TW202211918A - Novel inhibitors of autotaxin - Google Patents

Abstract

The present invention relates to novel heterocyclic compounds of general formula (I) and their pharmaceutically acceptable salts, enantiomers and their diastereomers that are autotaxin (ATX) inhibitors. Compounds of general formula (I), their pharmaceutically acceptable salts and pharmaceutical composition are useful for the treatment and prophylaxis of conditions or a disorder caused by autotaxin (ATX) activation or increased concentration of lysophosphatidic acid (LPA).

Description

Novel autotaxin inhibitors

The present invention describes novel compounds of formula (I) as autotaxin (ATX) inhibitors for the treatment and prophylaxis caused by autotaxin (ATX) activation or increased concentrations of lysophosphatidic acid (LPA) conditions or disorders, also describe pharmaceutical compositions containing the compounds. The present invention also describes pharmaceutically acceptable salts, enantiomers, tautomeric forms, nonenantiomers thereof, and pharmaceutical compositions of the novel otetacin (ATX) inhibitors.

As a biologically active messenger molecule, the ATX enzyme is important for the conversion of lysophosphatidylcholine (LPC) to LPA. ATX is a secretase of the exonucleotide phosphatase family, also known as exonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP-2 or NPP2). ATX plays an important role in driving pathological conditions including fibrosis, arthritic inflammation, neurodegeneration, neuropathic pain and cancer. LPA is a bioactive lipid that affects the migration, proliferation and survival of various cell types. LPA mediates various cellular and biological effects through the LPA receptor (LPAR). LPA shows a wide range of tissue manifestations, and it can couple to at least six different G proteins, termed LPAR1-6, which in turn enter multiple effector systems (Yung, Y.C. et al., J. Lipid Res. 2014, 55, 1192 and Kihara, Y. et al., Exp. Cell Res. 2015, 333, 171). Since the level of LPA in plasma is highly correlated with the activity of ATX, it is believed that ATX is an important source of extracellular LPA.

Inhibition of ATX has been shown to reduce LPA levels in pathological settings. Lowering LPA may provide therapeutic benefit in diseases of unmet need, including cancer, lymphocyte homing chronic inflammation, neuropathic pain, fibrotic diseases such as idiopathic pulmonary fibrosis (IPF), thrombosis and cholestasis, These diseases are caused and/or spread by increased LPA levels and/or activation of ATX.

IPF is characterized by progressive scarring of lung tissue, leading to worsening lung function and eventual death within 3 to 5 years of symptoms. Until 2014, the FDA approved Nintedanib (Ofev) and Pirfenidone (Esbriet) as a treatment option (King, T, E. et al., Lancet 2011, 378, 1949; Richeldi, L. at el., N. Engl. J. Med. 2014, 370, 2071; Roth, G. J. et al., J. Med. Chem. 2009, 52, 4466; J. Med. Chem. 2015, 58 , 1053; Hilberg, F. et al., Drugs Future 2010, 35, 5; and King, T. E. et al., N. Engl. J. Med. 2014, 370, 2083). Despite this progress, additional drugs are still needed to treat IPF. Patients with IPF have elevated levels of LPA in their bronchoalveolar lavage fluid (BALF) and exhaled breath condensate. LPAR1 has been identified as the major LPA receptor (Tager, A. M. et al., Nat. Med. 2008, 14, 45 and Montesi, S. B. et al., BMC Pulm. Med. 2014). In lung fibroblasts from IPF patients, LPAR1 was found to be responsible for enhancing fibroblast migration and vascular leakage. It is therefore envisaged that LPAR1 antagonists will be potential drug targets for the treatment of IPF. In recent years, several LPAR1 antagonists have been reported, some of which are currently being evaluated for the treatment of IPF (Budd, D. C et al., Future Med. Chem. 2013, 5, 1935; Qian, Y. et al. al., J. Med. Chem. 2012, 55, 7920 and Terakado, M. et al., ACS Med. Chem. Lett. 2016, 7, 913).

Fibrosis can develop in the liver, kidney, lung, dermis, vasculature, intestine, and other sites. Fibrosis develops due to the action of pathways including growth factors, cytokines, integrins and lipids. ATX, LPA and LPAR pathways are associated with fibrotic diseases. Elevated levels of ATX, LPA, and LPAR were observed in various rodent fibrosis models and in patient fluid and tissue sections. LPA induces proliferative, survival, and chemotactic responses in cells known to be critical to fibrotic disease, including: fibroblasts, smooth muscle cells, macrophages, epithelial and endothelial cells, and leukocytes. Inhibitors of LPAR show that antagonism of receptors in this pathway blocks or reverses fibrosis in rodent lung, liver, kidney and skin. Thus, in fibrotic diseases, it is desirable to reduce LPA levels. This can be accomplished by inhibiting enzymes involved in LPA biosynthesis, such as ATX.

各種刊物提及能夠抑制ATX的化合物，包括：WO2019228403、WO2019108943、WO2019029620、WO2019223721、WO2019158107、WO2018153312、WO2017152062、WO2017050791、WO2017050792、WO2017050747、WO2017050732、WO2015144605、WO2015042052、WO2014139882、WO2014139978、WO2014097151、WO2014048865、WO2014202458、WO2010130944、 WO2013186159. For the treatment and/or prevention of physiological and/or pathophysiological conditions such as cancer, chronic inflammation, neuropathic pain, fibrotic diseases, thrombosis caused, mediated and/or propagated by increased LPA levels and/or activation of ATX There is an unmet need for the resulting ATX inhibitors.

The present invention describes novel compounds that are inhibitors of altetaxine (ATX) for the treatment and prevention of conditions or disorders caused by ATX activation or increased concentrations of LAP, as well as pharmaceutical compositions containing the compounds.

。 本發明之實施例 The present invention includes certain substituted compounds described herein, their salts, their formulations, their pharmaceutical compositions and formulations, and methods of, for example, using them to treat diseases. The present invention includes novel compounds of formula ( I ), pharmaceutically acceptable salts, tautomeric forms, enantiomers and diastereoisomers thereof. In some embodiments, the compounds of the present invention are inhibitors of ATX. Embodiments of the present invention include the compounds herein, pharmaceutically acceptable salts thereof, any physical form thereof including solvates and hydrates, formulations of the compounds, intermediates and pharmaceutical compositions, and formulations thereof,

. Embodiments of the present invention

Embodiments of the present invention provide novel compounds represented by general formula ( I ), pharmaceutically acceptable salts, tautomeric forms, enantiomers, and diastereomers thereof.

In a further embodiment of the present invention, there is provided a pharmaceutical composition comprising the novel compound of general formula ( I ), its tautomeric forms, its enantiomers, its non-spiroisomers, its stereoisomers , their pharmaceutically acceptable salts or a mixture of them in combination with suitable excipients.

In yet further embodiments, there is provided the use of a novel compound of the present invention as an ATX inhibitor by administering to a mammal a therapeutically effective and non-toxic amount of a novel compound of general formula ( I ) or a pharmaceutically acceptable amount thereof composition.

In yet further embodiments, a method for preparing novel compounds of general formula ( I ) is provided. Description of the invention

其中， A係 - 含有一或多個獨立地選自O、N、及S之雜原子之4至10員單、雙或螺環雜環烷基； - 含有一個雙鍵、及一或多個獨立地選自O、N、及S之雜原子之5至6員雜環烯基； - 含有一或多個獨立地選自O、N、及S之雜原子之5至6員雜芳基； X係-C(O)O-、-NR ^a-C(O)-、-C(O)-、S(O) ₂-、-S(O) ₂NR ^a-； R ₁係選自(C ₁-C ₆)烷基、(C ₂-C ₆)烯基、(C ₂-C ₆)炔基、鹵烷基、環烷基、碳環、雜環基、雜芳基、芳基、芳基烷基、雜環烷基、雜芳基烷基、芳基烷氧基、芳氧基、雜芳氧基、雜環氧基、芳基烯基、芳基炔基、芳基環烷基，其中該等基團中之各者當適用時進一步獨立地經選自下列之取代基取代：鹵基、羥基、(C ₁-C ₆)烷基、(C ₁-C ₆)烷氧基、(C ₁-C ₆)醯氧基、鹵烷基、-NO ₂、-OCF ₃、-CN、 -(CR ^bR ^c)) _rNR ^dR ^e、-COOR ^d、-S(O) ₂NR ^dR ^e、-S(O) ₂(CR ^bR ^c) _r、-C(O)NR ^dR ^e； R ₂係選自H、(C ₁-C ₆)烷基、鹵基、鹵烷基、-(CR ^fR ^g) _s-COOR ^h、-(CR ^fR ^g) _s-CONR ^hR ⁱ、-(CR ^fR ^g) _s-OR ^h、-(CR ^fR ^g) _s-NR ^hR ⁱ、-S(O) ₂-(CR ^fR ^g) _s、-S(O) ₂-NR ^hR ⁱ、(C ₃-C ₇)環烷基、雜環基或芳基； m、n、p及q係獨立地選自0、1、2或3； Y不存在、或係選自-H、-(CR ^abR ^ac) _t-、-(CR ^abR ^ac) _t-C(O)-、-C(O)-(CR ^abR ^ac) _t-、-C(O)-C(O)-、-C(O)NR ^adR ^ae-、-(CR ^abR ^ac) _t-C(O)NR ^adR ^ae-、-(CR ^abR ^ac) _t-C(O)OR ^ad-、-C(O)-(CR ^abR ^ac) _t-OR ^ad-、-(CR ^abR ^ac) _t-OR ^ad-、-S(O) ₂-、 -S(O) ₂NR ^adR ^ae-、-S(O) _2-(CR ^abR ^ac) _t-； B不存在或係 含有一或多個獨立地選自O、N、及S之雜原子之4至10員單、雙或螺環雜環烷基； - 含有一個雙鍵、含有一或多個獨立地選自O、N、及S之雜原子之5至6員雜環烯基； - 含有一或多個獨立地選自O、N、及S之雜原子之5至10員雜芳基； - 芳基、芳基烷基； R ₃、R ₅、及R ₆係獨立地選自H、(C ₁-C ₆)烷基、鹵基、鹵烷基、-(CR ^afR ^ag) _v-COOR ^ah、-(CR ^afR ^ag) _v-CONR ^ahR ^ai、 -(CR ^afR ^ag) _v-OR ^ah、-(CR ^afR ^ag) _v-NR ^ahR ^ai、-S(O) ₂-(CR ^afR ^ag) _v、-S(O) ₂-NR ^ahR ^ai、(C ₃-C ₇)環烷基、雜環烷基、芳基； R ₄& R ₇係獨立地選自H、(C ₁-C ₆)烷基、鹵基、鹵烷基、-OR ^aj、-CN、-NR ^ajR ^ak、(C ₃-C ₇)環烷基、芳基； R ^a、R ^b、R ^c、R ^d、R ^e、R ^f、R ^g、R ^h、R ⁱ、R ^ab、R ^ac、R ^ad、R ^ae、R ^af、R ^ag、R ^ah、及R ^ai係獨立地選自H、(C ₁-C ₆)烷基、鹵基、鹵烷基、環烷基、芳基或芳基烷基； r、s、t及v表示0至6之整數。 Accordingly, the present invention relates to the following novel compounds of formula ( I ) and their pharmaceutically acceptable salts, tautomeric forms, enantiomers and their diastereoisomers,

wherein, A is - a 4- to 10-membered mono-, di- or spirocyclic heterocycloalkyl group containing one or more heteroatoms independently selected from O, N, and S; - containing a double bond, and one or more A 5- to 6-membered heterocycloalkenyl group containing heteroatoms independently selected from O, N, and S; - a 5- to 6-membered heteroaryl group containing one or more heteroatoms independently selected from O, N, and S ; X is -C(O)O-, -NR ^a -C(O)-, -C(O)-, S(O) ₂ -, -S(O) ₂ NR ^a -; R ₁ is selected from (C ₁ -C ₆ )alkyl, (C ₂ -C ₆ )alkenyl, (C ₂ -C ₆ )alkynyl, haloalkyl, cycloalkyl, carbocycle, heterocyclyl, heteroaryl, aryl aryl, arylalkyl, heterocycloalkyl, heteroarylalkyl, arylalkoxy, aryloxy, heteroaryloxy, heterocyclyloxy, arylalkenyl, arylalkynyl, aryl Cycloalkyl, wherein each of these groups, when applicable, is further independently substituted with a substituent selected from halo, hydroxy, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ ) Alkoxy, (C ₁ -C ₆ ) aryloxy, haloalkyl, -NO ₂ , -OCF ₃ , -CN, -(CR ^b R ^c )) _r NR ^{d Re} , -COOR ^d , -S (O) ₂ NR ^{d Re} , -S(O) ₂ (CR ^b R ^c ) _r , -C(O)NR ^{d Re} ; R ₂ is selected from H, (C ₁ -C ₆ ) alkyl, halo, haloalkyl, -(CR ^f R ^g ) _s -COOR ^h , -(CR ^f R ^g ) _s -CONR ^h R ⁱ , -(CR ^f R ^g ) _s -OR ^h , -(CR ^f R ^g ) _s -NR ^h R ⁱ , -S(O) ₂ -(CR ^f R ^g ) _s , -S(O) ₂ -NR ^h R ⁱ , (C ₃ -C ₇ ) cycloalkyl, heterocyclyl or aryl; m, n, p and q are independently selected from 0, 1, 2 or 3; Y is absent, or is selected from -H, -(CR ^ab R ^ac ) _t -, -(CR ^ab R ^ac ) _t -C(O)-, -C(O)-(CR ^ab R ^ac ) _t -, -C(O)-C(O)-, -C(O)NR ^ad R ^ae -, -( CR ^ab R ^ac ) _t- C(O)NR ^ad R ^ae -, -(CR ^ab R ^ac ) _t -C(O)OR ^ad -, -C(O)-(CR ^ab R ^ac ) _t -OR ^ad -, -(CR ^ab R ^ac ) _t -OR ^ad -, -S(O) ₂ -, -S(O) ₂ NR ^ad R ^ae -, -S(O) _2- (CR ^ab R ^ac ) _t -; B does not exist or is a 4- to 10-membered mono-, di- or spirocyclic heterocycloalkyl group containing one or more heteroatoms independently selected from O, N, and S; - contains a double bond, contains one or Multiple 5- to 6-membered heterocycloalkenyl groups independently selected from O, N, and S heteroatoms; - 5- to 10-membered heteroatoms containing one or more heteroatoms independently selected from O, N, and S Aryl; _-Aryl , arylalkyl; _R3 , _R5 , and R6 are independently selected from H, ( _C1 - _C6 )alkyl, halo, haloalkyl, -(CR ^af R ^ag ) _v -COOR ^ah , -(CR ^af R ^ag ) _v -CONR ^ah R ^ai , -(CR ^af R ^ag ) _v -OR ^ah , -(CR ^af R ^ag ) _v -NR ^ah R ^ai , -S( O) ₂ -(CR ^af R ^ag ) _v , -S(O) ₂ -NR ^ah R ^ai , (C ₃ -C ₇ ) cycloalkyl, heterocycloalkyl, aryl; R ₄ & R ₇ are independent is selected from H, (C ₁ -C ₆ )alkyl, halo, haloalkyl, -OR ^aj , -CN, -NR ^aj R ^ak , (C ₃ -C ₇ )cycloalkyl, aryl; R ^a , R ^b , R ^c , R ^d , R ^e , R ^f , R ^g , ^Rh , R ⁱ , R ^ab , R ^ac , R ^ad , ^Rae , R ^af , R ^ag , R ^ah , and R ^ai is independently selected from H, (C ₁ -C ₆ )alkyl, halo, haloalkyl, cycloalkyl, aryl or arylalkyl; r, s, t and v represent an integer from 0 to 6.

。 In one of the preferred embodiments, A is selected from the following structures:

.

。 In one of the preferred embodiments, B is selected from the following structures:

.

。 In one of the preferred embodiments, the present invention relates to the novel compounds of formula (I) represented by (Ia) and (Ib), their pharmaceutically acceptable salts, tautomeric forms, enantiomers and the like mirror image isomers, etc.,

.

For both compounds of formula (I-a) and (I-b), A is selected from 4 to 10 membered mono-, di- or spirocyclic heterocycloalkyl groups containing one or more heteroatoms independently selected from O, N, and S.

。 In another preferred embodiment, A is selected from the following structures:

.

X is selected from -C(O)O-, -NR ^a -C(O)-, -C(O)-, S(O) ₂ -, -S(O) ₂ NR ^a -.

In yet another preferred embodiment, X is selected from -C(O)O- and -C(O)-.

R ₁ is selected from (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, haloalkyl, cycloalkyl, carbocycle, heterocyclyl, Heteroaryl, aryl, arylalkyl, heterocycloalkyl, heteroarylalkyl, arylalkoxy, aryloxy, heteroaryloxy, heterocycleoxy, arylalkenyl, aryl Alkynyl, arylcycloalkyl, wherein each of these groups, when applicable, is further independently substituted with a substituent selected from halo, hydroxy, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ ) alkoxy, haloalkyl, -NO ₂ , -OCF ₃ , -CN, -(CR ^b R ^c )) _r NR ^{d Re} , - COOR ^d , -S(O) ₂ NR ^{d Re} , -S(O) ₂ (CR ^b R ^c ) _r , -C(O)NR ^{d Re} groups.

In preferred embodiments, R ₁ is selected from aryl or phenyl, arylalkyl, arylalkoxy optionally substituted with one or more of the following: halo, hydroxy, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ ) alkoxy, haloalkyl, -NO ₂ , -OCF ₃ , -CN, -(CR ^b R ^c )) _r NR ^{d Re} , -COOR ^d , -S(O) ₂ NR ^{d Re} , -S(O) ₂ (CR ^b R ^c ) _r and -C(O)NR ^{d Re} substituents.

_R2 is selected from H, alkyl, halo and haloalkyl.

In a preferred embodiment, R ₂ is H.

Y is absent, or is selected from -H, -(CR ^ab R ^ac ) _t -, -(CR ^ab R ^ac ) _t -C(O)-, -C(O)-(CR ^ab R ^ac ) _t - , -C(O)-C(O)-, -C(O)NR ^ad R ^ae -, -(CR ^ab R ^ac ) _t- C(O)NR ^ad R ^ae -, -(CR ^ab R ^ac ) _t -C(O)OR ^ad -, -C(O)-(CR ^ab R ^ac ) _t -OR ^ad -, -(CR ^ab R ^ac ) _t -OR ^ad -, -S(O) ₂ -, - S(O) ₂ NR ^ad R ^ae -, -S(O) _2- (CR ^ab R ^ac ) _t -.

In a preferred embodiment, Y is selected from the group consisting of -(CR ^ab R ^ac ) _t -C(O)-, -C(O)-(CR ^ab R ^ac ) _t - and -(CR ^ab R ^ac ) _t - C(O)OR ^ad- .

。 B is absent or - a 4- to 10-membered mono-, di- or spirocyclic heterocycloalkyl group containing one or more heteroatoms independently selected from O, N, and S; - containing a double bond, containing one or more A 5- to 6-membered heterocycloalkenyl group containing one or more heteroatoms independently selected from O, N, and S; - a 5- to 6-membered heteroaryl group containing one or more heteroatoms independently selected from O, N, and S - aryl, arylalkyl; - or selected from the following structures:

.

In another preferred embodiment, B is absent or selected from: - a 4- to 10-membered monocyclic heterocycloalkyl group containing one or more heteroatoms independently selected from O, N, and S; - A 5- to 6-membered heteroaryl group containing one or more heteroatoms independently selected from O, N, and S.

。 In yet another preferred embodiment, B is absent or selected from the following structures:

.

R ₃ , R ₅ , and R ₆ are independently selected from H, (C ₁ -C ₆ )alkyl, halo, haloalkyl, -(CR ^af R ^ag ) _v -COOR ^ah , -(CR ^af R ^ag ) _v -CONR ^ah R ^ai , -(CR ^af R ^ag ) _v -OR ^ah , -(CR ^af R ^ag ) _v -NR ^ah R ^ai , -S(O) ₂ -(CR ^af R ^ag ) _v , -S(O) ₂ ^{-NRahRai ,} (C3 _{- C7} )cycloalkyl, heterocycloalkyl, aryl.

In preferred embodiments, R ₃ , R ₅ , and R ₆ are independently selected from H, (C ₁ -C ₆ )alkyl, haloalkyl.

R ₄ & R ₇ are independently selected from H, (C ₁ -C ₆ )alkyl, halo, haloalkyl, -OR ^aj , -CN, -NR ^aj R ^ak , (C ₃ -C ₇ ) ring Alkyl, aryl.

In preferred embodiments, R ₄ & R ₇ are independently selected from haloalkyl and -OR ^aj .

^Ra , ^Rb , ^Rc , ^Rd , ^Re , ^Rf , ^Rg , ^Rh , Ri, ^Rab , ^Rac , ^Rad , ^Rae , ^Raf , ^Rag , ^Rah , and ^{R ai} is independently selected from H, (C ₁ -C ₆ )alkyl, halo, haloalkyl, cycloalkyl, aryl, or arylalkyl;

In another preferred embodiment, R ^a , R ^b , R ^c , R ^d , R ^e , R ^f , R ^g , ^Rh , R ⁱ , R ^ab , R ^ac , R ^ad , R ^ae , R ^af , R ^ag , R ^ah , and R ^ai are independently selected from H and (C ₁ -C ₆ )alkyl.

r, s, t and v represent integers from 0 to 6.

In a preferred embodiment, the above-mentioned groups and radicals can be selected from: "Alkyl" and other groups with the prefix "alk", such as alkoxy and alkanoyl, mean a carbon chain, which may be straight or branched, and combinations thereof, unless the carbon Chain is otherwise defined. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, tertiary butyl, pentyl, hexyl, and the like.

Where the specified number of carbon atoms allows, eg, _C3-10 , the term alkyl also includes cycloalkyl groups, and combinations of straight or branched alkyl chains combined with cycloalkyl structures.

"Cycloalkyl" is a subset of alkyl and means a saturated carbocyclic ring having the indicated number of carbon atoms, preferably 3 to 6 carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Unless otherwise stated, cycloalkyl groups are generally monocyclic. Cycloalkyls are saturated unless otherwise stated.

"Aryl" means a monocyclic or polycyclic aromatic ring system containing carbon ring atoms. Preferred aryl groups are monocyclic or bicyclic 6 to 10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryl groups.

(azepane)、二氮呾(diazetidine)、咪唑啶、哌

、二氮

(diazepane)、二氮雜環辛烷(diazocane)、三氮雜環己烷(triazinane)、氧雜氮

(oxaziridine)、氧雜氮呾(oxazetidine)、

唑啶(oxazolidine)、

啉、氧雜氮

(oxazepane)、氧雜氮雜環辛烷(oxazocane)、硫雜氮呾(thiazetidine)、四氫噻唑、硫代

啉、硫雜氮

(thiazepane)、及硫雜氮雜環辛烷(thiazocane)。"Heterocycloalkyl" means a monocyclic or polycyclic non-aromatic/saturated ring system containing carbon atoms and one or more heteroatoms selected from nitrogen, sulfur and oxygen. Examples of heterocycloalkyl include ethylene oxide, oxetane, tetrahydrofuran, tetrahydro-2H-piperan, thietane, tetrahydrothiophene, tetrahydro-2H-thiophene pyran, azetidine, pyrrolidone, piperidine, nitrogen

(azepane), diazetidine, imidazolidine, piperidine

, dinitrogen

(diazepane), diazocane (diazocane), triazinane (triazinane), oxazine

(oxaziridine), oxazetidine,

oxazolidine,

Linen, oxazine

(oxazepane), oxazocane, thiazetidine, tetrahydrothiazole, thio

Phosphine, Thiazepine

(thiazepane), and thiazepane (thiazocane).

"Heterocycloalkenyl" means a monocyclic or polycyclic partially unsaturated ring system containing a double bond, containing carbon atoms and one or more heteroatoms selected from nitrogen, sulfur and oxygen. Examples of heterocycloalkenyl groups include cyclobutenyl, cyclopentenyl, and cyclohexenyl.

基、嘧啶基、吡

基、三

基、四

基、苯并呋喃基、吲哚基、吲唑基、喹啉基、苯并噻唑基、苯并㗁唑基、苯并咪唑基、及苯并三唑基。"Heteroaryl" means an aromatic or partially aromatic heterocycle containing at least one ring heteroatom selected from nitrogen, sulfur and oxygen. Examples of heteroaryl groups include furanyl, piperanyl, imidazolyl, pyridyl, pyridyl

base, pyrimidinyl, pyridine

base, three

base, four

group, benzofuranyl, indolyl, indazolyl, quinolinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, and benzotriazolyl.

Suitable groups and substituents on the groups can be selected from those described anywhere in the specification.

As used herein, the term "substituted" means that any one or more hydrogens on a designated atom are selectively replaced by the indicated group, provided that the designated atom's normal valence is not exceeded and that the substitution results in a stable compound.

"Pharmaceutically acceptable salt" refers to a derivative of the disclosed compound, wherein the parent compound is modified by preparing an acid or base salt thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues. Such conventional non-toxic salts include, but are not limited to, salts derived from inorganic and organic acids selected from the group consisting of 1,2-ethanedisulfonate, 2-acetoxybenzoate, 2-hydroxyethanesulfonate Acid salts, acetates, ascorbates, benzenesulfonates, benzoates, bicarbonates, carbonates, citrates, ethylenediaminetetraacetic acid (eidetic) salts, ethanedisulfonates, ethanesulfonates acid salt, fumarate, glucoheptonic acid (glucoheptonic) salt, gluconate, glutamate, glycolic acid (glycolic) salt, ethylene glycol p-aminophenylarsonate, hexyl resorcinate , hydrabamic acid (hydrabamic) salt, hydrobromide, hydrochloride, hydroiodide, hydroxymaleate, hydroxynaphthoate, 2-isethionic (isethionic) salt, lactic acid Salt, lactobionic, lauryl sulfonic, maleate, malate, mandelic, mesylate, naphthalene sulfonate, nitrate , oxalate, pamoic, pantothenate, phenylacetate, phosphate, polygalacturonate, propionate, salicylate, stearate, acetate, succinate salts, sulfamate, sulfamate, sulfate, tannin, tartrate, and tosylate.

In general, the term "cation" includes H, Na, K, Mg, Ca, _NH4 ⁺ , ( _{CH3CH2 ) 3N} ⁺ , and the like.

The terms "casually" or "casually" mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted alkyl" means "alkyl" or "substituted alkyl." Furthermore, an optionally substituted group means unsubstituted.

Unless otherwise stated in the specification, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.

In the following examples, unless otherwise noted, molecules with a single chiral center are present as racemic mixtures. Unless otherwise noted, those molecules with two or more chiral centers exist as racemic mixtures of diastereoisomers. A single enantiomer/aspiroisomer can be obtained by methods known to those of ordinary skill in the art.

Particularly useful compounds can be selected from, but not limited to, the following compounds.

surface 1 : Compound number IUPAC name 1 3,5-Dichlorobenzyl(3R)-3-(2-(2-amino-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxyamido)pyrrolidine- 1-carboxylate 2 3,5-Dichlorobenzyl(3R)-3-(2-(2-(dimethylamino)-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxamide yl)pyrrolidine-1-carboxylate 3 3,5-Dichlorobenzyl(3R)-3-(2-(2-ethoxy-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxamido)pyrrolidine -1-Carboxylic acid ester 4 2-(5-(((R)-1-(((3,5-dichlorobenzyl)oxy)carbonyl)pyrrolidin-3-yl)aminocarboxy)hexahydrocyclopenta[c]pyrrole -2(1H)-yl)acetic acid 5 3,5-Dichlorobenzyl(3R)-3-(2-(2-hydroxyacetyl)octahydrocyclopenta[c]pyrrole-5-carboxyamido)pyrroleidine-1-carboxylate 6 3,5-Dichlorobenzyl(3R)-3-(2-(2-(nitro-1-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxylate Amino)pyrrolidine-1-carboxylate 7 3,5-Dichlorobenzyl(3R)-3-(2-(2-(3-hydroxynitro-1-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5 -Carboxamido)pyrrolidine-1-carboxylate 8 3,5-Dichlorobenzyl(3S)-3-(2-(2-(3-hydroxynitro-1-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5 -Carboxamido)pyrrolidine-1-carboxylate 9 3,5-Dichlorobenzyl(3R)-3-(2-(2-(3-methoxynitro-1-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole -5-Carboxamido)pyrrolidine-1-carboxylate 10 3,5-Dichlorobenzyl(3R)-3-(2-(2-(3-(hydroxymethyl)nitrogen-1-yl)-2-oxyethyl)octahydrocyclopenta[c ]pyrrole-5-carboxamido)pyrrolidine-1-carboxylate 11 3,5-Dichlorobenzyl(3R)-3-(2-(2-(3-aminonitro-1-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole- 5-Carboxamido)pyrrolidine-1-carboxylate 12 3,5-Dichlorobenzyl(3R)-3-(2-(2-(3,3-difluoroazepin-1-yl)-2-oxyethyl)octahydrocyclopenta[c] Pyrrole-5-carboxyamido)pyrrolidine-1-carboxylate 13 3,5-Dichlorobenzyl(3R)-3-(2-(2-oxy-2-(pyrrolidin-1-yl)ethyl)octahydrocyclopenta[c]pyrrole-5-carboxylate Amino)pyrrolidine-1-carboxylate 14 3,5-Dichlorobenzyl(3R)-3-(2-(2-((S)-3-hydroxypyrrolidin-1-yl)-2-oxyethyl)octahydrocyclopenta[c ]pyrrole-5-carboxamido)pyrrolidine-1-carboxylate 15 3,5-Dichlorobenzyl(3R)-3-(2-(2-((R)-3-hydroxypyrrolidin-1-yl)-2-oxyethyl)octahydrocyclopenta[c ]pyrrole-5-carboxamido)pyrrolidine-1-carboxylate 16 3,5-Dichlorobenzyl(3R)-3-(2-(2-oxy-2-(piperidin-1-yl)ethyl)octahydrocyclopenta[c]pyrrole-5-carboxylate Amino)pyrrolidine-1-carboxylate 17 3,5-Dichlorobenzyl(3R)-3-(2-(2-(4-hydroxypiperidin-1-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5 -Carboxamido)pyrrolidine-1-carboxylate 18 3,5-Dichlorobenzyl(3R)-3-(2-(2-(4-methoxypiperidin-1-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole -5-Carboxamido)pyrrolidine-1-carboxylate 19 3,5-Dichlorobenzyl(3R)-3-(2-(2-(4,4-difluoropiperidin-1-yl)-2-oxyethyl)octahydrocyclopenta[c] Pyrrole-5-carboxyamido)pyrrolidine-1-carboxylate 20

-1-基)乙基)八氫環戊[c]吡咯-5-羧醯胺基)吡咯啶-1-羧酸酯 3,5-Dichlorobenzyl(3R)-3-(2-(2-oxy-2-(piperidine)

-1-yl)ethyl)octahydrocyclopenta[c]pyrrole-5-carboxamido)pyrrolidine-1-carboxylate twenty one 3,5-Dichlorobenzyl(3R)-3-(2-(2-(4-methylpiperin)

-1-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxamido)pyrrolidine-1-carboxylate twenty two 3,5-Dichlorobenzyl(3R)-3-(2-(2-oxy-2-(4-(2,2,2-trifluoroethyl)piperidine)

-1-yl)ethyl)octahydrocyclopenta[c]pyrrole-5-carboxamido)pyrrolidine-1-carboxylate twenty three 3,5-Dichlorobenzyl(3R)-3-(2-(2-(4-Acetylpiperidine)

-1-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxamido)pyrrolidine-1-carboxylate twenty four 3,5-Dichlorobenzyl(3R)-3-(2-(2-(4-(methylsulfonyl)piperidine)

-1-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxamido)pyrrolidine-1-carboxylate 25 3,5-Dichlorobenzyl(3R)-3-(2-(2-N-

Linoyl-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxamido)pyrrolidine-1-carboxylate 26 3,5-Dichlorobenzyl(3R)-3-(2-(2-oxy-2-(2-oxa-7-azaspiro[3.5]nonan-7-yl)ethyl) Octahydrocyclopenta[c]pyrrole-5-carboxamido)pyrrolidine-1-carboxylate 27 3,5-Dichlorobenzyl(3R)-3-(2-(2-(((1-hydroxycyclobutyl)methyl)amino)-2-oxyethyl)octahydrocyclopenta[ c]pyrrole-5-carboxyamido)pyrrolidine-1-carboxylate 28 3,5-Dichlorobenzyl(3R)-3-(2-(2-oxy-2-(2,6-diazaspiro[3.3]hept-2-yl)ethyl)octahydrocycle Penta[c]pyrrole-5-carboxamido)pyrrolidine-1-carboxylate 29 3,5-Dichlorobenzyl(3R)-3-(2-(2-(6-hydroxy-2-azaspiro[3.3]hept-2-yl)-2-oxyethyl)octahydro Cyclopenta[c]pyrrole-5-carboxamido)pyrrolidine-1-carboxylate 30 3,5-Dichlorobenzyl(3R)-3-(2-(2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-2-pendoxyl) Octahydrocyclopenta[c]pyrrole-5-carboxamido)pyrrolidine-1-carboxylate 31 3,5-Dichlorobenzyl(3R)-3-(2-(2-oxy-2-(3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2( 1H)-yl)ethyl)octahydrocyclopenta[c]pyrrole-5-carboxamido)pyrrolidine-1-carboxylate 32 3,5-Dichlorobenzyl(3R)-3-(2-(2-(5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-2-oxyethyl)octa Hydrocyclopenta[c]pyrrole-5-carboxamido)pyrrolidine-1-carboxylate 33 3,5-Dichlorobenzyl(3R)-3-(2-(2-(2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-2-side Oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxyamido)pyrrolidine-1-carboxylate 34 3,5-Dichlorobenzyl(3R)-3-(2-(2-(2-methyl-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl )-2-Oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxamido)pyrrolidine-1-carboxylate 35 3,5-Dichlorobenzyl(3R)-3-(2-(2-(2-isopropyl-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)- yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxamido)pyrrolidine-1-carboxylate 36 3,5-Dichlorobenzyl(3R)-3-(2-(2-(2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5( 4H)-yl)-2-oxoethyl)octahydrocyclopenta[c]pyrrole-5-carboxamido)pyrrolidine-1-carboxylate 37 3,5-Dichlorobenzyl(3R)-3-(2-(2-(5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)acetyl) Octahydrocyclopenta[c]pyrrole-5-carboxamido)pyrrolidine-1-carboxylate 38 3,5-Dichlorobenzyl(3R)-3-(2-(2-(5-methyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl )Acetyl)octahydrocyclopenta[c]pyrrole-5-carboxyamido)pyrrolidine-1-carboxylate 39 3,5-Dichlorobenzyl(3R)-3-(2-(2-(5-(methylsulfonyl)-5,6-dihydropyrrolo[3,4-c]pyrazole-2( 4H)-yl)acetyl)octahydrocyclopenta[c]pyrrole-5-carboxyamido)pyrrolidine-1-carboxylate 40 3,5-Dichlorobenzyl(3R)-3-(2-(2-oxy-2-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo) [4,5-c]pyridin-5-yl)ethyl)octahydrocyclopenta[c]pyrrole-5-carboxamido)pyrroleidine-1-carboxylate 41 3,5-Dichlorobenzyl(3R)-3-(2-(2-(5,6-dihydro-[1,2,4]triazolo[4,3-a]pyridine

-7(8H)-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxamido)pyrroleidine-1-carboxylate 42 3,5-Dichlorobenzyl(3R)-3-(2-(2-(6,7-dihydro-[1,2,3]triazolo[1,5-a]pyridine

5(4H)-yl)-2-oxoethyl)octahydrocyclopenta[c]pyrrole-5-carboxamido)pyrrolidine-1-carboxylate 43 3,5-Dichlorobenzyl(3R)-3-(2-(2-oxy-2-(1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine) -5-yl)ethyl)octahydrocyclopenta[c]pyrrole-5-carboxamido)pyrrolidine-1-carboxylate 44 3,5-Dichlorobenzyl(3R)-3-(2-(2-oxy-2-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]) Triazolo[4,3-a]pyridine

-7(8H)-yl)ethyl)octahydrocyclopenta[c]pyrrole-5-carboxamido)pyrrolidine-1-carboxylate 45 3,5-Dichlorobenzyl(3R)-3-(2-(2-(isoindolin-2-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5- Carboxamido)pyrrolidine-1-carboxylate 46 3,5-Dichlorobenzyl(3R)-3-(2-(2-(indolin-1-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxy Amido)pyrrolidine-1-carboxylate 47 3,5-Dichlorobenzyl(3R)-3-(2-(2-(3-hydroxynitro-1-yl)acetyl)octahydrocyclopenta[c]pyrrole-5-carboxamido ) pyrrolidine-1-carboxylate 48 3,5-Dichlorobenzyl(3R)-3-(2-(2-(3-hydroxynitro-1-yl)-2-oxyethanoyl)octahydrocyclopenta[c]pyrrole- 5-Carboxamido)pyrrolidine-1-carboxylate 49 3,5-Dichlorobenzyl(3R)-3-(2-(3-(3-hydroxynitro-1-yl)-3-oxypropyl)octahydrocyclopenta[c]pyrrole-5 -Carboxamido)pyrrolidine-1-carboxylate 50 3,5-Dichlorobenzyl(3R)-3-(2-(3-hydroxynitro-1-carbonyl)octahydrocyclopenta[c]pyrrole-5-carboxamido)pyrroleidine-1-carboxyl acid ester 51 3,5-Dichlorobenzyl(3R)-3-(2-((S)-3-hydroxypyrrolidine-1-carbonyl)octahydrocyclopenta[c]pyrrole-5-carboxamido)pyrrolidine -1-Carboxylic acid ester 52 3,5-Dichlorobenzyl(3R)-3-(2-((R)-3-hydroxypyrrolidine-1-carbonyl)octahydrocyclopenta[c]pyrrole-5-carboxamido)pyrrolidine -1-Carboxylic acid ester 53 3,5-Dichlorobenzyl(3R)-3-(2-(4-hydroxypiperidine)

-1-Carbonyl)octahydrocyclopenta[c]pyrrole-5-carboxyamido)pyrrolidine-1-carboxylate 54 3,5-Dichlorobenzyl(3R)-3-(2-(piperidine)

-1-Carbonyl)octahydrocyclopenta[c]pyrrole-5-carboxyamido)pyrrolidine-1-carboxylate 55 3,5-Dichlorobenzyl(3R)-3-(2-(4-methylpiperin)

-1-Carbonyl)octahydrocyclopenta[c]pyrrole-5-carboxyamido)pyrrolidine-1-carboxylate 56 3,5-Dichlorobenzyl(3R)-3-(2-(nitro-3-ylaminocarbamoyl)octahydrocyclopenta[c]pyrrole-5-carboxyamido)pyrrolidine-1- Carboxylate 57 3,5-Dichlorobenzyl(3R)-3-(2-(piperidin-4-ylaminocarbamoyl)octahydrocyclopenta[c]pyrrole-5-carboxamido)pyrrolidine-1- Carboxylate 58 3,5-Dichlorobenzyl(3R)-3-(2-(oxygen-3-yl)octahydrocyclopenta[c]pyrrole-5-carboxyamido)pyrrolidine-1-carboxylate 59 3,5-Dichlorobenzyl(3R)-3-(2-(nitro-3-yl)octahydrocyclopenta[c]pyrrole-5-carboxamido)pyrrolidine-1-carboxylate 60 3,5-Dichlorobenzyl(3R)-3-(2-(1-methylnitro-3-yl)octahydrocyclopenta[c]pyrrole-5-carboxamido)pyrrolidine-1- Carboxylate 61 3,5-Dichlorobenzyl(3R)-3-(2-(1-acetylazide-3-yl)octahydrocyclopenta[c]pyrrole-5-carboxyamido)pyrrolidine-1 - Carboxylate 62 3,5-Dichlorobenzyl(3R)-3-(2-(1-(methylsulfonyl)azopyridine-3-yl)octahydrocyclopenta[c]pyrrole-5-carboxamido)pyrrole pyridine-1-carboxylate 63 3,5-Dichlorobenzyl(3R)-3-(2-(piperidin-4-yl)octahydrocyclopenta[c]pyrrole-5-carboxamido)pyrrolidine-1-carboxylate 64 3,5-Dichlorobenzyl(3R)-3-(2-(1-methylpiperidin-4-yl)octahydrocyclopenta[c]pyrrole-5-carboxamido)pyrrolidine-1- Carboxylate 65 3,5-Dichlorobenzyl(3R)-3-(2-(1-Acetylpiperidin-4-yl)octahydrocyclopenta[c]pyrrole-5-carboxamido)pyrrolidine-1 - Carboxylate 66 3,5-Dichlorobenzyl(3R)-3-(2-(1-(methylsulfonyl)piperidin-4-yl)octahydrocyclopenta[c]pyrrole-5-carboxamido)pyrrole pyridine-1-carboxylate 67 3,5-Dichlorobenzyl(3R)-3-(2-(2-(3-hydroxynitro-1-yl)-2-oxyethyl)-N-methyloctahydrocyclopenta[ c]pyrrole-5-carboxyamido)pyrrolidine-1-carboxylate 68 3,5-Dichlorobenzyl(3R)-3-(2-(2-(4-hydroxypiperidin-1-yl)-2-oxyethyl)-N-methyloctahydrocyclopenta[ c]pyrrole-5-carboxyamido)pyrrolidine-1-carboxylate 69 3,5-Dichlorobenzyl(3R)-3-(2-(2-(3-hydroxynitro-1-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5 -Carboxamido)pyrrolidine-1-carboxylate 70 3,5-Bis(trifluoromethyl)benzyl(3R)-3-(2-(2-(3-hydroxynitro-1-yl)-2-oxyethyl)octahydrocyclopenta[ c]pyrrole-5-carboxyamido)pyrrolidine-1-carboxylate 71 3-cyanobenzyl(3R)-3-(2-(2-(3-hydroxynitro-1-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxy Amido)pyrrolidine-1-carboxylate 72 4-cyanobenzyl(3R)-3-(2-(2-(3-hydroxynitro-1-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxy Amido)pyrrolidine-1-carboxylate 73 4-Fluorobenzyl(3R)-3-(2-(2-(3-hydroxynitro-1-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxylate Amino)pyrrolidine-1-carboxylate 74 4-(Trifluoromethoxy)benzyl(3R)-3-(2-(2-(3-hydroxynitro-1-yl)-2-oxyethyl)octahydrocyclopenta[c] Pyrrole-5-carboxyamido)pyrrolidine-1-carboxylate 75 N-((R)-1-((3,5-Dichlorobenzyl)aminocarbamoyl)pyrrolidin-3-yl)-2-(2-(3-hydroxyazepin-1-yl)- 2-Oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxamide 76 N-((R)-1-((3,5-difluorobenzyl)aminocarbamoyl)pyrrolidin-3-yl)-2-(2-(3-hydroxyazepin-1-yl)- 2-Oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxamide 77 N-((R)-1-(3-(3,5-Dichlorophenyl)propionyl)pyrrolidin-3-yl)-2-(2-(3-hydroxyazepin-1-yl) -2-Oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxamide 78 N-((R)-1-(3-(4-Fluorophenyl)propionyl)pyrrolidin-3-yl)-2-(2-(3-hydroxyazepin-1-yl)-2- pendant oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxamide 79 N-((R)-1-(3-(4-Fluorophenyl)propionyl)pyrrolidin-3-yl)-2-(2-(3-hydroxyazepin-1-yl)-2- pendant oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxamide 80 N-((R)-1-(2-(3,5-Dichlorophenoxy)-2-methylpropionyl)pyrrolidin-3-yl)-2-(2-(3-hydroxynitrogen) pyrrole-5-carboxamide 81 N-((R)-1-(2-(3,5-Dichlorophenoxy)-2,2-difluoroacetyl)pyrrolidin-3-yl)-2-(2-(3- Hydroxynitro-1-yl)-2-side oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxamide 82 N-((R)-1-(2-(3,5-Difluorophenoxy)acetyl)pyrrolidin-3-yl)-2-(2-(3-hydroxyazepin-1-yl) )-2-Oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxamide 83 2-(2-(3-Hydroxynitrogen-1-yl)-2-oxyethyl)-N-((R)-1-(2-(4-(trifluoromethoxy)phenoxy) yl)acetyl)pyrrolidin-3-yl)octahydrocyclopenta[c]pyrrole-5-carboxamide 84 N-((R)-1-((E)-3-(3,5-dichlorophenyl)acryloyl)pyrrolidin-3-yl)-2-(2-(3-hydroxynitrogen- 1-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxamide 85 2-(2-(3-Hydroxynitro-1-yl)-2-oxyethyl)-N-((R)-1-((E)-3-(4-(trifluoromethoxy) yl)phenyl)acryloyl)pyrrolidin-3-yl)octahydrocyclopenta[c]pyrrole-5-carboxyamide 86 3,5-Dichlorobenzyl 4-(2-(2-(3-hydroxynitro-1-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxamide yl)piperidine-1-carboxylate 87 3,5-Dichlorobenzyl 4-(2-(2-(3-methoxynitro-1-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxy Amido)piperidine-1-carboxylate 88 3,5-Dichlorobenzyl 4-(2-(2-(3,3-difluoroazepin-1-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5- Carboxamido)piperidine-1-carboxylate 89 3,5-Dichlorobenzyl-4-(2-(2-oxy-2-(pyrrolidin-1-yl)ethyl)octahydrocyclopenta[c]pyrrole-5-carboxamido) Piperidine-1-carboxylate 90 3,5-Dichlorobenzyl 4-(2-(2-((S)-3-hydroxypyrrolidin-1-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5 -Carboxamido)piperidine-1-carboxylate 91 3,5-Dichlorobenzyl 4-(2-(2-((R)-3-hydroxypyrrolidin-1-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5 -Carboxamido)piperidine-1-carboxylate 92 3,5-Dichlorobenzyl 4-(2-(2-(4-hydroxypiperidin-1-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxamide yl)piperidine-1-carboxylate 93 3,5-Dichlorobenzyl 4-(2-(2-(4-methoxypiperidin-1-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxy Amido)piperidine-1-carboxylate 94 3,5-Dichlorobenzyl 4-(2-(2-(4,4-difluoropiperidin-1-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5- Carboxamido)piperidine-1-carboxylate 95 3,5-Dichlorobenzyl 4-(2-(2-oxy-2-(piperidine)

-1-yl)ethyl)octahydrocyclopenta[c]pyrrole-5-carboxyamido)piperidine-1-carboxylate 96 3,5-Dichlorobenzyl 4-(2-(2-(4-methylpiperidine)

-1-yl)-2-oxoethyl)octahydrocyclopenta[c]pyrrole-5-carboxamido)piperidine-1-carboxylate 97 3,5-Dichlorobenzyl-4-(2-(2-oxy-2-(4-(2,2,2-trifluoroethyl)piperidine)

-1-yl)ethyl)octahydrocyclopenta[c]pyrrole-5-carboxyamido)piperidine-1-carboxylate 98 3,5-Dichlorobenzyl 4-(2-(2-(4-Acetylpiperidine)

-1-yl)-2-oxoethyl)octahydrocyclopenta[c]pyrrole-5-carboxamido)piperidine-1-carboxylate 99 3,5-Dichlorobenzyl 4-(2-(2-(4-(methylsulfonyl)piperyl)

-1-yl)-2-oxoethyl)octahydrocyclopenta[c]pyrrole-5-carboxamido)piperidine-1-carboxylate 100 3,5-Dichlorobenzyl 4-(2-(2-N-

Lino-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxamido)piperidine-1-carboxylate 101 3,5-Dichlorobenzyl 4-(2-(2-oxy-2-(2-oxa-7-azaspiro[3.5]nonan-7-yl)ethyl)octahydrocyclopenta [c]pyrrole-5-carboxyamido)piperidine-1-carboxylate 102 3,5-Dichlorobenzyl 4-(2-(2-(((1-hydroxycyclobutyl)methyl)amino)-2-oxyethyl)octahydrocyclopenta[c]pyrrole- 5-Carboxamido)piperidine-1-carboxylate 103 3,5-Dichlorobenzyl 4-(2-(2-oxy-2-(2,6-diazaspiro[3.3]hept-2-yl)ethyl)octahydrocyclopenta[c] Pyrrole-5-carboxyamido)piperidine-1-carboxylate 104 3,5-Dichlorobenzyl 4-(2-(2-(6-hydroxy-2-azaspiro[3.3]hept-2-yl)-2-oxyethyl)octahydrocyclopenta[c ]pyrrole-5-carboxyamido)piperidine-1-carboxylate 105 3,5-Dichlorobenzyl 4-(2-(2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-2-oxyethyl)octahydrocyclopenta [c]pyrrole-5-carboxyamido)piperidine-1-carboxylate 106 3,5-Dichlorobenzyl 4-(2-(2-Oxy-2-(3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl )ethyl)octahydrocyclopenta[c]pyrrole-5-carboxyamido)piperidine-1-carboxylate 107 3,5-Dichlorobenzyl 4-(2-(2-(5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-2-oxyethyl)octahydrocyclopenta[ c]pyrrole-5-carboxyamido)piperidine-1-carboxylate 108 3,5-Dichlorobenzyl 4-(2-(2-(2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-2-side oxyethyl ) octahydrocyclopenta[c]pyrrole-5-carboxamido)piperidine-1-carboxylate 109 3,5-Dichlorobenzyl 4-(2-(2-(2-methyl-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-2- Pendant oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxyamido)piperidine-1-carboxylate 110 3,5-Dichlorobenzyl 4-(2-(2-(2-isopropyl-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-2 -Pendant oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxyamido)piperidine-1-carboxylate 111 3,5-Dichlorobenzyl 4-(2-(2-(2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl )-2-Oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxamido)piperidine-1-carboxylate 112 3,5-Dichlorobenzyl 4-(2-(2-oxy-2-(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5 -c]pyridin-5-yl)ethyl)octahydrocyclopenta[c]pyrrole-5-carboxamido)piperidine-1-carboxylate 113 3,5-Dichlorobenzyl 4-(2-(2-oxy-2-(1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5- yl)ethyl)octahydrocyclopenta[c]pyrrole-5-carboxyamido)piperidine-1-carboxylate 114 3,5-Dichlorobenzyl 4-(2-(2-(5,6-dihydro-[1,2,4]triazolo[4,3-a]pyridine

-7(8H)-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxamido)piperidine-1-carboxylate 115 3,5-Dichlorobenzyl 4-(2-(2-(6,7-dihydro-[1,2,3]triazolo[1,5-a]pyridine

-5(4H)-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxamido)piperidine-1-carboxylate 116 3,5-Dichlorobenzyl 4-(2-(2-oxy-2-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[ 4,3-a]pyridine

-7(8H)-yl)ethyl)octahydrocyclopenta[c]pyrrole-5-carboxamido)piperidine-1-carboxylate 117 3,5-Dichlorobenzyl 4-(2-(2-oxy-2-(1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl )ethyl)octahydrocyclopenta[c]pyrrole-5-carboxyamido)piperidine-1-carboxylate 118 3,5-Dichlorobenzyl 4-(2-(2-(isoindolin-2-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxamido ) piperidine-1-carboxylate 119 3,5-Dichlorobenzyl 4-(2-(2-(Indolin-1-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxamido) Piperidine-1-carboxylate 120 3,5-Dichlorobenzyl 4-(2-(2-(3-hydroxynitro-1-yl)acetyl)octahydrocyclopenta[c]pyrrole-5-carboxamido)piperidine- 1-carboxylate 121 3,5-Dichlorobenzyl 4-(2-(2-(3-hydroxynitro-1-yl)-2-oxyacetyl)octahydrocyclopenta[c]pyrrole-5-carboxylate Amino)piperidine-1-carboxylate 122 3,5-Dichlorobenzyl 4-(2-(3-(3-hydroxynitro-1-yl)-3-oxypropyl)octahydrocyclopenta[c]pyrrole-5-carboxamide yl)piperidine-1-carboxylate 123 3,5-Dichlorobenzyl 4-(2-(2-(5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)acetyl)octahydrocyclopenta [c]pyrrole-5-carboxyamido)piperidine-1-carboxylate 124 3,5-Dichlorobenzyl 4-(2-(2-(5-methyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)acetinyl ) octahydrocyclopenta[c]pyrrole-5-carboxamido)piperidine-1-carboxylate 125 3,5-Dichlorobenzyl 4-(2-(2-(5-(methylsulfonyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl )Acetyl)octahydrocyclopenta[c]pyrrole-5-carboxyamido)piperidine-1-carboxylate 126 3,5-Dichlorobenzyl 4-(2-(3-hydroxynitro-1-carbonyl)octahydrocyclopenta[c]pyrrole-5-carboxamido)piperidine-1-carboxylate 127 3,5-Dichlorobenzyl 4-(2-(nitro-3-ylaminocarboxy)octahydrocyclopenta[c]pyrrole-5-carboxyamido)piperidine-1-carboxylate 128 3,5-Dichlorobenzyl 4-(2-((R)-3-hydroxypyrrolidine-1-carbonyl)octahydrocyclopenta[c]pyrrole-5-carboxamido)piperidine-1-carboxyl acid ester 129 3,5-Dichlorobenzyl 4-(2-((S)-3-hydroxypyrrolidine-1-carbonyl)octahydrocyclopenta[c]pyrrole-5-carboxamido)piperidine-1-carboxyl acid ester 130 3,5-Dichlorobenzyl 4-(2-(piperidin-4-ylaminocarboxy)octahydrocyclopenta[c]pyrrole-5-carboxyamido)piperidine-1-carboxylate 131 3,5-Dichlorobenzyl 4-(2-(4-hydroxypiperidine)

-1-Carbonyl)octahydrocyclopenta[c]pyrrole-5-carboxyamido)piperidine-1-carboxylate 132 3,5-Dichlorobenzyl 4-(2-(piperidine)

-1-Carbonyl)octahydrocyclopenta[c]pyrrole-5-carboxyamido)piperidine-1-carboxylate 133 3,5-Dichlorobenzyl 4-(2-(4-methylpiperin)

-1-Carbonyl)octahydrocyclopenta[c]pyrrole-5-carboxyamido)piperidine-1-carboxylate 134 3,5-Dichlorobenzyl 4-(2-(Oxy-3-yl)octahydrocyclopenta[c]pyrrole-5-carboxamido)piperidine-1-carboxylate 135 3,5-Dichlorobenzyl 4-(2-(nitro-3-yl)octahydrocyclopenta[c]pyrrole-5-carboxamido)piperidine-1-carboxylate 136 3,5-Dichlorobenzyl 4-(2-(1-methylnitro-3-yl)tetrahydrocyclopenta[c]pyrrole-5-carboxyamido)piperidine-1-carboxylate 137 3,5-Dichlorobenzyl 4-(2-(1-Acetylazide-3-yl)octahydrocyclopenta[c]pyrrole-5-carboxamido)piperidine-1-carboxylate 138 3,5-Dichlorobenzyl 4-(2-(1-(methylsulfonyl)azopyridine-3-yl)octahydrocyclopenta[c]pyrrole-5-carboxyamido)piperidine-1- Carboxylate 139 3,5-Dichlorobenzyl 4-(2-(piperidin-4-yl)octahydrocyclopenta[c]pyrrole-5-carboxamido)piperidine-1-carboxylate 140 3,5-Dichlorobenzyl 4-(2-(1-methylpiperidin-4-yl)octahydrocyclopenta[c]pyrrole-5-carboxamido)piperidine-1-carboxylate 141 3,5-Dichlorobenzyl 4-(2-(1-Acetylpiperidin-4-yl)octahydrocyclopenta[c]pyrrole-5-carboxamido)piperidine-1-carboxylate 142 3,5-Dichlorobenzyl 4-(2-(1-(methylsulfonyl)piperidin-4-yl)octahydrocyclopenta[c]pyrrole-5-carboxamido)piperidine-1- Carboxylate 143 3,5-Dichlorobenzyl 4-(2-(2-(3-hydroxynitro-1-yl)-2-oxyethyl)-N-methyloctahydrocyclopenta[c]pyrrole- 5-Carboxamido)piperidine-1-carboxylate 144 3,5-Dichlorobenzyl(3R)-3-(2-(2-(3-hydroxynitro-1-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5 -Carboxamido)piperidine-1-carboxylate 145 3,5-Dichlorobenzyl(3S)-3-(2-(2-(3-hydroxynitro-1-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5 -Carboxamido)piperidine-1-carboxylate 146 3,5-Bis(trifluoromethyl)benzyl 4-(2-(2-(3-hydroxynitro-1-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole- 5-Carboxamido)piperidine-1-carboxylate 147 3,5-Difluorobenzyl 4-(2-(2-(3-hydroxynitro-1-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxamide yl)piperidine-1-carboxylate 148 4-Fluorobenzyl 4-(2-(2-(3-hydroxynitro-1-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxamido)piperidine pyridine-1-carboxylate 149 4-cyanobenzyl 4-(2-(2-(3-hydroxynitro-1-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxamido) Piperidine-1-carboxylate 150 4-(Trifluoromethoxy)benzyl 4-(2-(2-(3-hydroxynitro-1-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5- Carboxamido)piperidine-1-carboxylate 151 N-(1-((3,5-Dichlorobenzyl)aminocarboxy)piperidin-4-yl)-2-(2-(3-hydroxyazepin-1-yl)-2-oxygen ethyl)octahydrocyclopenta[c]pyrrole-5-carboxamide 152 N-(1-((3,5-Bis(trifluoromethyl)benzyl)amidocarboxyl)piperidin-4-yl)-2-(2-(3-hydroxyazepin-1-yl) -2-Oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxamide 153 N-(1-(3-(3,5-Dichlorophenyl)propionyl)piperidin-4-yl)-2-(2-(3-hydroxyazepin-1-yl)-2-side Oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxamide 154 N-(1-(3-(3,5-Bis(trifluoromethyl)phenyl)propionyl)piperidin-4-yl)-2-(2-(3-hydroxyazepin-1-yl) )-2-Oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxamide 155 N-(1-(3-(4-Cyanophenyl)propionyl)piperidin-4-yl)-2-(2-(3-hydroxyazepin-1-yl)-2-pendantoxy Ethyl)octahydrocyclopenta[c]pyrrole-5-carboxamide 156 N-(1-(3-(4-Fluorophenyl)propionyl)piperidin-4-yl)-2-(2-(3-hydroxyazepin-1-yl)-2-side oxyethyl base) octahydrocyclopenta[c]pyrrole-5-carboxamide 157 N-(1-(2-(3,5-Dichlorophenoxy)acetyl)piperidin-4-yl)-2-(2-(3-hydroxyazepin-1-yl)-2- pendant oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxamide 158 N-(1-(2-(3,5-Bis(trifluoromethyl)phenoxy)acetyl)piperidin-4-yl)-2-(2-(3-hydroxynitrogen-1- yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxamide 159 N-(1-(2-(4-Cyanophenoxy)acetyl)piperidin-4-yl)-2-(2-(3-hydroxyazepin-1-yl)-2-oxygen ethyl)octahydrocyclopenta[c]pyrrole-5-carboxamide 160 N-(1-(2-(4-Fluorophenoxy)acetyl)piperidin-4-yl)-2-(2-(3-hydroxyazepin-1-yl)-2-pendantoxy Ethyl)octahydrocyclopenta[c]pyrrole-5-carboxamide 161 2-(2-(3-Hydroxynitrogen-1-yl)-2-oxyethyl)-N-(1-(2-(4-(trifluoromethoxy)phenoxy)acetone) yl)piperidin-4-yl)octahydrocyclopenta[c]pyrrole-5-carboxamide 162 (E)-N-(1-(3-(3,5-Dichlorophenyl)acryloyl)piperidin-4-yl)-2-(2-(3-hydroxyazepin-1-yl) -2-Oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxamide 163 E)-2-(2-(3-Hydroxynitrogen-1-yl)-2-oxyethyl)-N-(1-(3-(4-(trifluoromethoxy)phenyl) Acryloyl)piperidin-4-yl)octahydrocyclopenta[c]pyrrole-5-carboxyamide 164 3,5-Dichlorobenzyl 3-(2-(2-(3-hydroxynitro-1-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxamide base) nitro-1-carboxylate 165 3,5-Dichlorobenzyl 5-(2-(2-(3-hydroxynitro-1-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxamide yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate 166 3,5-Dichlorobenzyl 6-(2-(2-(3-hydroxynitro-1-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxamide yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate 167 3,5-Dichlorobenzyl 3-(2-(2-(3-hydroxynitro-1-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxamide yl)-6-azabicyclo[3.1.1]heptane-6-carboxylate 168 3,5-Dichlorobenzyl 3-(2-(2-(3-hydroxynitro-1-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxamide yl)-8-azabicyclo[3.2.1]octane-8-carboxylate 169 3,5-Dichlorobenzyl 4-(2-(2-(3-hydroxynitro-1-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5-carbonyl)piperidine

-1-Carboxylic acid ester 170 3,5-Dichlorobenzyl 6-(2-(2-(3-hydroxynitro-1-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5-carbonyl)- 2,6-Diazaspiro[3.3]heptane-2-carboxylate 171 3,5-Dichlorobenzyl 5-(2-(2-(3-hydroxynitro-1-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5-carbonyl)hexa Hydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate 172 3,5-Dichlorobenzyl 5-(2-(2-(3-hydroxynitro-1-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5-carbonyl)- 3,4,5,6-Tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate 173 3,5-Dichlorobenzyl((3S)-1-(2-(2-(3-hydroxynitro-1-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole- 5-Carbonyl)pyrrolidin-3-yl)carbamate 174 3,5-Dichlorobenzyl((3R)-1-(2-(2-(3-hydroxynitro-1-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole- 5-Carbonyl)pyrrolidin-3-yl)carbamate 175 3,5-Dichlorobenzyl (1-(2-(2-(3-hydroxynitro-1-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5-carbonyl) piperidin-4-yl)carbamate 176 3,5-Dichlorobenzyl (2-(2-(2-(3-hydroxynitro-1-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5-carbonyl) Octahydrocyclopenta[c]pyrrol-5-yl)carbamate 177 3,5-Dichlorobenzyl (3-(2-(2-(3-hydroxynitro-1-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5-carbonyl) -3-Azabicyclo[3.1.0]hex-6-yl)carbamate 178 3,5-Dichlorobenzyl(3R)-3-(3-(2-(3-hydroxyazepin-1-yl)-2-oxyethyl)-3-azabicyclo[3.1.0 ]Hexane-6-carboxyamido)pyrrolidine-1-carboxylate 179 3,5-Dichlorobenzyl (3S)-3-(3-(2-(3-hydroxynitro-1-yl)-2-oxyethyl)-3-azabicyclo[3.1.0 ]Hexane-6-carboxyamido)pyrrolidine-1-carboxylate 180 3,5-Dichlorobenzyl(3R)-3-(3-(2-((S)-3-hydroxypyrrolidin-1-yl)-2-oxyethyl)-3-azabicyclo [3.1.0] Hexane-6-carboxyamido)pyrrolidine-1-carboxylate 181 3,5-Dichlorobenzyl(3R)-3-(3-(2-((R)-3-hydroxypyrrolidin-1-yl)-2-oxyethyl)-3-azabicyclo [3.1.0] Hexane-6-carboxyamido)pyrrolidine-1-carboxylate 182 3,5-Dichlorobenzyl(3R)-3-(3-(2-(4-hydroxypiperidin-1-yl)-2-oxyethyl)-3-azabicyclo[3.1.0 ]Hexane-6-carboxyamido)pyrrolidine-1-carboxylate 183 3,5-Dichlorobenzyl(3R)-3-(3-(2-oxy-2-(piperidine)

-1-yl)ethyl)-3-azabicyclo[3.1.0]hexane-6-carboxyamido)pyrrolidine-1-carboxylate 184 3,5-Dichlorobenzyl(3R)-3-(3-(2-(4-methylpiperidine)

-1-yl)-2-oxoethyl)-3-azabicyclo[3.1.0]hexane-6-carboxamido)pyrrolidine-1-carboxylate 185 3,5-Dichlorobenzyl(3R)-3-(3-(2-(4-Acetylpiperidine)

-1-yl)-2-oxoethyl)-3-azabicyclo[3.1.0]hexane-6-carboxamido)pyrrolidine-1-carboxylate

The following is a list of abbreviations used to describe the preparation of the compounds _of the invention: ACN: acetonitrile BOC: tertiary butoxycarbonyl _Cs2CO3 : cesium carbonate CDI: carbonyldiimidazole DCM: dichloromethane DIEA: diisopropylethyl Amine DIPE: diisopropyl ether DMA: N,N-dimethylacetamide DMF: N,N-dimethylformamide DMSO: dimethylsulfoxide EtOH: ethanol EtOAc: ethyl acetate h: hours HBTU: O- (benzotriazol-1-yl) -N,N,N',N' -tetramethylurea hexafluorophosphate HCl: hydrochloric acid H ₂ O ₂ : hydrogen peroxide HPLC: high performance liquid chromatography IPA: Isopropanol K ₂ CO ₃ : Potassium carbonate MeOH: Methanol MsCl: Methylsulfonyl chloride MeI: Iodomethane NaBH ₄ : Sodium borohydride Na ₂ CO ₃ : Sodium carbonate NaOH: Sodium hydroxide Na ₂ SO ₄ : Sodium sulfate _NaHCO3 : sodium bicarbonate NMP: N-methyl- ₂ -pyrrolidone NaN3: sodium azide NaCN: sodium cyanide _POCl3 : phosphonium chloride PTSA: p-toluenesulfonic acid t BuOK: sodium tertiary butoxide TEA: triethylamine TFA: trifluoroacetic acid THF: tetrahydrofuran TLC: thin layer chromatography

The novel compounds of the present invention are prepared using the reactions and techniques described below, together with conventional techniques known to those of ordinary skill in the art of organic synthesis, or variations as understood by those of ordinary skill in the art.

The reactions can be carried out in solvents appropriate to the reagents and materials employed and suitable for carrying out the transformation. Preferred methods include, but are not limited to, the methods described below, wherein all symbols are as defined above unless otherwise defined below.

Compounds of formula ( I ) can be prepared as described in General Scheme -1 below with suitable modifications/variations within the purview of those of ordinary skill in the art.

Substituted bicyclic acids ( II ) can be treated with diversified amines ( III ) in suitable solvents to prepare amide linkages under coupling reaction conditions to give compounds ( IV ), or can be obtained by methods reported in the literature. Methods and can be prepared with appropriate modifications as desired. Deprotection of the Boc group of compound ( IV ) can be achieved by using a suitable acid such as HCl, HBr and TFA in a suitable solvent to give compound ( V ). N of compound ( V ₎ can be carried out using alkyl halides or acyl halides _of type ( VI ₎ and preferably with bases such as K2CO3 or _Cs2CO3 in suitable solvents such as ACN, acetone and DMF - Alkylation or N-acylation, or can be prepared by conventional methods reported in the literature or by conventional techniques known to those of ordinary skill in the art of organic synthesis to provide compounds of formula ( I ).

一般方法 General Scenario -1 :

general method

Melting points were recorded and uncorrected on a scientific melting point apparatus. IR spectra were recorded on a FT-IR 8300 Shimadzu with pure (for oil) or KBr particles (for solids) and are reported in wavenumber ν (cm ⁻¹ ). NMR spectra were measured on a Varian Unity 400 ( ^1H at 400 MHz, ^13C at 100 MHz) magnetic resonance spectrometer. Spectra were acquired in the indicated solvents at ambient temperature. Chemical shifts (δ) are expressed in parts per million (ppm) using tetramethylsilane as an internal standard. Multiplicities were recorded as follows: s = singlet, d = doublet, t = triplet, q = quartet, br = broad. Coupling constants ( J values) are in Hz. Mass spectra were recorded on a Perkin-Elmer Sciex API 3000. ESI-Q-TOF-MS measurements were performed with a micrOTOF-Q II (Bruker Daltonics) mass spectrometer. HPLC analysis was performed on an AGILENT 1100 series using column ODS C-18, 150 mm x 4.6 mm x 4 μm at λmax 220 nm. Reactions were monitored using thin layer silica chromatography (TLC) using Merck's 0.25 mm silica gel 60F plates. Plates were visualized by treatment with UV, acid p _- anisaldehyde stain, KMnO4 stain, and mild heat. The product was purified by column chromatography using 100 to 200 mesh silica gel and the indicated solvent system.

All reactions involving air or moisture sensitive compounds were carried out in flame-dried glassware under nitrogen atmosphere. Tetrahydrofuran (THF) and diethyl ether (Et ₂ O) were freshly distilled from sodium/benzophenone under nitrogen atmosphere. Other solvents used in the reaction were purified according to standard procedures. Unless otherwise stated, starting reagents were purchased from commercial suppliers and used without further purification.

Compound - 49 [3,5 -Dichlorobenzyl (3R)-3-(2-(3-(3- hydroxynitro- 1 -yl )-3 -oxypropyl ) octahydrocyclopenta [c ] Synthesis of pyrrole -5- carboxamido ) pyrrolidine- 1 - carboxylate ]

Compound-49 (3,5-Dichlorobenzyl(3R)-3-(2-(3-(3-hydroxynitro-1-yl)-3-oxypropyl)octahydrocyclopenta[c ] The synthesis of pyrrole-5-carboxamido)pyrrolidine-1-carboxylate was carried out as shown in Scheme -2 , and the step-by-step procedure is shown below:

Scenario -2 :

Step-1: Preparation of 3,5-dichlorobenzyl(R)-3-aminopyrrolidine-1-carboxylate ( 2 ) To (3,5-dichlorophenyl)methanol (3,5-dichlorophenyl)methanol (2) at room temperature To a solution of 1.25 g, 7.09 mmol) in DMF was added 1,1'-carbonyldiimidazole (1.15 g, 7.09 mmol) and stirred for 30 minutes. To the reaction mixture was added (R)-pyrrolidin-3-ylcarbamate ( 1 ) (1.2 g, 6.44 mmol) portionwise and stirred at room temperature for 1 hour. The reaction was poured into cold water and extracted with EtOAc (2 x 100 ml). The combined organic layers were washed with water (1 x 150 ml) and brine (1 x 100 ml), dried over anhydrous Na ₂ SO ₄ and evaporated to dryness under reduced pressure to give 3,5-dichlorobenzyl as a solid (R)-3-((tertiary butoxycarbonyl)amino)pyrrolidine-1-carboxylate (2.4 g). To the product thus obtained was added DCM (48 ml) followed by TFA (5.5 ml) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was then treated with saturated NaHCO3 _(aq) solution (100 ml). The layers were separated and the organic layer was washed with water (100 ml) and brine solution (100 ml), dried over Na ₂ SO ₄ , filtered, and concentrated to provide 3,5-dichlorobenzyl (R) as a white solid -3-Aminopyrrolidine-1-carboxylate ( 2 ) (1.7 g, 91.4% yield). ¹ H NMR: (CDCl ₃ , 400 MHz): δ 7.31 (t, 1H, J = 2.0Hz), 7.28-7.26 (m, 2H), 5.13 (s, 2H), 3.68-3.57 (m, 3H), 3.52-3.45 (m, 1H), 3.19-3.11 (m, 1H), 2.14-2.04 (m, 1H), 1.77-1.65 (m, 1H); ESI-MS: (+ve mode) 289.04 (M+H) ) ⁺ (100%).

Step-2: 5-(((R)-1-(((3,5-dichlorobenzyl)oxy)carbonyl)pyrrolidin-3-yl)aminocarboxy)hexahydrocyclopenta[c] Pyrrole-2(1H)-carboxylate tertiary butyl ester ( 4 ) was converted to 3,5-dichlorobenzyl (R)-3-aminopyrrolidine-1-carboxylate ( 2 ) at 0°C to 5°C ) (1.5 g, 5.19 mmol), 2-(tertiary butoxycarbonyl)octahydrocyclopenta[c]pyrrole- 5 -carboxylic acid3) (1.46 g, 5.71 mmol) and DIEA (2.72 ml, 15.56 mmol) To a solution in DMF (30 ml) was added HBTU (2.36 g, 6.23 mmol) portionwise. After 1 hour, the reaction mixture was gradually warmed to room temperature and stirred for 18 hours. To the reaction mixture were added EtOAc (75 ml) and water (150 ml). The layers were separated and the aqueous layer was extracted with EtOAc (2 x 75 ml). The combined EtOAc layers were washed with water (2 x 150 ml) followed by brine (150 ml), dried _{over Na2SO4} , filtered, and concentrated to provide the crude compound. It was purified by column chromatography to obtain 5-(((R)-1-(((3,5-dichlorobenzyl)oxy)carbonyl)pyrrolidin-3-yl)aminecarboxyl ) tert-butyl hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate ( 4 ) (2.6 g, 95.2% yield). ¹ H NMR : (CDCI ₃ , 400 MHz); δ 7.36 (d, 1H, J = 2.0Hz), 7.28-7.25 (m, 2H), 5.08 (s, 2H), 4.68-4.65 (m, 1H), 4.31-4.25 (m, 1H), 3.72-3.67 (m, 1H), 3.53-3.50 (m, 4H), 3.32-3.25 (m, 1H), 3.12-3.07 (m, 2H), 2.96-2.92 (m , 1H), 2.78-2.76 (m, 2H), 2.23-2.17 (m, 1H), 2.10-2.01 (m, 2H), 1.97-1.81 (m, 1H), 1.80-1.76 (m, 1H), 1.46 (s, 9H). ESI-MS: (+ve mode) 426.13 (M-Boc) ⁺ (100%).

Step-3: 3,5-Dichlorobenzyl(3R)-3-(octahydrocyclopenta[c]pyrrole-5-carboxamido)pyrroleidine-1-carboxylate ( 5 ) at room temperature To 5-(((R)-1-(((3,5-dichlorobenzyl)oxy)carbonyl)pyrrolidin-3-yl)aminocarboxy)hexahydrocyclopenta[c]pyrrole-2 (1H)-Carboxylic acid tert-butyl ester (4) (2.7 g, 5.13 mmol) in DCM (54 ml) was added TFA (3.95 ml, 51.32 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was then treated with saturated _NaHCO3 (aq) solution (100 ml). The layers were separated and the organic layer was washed with water (100 ml) and brine solution (75 ml), dried over Na ₂ SO ₄ , filtered, and concentrated to provide 3,5-dichlorobenzyl (3R)-3-( Octahydrocyclopenta[c]pyrrole-5-carboxamido)pyrrolidine-1-carboxylate (5) (2.28 g, 82.2% yield). ¹ H NMR: (CDCI3, 400 MHz); δ 7.48 (d, 1H, J = 2.0Hz), 7.45-7.42 (m, 2H), 5.08 (s, 2H), 4.69-4.67 (m, 1H), 4.32 -4.25 (m, 1H), 3.74-3.67 (m, 1H), 3.56-3.49 (m, 4H), 3.32-3.24 (m, 1H), 3.12-3.07 (m, 2H), 2.96-2.92 (m, 1H), 2.78-2.76 (m, 2H), 2.23-2.18 (m, 1H), 2.10-2.01 (m, 2H), 1.98-1.81 (m, 1H), 1.80-1.76 (m, 1H). ESI-MS: (+ve mode) 427.12 (M)+ (100%).

Step-4: 3,5-Dichlorobenzyl(3R)-3-(2-(3-(3-hydroxyazepin-1-yl)-3-oxypropyl)octahydrocyclopenta[c ]pyrrole-5-carboxamido)pyrrolidine-1-carboxylate ( Compound - 49 ) to 3,5-dichlorobenzyl(3R)-3-(octahydrocyclopenta[c]pyrrole-5- To a stirred solution of carboxyamido)pyrrolidine-1-carboxylate ( 5 ) (2.0 g, 4.71 mmol) in acetonitrile (40 ml) was added 3-chloro-1-(3-hydroxyazepine-1- yl)propan-1-one ( 6 ) (1.46 g, 7.04 mmol) and K ₂ CO ₃ (1.94 g, 14.08 mmol), and the mixture was heated to 60 °C. The reaction mass was filtered through celite and washed with ACN (2 x 20 ml). The combined filtrates were evaporated under reduced pressure and the residue thus obtained was purified by column chromatography to afford the title compound 3,5-dichlorobenzyl(3R)-3-(2 as a white solid -(3-(3-Hydroxynitro-1-yl)-3-oxypropyl)octahydrocyclopenta[c]pyrrole-5-carboxamido)pyrrolidine-1-carboxylate ( compound -49 ) (2.46 g, 94.6% yield). ¹ H NMR : (CDCI ₃ , 400 MHz); δ 7.48 (d, 1H, J = 2.0Hz), 7.45-7.42 (m, 2H), 5.08 (s, 2H), 4.69-4.67 (m, 1H), 4.32-4.25 (m, 1H), 3.74-3.67 (m, 1H), 3.56-3.49 (m, 4H), 3.32-3.24 (m, 1H), 3.12-3.07 (m, 2H), 2.96-2.92 (m , 1H), 2.78-2.76 (m, 2H), 2.64-2.61 (m, 2H), 2.52-2.49 (m, 3H), 2.23-2.18 (m, 2H), 2.10-2.01 (m, 3H), 1.98 -1.81 (m, 3H), 1.80-1.76 (m, 2H). ESI-MS: (+ve mode) 553.19 (M+H) ⁺ (100%).

Synthesis of Intermediate 3 [2-( tertiary butoxycarbonyl ) octahydrocyclopenta [c] pyrrole -5- carboxylic acid ]

The synthesis of the substituent _R3 (2-(tertiary butoxycarbonyl)octahydrocyclopenta[c]pyrrole-5-carboxylic acid) was carried out as shown in Scheme -3 , and the step-by-step procedure is shown below:

Scenario -3 :

Step-1: 5-Hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate tertiary butyl ester ( 8 ) was converted to 5-oxyhexahydrocyclopenta[c] at a temperature below 5°C Tri-butyl pyrrole-2(1H)-carboxylate ( 7 ) (20 g, 88.8 mmol) (Bahekar Rajesh H. et al., 2017, 21(2), 266-272) in MeOH (200 ml) To the solution was added NaBH4 (5.04 g, _133.21 mmol) in small portions. The reaction mixture was stirred for 3 hours and then concentrated under reduced pressure. The residue was dissolved in DCM (200 ml) and washed with 1N HCl (135 ml). The organic layer was washed with water (100 ml) and brine solution (75 ml), dried over Na ₂ SO ₄ , filtered, and concentrated to provide 5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H as a white solid )-tertiary butyl carboxylate ( 8 ) (19.45 g, 96.4% yield). ¹ H NMR: (CDCl ₃ , 400 MHz): δ 4.31 (qint, 1H, J = 6.4 Hz), 3.50 (dd, 2H, J ₁ = 8.0 Hz, J ₂ = 11.2 Hz), 3.36 (dd, 2H, J ₁ = 3.6Hz, J ₂ = 11.2Hz), 2.64-2.60 (m, 2H), 2.21-2.14 (m, 2H), 1.45-1.48 (m, 12H); ESI-MS: (+ve mode) 172.1 (M-OtBu) ⁺ (80%).

Step-2: 5-((Methylsulfonyl)oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate tertiary butyl ester ( 9 ) was added to 5-hydroxyhexanol at 0 to 5°C Hydrocyclopenta[c]pyrrole-2(1H)-carboxylate tert-butyl ester ( 8 ) (20 g, 88.0 mmol) in DCM (200 ml) was added TEA (24.53 ml, 176.0 mmol), followed by MsCl (8.23 ml, 105.6 mmol) was added dropwise. The reaction mixture was stirred at 25°C for 3 hours. The reaction mixture was washed sequentially with saturated NaHCO3 _(aq) solution (150 ml), water and brine (150 ml each). The organic layer was separated, dried, and evaporated to dryness under reduced pressure to give 5-((methylsulfonyl)oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxy as a viscous oil Tertiary butyl acid ( 9 ) (26.3 g, 97.8% yield), which solidified over time at room temperature. The product was used as such in the next reaction step without any purification. ¹ H NMR: (CDCl ₃ , 400 MHz): δ 5.14-5.09 (m, 1H), 3.55-3.50 (m, 2H), 3.36-3.31 (m, 2H), 3.01 (s, 3H), 2.70-2.65 (m, 2H), 2.38-2.30 (m, 2H), 1.90-1.84 (m, 2H), 1.47(s, 9H); ESI-MS: (+ve mode) 250.07 (M- t Bu) ⁺ (90 %).

Step-3: 5-Cyanohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate tert-butyl ester ( 10 ) to 5-((methylsulfonyl)oxy)hexahydrocyclopenta[c ] pyrrole-2(1H)-carboxylate tertiary butyl ester ( 9 ) (10 g, 32.74 mmol) in DMSO (10 ml) was added 18-crown-6 (0.606 g, 2.29 mmol) followed by NaCN (8.02 g, 164.0 mmol). The reaction mixture was heated at 80°C for 5 hours. The reaction mixture was cooled at room temperature, diluted with water (500 ml), extracted with ethyl acetate (200 ml x 3), and the combined organic layers were washed with water (200 ml), brine (100 ml), _{Na2SO 4} was dried and evaporated to dryness under reduced pressure to give tert-butyl 5-cyanohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate ( 10 ) (7.58 g) as a pale yellow oil , the yield is 97.9%). The product was used in the next reaction step without any purification. ¹ H NMR: (CDCl ₃ , 400 MHz): δ 3.53-3.51 (m, 2H), 3.17-3.12 (m, 2H), 3.02-2.96 (m, 1H), 2.91-2.86 (m, 2H), 2.22 -2.15 (m, 2H), 1.96-1.91 (m, 2H), 1.46 (s, 9H); ESI-MS: (+ve mode) 181.1 (M- t Bu) ⁺ (100%).

Step-4: 2-(tertiarybutyl)5-methylhexahydrocyclopenta[c]pyrrole-2,5(1H)-dicarboxylate ( 11 ) Pass HCl _(g) into 5-cyano A cold solution of hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate tert-butyl ester (4.5 g, 19.04 mmol) in MeOH (45.0 ml) was maintained at a temperature of 0°C to 5°C for one hour. The reaction mixture was gradually warmed to room temperature and stirred for 2 hours. The reaction mixture was then concentrated and dried in vacuo and the residue thus obtained was dissolved in a mixture of water (22.50 ml) and acetonitrile (45 ml). To this was added _Na2CO3 (6.05 _g , 57.1 mmol) slowly followed by BOC-anhydride (6.63 ml, 28.6 mmol) dropwise maintaining a temperature of 0°C to 5°C. The reaction mixture was stirred at room temperature overnight and concentrated in vacuo to remove acetonitrile. The obtained residue was dissolved in ethyl acetate (100 ml), washed with a solution of water (50 ml) and brine (50 ml), and the solvent was removed under reduced pressure to provide the crude product, which was filtered by flash column Purified by chromatography (Gradient: 0 to 30% ethyl acetate in hexanes). The desired product, 2-(tert-butyl)5-methylhexahydrocyclopenta[c]pyrrole-2,5(1H)-dicarboxylate, was isolated as a colorless viscous oil ( 11 ) (3.78 g, yield 73.7%). ¹ H NMR: (CDCl ₃ , 400 MHz): δ 4.08 (s, 3H), 3.51-3.45 (m, 2H), 3.12-3.07 (m, 2H), 2.96-2.92 (m, 1H), 2.78-2.76 (m, 2H), 2.10-2.01 (m, 2H), 1.82-1.78 (m, 2H), 1.44 (s, 9H); ESI-MS: (+ve mode) 170.1 (M-Boc) ⁺ (90% ).

Step-5: 2-( tertiary butoxycarbonyl ) octahydrocyclopenta [c] pyrrole -5-carboxylic acid ( 3 ) was added to 2-(tertiarybutyl) 5- carboxylic acid ( 3 ) at a temperature of 0°C to 5°C To a stirred solution of methylhexahydrocyclopenta[c]pyrrole-2,5(1H)-dicarboxylate ( 11 ) (2.5 g, 9.28 mmol) in MeOH (25 ml) was added 5M NaOH _(aq.) (5.57 ml, 27.8 mmol). The reaction mixture was gradually warmed to ambient temperature and stirred overnight. The reaction mixture was then concentrated in vacuo to remove methanol, the residue obtained was dissolved in water (25 ml) and acidified to pH 4 using citric acid solution. The aqueous mixture was extracted with DCM (25 ml x 3) and the combined organic layers were washed with brine (25 ml), dried _{over Na2SO4} . The solvent was removed in vacuo to give 2-(tertiary butoxycarbonyl)octahydrocyclopenta[c]pyrrole-5-carboxylic acid ( 3 ) (2.35 g, 9.20 mmol, yield) as a colorless viscous oil rate 99%), let it solidify. ¹ H NMR: (CDCl ₃ , 400 MHz): δ 9.13 (bs, 1H), 3.55-3.49 (m, 2H), 3.28-3.25 (m, 1H), 3.13-3.07 (m, 1H), 2.97-2.91 (m, 1H), 2.80-2.78 (m, 1H), 2.65-2.64 (m, 1H), 2.25-2.16 (m, 1H), 2.14-2.11 (m, 1H), 2.09-1.76 (m, 2H) , 1.46 (s, 9H); ESI-MS: (+ve mode) 200.11 (M-OtBu) ⁺ (90%).

The following specific novel compounds of general formula ( I ) of the present invention were prepared by using the methods described in General Scheme -1 and Scheme 2 .

¹ H NMR: (CDCI ₃, 400 MHz); δ 7.32 (d, 1H, J= 2.3Hz), 7.26-7.25 (m, 2H), 5.08 (s, 2H), 4.52-4.46 (m, 2H), 4.28-4.14 (m, 2H), 4.12-4.07 (m, 3H), 3.70-3.61 (m, 2H), 3.59-3.58 (m, 2H), 3.34-3.27 (m, 3H), 3.24-3.16 (m, 2H), 2.19-2.15 (m, 3H), 1.90-1.84 (m, 3H), 1.39-1.32 (m, 4H)。 ESI-MS:(+ve模式) 512.43 (M+H) ⁺(100%)。 Compound -3 : 3,5-Dichlorobenzyl-(3R)-3-(2-(2-ethoxy-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxylate Amino)pyrrolidine-1-carboxylate

¹ H NMR : (CDCI ₃ , 400 MHz); δ 7.32 (d, 1H, J = 2.3Hz), 7.26-7.25 (m, 2H), 5.08 (s, 2H), 4.52-4.46 (m, 2H), 4.28-4.14 (m, 2H), 4.12-4.07 (m, 3H), 3.70-3.61 (m, 2H), 3.59-3.58 (m, 2H), 3.34-3.27 (m, 3H), 3.24-3.16 (m , 2H), 2.19-2.15 (m, 3H), 1.90-1.84 (m, 3H), 1.39-1.32 (m, 4H). ESI-MS: (+ve mode) 512.43 (M+H) ⁺ (100%).

¹ H NMR: (CDCI ₃, 400 MHz); δ 7.54 (d, 1H, J= 2.0Hz), 7.46-7.41 (m, 2H), 6.35-6.28 (m, 1H), 5.08 (s, 2H), 4.99-4.97 (m, 1H), 4.96-4.95 (m, 1H), 4.69-4.67 (m, 1H), 4.46-4.38 (m, 1H), 4.26-4.24 (m, 1H), 3.98-3.92 (m, 1H), 3.81-3.78 (m, 1H), 3.67-3.52 (m, 2H), 3.36-3.29 (m, 1H), 3.20-3.11 (m, 1H), 2.95-2.92 (m, 1H), 2.89-2.75 (m, 2H), 2.67-2.61 (m, 2H), 2.55-2.44 (m, 2H), 2.34-2.31 (m, 1H), 2.23-2.18 (m, 1H), 2.11-2.01 (m, 2H), 1.98-1.81 (m, 2H), 1.80-1.76 (m, 2H)。 ESI-MS:(+ve模式) 539.14 (M+H) ⁺(100%)。 Compound -7 : 3,5-Dichlorobenzyl-(3R)-3-(2-(2-(3-hydroxyazepin-1-yl)-2-oxyethyl)octahydrocyclopenta[ c]pyrrole-5-carboxyamido)pyrrolidine-1-carboxylate

¹ H NMR : (CDCI ₃ , 400 MHz); δ 7.54 (d, 1H, J = 2.0Hz), 7.46-7.41 (m, 2H), 6.35-6.28 (m, 1H), 5.08 (s, 2H), 4.99-4.97 (m, 1H), 4.96-4.95 (m, 1H), 4.69-4.67 (m, 1H), 4.46-4.38 (m, 1H), 4.26-4.24 (m, 1H), 3.98-3.92 (m , 1H), 3.81-3.78 (m, 1H), 3.67-3.52 (m, 2H), 3.36-3.29 (m, 1H), 3.20-3.11 (m, 1H), 2.95-2.92 (m, 1H), 2.89 -2.75 (m, 2H), 2.67-2.61 (m, 2H), 2.55-2.44 (m, 2H), 2.34-2.31 (m, 1H), 2.23-2.18 (m, 1H), 2.11-2.01 (m, 2H), 1.98-1.81 (m, 2H), 1.80-1.76 (m, 2H). ESI-MS: (+ve mode) 539.14 (M+H) ⁺ (100%).

¹ H NMR: (CDCI ₃, 400 MHz); δ 7.54 (d, 1H, J= 2.0Hz), 7.46-7.42 (m, 2H), 6.35-6.27 (m, 1H), 5.08 (s, 2H), 4.99-4.97 (m, 1H), 4.96-4.95 (m, 1H), 4.69-4.67 (m, 1H), 4.48-4.38 (m, 1H), 4.26-4.24 (m, 1H), 3.98-3.90 (m, 1H), 3.81-3.78 (m, 1H), 3.68-3.52 (m, 2H), 3.37-3.29 (m, 1H), 3.20-3.11 (m, 1H), 2.95-2.92 (m, 1H), 2.89-2.75 (m, 2H), 2.67-2.61 (m, 2H), 2.55-2.44 (m, 2H), 2.34-2.31 (m, 1H), 2.23-2.18 (m, 1H), 2.10-2.01 (m, 2H), 1.98-1.81 (m, 2H), 1.80-1.76 (m, 2H)。 ESI-MS:(+ve模式) 539.17 (M+H) ⁺(100%)。 Compound - 8 : 3,5-Dichlorobenzyl-(3S)-3-(2-(2-(3-hydroxyazepin-1-yl)-2-oxyethyl)octahydrocyclopenta[ c]pyrrole-5-carboxyamido)pyrrolidine-1-carboxylate

¹ H NMR : (CDCI ₃ , 400 MHz); δ 7.54 (d, 1H, J = 2.0Hz), 7.46-7.42 (m, 2H), 6.35-6.27 (m, 1H), 5.08 (s, 2H), 4.99-4.97 (m, 1H), 4.96-4.95 (m, 1H), 4.69-4.67 (m, 1H), 4.48-4.38 (m, 1H), 4.26-4.24 (m, 1H), 3.98-3.90 (m , 1H), 3.81-3.78 (m, 1H), 3.68-3.52 (m, 2H), 3.37-3.29 (m, 1H), 3.20-3.11 (m, 1H), 2.95-2.92 (m, 1H), 2.89 -2.75 (m, 2H), 2.67-2.61 (m, 2H), 2.55-2.44 (m, 2H), 2.34-2.31 (m, 1H), 2.23-2.18 (m, 1H), 2.10-2.01 (m, 2H), 1.98-1.81 (m, 2H), 1.80-1.76 (m, 2H). ESI-MS: (+ve mode) 539.17 (M+H) ⁺ (100%).

¹ H NMR: (CDCI ₃, 400 MHz); δ 7.56 (d, 1H, J= 2.2Hz), 7.47-7.43 (m, 2H), 5.94-5.86 (m, 1H), 5.08 (s, 2H), 4.49-4.37 (m, 1H), 4.28-4.16 (m, 1H), 3.90-3.87 (m, 2H), 3.77-3.68 (m, 1H), 3.38-3.31 (m, 3H), 3.18-3.11 (m, 2H), 2.92-2.90 (m, 2H), 2.76-2.69 (m, 2H), 2.61-2.57 (m, 2H), 2.30-2.27 (m, 1H), 1.92-1.81 (m, 7H), 1.74-1.69 (m, 2H), 1.53-1.49 (m, 2H), 1.33-1.27 (m, 1H)。 ESI-MS:(+ve模式) 553.80 (M+H) ⁺(100%)。 Compound - 14 : 3,5-Dichlorobenzyl(3R)-3-(2-(2-((S)-3-hydroxypyrrolidin-1-yl)-2-oxyethyl)octahydro Cyclopenta[c]pyrrole-5-carboxamido)pyrrolidine-1-carboxylate

¹ H NMR : (CDCI ₃ , 400 MHz); δ 7.56 (d, 1H, J = 2.2Hz), 7.47-7.43 (m, 2H), 5.94-5.86 (m, 1H), 5.08 (s, 2H), 4.49-4.37 (m, 1H), 4.28-4.16 (m, 1H), 3.90-3.87 (m, 2H), 3.77-3.68 (m, 1H), 3.38-3.31 (m, 3H), 3.18-3.11 (m , 2H), 2.92-2.90 (m, 2H), 2.76-2.69 (m, 2H), 2.61-2.57 (m, 2H), 2.30-2.27 (m, 1H), 1.92-1.81 (m, 7H), 1.74 -1.69 (m, 2H), 1.53-1.49 (m, 2H), 1.33-1.27 (m, 1H). ESI-MS: (+ve mode) 553.80 (M+H) ⁺ (100%).

¹ H NMR: (CDCI ₃, 400 MHz); δ 7.54 (d, 1H, J= 2.0Hz), 7.46-7.42 (m, 2H), 5.94-5.86 (m, 1H), 5.08 (s, 2H), 4.49-4.37 (m, 1H), 4.28-4.16 (m, 1H), 3.90-3.87 (m, 2H), 3.77-3.68 (m, 1H), 3.52-3.42 (m, 2H), 3.38-3.31 (m, 3H), 3.18-3.11 (m, 2H), 2.92-2.90 (m, 2H), 2.76-2.69 (m, 2H), 2.61-2.57 (m, 2H), 2.30-2.27 (m, 1H), 1.90-1.81 (m, 7H), 1.72-1.69 (m, 2H), 1.51-1.48 (m, 2H), 1.33-1.27 (m, 1H)。 ESI-MS:(+ve模式) 567.21 (M+H) ⁺(100%)。 Compound -17 : 3,5-Dichlorobenzyl-(3R)-3-(2-(2-(4-hydroxypiperidin-1-yl)-2-oxyethyl)octahydrocyclopenta[ c]pyrrole-5-carboxyamido)pyrrolidine-1-carboxylate

¹ H NMR : (CDCI ₃ , 400 MHz); δ 7.54 (d, 1H, J = 2.0Hz), 7.46-7.42 (m, 2H), 5.94-5.86 (m, 1H), 5.08 (s, 2H), 4.49-4.37 (m, 1H), 4.28-4.16 (m, 1H), 3.90-3.87 (m, 2H), 3.77-3.68 (m, 1H), 3.52-3.42 (m, 2H), 3.38-3.31 (m , 3H), 3.18-3.11 (m, 2H), 2.92-2.90 (m, 2H), 2.76-2.69 (m, 2H), 2.61-2.57 (m, 2H), 2.30-2.27 (m, 1H), 1.90 -1.81 (m, 7H), 1.72-1.69 (m, 2H), 1.51-1.48 (m, 2H), 1.33-1.27 (m, 1H). ESI-MS: (+ve mode) 567.21 (M+H) ⁺ (100%).

¹ H NMR: (DMSO, 400 MHz); δ 12.71 (s, 1H), 8.09 (s, 1H), 7.56-7.50 (m, 2H), 7.43-7.40 (m, 2H), 5.15-5.05 (m, 2H), 5.08 (s, 2H), 4.67-4.62 (m, 2H), 4.36-4.18 (m, 3H), 3.56-3.53 (m, 1H), 3.48-3.43 (m, 2H), 3.31-3.27 (m, 2H), 2.79-2.72 (m, 2H), 2.68-2.63 (m, 2H), 2.56-2.53 (m, 2H), 1.77-1.71 (m, 2H), 1.54 (m, 4H)。 ESI-MS:(+ve模式) 575.19 (M+H) ⁺(100%)。 Compound - 33 : 3,5-Dichlorobenzyl(3R)-3-(2-(2-(2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl) -2-Oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxamido)pyrrolidine-1-carboxylate

¹ H NMR : (DMSO, 400 MHz); δ 12.71 (s, 1H), 8.09 (s, 1H), 7.56-7.50 (m, 2H), 7.43-7.40 (m, 2H), 5.15-5.05 (m, 2H), 5.08 (s, 2H), 4.67-4.62 (m, 2H), 4.36-4.18 (m, 3H), 3.56-3.53 (m, 1H), 3.48-3.43 (m, 2H), 3.31-3.27 ( m, 2H), 2.79-2.72 (m, 2H), 2.68-2.63 (m, 2H), 2.56-2.53 (m, 2H), 1.77-1.71 (m, 2H), 1.54 (m, 4H). ESI-MS: (+ve mode) 575.19 (M+H) ⁺ (100%).

¹ H NMR: (DMSO, 400 MHz); δ 8.09 (s, 1H), 7.56-7.50 (m, 2H), 7.43-7.40 (m, 2H), 5.15-5.05 (m, 2H), 5.08 (s, 2H), 4.67-4.62 (m, 2H), 4.36-4.18 (m, 3H), 3.83 (s, 3H), 3.56-3.53 (m, 1H), 3.48-3.43 (m, 2H), 3.31-3.27 (m, 2H), 2.79-2.72 (m, 2H), 2.68-2.63 (m, 2H), 2.56-2.53 (m, 2H), 1.77-1.71 (m, 2H), 1.54 (m, 4H)。 ESI-MS:(+ve模式) 589.20 (M+H) ⁺(100%)。 Compound - 34 : 3,5-Dichlorobenzyl(3R)-3-(2-(2-(2-methyl-2,6-dihydropyrrolo[3,4-c]pyrazole-5( 4H)-yl)-2-oxoethyl)octahydrocyclopenta[c]pyrrole-5-carboxamido)pyrrolidine-1-carboxylate

¹ H NMR : (DMSO, 400 MHz); δ 8.09 (s, 1H), 7.56-7.50 (m, 2H), 7.43-7.40 (m, 2H), 5.15-5.05 (m, 2H), 5.08 (s, 2H), 4.67-4.62 (m, 2H), 4.36-4.18 (m, 3H), 3.83 (s, 3H), 3.56-3.53 (m, 1H), 3.48-3.43 (m, 2H), 3.31-3.27 ( m, 2H), 2.79-2.72 (m, 2H), 2.68-2.63 (m, 2H), 2.56-2.53 (m, 2H), 1.77-1.71 (m, 2H), 1.54 (m, 4H). ESI-MS: (+ve mode) 589.20 (M+H) ⁺ (100%).

¹ H NMR: (CDCI ₃, 400 MHz); δ 7.32-7.25 (m, 4H), 5.84-5.82 (m, 1H), 5.08 (s, 2H), 4.67-4.51 (m, 3H), 4.48-4.46 (m, 2H), 3.75-3.68 (m, 1H), 3.54-3.52 (m, 2H), 3.31-3.27 (m, 2H), 2.79-2.72 (m, 2H), 2.68-2.63 (m, 2H), 2.56-2.53 (m, 2H), 2.19-2.16 (m, 1H), 1.97-1.85 (m, 6H), 1.77-1.71 (m, 2H), 1.54 (d, 6H, J= 6.8Hz)。 ESI-MS:(+ve模式) 617.23 (M+H) ⁺(100%)。 Compound - 35 : 3,5-Dichlorobenzyl-(3R)-3-(2-(2-(2-isopropyl-2,6-dihydropyrrolo[3,4-c]pyrazole- 5(4H)-yl)-2-oxoethyl)octahydrocyclopenta[c]pyrrole-5-carboxamido)pyrrolidine-1-carboxylate

¹ H NMR : (CDCI ₃ , 400 MHz); δ 7.32-7.25 (m, 4H), 5.84-5.82 (m, 1H), 5.08 (s, 2H), 4.67-4.51 (m, 3H), 4.48-4.46 (m, 2H), 3.75-3.68 (m, 1H), 3.54-3.52 (m, 2H), 3.31-3.27 (m, 2H), 2.79-2.72 (m, 2H), 2.68-2.63 (m, 2H) , 2.56-2.53 (m, 2H), 2.19-2.16 (m, 1H), 1.97-1.85 (m, 6H), 1.77-1.71 (m, 2H), 1.54 (d, 6H, J = 6.8Hz). ESI-MS: (+ve mode) 617.23 (M+H) ⁺ (100%).

-7(8H)-基)-2-側氧基乙基)八氫環戊[c]吡咯-5-羧醯胺基)吡咯啶-1-羧酸酯

¹ H NMR: (CDCI ₃, 400 MHz); δ 8.04-7.97 (m, 1H), 7.62 (d, 1H, J= 2.5Hz), 7.46-7.42 (m, 3H), 5.84-5.82 (m, 1H), 5.07 (s, 2H), 4.67-4.51 (m, 3H), 4.48-4.46 (m, 2H), 3.75-3.68 (m, 1H), 3.54-3.52 (m, 2H), 3.31-3.27 (m, 2H), 2.79-2.72 (m, 2H), 2.68-2.63 (m, 2H), 2.56-2.53 (m, 2H), 2.19-2.16 (m, 2H), 1.97-1.94 (m, 2H), 1.91-1.85 (m, 4H), 1.39-1.36 (m, 2H)。 ESI-MS:(+ve模式) 519.20 (M+H) ⁺(100%)。 Compound - 41 : 3,5-Dichlorobenzyl(3R)-3-(2-(2-(5,6-dihydro-[1,2,4]triazolo[4,3-a]pyridine

-7(8H)-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxamido)pyrroleidine-1-carboxylate

¹ H NMR : (CDCI ₃ , 400 MHz); δ 8.04-7.97 (m, 1H), 7.62 (d, 1H, J = 2.5Hz), 7.46-7.42 (m, 3H), 5.84-5.82 (m, 1H) ), 5.07 (s, 2H), 4.67-4.51 (m, 3H), 4.48-4.46 (m, 2H), 3.75-3.68 (m, 1H), 3.54-3.52 (m, 2H), 3.31-3.27 (m , 2H), 2.79-2.72 (m, 2H), 2.68-2.63 (m, 2H), 2.56-2.53 (m, 2H), 2.19-2.16 (m, 2H), 1.97-1.94 (m, 2H), 1.91 -1.85 (m, 4H), 1.39-1.36 (m, 2H). ESI-MS: (+ve mode) 519.20 (M+H) ⁺ (100%).

-7(8H)-基)乙基)八氫環戊[c]吡咯-5-羧醯胺基)吡咯啶-1-羧酸酯

¹ H NMR: (CDCI ₃, 400 MHz); δ 7.54 (d, 1H, J= 2.0Hz), 7.46-7.42 (m, 2H), 5.84-5.82 (m, 1H), 5.08 (s, 2H), 4.67-4.51 (m, 3H), 4.48-4.46 (m, 2H), 3.75-3.68 (m, 1H), 3.54-3.52 (m, 2H), 3.31-3.27 (m, 2H), 2.79-2.72 (m, 2H), 2.68-2.63 (m, 2H), 2.56-2.53 (m, 2H), 2.19-2.16 (m, 2H), 1.97-1.94 (m, 2H), 1.91-1.85 (m, 4H), 1.74-1.71 (m, 2H)。 ESI-MS:(+ve模式) 658.18 (M+H) ⁺(100%)。 Compound - 44 : 3,5-dichlorobenzyl-(3R)-3-(2-(2-oxo-2-(3-(trifluoromethyl)-5,6-dihydro-[1] ,2,4]Triazolo[4,3-a]pyridine

-7(8H)-yl)ethyl)octahydrocyclopenta[c]pyrrole-5-carboxamido)pyrrolidine-1-carboxylate

¹ H NMR : (CDCI ₃ , 400 MHz); δ 7.54 (d, 1H, J = 2.0Hz), 7.46-7.42 (m, 2H), 5.84-5.82 (m, 1H), 5.08 (s, 2H), 4.67-4.51 (m, 3H), 4.48-4.46 (m, 2H), 3.75-3.68 (m, 1H), 3.54-3.52 (m, 2H), 3.31-3.27 (m, 2H), 2.79-2.72 (m , 2H), 2.68-2.63 (m, 2H), 2.56-2.53 (m, 2H), 2.19-2.16 (m, 2H), 1.97-1.94 (m, 2H), 1.91-1.85 (m, 4H), 1.74 -1.71 (m, 2H). ESI-MS: (+ve mode) 658.18 (M+H) ⁺ (100%).

¹ H NMR: (CDCI ₃, 400 MHz); δ 7.56 (d, 1H, J= 2.1Hz), 7.47-7.42 (m, 2H), 6.35-6.28 (m, 1H), 5.08 (s, 2H), 4.99-4.97 (m, 1H), 4.96-4.95 (m, 1H), 4.70-4.67 (m, 1H), 4.46-4.38 (m, 1H), 4.26-4.24 (m, 1H), 3.98-3.92 (m, 1H), 3.81-3.78 (m, 1H), 3.67-3.52 (m, 2H), 3.36-3.29 (m, 1H), 3.20-3.11 (m, 1H), 2.95-2.92 (m, 1H), 2.89-2.75 (m, 4H), 2.67-2.61 (m, 2H), 2.55-2.44 (m, 2H), 2.34-2.31 (m, 1H), 2.23-2.18 (m, 1H), 2.11-2.01 (m, 2H), 1.97-1.90 (m, 2H), 1.80-1.76 (m, 2H)。 ESI-MS:(+ve模式) 553.68 (M+H) ⁺(100%)。 Compound - 49 : 3,5-Dichlorobenzyl-(3R)-3-(2-(3-(3-hydroxynitro-1-yl)-3-oxyethyl)octahydrocyclopenta[ c]pyrrole-5-carboxyamido)pyrrolidine-1-carboxylate

¹ H NMR : (CDCI ₃ , 400 MHz); δ 7.56 (d, 1H, J = 2.1Hz), 7.47-7.42 (m, 2H), 6.35-6.28 (m, 1H), 5.08 (s, 2H), 4.99-4.97 (m, 1H), 4.96-4.95 (m, 1H), 4.70-4.67 (m, 1H), 4.46-4.38 (m, 1H), 4.26-4.24 (m, 1H), 3.98-3.92 (m , 1H), 3.81-3.78 (m, 1H), 3.67-3.52 (m, 2H), 3.36-3.29 (m, 1H), 3.20-3.11 (m, 1H), 2.95-2.92 (m, 1H), 2.89 -2.75 (m, 4H), 2.67-2.61 (m, 2H), 2.55-2.44 (m, 2H), 2.34-2.31 (m, 1H), 2.23-2.18 (m, 1H), 2.11-2.01 (m, 2H), 1.97-1.90 (m, 2H), 1.80-1.76 (m, 2H). ESI-MS: (+ve mode) 553.68 (M+H) ⁺ (100%).

¹ H NMR: (CDCI ₃, 400 MHz); δ 7.54 (d, 1H, J= 2.0Hz), 7.46-7.41 (m, 2H), 6.35-6.28 (m, 1H), 5.08 (s, 2H), 4.99-4.97 (m, 1H), 4.96-4.95 (m, 1H), 4.69-4.67 (m, 1H), 4.46-4.38 (m, 1H), 4.26-4.24 (m, 1H), 3.98-3.92 (m, 1H), 3.81-3.78 (m, 1H), 3.67-3.52 (m, 2H), 3.36-3.29 (m, 1H), 3.27 (s, 3H), 3.20-3.11 (m, 1H), 2.95-2.92 (m, 1H), 2.89-2.75 (m, 2H), 2.67-2.61 (m, 2H), 2.55-2.44 (m, 2H), 2.34-2.31 (m, 1H), 2.23-2.18 (m, 1H), 2.11-2.01 (m, 2H), 1.98-1.81 (m, 2H), 1.80-1.76 (m, 2H)。 ESI-MS:(+ve模式) 553.80 4 (M+H) ⁺(100%)。 Compound - 67 : 3,5-Dichlorobenzyl(3R)-3-(2-(2-(3-hydroxyazepin-1-yl)-2-oxyethyl)-N-methylocta Hydrocyclopenta[c]pyrrole-5-carboxamido)pyrrolidine-1-carboxylate

¹ H NMR : (CDCI ₃ , 400 MHz); δ 7.54 (d, 1H, J = 2.0Hz), 7.46-7.41 (m, 2H), 6.35-6.28 (m, 1H), 5.08 (s, 2H), 4.99-4.97 (m, 1H), 4.96-4.95 (m, 1H), 4.69-4.67 (m, 1H), 4.46-4.38 (m, 1H), 4.26-4.24 (m, 1H), 3.98-3.92 (m , 1H), 3.81-3.78 (m, 1H), 3.67-3.52 (m, 2H), 3.36-3.29 (m, 1H), 3.27 (s, 3H), 3.20-3.11 (m, 1H), 2.95-2.92 (m, 1H), 2.89-2.75 (m, 2H), 2.67-2.61 (m, 2H), 2.55-2.44 (m, 2H), 2.34-2.31 (m, 1H), 2.23-2.18 (m, 1H) , 2.11-2.01 (m, 2H), 1.98-1.81 (m, 2H), 1.80-1.76 (m, 2H). ESI-MS: (+ve mode) 553.80 4 (M+H) ⁺ (100%).

¹ H NMR: (CDCI ₃, 400 MHz); δ 7.54 (d, 1H, J= 2.0Hz), 7.46-7.41 (m, 2H), 6.35-6.28 (m, 1H), 5.08 (s, 2H), 4.99-4.97 (m, 1H), 4.96-4.95 (m, 1H), 4.69-4.67 (m, 1H), 4.46-4.38 (m, 1H), 4.26-4.24 (m, 1H), 3.98-3.92 (m, 1H), 3.81-3.78 (m, 1H), 3.67-3.52 (m, 2H), 3.36-3.29 (m, 1H), 3.20-3.11 (m, 1H), 2.95-2.92 (m, 1H), 2.89-2.75 (m, 2H), 2.67-2.61 (m, 2H), 2.55-2.44 (m, 2H), 2.34-2.31 (m, 1H), 2.23-2.18 (m, 1H), 2.11-2.01 (m, 2H), 1.98-1.81 (m, 2H), 1.80-1.76 (m, 2H)。 ESI-MS:(+ve模式) 507.23 (M+H) ⁺(100%)。 Compound - 69 : 3,5-Dichlorobenzyl-(3R)-3-(2-(2-(3-hydroxyazepin-1-yl)-2-oxyethyl)octahydrocyclopenta[ c]pyrrole-5-carboxyamido)pyrrolidine-1-carboxylate

¹ H NMR : (CDCI ₃ , 400 MHz); δ 7.54 (d, 1H, J = 2.0Hz), 7.46-7.41 (m, 2H), 6.35-6.28 (m, 1H), 5.08 (s, 2H), 4.99-4.97 (m, 1H), 4.96-4.95 (m, 1H), 4.69-4.67 (m, 1H), 4.46-4.38 (m, 1H), 4.26-4.24 (m, 1H), 3.98-3.92 (m , 1H), 3.81-3.78 (m, 1H), 3.67-3.52 (m, 2H), 3.36-3.29 (m, 1H), 3.20-3.11 (m, 1H), 2.95-2.92 (m, 1H), 2.89 -2.75 (m, 2H), 2.67-2.61 (m, 2H), 2.55-2.44 (m, 2H), 2.34-2.31 (m, 1H), 2.23-2.18 (m, 1H), 2.11-2.01 (m, 2H), 1.98-1.81 (m, 2H), 1.80-1.76 (m, 2H). ESI-MS: (+ve mode) 507.23 (M+H) ⁺ (100%).

¹ H NMR: (CDCI ₃, 400 MHz); δ 8.06-8.01 (m, 1H), 7.41 (d, 1H, J= 2.0Hz), 7.39-7.34 (m, 2H), 6.35-6.28 (m, 1H), 5.69 (s, 1H), 4.99-4.97 (m, 1H), 4.96-4.95 (m, 1H), 4.69-4.67 (m, 1H), 4.46-4.38 (m, 1H), 4.26-4.24 (m, 2H), 3.98-3.92 (m, 1H), 3.81-3.78 (m, 1H), 3.67-3.52 (m, 2H), 3.36-3.29 (m, 1H), 3.20-3.11 (m, 1H), 2.95-2.92 (m, 2H), 2.89-2.75 (m, 2H), 2.67-2.61 (m, 2H), 2.55-2.44 (m, 2H), 2.34-2.31 (m, 1H), 2.23-2.18 (m, 1H), 2.11-2.01 (m, 2H), 1.98-1.81 (m, 2H), 1.80-1.76 (m, 2H)。 ESI-MS:(+ve模式) 537.20 (M+H) ⁺(100%)。 Compound - 77 : N-((R)-1-(3-(3,5-dichlorophenyl)propionyl)pyrrolidin-3-yl)-2-(2-(3-hydroxynitrogen- 1-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxamide

¹ H NMR : (CDCI ₃ , 400 MHz); δ 8.06-8.01 (m, 1H), 7.41 (d, 1H, J = 2.0Hz), 7.39-7.34 (m, 2H), 6.35-6.28 (m, 1H ), 5.69 (s, 1H), 4.99-4.97 (m, 1H), 4.96-4.95 (m, 1H), 4.69-4.67 (m, 1H), 4.46-4.38 (m, 1H), 4.26-4.24 (m , 2H), 3.98-3.92 (m, 1H), 3.81-3.78 (m, 1H), 3.67-3.52 (m, 2H), 3.36-3.29 (m, 1H), 3.20-3.11 (m, 1H), 2.95 -2.92 (m, 2H), 2.89-2.75 (m, 2H), 2.67-2.61 (m, 2H), 2.55-2.44 (m, 2H), 2.34-2.31 (m, 1H), 2.23-2.18 (m, 1H), 2.11-2.01 (m, 2H), 1.98-1.81 (m, 2H), 1.80-1.76 (m, 2H). ESI-MS: (+ve mode) 537.20 (M+H) ⁺ (100%).

¹ H NMR: (CDCI ₃, 400 MHz); δ 7.32 (s, 1H), 7.24 (s, 2H), 5.89-5.87 (d, 1H, J= 7.6Hz), 5.07 (s, 2H), 4.68-4.65 (m, 1H), 4.41-4.37 (m, 1H), 4.28-4.24 (m, 1H), 4.11-4.08 (m, 3H), 3.96-3.89 (m, 2H), 3.14-3.10 (m, 1H), 2.99-2.89 (m, 3H), 2.79-2.76 (m, 3H), 2.69-2.58 (m, 2H), 2.46-2.41 (m, 2H), 2.33-2.16 (m, 4H), 1.95-1.93 (m, 2H), 1.74-1.71 (m, 2H), 1.27-1.22 (m, 1H)。 ESI-MS:(+ve模式) 553.19 (M+H) ⁺(100%)。 Compound - 86 : 3,5-Dichlorobenzyl 4-(2-(2-(3-hydroxynitro-1-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5 -Carboxamido)piperidine-1-carboxylate

¹ H NMR : (CDCI ₃ , 400 MHz); δ 7.32 (s, 1H), 7.24 (s, 2H), 5.89-5.87 (d, 1H, J = 7.6Hz), 5.07 (s, 2H), 4.68- 4.65 (m, 1H), 4.41-4.37 (m, 1H), 4.28-4.24 (m, 1H), 4.11-4.08 (m, 3H), 3.96-3.89 (m, 2H), 3.14-3.10 (m, 1H) ), 2.99-2.89 (m, 3H), 2.79-2.76 (m, 3H), 2.69-2.58 (m, 2H), 2.46-2.41 (m, 2H), 2.33-2.16 (m, 4H), 1.95-1.93 (m, 2H), 1.74-1.71 (m, 2H), 1.27-1.22 (m, 1H). ESI-MS: (+ve mode) 553.19 (M+H) ⁺ (100%).

啉基-2-側氧基乙基)-八氫環戊[c]吡咯-5-羧醯胺基)哌啶-1-羧酸酯

¹ H NMR: (CDCI ₃, 400 MHz); δ 7.34 (s, 1H), 7.24 (s, 2H), 5.89-5.87 (d, 1H, J= 7.6Hz), 5.07 (s, 2H), 4.68-4.65 (m, 1H), 4.41-4.37 (m, 1H), 4.28-4.24 (m, 1H), 4.11-4.08 (m, 3H), 3.96-3.89 (m, 2H), 3.14-3.10 (m, 1H), 2.99-2.89 (m, 3H), 2.79-2.76 (m, 3H), 2.69-2.58 (m, 4H), 2.46-2.41 (m, 4H), 2.33-2.16 (m, 4H), 1.95-1.93 (m, 2H), 1.74-1.71 (m, 2H), 1.27-1.22 (m, 1H)。 ESI-MS:(+ve模式) 567.80 (M+H) ⁺(100%)。 Compound - 100 : 3,5-dichlorobenzyl-4-(2-(2-N-

Lino-2-oxyethyl)-octahydrocyclopenta[c]pyrrole-5-carboxamido)piperidine-1-carboxylate

¹ H NMR : (CDCI ₃ , 400 MHz); δ 7.34 (s, 1H), 7.24 (s, 2H), 5.89-5.87 (d, 1H, J = 7.6Hz), 5.07 (s, 2H), 4.68- 4.65 (m, 1H), 4.41-4.37 (m, 1H), 4.28-4.24 (m, 1H), 4.11-4.08 (m, 3H), 3.96-3.89 (m, 2H), 3.14-3.10 (m, 1H) ), 2.99-2.89 (m, 3H), 2.79-2.76 (m, 3H), 2.69-2.58 (m, 4H), 2.46-2.41 (m, 4H), 2.33-2.16 (m, 4H), 1.95-1.93 (m, 2H), 1.74-1.71 (m, 2H), 1.27-1.22 (m, 1H). ESI-MS: (+ve mode) 567.80 (M+H) ⁺ (100%).

¹ H NMR: (CDCI ₃, 400 MHz); δ 7.33 (s, 1H), 7.28-7.21 (m, 2H), 5.63-5.59 (d, 1H, J= 7.6Hz), 5.07 (s, 2H), 4.68-4.62 (m, 1H), 4.57-4.53 (m, 1H), 4.52-4.48 (m, 2H), 4.11-4.08 (m, 3H), 3.96-3.89 (m, 1H), 3.30-3.27 (m, 1H), 2.97-2.79 (m, 2H), 2.79-2.76 (m, 4H), 2.58-2.54 (m, 2H), 2.06-2.01 (m, 3H), 2.33-2.16 (m, 4H), 1.96-1.93 (m, 5H), 1.54-1.50 (m, 6H), 1.29-1.26 (m, 2H)。 ESI-MS:(+ve模式) 631.24 (M+H) ⁺(100%)。 Compound - 110 : 3,5-Dichlorobenzyl 4-(2-(2-(2-isopropyl-2,6-dipyrrolo[3,4-c]pyrazol-5(4H)-yl )-2-Oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxamido)piperidine-1-carboxylate

¹ H NMR : (CDCI ₃ , 400 MHz); δ 7.33 (s, 1H), 7.28-7.21 (m, 2H), 5.63-5.59 (d, 1H, J = 7.6Hz), 5.07 (s, 2H), 4.68-4.62 (m, 1H), 4.57-4.53 (m, 1H), 4.52-4.48 (m, 2H), 4.11-4.08 (m, 3H), 3.96-3.89 (m, 1H), 3.30-3.27 (m , 1H), 2.97-2.79 (m, 2H), 2.79-2.76 (m, 4H), 2.58-2.54 (m, 2H), 2.06-2.01 (m, 3H), 2.33-2.16 (m, 4H), 1.96 -1.93 (m, 5H), 1.54-1.50 (m, 6H), 1.29-1.26 (m, 2H). ESI-MS: (+ve mode) 631.24 (M+H) ⁺ (100%).

¹ H NMR: (CDCI ₃, 400 MHz); δ 7.58 (s, 1H), 7.43-7.40 (m, 2H), 5.69-5.63 (d, 1H, J= 7.6Hz), 5.08 (s, 2H), 4.68-4.65 (m, 1H), 4.41-4.37 (m, 1H), 4.28-4.24 (m, 1H), 4.11-4.08 (m, 3H), 3.96-3.89 (m, 2H), 3.14-3.10 (m, 1H), 2.99-2.89 (m, 3H), 2.84 (s, 3H), 2.79-2.76 (m, 3H), 2.69-2.58 (m, 2H), 2.46-2.41 (m, 2H), 2.33-2.16 (m, 3H), 1.95-1.93 (m, 2H), 1.74-1.71 (m, 2H), 1.27-1.22 (m, 1H)。 ESI-MS:(+ve模式) 567.21 (M+H) ⁺(100%)。 Compound - 143 : 3,5-Dichlorobenzyl-4-(2-(2-(3-hydroxynitro-1-yl)-2-oxyethyl)-N-methyloctahydrocyclopenta [c]pyrrole-5-carboxyamido)piperidine-1-carboxylate

¹ H NMR : (CDCI ₃ , 400 MHz); δ 7.58 (s, 1H), 7.43-7.40 (m, 2H), 5.69-5.63 (d, 1H, J = 7.6Hz), 5.08 (s, 2H), 4.68-4.65 (m, 1H), 4.41-4.37 (m, 1H), 4.28-4.24 (m, 1H), 4.11-4.08 (m, 3H), 3.96-3.89 (m, 2H), 3.14-3.10 (m , 1H), 2.99-2.89 (m, 3H), 2.84 (s, 3H), 2.79-2.76 (m, 3H), 2.69-2.58 (m, 2H), 2.46-2.41 (m, 2H), 2.33-2.16 (m, 3H), 1.95-1.93 (m, 2H), 1.74-1.71 (m, 2H), 1.27-1.22 (m, 1H). ESI-MS: (+ve mode) 567.21 (M+H) ⁺ (100%).

¹ H NMR: (CDCI ₃, 400 MHz); δ 7.33 (s, 1H), 7.28-7.25 (m, 2H), 5.93 (d, 1H, J= 7.2Hz), 5.09 (s, 2H), 4.65-4.64 (m, 1H), 4.38-4.29 (m, 1H), 4.28-4.25 (m, 1H), 4.13-4.11 (m, 1H), 3.99-3.97 (m, 1H), 3.89-3.88 (m, 1H), 3.73-3.68 (m, 1H), 3.37-3.29 (m, 2H), 3.18-3.11 (m, 1H), 2.97-2.92 (m, 1H), 2.89-2.74 (m, 3H), 2.67-2.62 (m, 2H), 2.55-2.44 (m, 2H), 2.26-2.21 (m, 7H), 1.98-1.81 (m, 1H), 1.73-1.61 (m, 2H)。 ESI-MS:(+ve模式) 539.17 (M+H) ⁺(100%)。 Compound - 144 : 3,5-Dichlorobenzyl-(3R)-3-(2-(2-(3-hydroxynitro-1-yl)-2-oxyethyl)octahydrocyclopenta[ c]pyrrole-5-carboxyamido)piperidine-1-carboxylate

¹ H NMR : (CDCI ₃ , 400 MHz); δ 7.33 (s, 1H), 7.28-7.25 (m, 2H), 5.93 (d, 1H, J = 7.2Hz), 5.09 (s, 2H), 4.65- 4.64 (m, 1H), 4.38-4.29 (m, 1H), 4.28-4.25 (m, 1H), 4.13-4.11 (m, 1H), 3.99-3.97 (m, 1H), 3.89-3.88 (m, 1H) ), 3.73-3.68 (m, 1H), 3.37-3.29 (m, 2H), 3.18-3.11 (m, 1H), 2.97-2.92 (m, 1H), 2.89-2.74 (m, 3H), 2.67-2.62 (m, 2H), 2.55-2.44 (m, 2H), 2.26-2.21 (m, 7H), 1.98-1.81 (m, 1H), 1.73-1.61 (m, 2H). ESI-MS: (+ve mode) 539.17 (M+H) ⁺ (100%).

¹ H NMR: (CDCI ₃, 400 MHz); δ 7.77 (s, 1H), 7.41 (s, 2H), 5.09 (s, 2H), 4.68-4.65 (m, 1H), 4.41-4.37 (m, 1H), 4.28-4.24 (m, 1H), 4.11-4.08 (m, 3H), 3.96-3.89 (m, 2H), 3.14-3.10 (m, 1H), 2.99-2.89 (m, 3H), 2.79-2.76 (m, 3H), 2.69-2.58 (m, 2H), 2.46-2.41 (m, 2H), 2.33-2.16 (m, 4H), 1.95-1.93 (m, 2H), 1.74-1.71 (m, 2H), 1.27-1.18 (m, 4H)。 ESI-MS:(+ve模式) 551.21 (M+H) ⁺(100%)。 Compound - 153: N-(1-(3-(3,5-Dichlorophenyl)propionyl)piperidin-4-yl)-2-(2-(3-hydroxyazepin-1-yl) -2-Oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxamide

¹ H NMR : (CDCI ₃ , 400 MHz); δ 7.77 (s, 1H), 7.41 (s, 2H), 5.09 (s, 2H), 4.68-4.65 (m, 1H), 4.41-4.37 (m, 1H) ), 4.28-4.24 (m, 1H), 4.11-4.08 (m, 3H), 3.96-3.89 (m, 2H), 3.14-3.10 (m, 1H), 2.99-2.89 (m, 3H), 2.79-2.76 (m, 3H), 2.69-2.58 (m, 2H), 2.46-2.41 (m, 2H), 2.33-2.16 (m, 4H), 1.95-1.93 (m, 2H), 1.74-1.71 (m, 2H) , 1.27-1.18 (m, 4H). ESI-MS: (+ve mode) 551.21 (M+H) ⁺ (100%).

¹ H NMR: (CDCI ₃, 400 MHz); δ 7.81 (s, 1H), 7.13-7.04 (m, 3H), 5.89-5.87 (d, 1H, J= 7.6Hz), 5.07 (s, 2H), 4.69-4.65 (m, 1H), 4.41-4.38 (m, 1H), 4.28-4.24 (m, 1H), 4.11-4.08 (m, 3H), 3.96-3.89 (m, 2H), 3.14-3.10 (m, 1H), 2.98-2.89 (m, 3H), 2.79-2.76 (m, 3H), 2.69-2.58 (m, 2H), 2.46-2.41 (m, 2H), 2.33-2.16 (m, 3H), 1.95-1.93 (m, 2H), 1.74-1.71 (m, 2H), 1.29-1.23 (m, 1H)。 ESI-MS:(+ve模式) 553.27 (M+H) ⁺(100%)。 Compound - 157: N-(1-(2-(3,5-Dichlorophenoxy)acetyl)piperidin-4-yl)-2-(2-(3-hydroxynitro-1-yl)- 2-Oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxamide

¹ H NMR : (CDCI ₃ , 400 MHz); δ 7.81 (s, 1H), 7.13-7.04 (m, 3H), 5.89-5.87 (d, 1H, J = 7.6Hz), 5.07 (s, 2H), 4.69-4.65 (m, 1H), 4.41-4.38 (m, 1H), 4.28-4.24 (m, 1H), 4.11-4.08 (m, 3H), 3.96-3.89 (m, 2H), 3.14-3.10 (m , 1H), 2.98-2.89 (m, 3H), 2.79-2.76 (m, 3H), 2.69-2.58 (m, 2H), 2.46-2.41 (m, 2H), 2.33-2.16 (m, 3H), 1.95 -1.93 (m, 2H), 1.74-1.71 (m, 2H), 1.29-1.23 (m, 1H). ESI-MS: (+ve mode) 553.27 (M+H) ⁺ (100%).

¹ H NMR: (CDCI ₃, 400 MHz); δ 7.32 (s, 1H), 7.24 (s, 2H), 5.89-5.87 (d, 1H, J= 7.6Hz), 5.07 (s, 2H), 4.68-4.65 (m, 1H), 4.41-4.37 (m, 1H), 4.28-4.24 (m, 1H), 4.11-4.08 (m, 3H), 3.96-3.89 (m, 2H), 3.14-3.10 (m, 1H), 2.99-2.89 (m, 2H), 2.79-2.76 (m, 3H), 2.69-2.58 (m, 2H), 2.46-2.41 (m, 2H), 2.33-2.16 (m, 4H), 1.95-1.93 (m, 2H), 1.74-1.71 (m, 2H), 1.27-1.22 (m, 1H)。 ESI-MS:(+ve模式) 579.21 (M+H) ⁺(100%)。 Compound - 165 : 3,5-Dichlorobenzyl-5-(2-(2-(3-hydroxynitro-1-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole- 5-Carboxamido)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

¹ H NMR : (CDCI ₃ , 400 MHz); δ 7.32 (s, 1H), 7.24 (s, 2H), 5.89-5.87 (d, 1H, J = 7.6Hz), 5.07 (s, 2H), 4.68- 4.65 (m, 1H), 4.41-4.37 (m, 1H), 4.28-4.24 (m, 1H), 4.11-4.08 (m, 3H), 3.96-3.89 (m, 2H), 3.14-3.10 (m, 1H) ), 2.99-2.89 (m, 2H), 2.79-2.76 (m, 3H), 2.69-2.58 (m, 2H), 2.46-2.41 (m, 2H), 2.33-2.16 (m, 4H), 1.95-1.93 (m, 2H), 1.74-1.71 (m, 2H), 1.27-1.22 (m, 1H). ESI-MS: (+ve mode) 579.21 (M+H) ⁺ (100%).

-1-羧酸酯

¹ H NMR: (CDCI ₃, 400 MHz); δ 7.34 (s, 1H), 7.28 (s, 2H), 5.10 (s, 2H), 4.68-4.65 (m, 1H), 4.41-4.37 (m, 1H), 4.28-4.24 (m, 1H), 4.11-4.08 (m, 3H), 3.96-3.89 (m, 2H), 3.14-3.10 (m, 1H), 2.99-2.89 (m, 3H), 2.79-2.76 (m, 3H), 2.69-2.58 (m, 2H), 2.46-2.41 (m, 4H), 2.33-2.16 (m, 4H), 1.95-1.93 (m, 2H), ESI-MS:(+ve模式) 553.19 (M+H) ⁺(100%)。 Compound - 169 : 3,5-Dichlorobenzyl-4-(2-(2-(3-hydroxynitro-1-yl)-2-oxyethyl)-octahydrocyclopenta[c]pyrrole -5-Carbonyl)piperidine

-1-Carboxylic acid ester

¹ H NMR : (CDCI ₃ , 400 MHz); δ 7.34 (s, 1H), 7.28 (s, 2H), 5.10 (s, 2H), 4.68-4.65 (m, 1H), 4.41-4.37 (m, 1H) ), 4.28-4.24 (m, 1H), 4.11-4.08 (m, 3H), 3.96-3.89 (m, 2H), 3.14-3.10 (m, 1H), 2.99-2.89 (m, 3H), 2.79-2.76 (m, 3H), 2.69-2.58 (m, 2H), 2.46-2.41 (m, 4H), 2.33-2.16 (m, 4H), 1.95-1.93 (m, 2H), ESI-MS: (+ve mode ) 553.19 (M+H) ⁺ (100%).

¹ H NMR: (CDCI ₃, 400 MHz); δ 7.33 (s, 1H), 7.28-7.25 (m, 2H), 5.10-5.05 (m, 2H), 4.66-4.64 (m, 1H), 4.44-4.42 (m, 1H), 4.40-4.37 (m, 1H), 4.29-4.11 (m, 1H), 3.91-3.90 (m, 1H), 3.89-3.88 (m, 1H), 3.78-3.72 (m, 3H), 3.68-3.65 (m, 2H), 3.43-3.41 (m, 2H), 3.15-3.12 (m, 1H), 3.03-2.93 (m, 3H), 2.91-2.80 (m, 3H), 2.76-2.74 (m, 1H), 2.44-2.41(m, 1H), 2.34-2.31 (m, 1H), 2.07-1.97 (m, 3H), 1.72-1.69 (m, 1H), 1.29-1.27 (m, 1H)。 ESI-MS:(+ve模式) 565.19 (M+H) ⁺(100%)。 Compound - 171 : 3,5-Dichlorobenzyl-5-(2-(2-(3-hydroxynitro-1-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole- 5-Carbonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

¹ H NMR : (CDCI ₃ , 400 MHz); δ 7.33 (s, 1H), 7.28-7.25 (m, 2H), 5.10-5.05 (m, 2H), 4.66-4.64 (m, 1H), 4.44-4.42 (m, 1H), 4.40-4.37 (m, 1H), 4.29-4.11 (m, 1H), 3.91-3.90 (m, 1H), 3.89-3.88 (m, 1H), 3.78-3.72 (m, 3H) , 3.68-3.65 (m, 2H), 3.43-3.41 (m, 2H), 3.15-3.12 (m, 1H), 3.03-2.93 (m, 3H), 2.91-2.80 (m, 3H), 2.76-2.74 ( m, 1H), 2.44-2.41(m, 1H), 2.34-2.31 (m, 1H), 2.07-1.97 (m, 3H), 1.72-1.69 (m, 1H), 1.29-1.27 (m, 1H). ESI-MS: (+ve mode) 565.19 (M+H) ⁺ (100%).

¹ H NMR: (CDCI ₃, 400 MHz); δ 7.35 (s, 1H), 7.26-7.24 (m, 2H), 5.12-5.05 (m, 2H), 4.67-4.64 (m, 1H), 4.44-4.42 (m, 1H), 4.40-4.37 (m, 1H), 4.29-4.11 (m, 1H), 3.91-3.90 (m, 1H), 3.89-3.88 (m, 1H), 3.78-3.72 (m, 3H), 3.67-3.65 (m, 2H), 3.43-3.41 (m, 2H), 3.15-3.12 (m, 1H), 3.03-2.93 (m, 3H), 2.91-2.80 (m, 3H), 2.75-2.76 (m, 1H), 2.44-2.41(m, 1H), 2.34-2.31 (m, 1H), 2.11-1.97 (m, 4H), 1.72-1.69 (m, 2H), 1.30-1.27 (m, 2H)。 ESI-MS:(+ve模式) 579.52 (M+H) ⁺(100%)。 Compound - 176 : 3,5-Dichlorobenzyl-(2-(2-(2-(3-hydroxynitro-1-yl)-2-oxyethyl)-octahydrocyclopenta[c] Pyrrole-5-carbonyl)octahydrocyclopenta[c]pyrrol-5-yl)carbamate

¹ H NMR : (CDCI ₃ , 400 MHz); δ 7.35 (s, 1H), 7.26-7.24 (m, 2H), 5.12-5.05 (m, 2H), 4.67-4.64 (m, 1H), 4.44-4.42 (m, 1H), 4.40-4.37 (m, 1H), 4.29-4.11 (m, 1H), 3.91-3.90 (m, 1H), 3.89-3.88 (m, 1H), 3.78-3.72 (m, 3H) , 3.67-3.65 (m, 2H), 3.43-3.41 (m, 2H), 3.15-3.12 (m, 1H), 3.03-2.93 (m, 3H), 2.91-2.80 (m, 3H), 2.75-2.76 ( m, 1H), 2.44-2.41(m, 1H), 2.34-2.31 (m, 1H), 2.11-1.97 (m, 4H), 1.72-1.69 (m, 2H), 1.30-1.27 (m, 2H). ESI-MS: (+ve mode) 579.52 (M+H) ⁺ (100%).

In some embodiments, the present invention includes pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically acceptable salt, tautomeric form, enantiomer, and non-enantiomer thereof, with or without One or more pharmaceutical excipients are formulated.

In some embodiments, the invention includes a method of treating at least one of cancer, chronic inflammation, neuropathic pain, fibrotic diseases mediated in part by ATX, comprising administering to a subject in need thereof a therapeutically effective amount of formula ( Compounds or salts of novel compounds of I ). Biological Research:

ATX inhibitory activity (IC ₅₀ determination ) : ATX inhibitory activity was determined in biochemical or whole blood assays as previously described (Bretschneider, T. et al., SLAS Discov 2017, 22, 425). Biochemical reactions consisted of 50 mM Tris (pH 8.0), 3 mM KCl, 1 mM _CaCl2 , 1 mM _MgCl2 , 0.14 mM NaCl, and 0.1% bovine serum albumin supplemented with 5 nM recombinant rat ATX, 5 μM 18:1 LPC and test compound (0.1 to 10 μM). The reaction was stopped at 2 hours by the addition of butanol prior to RapidFire-MS based analysis.

The whole blood assay consists of 45 μL of heparinized mouse/rat whole blood and test compound (0.12 to 100 μM). The reaction was stopped after 1 hour at 37°C by adding 100 μL of 40 mM disodium hydrogen phosphate buffer containing 30 mM citric acid (pH 4) and 1 μM 17:0 LPA (internal standard). Afterwards, samples were processed as described above and analyzed by LC-MS/MS. Data were analyzed using the biostatistical graphing software graph pad prism (v 7.03) to obtain half-maximal inhibitory concentrations ( _IC50 ) of test compounds.

The mouse serum ATX inhibitory activity ( _IC50 ) of representative compounds is listed in Table 2.

Table 2 :

In one embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) and optionally one or more pharmaceutically acceptable excipients. The novel compounds of the present invention can be formulated into suitable pharmaceutically acceptable compositions by well-known techniques and methods and concentrations in combination with suitable excipients.

The one or more pharmaceutical excipients are selected from those known to those of ordinary skill in the art, such as diluents, carriers, lubricant fillers, and the like. The pharmaceutical composition further comprises an effective amount of a compound of formula ( I ) or a pharmaceutically acceptable salt thereof. The dosage of the compound of formula ( I ) can vary within wide limits and should be adjusted in each particular case according to the individual conditions.

In one embodiment, compounds of formula (I) may be used alone or in combination with one or more therapeutic agents such as anti-inflammatory agents, anti-tumor agents, anti-fibrotic agents, octostatine inhibitors, immunomodulatory agents, and cardiovascular agents and other therapeutic agents known to practitioners. The selection of such therapeutic agents may depend on the type and severity of the disease, the condition of the patient being treated, and other medications the patient is taking, among others.

The compounds of formula ( I ) or pharmaceutical compositions containing the compounds are useful as drugs for inhibiting ATX activity and are suitable for humans and other warm-blooded animals, and can be administered by oral, topical or parenteral administration.

In some embodiments, the invention includes a method of treating at least one of cancer, chronic inflammation, neuropathic pain, fibrotic diseases mediated in part by ATX, comprising administering to a subject in need thereof a therapeutically effective amount of formula ( Compounds or salts of novel compounds of I ).

Claims (16)

a compound of formula ( I ),

Its pharmaceutically acceptable salts, enantiomers, and non-spiroisomers thereof, wherein A is selected from - a 4- to 10-member list containing one or more heteroatoms independently selected from O, N, and S , bis or spirocyclic heterocycloalkyl; - 5- to 6-membered heterocycloalkenyl containing one double bond, containing one or more heteroatoms independently selected from O, N, and S; - containing one or more 5- to 6-membered heteroaryl groups independently selected from heteroatoms of O, N, and S; X is selected from -C(O)O-, -NR ^a -C(O)-, -C(O)- , S(O) ₂ -, -S(O) ₂ NR ^a -; R ₁ is selected from (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) Alkynyl, haloalkyl, cycloalkyl, carbocycle, heterocyclyl, heteroaryl, aryl, arylalkyl, heterocycloalkyl, heteroarylalkyl, arylalkoxy, aryloxy , heteroaryloxy, heterocyclyloxy, arylalkenyl, arylalkynyl, arylcycloalkyl, wherein each of these groups, when applicable, is further independently substituted with a substituent selected from : Halo, hydroxyl, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ ) alkoxy, haloalkyl, -NO ₂ , -OCF ₃ , -CN, -(CR ^b R ^c )) _r NR ^{d Re} , -COOR ^d , -S(O) ₂ NR ^{d Re} , -S(O) ₂ (CR ^b R ^c ) _r , -C(O ) NR ^{d Re} ; R ₂ is selected from H, (C ₁ -C ₆ )alkyl, halo, haloalkyl, -(CR ^f R ^g ) _s -COOR ^h , -(CR ^f R ^g ) _s -CONR ^h R ⁱ , -(CR ^f R ^g ) _s -OR ^h , -(CR ^f R ^g ) _s -NR ^h R ⁱ , -S(O) ₂ -(CR ^f R ^g ) _s , -S( O) ₂ -NR ^h R ⁱ , (C ₃ -C ₇ )cycloalkyl, heterocyclyl or aryl; m, n, p and q are independently selected from 0, 1, 2 or 3; Y is absent , or is selected from -H, -(CR ^ab R ^ac ) _t -, -(CR ^ab R ^ac ) _t -C(O)-, -C(O)-(CR ^ab R ^ac ) _t -, -C (O)-C(O)-, -C(O)NR ^ad R ^ae -, -(CR ^ab R ^ac ) _t- C(O)NR ^ad R ^ae -, -(CR ^ab R ^ac ) _t -C (O)OR ^ad -, -C(O)-(CR ^ab R ^ac ) _t -OR ^ad -, -(CR ^ab R ^ac ) _t -OR ^ad -, -S(O) ₂ -, -S(O ) ₂ NR ^{ad Rae} -, -S(O) _2- (CR ^ab R ^ac ) _t -; B is absent or is - 4- to 10-membered mono- or di-membered containing one or more heteroatoms independently selected from O, N, and S or spirocyclic heterocycloalkyl; - a 5- to 6-membered heterocycloalkenyl group containing one double bond, containing one or more heteroatoms independently selected from O, N, and S; - containing one or more independently 5- to 10-membered heteroaryl with heteroatoms selected from O, N, and S; - aryl, arylalkyl; R ₃ , R ₅ , and R ₆ are independently selected from H, (C ₁ -C ₆ ) alkyl, halo, haloalkyl, -(CR ^af R ^ag ) _v -COOR ^ah , -(CR ^af R ^ag ) _v -CONR ^ah R ^ai , -(CR ^af R ^ag ) _v -OR ^ah , -(CR ^af R ^ag ) _v -NR ^ah R ^ai , -S(O) ₂ -(CR ^af R ^ag ) _v , -S(O) ₂ -NR ^ah R ^ai , (C ₃ -C ₇ )cycloalkane group, heterocycloalkyl, aryl; R ₄ & R ₇ are independently selected from H, (C ₁ -C ₆ )alkyl, halo, haloalkyl, -OR ^aj , -CN, -NR ^aj R ^ak , (C ₃ -C ₇ )cycloalkyl, aryl; R ^a , R ^b , R ^c , R ^d , ^Re , R ^f , R ^g , ^Rh , R ⁱ , R ^ab , R ^ac , R ^ad , ^Rae , ^Raf , ^Rag , ^Rah , and ^Rai are independently selected from H, ( _C1 - _C6 )alkyl, halo, haloalkyl, cycloalkyl, aryl, or aryl alkyl; r, s, t and v are integers selected from 0-6. The compound of claim 1, wherein A is selected from the following structures:

. The compound of claim 1, wherein B is selected from the following structures:

. A compound of formula (I) as claimed in claim 1, which has formula (Ia),

Its pharmaceutically acceptable salts, enantiomers, and non-spiroisomers thereof, wherein A is selected from - a 4- to 10-member list containing one or more heteroatoms independently selected from O, N, and S , bis or spirocyclic heterocycloalkyl; - 5- to 6-membered heterocycloalkenyl containing one double bond, containing one or more heteroatoms independently selected from O, N, and S; - containing one or more 5- to 6-membered heteroaryl groups independently selected from heteroatoms of O, N, and S; X is selected from -C(O)O-, -NR ^a -C(O)-, -C(O)- , S(O) ₂ -, -S(O) ₂ NR ^a -; R ₁ is selected from (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) Alkynyl, haloalkyl, cycloalkyl, carbocycle, heterocyclyl, heteroaryl, aryl, arylalkyl, heterocycloalkyl, heteroarylalkyl, arylalkoxy, aryloxy , heteroaryloxy, heterocyclyloxy, arylalkenyl, arylalkynyl, arylcycloalkyl, wherein each of these groups, when applicable, is further independently substituted with a substituent selected from : Halo, hydroxyl, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ ) alkoxy, haloalkyl, -NO ₂ , -OCF ₃ , -CN, -(CR ^b R ^c )) _r NR ^{d Re} , -COOR ^d , -S(O) ₂ NR ^{d Re} , -S(O) ₂ (CR ^b R ^c ) _r , -C(O ) NR ^{d Re} ; R ₂ is selected from H, (C ₁ -C ₆ )alkyl, halo, haloalkyl, -(CR ^f R ^g ) _s -COOR ^h , -(CR ^f R ^g ) _s -CONR ^h R ⁱ , -(CR ^f R ^g ) _s -OR ^h , -(CR ^f R ^g ) _s -NR ^h R ⁱ , -S(O) ₂ -(CR ^f R ^g ) _s , -S( O) ₂ -NR ^h R ⁱ , (C ₃ -C ₇ ) cycloalkyl, heterocyclyl or aryl; Y is absent, or is selected from -H, -(CR ^ab R ^ac ) _t -, -( CR ^ab R ^ac ) _t -C(O)-, -C(O)-(CR ^ab R ^ac ) _t -, -C(O)-C(O)-, -C(O)NR ^{ad Rae} - , -(CR ^ab R ^ac ) _t- C(O)NR ^ad R ^ae -, -(CR ^ab R ^ac ) _t -C(O)OR ^ad -, -C(O)-(CR ^ab R ^ac ) _t -OR ^ad -, -(CR ^ab R ^ac ) _t -OR ^ad -, -S(O) ₂ -, -S(O) ₂ NR ^ad R ^ae -, -S(O) _2- (CR ^ab R ^{a c} ) _t- ; B is absent or selected from- 4- to 10-membered mono-, di- or spirocyclic heterocycloalkyl containing one or more heteroatoms independently selected from O, N, and S; - containing one Double bond, 5- to 6-membered heterocycloalkenyl containing one or more heteroatoms independently selected from O, N, and S; - containing one or more heteroatoms independently selected from O, N, and S 5- to 10-membered heteroaryl; - aryl, arylalkyl; R ₃ , R ₅ , and R ₆ are independently selected from H, (C ₁ -C ₆ )alkyl, halo, haloalkyl , -(CR ^af R ^ag ) _v -COOR ^ah , -(CR ^af R ^ag ) _v -CONR ^ah R ^ai , -(CR ^af R ^ag ) _v -OR ^ah , -(CR ^af R ^ag ) _v -NR ^ah R ^ai , -S(O) ₂ -(CR ^af R ^ag ) _v , -S(O) ₂ -NR ^ah R ^ai , (C ₃ -C ₇ )cycloalkyl, heterocycloalkyl, aryl; R ₄ & R ₇ are independently selected from H, (C ₁ -C ₆ )alkyl, halo, haloalkyl, -OR ^aj , -CN, -NR ^aj R ^ak , (C ₃ -C ₇ )cycloalkane R ^a , R ^b , R ^c , R ^d , R ^e , R ^f , R ^g , ^Rh , R ⁱ , R ^ab , R ^ac , R ^ad , R ^ae , R ^af , R ^ag , R ^ah , and R ^ai are independently selected from H, (C ₁ -C ₆ )alkyl, halo, haloalkyl, cycloalkyl, aryl or arylalkyl; r, s, t and v are Integer selected from 0 to 6. The compound of claim 1, having formula (I-a), wherein A is selected from 4- to 10-membered mono-, di- or spirocyclic heterocycles containing one or more heteroatoms independently selected from O, N, and S alkyl. The compound of claim 5, wherein A is selected from the following structures:

. The compound of claim 1 having formula (I-a) wherein B is absent or selected from 4 to 10 membered monocyclic heterocycloalkanes containing one or more heteroatoms independently selected from O, N, and S or a 5- to 10-membered heteroaryl group containing one or more heteroatoms independently selected from O, N, and S. The compound of claim 7, wherein B is selected from the following structures:

. The compound of claim 1 having formula (Ia), wherein X is selected from -C(O)O- and -C(O)- and Y is selected from -(CR ^ab R ^ac ) _t -C(O )-, -C(O)-(CR ^ab R ^ac ) _t - and -(CR ^ab R ^ac ) _t -C(O)OR ^ad - groups. A compound of claim 1, having formula (Ia), wherein R ₁ is selected from aryl or phenyl, arylalkyl, arylalkoxy, optionally substituted with one or more selected from : Halo, hydroxyl, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ ) alkoxy, haloalkyl, -NO ₂ , -OCF ₃ , -CN, -(CR ^b R ^c )) _r NR ^{d Re} , -COOR ^d , -S(O) ₂ NR ^{d Re} , -S(O) ₂ (CR ^b R ^c ) _r and -C(O ) NR ^{d Re} substituent, and R ₂ is H. The compound of claim 1, having formula (Ia), wherein R ₃ , R ₅ and R ₆ are independently selected from H, (C ₁ -C ₆ )alkyl, haloalkyl; R ₄ & R _{7 are} independently selected from haloalkyl and ^-ORaj groups and R ^a , R ^b , R ^c , R ^d , ^Re , R ^f , R ^g , ^Rh , R ⁱ , ^Rab , R ^ac , R ^ad , ^Rae , ^Raf , ^Rag , ^Rah , and ^Rai are independently selected from H and ( _C1 - _C6 )alkyl. The compound of claim 1, which has formula (Ia), which is selected from the group consisting of: 3,5-dichlorobenzyl(3R)-3-(2-(2-ethoxy-2-pendantoxy) ethyl)octahydrocyclopenta[c]pyrrole-5-carboxamido)pyrrolidine-1-carboxylate; 3,5-dichlorobenzyl(3R)-3-(2-(2-(3 -Hydroxynitrogen-1-yl)-2-side oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxamido)pyrrolidine-1-carboxylate; 3,5-dichlorobenzyl (3S)-3-(2-(2-(3-hydroxynitro-1-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxamido)pyrrole pyridine-1-carboxylate; 3,5-dichlorobenzyl(3R)-3-(2-(2-((S)-3-hydroxypyrrolidin-1-yl)-2-side oxyethyl yl)octahydrocyclopenta[c]pyrrole-5-carboxamido)pyrrolidine-1-carboxylate; 3,5-dichlorobenzyl(3R)-3-(2-(2-(4- Hydroxypiperidin-1-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxamido)pyrrolidine-1-carboxylate; 3,5-dichlorobenzyl (3R)-3-(2-(2-(2,6-Dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-2-oxyethyl)octahydrocycle Penta[c]pyrrole-5-carboxamido)pyrrolidine-1-carboxylate; 3,5-dichlorobenzyl(3R)-3-(2-(2-(2-methyl-2, 6-Dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxamido)pyrrolidine -1-carboxylate; 3,5-dichlorobenzyl(3R)-3-(2-(2-(2-isopropyl-2,6-dihydropyrrolo[3,4-c]pyridine) oxazol-5(4H)-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxamido)pyrrolidine-1-carboxylate; 3,5-dichlorobenzyl Base (3R)-3-(2-(2-(5,6-dihydro-[1,2,4]triazolo[4,3-a]pyridine

-7(8H)-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxamido)pyrrolidine-1-carboxylate; 3,5-dichlorobenzyl (3R)-3-(2-(2-Oxy-2-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3- a]pyridine

-7(8H)-yl)ethyl)octahydrocyclopenta[c]pyrrole-5-carboxamido)pyrrolidine-1-carboxylate; 3,5-dichlorobenzyl(3R)-3- (2-(3-(3-Hydroxynitro-1-yl)-3-oxypropyl)octahydrocyclopenta[c]pyrrole-5-carboxamido)pyrroleidine-1-carboxylate ; 3,5-Dichlorobenzyl(3R)-3-(2-(2-(3-hydroxynitro-1-yl)-2-oxyethyl)-N-methyloctahydrocyclopenta [c]pyrrole-5-carboxyamido)pyrrolidine-1-carboxylate; 3,5-dichlorobenzyl(3R)-3-(2-(2-(3-hydroxynitrogen-1- base)-2-oxyethyl) octahydrocyclopenta[c]pyrrole-5-carboxamido)pyrrolidine-1-carboxylate; ,5-Dichlorophenyl)propionyl))pyrrolidin-3-yl)-2-(2-(3-hydroxyazepin-1-yl)-2-oxyethyl)octahydrocyclopenta [c]pyrrole-5-carboxyamide; 3,5-dichlorobenzyl 4-(2-(2-(3-hydroxynitro-1-yl)-2-oxyethyl)octahydrocycle Penta[c]pyrrole-5-carboxyamido)piperidine-1-carboxylate; 3,5-dichlorobenzyl 4-(2-(2-N-

Linoyl-2-oxyethyl) octahydrocyclopenta[c]pyrrole-5-carboxamido)piperidine-1-carboxylate; 3,5-dichlorobenzyl 4-(2-( 2-(2-Isopropyl-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-2-oxyethyl)octahydrocyclopenta[c] Pyrrole-5-carboxyamido)piperidine-1-carboxylate 3,5-dichlorobenzyl 4-(2-(2-(3-hydroxyazepin-1-yl)-2-oxygen ethyl)-N-methyloctahydrocyclopenta[c]pyrrole-5-carboxamido)piperidine-1-carboxylate; 3,5-dichlorobenzyl(3R)-3-(2- (2-(3-Hydroxynitro-1-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxamido)piperidine-1-carboxylate; N- (1-(3-(3,5-Dichlorophenyl)propionyl)piperidin-4-yl)-2-(2-(3-hydroxyazepin-1-yl)-2-oxygen ethyl)octahydrocyclopenta[c]pyrrole-5-carboxamide; N-(1-(2-(3,5-dichlorophenoxy)acetyl)piperidin-4-yl)-2 -(2-(3-Hydroxynitro-1-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxamide; 3,5-dichlorobenzyl 5-( 2-(2-(3-Hydroxynitro-1-yl)-2-oxyethyl)octahydrocyclopenta[c]pyrrole-5-carboxamido)octahydrocyclopenta[c]pyrrole- 2(1H)-carboxylate; 3,5-dichlorobenzyl 4-(2-(2-(3-hydroxynitro-1-yl)-2-oxyethyl)octahydrocyclopenta[ c]pyrrole-5-carbonyl)piperidine

-1-carboxylate; 3,5-dichlorobenzyl 5-(2-(2-(3-hydroxynitro-1-yl)-2-oxyethyl) octahydrocyclopenta[c] Pyrrole-5-carbonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate; and 3,5-dichlorobenzyl(2-(2-(2-(3-hydroxy) Nitrogen-1-yl)-2-oxoethyl)octahydrocyclopenta[c]pyrrole-5-carbonyl)octahydrocyclopenta[c]pyrrol-5-yl)carbamate. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) as claimed in any one of the preceding claims and optionally one or more pharmaceutically acceptable excipients. The pharmaceutical composition of claim 13, in combination with other suitable therapeutic agents such as anti-inflammatory agents, anti-tumor agents, anti-fibrotic agents, octostatine inhibitors, immunomodulatory agents and cardiovascular agents. The compound of claim 1 or a pharmaceutical composition thereof, which can be used to prevent or treat at least one of cancer, lymphocyte homing, chronic inflammation, neuropathic pain, fibrotic diseases, thrombosis and cholestasis. A method of treating fibrosis, inflammation, cancer or angiogenic disease, preferably cancer, lymphocyte homing, chronic inflammation, neuropathic pain, fibrotic disease, thrombosis and cholestasis, comprising A subject in need thereof is administered an effective amount of a compound of formula (I) as claimed in claim 1.