effective amount of a compound as defined in any one of claims 1, 16 or 24 to 32 or a pharmaceutically acceptable salt thereof and a pharmaceutically inert carrier ( Pharmaceutical compositions for use in the treatment of diseases mediated by HIV).