Dopamine-b-hydroxylase inhibitors

This application is a U.S. national stage filing, under 35 U.S.C. § 371(c), of International Application No. PCT/PT2018/050043, filed on Nov. 30, 2018, which claims priority to United Kingdom Patent Application No. 1720189.8, filed on Dec. 4, 2017, and United Kingdom Patent Application No. 1804439.6, filed on Mar. 20, 2018. The entire contents of each of the aforementioned applications are incorporated herein by reference.

This invention relates to: (a) compounds and pharmaceutically acceptable salts or solvates thereof that are useful as dopamine-p-hydroxylase inhibitors; (b) pharmaceutical compositions comprising such compounds, salts or solvates; (c) the use of such compounds, salts or solvates in therapy; and (d) therapeutic methods of treatment using such compounds, salts or solvates.

The enzyme dopamine-μ-hydroxylase (DβH), also known as dopamine β-monooxygenase, is expressed both in the periphery and the central nervous system (CNS). DβH catalyses the specific hydroxylation of dopamine (DA) to produce norepinephrine, also known as noradrenaline (NA). As such, inhibitors of DβH can inhibit the biosynthesis of NA, limiting its concentration and increasing DA levels.

In recent years, interest in the development of inhibitors of DβH has centred on the hypothesis that inhibition of this enzyme may provide significant clinical improvements in patients suffering from cardiovascular disorders such as hypertension or chronic heart failure. The rationale for the use of DβH inhibitors is based on their capacity to inhibit the biosynthesis of NA, which is achieved via enzymatic hydroxylation of DA. Reduction of the biosynthesis of NA via inhibition of DβH can directly dampen sympathetic nerve function, the activation of which is the principal clinical manifestation of congestive heart failure (Parmley, W. W., Clin. Cardiol., 18: 440-445, 1995). Congestive heart failure patients have elevated concentrations of plasma noradrenaline (Levine, T. B. et al., Am. J. Cardiol., 49:1659-1666, 1982), increased central sympathetic outflow (Leimbach, W. N. et al., Circulation, 73: 913-919, 1986) and augmented cardiorenal noradrenaline spillover (Hasking, G. J. et al., Circulation, 73:615-621, 1966). Prolonged and excessive exposure of the myocardium to noradrenaline may lead to down-regulation of cardiac β 1 -adrenoceptors, remodelling of the left ventricle, arrhythmias and necrosis, all of which can diminish the functional integrity of the heart. Congestive heart failure patients who have high plasma concentrations of noradrenaline also have the most unfavourable long-term prognosis (Cohn, J. N. et al., N. Engl. J. Med., 311:819-823, 1984). Of greater significance is the observation that plasma noradrenaline concentrations are already elevated in asymptomatic patients with no overt heart failure and can predict ensuing mortality and morbidity (Benedict, C. R. et al., Circulation, 94:690-697, 1996). An activated sympathetic drive is not therefore merely a clinical marker of congestive heart failure, but may contribute to progressive worsening of the disease.

DβH inhibitors may also display activity the CNS, if they cross the blood-brain barrier (BBB).

Several inhibitors of DβH have been thus far reported in the literature. Early first and second generation examples such as disulfiram (Goldstein, M. et al., Life Sci., 3:763, 1964) and diethyldithiocarbamate (Lippmann, W. et al., Biochem. Pharmacol., 18: 2507, 1969) or fusaric acid (Hidaka, H. Nature, 231, 1971) and aromatic or alkyl thioureas (Johnson, G. A. et al, J. Pharmacol. Exp. Ther., 171: 80, 1970) were found to be of low potency, exhibited poor selectivity for DβH and caused toxic side effects. The third generation of DβH inhibitors, however, were found to have much greater potency, such as, for example, nepicastat (RS-25560-197, IC 50 9 nM) (Stanley, W. C., et al., Br. J. Pharmacol., 121: 1803-1809, 1997), which was developed to early clinical trials. Although it was initially developed for peripheral indications (hypertension and congestive heart failure), an important discovery was that nepicastat was found to cross the BBB, and was thereby able to cause central as well as peripheral effects.

Nepicastat and its analogues are disclosed in WO95/29165. Furthermore, WO 2004/033447 and WO 2008/136695 disclose DβH inhibitors having high potency and significantly reduced brain access, giving rise to potent and peripherally selective DβH inhibitors. However, these compounds are also difficult to synthesise requiring many steps in the synthetic route making them expensive to manufacture. In particular, potent compounds disclosed in WO 2008/136695 are sparingly soluble and display improved levels of exposure when administered with high-fat meals. A review of the mechanism, substrates and inhibitors of DβH, is given by Beliaev, A., et al. in Current Enzyme Inhibition, 5, 27-43, 2009.

WO2018/056854 and WO2018/056855 disclose DβH inhibitors which are useful for the treatment of conditions ameliorated by inhibition of DβH within the CNS. Compared with the compounds of formula Ia of the present invention, the compounds of WO2018/056854 and WO2018/056855 have different substituents at position R 6 . In addition, the sub-headings to Step 3 of Example 80 of WO2018/056854 and Step 3 of Example 3 of WO2018/056855 incorrectly disclose the chemical name (S)-1-benzyl-6-(3,5-difluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione instead of the actual compound name (S)-1-butyl-6-(3,5-difluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione (emphasis added).

Therefore, there remains an unfulfilled clinical requirement for a potent, non-toxic and peripherally selective inhibitor of DβH, which could be used for treatment of certain cardiovascular disorders. A DβH inhibitor with similar or even greater potency than nepicastat, but devoid of CNS effects (i.e. unable to efficiently cross the BBB), yet exhibiting a long residence time in the periphery so as to provide a long duration of DβH inhibition would provide a significant improvement over all DβH inhibitor compounds thus far described in the prior art. Additionally, such compounds would preferably be orally bioavailable, highly soluble and easier and cheaper to synthesise.

The present invention provides a compound of formula Ia, or a pharmaceutically acceptable salt or solvate thereof:

wherein:

R 1 is hydrogen, C 1 -C 6 alkyl, partially or fully deuterated C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl;

R 4 is hydrogen or C 1 -C 3 alkyl;

R 5 is hydrogen;

or R 4 and R 5 combine, together with the carbon atoms to which they are attached, to form a cyclopropyl ring;

R 6 is —COOH, —CHO, or —(CH 2 ) m —X,

wherein: m is 1, 2 or 3 and one —CH 2 — moiety within —(CH 2 ) m may optionally be replaced by

X is hydroxy, C 1 -C 3 alkoxy, cyano, —N═CH(NHCN)(NH 2 ), —NH—C(pyrrolidin-1-yl)=NCN, 5- or 6-membered heteroaryl optionally substituted with one methyl group, phenyl, —SO 2 —R 7 , —NR 8 R 9 , —CO 2 R 10 , —CH(CO 2 R 10 ) 2 , —CONR 11 R 12 or —NR 13 COR 14 ;

wherein: R 7 is C 1 -C 3 alkyl; R 8 is hydrogen or C 1 -C 3 alkyl; R 9 is hydrogen,

C 1 -C 4 alkyl optionally substituted with up to three fluoro substituents or with one substituent selected from the group consisting of hydroxy, methylsulfonyl, C 3 -C 6 cycloalkyl, phenyl, 5- or 6-membered heterocyclyl and 5- or 6-membered heteroaryl optionally substituted with one methyl substituent, C 3 -C 6 cycloalkyl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclyl optionally substituted with one or two oxo substituents;

or R 8 and R 9 combine together with the N atom to which they are attached to form a

5- or 6-membered N-heterocyclyl group optionally substituted with one substituent selected from methyl, trifluoromethyl, hydroxy, hydroxymethyl, methoxymethyl, methylsulfonyl, amido, (N,N-dimethyl)acetamide and pyridyl or with one or two substituents selected from fluoro and oxo, or a 9- or 10-membered heterospirocyclyl group;

R 10 is hydrogen or C 1 -C 3 alkyl; R 11 is hydrogen or C 1 -C 3 alkyl; R 12 is hydrogen,

C 1 -C 4 alkyl optionally substituted with up to three fluoro substituents or with one substituent selected from the group consisting of cyano, hydroxy, methylsulfonyl, C 1 -C 2 alkoxy, dimethylamino, C 3 -C 6 cycloalkyl, phenyl, 5- or 6-membered heteroaryl optionally substituted with one methyl substituent and 5- or 6-membered heterocyclyl optionally substituted with one t-Boc group or with one or two fluoro substituents, C 3 -C 6 cycloalkyl optionally substituted with one substituent selected from the group consisting of cyano, hydroxy, hydroxymethyl and oxo, cyano, methylsulfonyl, CH 2 COO(C 1 -C 3 alkyl), 5- or 6-membered heteroaryl optionally substituted with one methyl substituent, 4-, 5- or 6-membered heterocyclyl optionally substituted with one or two substituents selected from oxo and methyl, CH 2 CH(NH 2 )(COOH), or CH(CH 3 )CONH 2 ;

or R 11 and R 12 combine together with the N atom to which they are attached to form a

5- or 6-membered N-heterocyclyl group optionally substituted with one substituent selected from monofluoromethyl, trifluoromethyl, hydroxy, hydroxymethyl, methoxymethyl, methylsulfonyl, cyano, amido, (N,N-dimethyl)acetamide and pyridyl, or with one or two substituents selected from fluoro, methyl and oxo, or optionally fused to a cyclopropyl ring which may be substituted with one or two methyl substituents, or a 9- or 10-membered heterospirocyclyl group;

R 13 is hydrogen or C 1 -C 3 alkyl; R 14 is C 1 -C 4 alkyl optionally substituted with up to three fluoro substituents or with one substituent selected from the group consisting of hydroxy, methylsulfonyl, C 3 -C 6 cycloalkyl and phenyl,

C 3 -C 6 cycloalkyl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclyl optionally substituted with one or two oxo substituents;

A is C 5 -C 7 cycloalkyl, furanyl, thiophenyl, methylthiophenyl or

wherein:

X 1 is hydrogen, halo or methyl;

X 1 ′ is hydrogen or halo;

X 2 is hydrogen, halo or methyl;

X 2 ′ is hydrogen or halo;

X 3 is hydrogen or fluoro;

n is 0 or 1, and when n is 0 a single bond joins the carbon atoms to which the CH 2 moiety would be attached when n is 1.

This invention is also directed to a compound of formula Ia, as defined above, or a pharmaceutically acceptable salt or solvate thereof, for use in therapy.

This invention is also directed to a compound of formula Ia, as defined above, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of conditions ameliorated by inhibition of DβH outside the CNS.

This invention is also directed to a compound of formula Ia, as defined above, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for treatment of conditions ameliorated by inhibition of DβH outside the CNS.

This invention is also directed to a method for treating or preventing conditions ameliorated by inhibition of DβH outside the CNS comprising administering a therapeutically effective amount of a compound of formula Ia, as defined above, or a pharmaceutically acceptable salt or solvate thereof, to a patient in need thereof.

This invention is also directed to a pharmaceutical composition comprising (i) a therapeutically effective amount of a compound of formula Ia, as defined above, or a pharmaceutically acceptable salt or solvate thereof; and (ii) a pharmaceutically acceptable excipient.

This invention is also directed to a compound of formula Ia, as defined above, or a pharmaceutically acceptable salt or solvate thereof, with the proviso that the compound (S)-1-benzyl-6-(3,5-difluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione is excluded.

Certain compounds of formula Ia may exist as tautomers. Where tautomers exist, each tautomeric form, and mixtures thereof, are contemplated as included in the present invention. Any reference in this specification to one specific tautomer of a compound of formula Ia is understood to encompass every tautomeric form as well as any mixtures thereof, in any ratio. The same applies to tautomers of more specific embodiments of compounds of formula Ia described herein, such as, but not limited to, tautomers of compounds of formula Ib, Ic, Id, Ie, If, Ig, Ih, Ii and Ij described below, and tautomers of the specific examples described in the experimental section below.

A. Definitions

“C 1 -C 6 alkyl” means a monovalent unsubstituted saturated straight-chain or branched-chain hydrocarbon radical having from 1 to 6 carbon atoms. “C 1 -C 2 alkyl”, “C 1 -C 3 alkyl”, “C 1 -C 4 alkyl” and “C 1 -C 5 alkyl” have analogous meanings.

“partially or fully deuterated C 1 -C 6 alkyl” means a C 1 -C 6 alkyl wherein some or all of the hydrogen atoms have been replaced by deuterium.

“C 3 -C 6 cycloalkyl” means a monovalent unsubstituted saturated cyclic hydrocarbon radical having from 3 to 6 carbon atoms. “C 5 -C 7 cycloalkyl” has analogous meaning.

“C 1 -C 3 alkoxy” means a monovalent unsubstituted saturated straight-chain or branched-chain hydrocarbon having from 1 to 3 carbon atoms connected to the rest of the compound of formula Ia via a single oxygen atom. “C 1 -C 2 alkoxy” has analogous meaning.

“5- or 6-membered heteroaryl” means a monocyclic aromatic group with a total of 5 atoms in the ring wherein from 1 to 4 of those atoms are each independently selected from N, O and S; or a monocyclic aromatic group with a total of 6 atoms in the ring wherein from 1 to 3 of those atoms are N. 5-membered heteroaryl groups include pyrrolyl (also called azolyl), furanyl, thienyl (also called thiophenyl), pyrazolyl (also called 1H-pyrazolyl and 1,2-diazolyl), imidazolyl, oxazolyl (also called 1,3-oxazolyl), isoxazolyl (also called 1,2-oxazolyl), thiazolyl (also called 1,3-thiazolyl), isothiazolyl (also called 1,2-thiazolyl), triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl and thiatriazolyl. 6-membered heteroaryl groups include pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl and triazinyl.

“4-, 5- or 6-membered heterocyclyl” means a saturated monocyclic group with a total of 4 atoms in the ring wherein 1 of those atoms is selected from N, O and S; or a saturated monocyclic group with a total of 5 atoms in the ring wherein 1 or 2 of those atoms are each independently selected from N, O and S; or a saturated monocyclic group with a total of 6 atoms in the ring wherein 1 or 2 of those atoms are each independently selected from N, O and S. 4-membered heterocyclyl groups include azetidine, oxetane and thietane. 5-membered heterocyclyl groups include pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl (also called terahydrothiophenyl), imidazolidinyl, pyrazolidinyl, dioxolanyl, dithiolanyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl and isothiazolidinyl. 6-membered heterocyclyl groups include piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, dioxanyl, dithianyl, morpholinyl and thiomorpholinyl.

“5- or 6-membered N-heterocyclyl” means a saturated monocyclic group with a total of 5 atoms in the ring wherein 1 of those atoms is N and another one of those atoms is optionally selected from N, O and S; or a saturated monocyclic group with a total of 6 atoms in the ring wherein 1 of those atoms is N and another one of those atoms is optionally independently selected from N, O and S. 5-membered N-heterocyclyl groups include pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl and isothiazolidinyl. 6-membered N-heterocyclyl groups include piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl.

“9- or 10-membered heterospirocyclyl” means a saturated spirocyclic group with a total of 9 atoms in the two rings wherein from 1 to 4 of those atoms are each independently selected from N, O and S; or a saturated spirocyclic group with a total of 10 atoms in the two rings wherein from 1 to 5 of those atoms are each independently selected from N, O and S. 9-membered heterospirocyclyl groups include 2-oxa-7-azaspiro[4.4]nonanyl. 10-membered heterospirocyclyl groups include 2-oxa-8-azaspiro[4.5]decanyl and 1,4-dioxa-8-azaspiro[4.5]decanyl.

“oxo” means an oxo radical, and may be depicted as ═O.

“halo” means a fluorine (which may be depicted as —F), chlorine (which may be depicted as —Cl), bromine (which may be depicted as —Br) or iodine (which may be depicted as —I) radical.

“amido” means —CONH 2 .

“t-Boc” means tert-butyloxycarbonyl.

“pharmaceutically acceptable salt” means a salt such as those described in standard texts on salt formation, see for example: P. Stahl, et al., Handbook of Pharmaceutical Salts: Properties, Selection and Use (VCHA/Wiley-VCH, 2002), or S. M. Berge, et al., “Pharmaceutical Salts” (1977) Journal of Pharmaceutical Sciences, 66, 1-19.

“pharmaceutically acceptable solvate” means a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, water or ethanol. The term “hydrate” maybe employed when said solvent is water. Pharmaceutically acceptable solvates include hydrates and other solvates wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 O, d 6 -acetone, d 6 -DMSO.

“pharmaceutically acceptable excipient” means any ingredient other than the compound(s) of the invention, or other known pharmacologically active components. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

“therapy”, “treatment” and “treating” include both preventative and curative treatment of a condition, disease or disorder. It also includes slowing, interrupting, controlling or stopping the progression of a condition, disease or disorder. It also includes preventing, curing, slowing, interrupting, controlling or stopping the symptoms of a condition, disease or disorder.

Other variations to the disclosed embodiments can be understood and effected by those skilled in the art in practicing the claimed invention, from a study of the disclosure, and the appended claims. In the claims, the word “comprising” does not exclude other elements or steps, and the indefinite article “a” or “an” does not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage.

B. Compounds

The invention provides a compound of formula Ia, as defined above, or a pharmaceutically acceptable salt or solvate thereof:

The invention also provides a compound of formula Ia, as defined above, or a pharmaceutically acceptable salt or solvate thereof, with the proviso that the compound (S)-1-benzyl-6-(3,5-difluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione is excluded.

B0. Core Structures

In some embodiments of formula Ia, n is 0 and a single bond joins the carbon atoms to which the CH 2 moeity would be attached when n is 1 to form a structure of formula Ib

In some embodiments of formula Ia, R 4 and R 5 combine, together with the carbon atom to which they are attached, to form a structure of formula Ic:

In some embodiments more than 50%, preferably more than 90%, more preferably more than 95% and even more preferably more than 99% of substituents R 5 and A of compounds of formula Ia have the stereochemical configuration of formula Id

In some embodiments more than 50%, preferably more than 90%, more preferably more than 95% and even more preferably more than 99% of substituents R 5 and A of compounds of formula Ia have the stereochemical configuration of formula Ie

Preferred embodiments of formula Ia include compounds of formula If.

In some particularly preferred embodiments of formula If more than 50%, preferably more than 90%, more preferably more than 95% and even more preferably more than 99% of substituents R 5 and A of compounds of formula If have the stereochemical configuration of formula Ig

In other more particularly preferred embodiments of formula If more than 50%, preferably more than 90%, more preferably more than 95% and even more preferably more than 99% of substituents R 5 and A of compounds of formula If have the stereochemical configuration of formula Ih

More preferred embodiments of formula Ia include compounds of formula Ii.

In some particularly preferred embodiments of formula Ii more than 50%, preferably more than 90%, more preferably more than 95% and even more preferably more than 99% have the stereochemical configuration of formula Ij.

B1. Substituent R 1

R 1 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, partially or fully deuterated C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl.

R 1 is preferably selected from the group consisting of hydrogen, C 1 -C 6 alkyl and partially or fully deuterated C 1 -C 6 alkyl.

In some embodiments R 1 is hydrogen. In some embodiments R 1 is C 1 -C 6 alkyl. In some embodiments R 1 is partially deuterated C 1 -C 6 alkyl. In some embodiments R 1 is fully deuterated C 1 -C 6 alkyl. In some embodiments R 1 is C 3 -C 6 cycloalkyl.

R 1 is preferably selected from the group consisting of hydrogen, methyl, d3-methyl, propyl and cyclopropyl.

R 1 is more preferably selected from the group consisting of hydrogen, methyl and d3-methyl.

In some embodiments R 1 is preferably hydrogen. In some embodiments R 1 is preferably methyl. In some embodiments R 1 is preferably d3-methyl.

R 1 is most preferably hydrogen or methyl.

B2. Substituent R 4 (when not Combined with R 5 )

R 4 is selected from the group consisting of hydrogen and C 1 -C 3 alkyl.

In some embodiments R 4 is hydrogen. In some embodiments R 4 is C 1 -C 3 alkyl.

R 4 is preferably selected from the group consisting of hydrogen and methyl.

In some embodiments R 4 is preferably hydrogen. In some embodiments R 4 is preferably methyl.

R 4 is most preferably hydrogen.

B3. Substituent R 5 (when not Combined with R 4 )

R 5 is hydrogen.

B4. Substituent R 6

R 6 is selected from the group consisting of —COOH, —CHO, or —(CH 2 ) m —X,

wherein:

m is 1, 2 or 3 and one —CH 2 — moiety within —(CH 2 ) m may optionally be replaced by

X is hydroxy, C 1 -C 3 alkoxy, cyano, —N═CH(NHCN)(NH 2 ), —NH—C(pyrrolidin-1-yl)=NCN, 5- or 6-membered heteroaryl optionally substituted with one methyl group, phenyl, —SO 2 —R 7 , —NR 8 R 9 , —CO 2 R 10 , —CH(CO 2 R 10 ) 2 , —CONR 11 R 12 or —NR 13 COR 14 ;

wherein: R 7 is C 1 -C 3 alkyl; R 8 is hydrogen or C 1 -C 3 alkyl; R 9 is hydrogen,

C 1 -C 4 alkyl optionally substituted with up to three fluoro substituents or with one substituent selected from the group consisting of cyano, hydroxy, methylsulfonyl, C 1 -C 2 alkoxy, dimethylamino, C 3 -C 6 cycloalkyl, phenyl, 5- or 6-membered heteroaryl optionally substituted with one methyl substituent and 5- or 6-membered heterocyclyl optionally substituted with one t-Boc group or with one or two fluoro substituents, C 3 -C 6 cycloalkyl optionally substituted with one substituent selected from the group consisting of cyano, hydroxy, hydroxymethyl and oxo, cyano, methylsulfonyl, CH 2 COO(C 1 -C 3 alkyl), 5- or 6-membered heteroaryl optionally substituted with one methyl substituent, 4-, 5- or 6-membered heterocyclyl optionally substituted with one or two substituents selected from oxo and methyl, CH 2 CH(NH 2 )(COOH), or CH(CH 3 )CONH 2 ;

or R 11 and R 12 combine together with the N atom to which they are attached to form a

5- or 6-membered N-heterocyclyl group optionally substituted with one substituent selected from monofluoromethyl trifluoromethyl, hydroxy, hydroxymethyl, methoxymethyl, methylsulfonyl, cyano, amido, (N,N-dimethyl)acetamide and pyridyl, or with one or two substituents selected from fluoro, methyl and oxo, or optionally fused to a cyclopropyl ring which may be substituted with one or two methyl substituents, or a 9- or 10-membered heterospirocyclyl group;

R 13 is hydrogen or C 1 -C 3 alkyl;

R 14 is C 1 -C 4 alkyl optionally substituted with up to three fluoro substituents or with one substituent selected from the group consisting of hydroxy, methylsulfonyl, C 3 -C 6 cycloalkyl and phenyl,

C 3 -C 6 cycloalkyl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclyl optionally substituted with one or two oxo substituents.

In one embodiment R 6 is as defined above with the proviso that R 9 may not be 5- or 6-membered heterocyclyl.

In another embodiment R 6 is —COOH, —CHO, or —(CH 2 ) m —X,

wherein:

m is 1, 2 or 3 and one —CH 2 — moiety within —(CH 2 ) m may optionally be replaced by

X is hydroxy, C 1 -C 3 alkoxy, cyano, —N═CH(NHCN)(NH 2 ), —NH—C(pyrrolidin-1-yl)=NCN, 5- or 6-membered heteroaryl optionally substituted with one methyl group, phenyl, —SO 2 —R 7 , —NR 8 R 9 , —CO 2 R 10 , —CH(CO 2 R 10 ) 2 , —CONR 11 R 12 or —NR 13 COR 14 ;

wherein: R 7 is C 1 -C 3 alkyl; R 8 is hydrogen or C 1 -C 3 alkyl; R 9 is hydrogen,

R 6 is preferably —(CH 2 ) m —X wherein m and X are as defined above.

In some preferred embodiments R 6 is —CH 2 —X wherein X is as defined above. In some preferred embodiments R 6 is —CH 2 CH 2 —X wherein X is as defined above. In some preferred embodiments R 6 is —CH 2 CH 2 CH 2 —X wherein X is as defined above. In some preferred embodiments R 6 is —(CH 2 ) m —X wherein m is 1, 2 or 3 and one —CH 2 — moiety within —(CH 2 ) m is replaced by

and X is as defined above.

In some preferred embodiments R 6 is —(CH 2 ) m —X wherein m is 1, 2 or 3 and one —CH 2 — moiety within —(CH 2 ) m — may optionally be replaced by

and X is hydroxy.

In some preferred embodiments R 6 is —(CH 2 ) m —X wherein m is 1, 2 or 3 and one —CH 2 — moiety within —(CH 2 ) m may optionally be replaced by

and X is C 1 -C 3 alkoxy.

In some preferred embodiments R 6 is —(CH 2 ) m —X wherein m is 1, 2 or 3 and one —CH 2 — moiety within —(CH 2 ) m may optionally be replaced by

and X is cyano.

In some preferred embodiments R 6 is —(CH 2 ) m —X wherein m is 1, 2 or 3 and one —CH 2 — moiety within —(CH 2 ) m may optionally be replaced by

and X is —N═CH(NHCN)(NH 2 ) or —NH—C(pyrrolidin-1-yl)=NCN.

In some preferred embodiments R 6 is —(CH 2 ) m —X wherein m is 1, 2 or 3 and one —CH 2 — moiety within —(CH 2 ) m may optionally be replaced by

and X is 5- or 6-membered heteroaryl optionally substituted with one methyl group.

In some preferred embodiments R 6 is —(CH 2 ) m —X wherein m is 1, 2 or 3 and one —CH 2 — moiety within —(CH 2 ) m may optionally be replaced by

and X is phenyl.

In some preferred embodiments R 6 is —(CH 2 ) m —X wherein m is 1, 2 or 3 and one —CH 2 — moiety within —(CH 2 ) m may optionally be replaced by

and X is —SO 2 —R 7 wherein R 7 is as defined above.

In some preferred embodiments R 6 is —(CH 2 ) m —X wherein m is 1, 2 or 3 and one —CH 2 — moiety within —(CH 2 ) m may optionally be replaced by

and X is —NR 8 R 9 wherein R 8 and R 9 are as defined above.

In some preferred embodiments R 6 is —(CH 2 ) m —X wherein m is 1, 2 or 3 and one —CH 2 — moiety within —(CH 2 ) m — may optionally be replaced by

and X is —CO 2 R 10 wherein R 10 is as defined above.

In some preferred embodiments R 6 is —(CH 2 ) m —X wherein m is 1, 2 or 3 and one —CH 2 — moiety within —(CH 2 ) m may optionally be replaced by

and X is —CH(CO 2 R 10 ) 2 wherein R 10 is as defined above.

In some preferred embodiments R 6 is —(CH 2 ) m —X wherein m is 1, 2 or 3 and one —CH 2 — moiety within —(CH 2 ) m may optionally be replaced by

and X is —CONR 11 R 12 wherein R 11 and R 12 are as defined above.

In some preferred embodiments R 6 is —(CH 2 ) m —X wherein m is 1, 2 or 3 and one —CH 2 — moiety within (CH 2 ) m may optionally be replaced by

and X is-NR 13 COR 14 wherein R 13 and R 14 are as defined above.

R 6 is preferably —(CH 2 ) m —X wherein m is 1, 2 or 3 and one —CH 2 — moiety within —(CH 2 ) m may optionally be replaced by

and X is hydroxy, ethoxy, cyano, —N═C(NHCN)(NH 2 ), —NH—C(pyrrolidin-1-yl)=NCN, 1-methylimidazol-2-yl, 3-methyl-1,2,4-oxadiazol-5-yl, tetrazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, phenyl,

—SO 2 —R 7 , —NR 8 R 9 , —COOR 10 , —CH(COOR 10 ) 2 , —CONR 11 R 12 or —NR 3 COR 14 ;

wherein: R 7 is methyl; R 8 is hydrogen or methyl; R 9 is hydrogen, methyl, cyclopropylmethyl, benzyl, 2-hydroxyethyl, 2,2,2-trifluoroethyl, 2-methylsulfonylethyl, 1-cyclohexylethyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, tetrahydrofuran-3-yl, (tetrahydrofuran-2-yl)methyl, (1,1-dioxido)tetrahydrothiopyran-4-yl, (tetrahydro-2H-pyran-4-yl)methyl, pyridin-2-yl, pyridin-3-yl, tetrahydropyran-3-yl, cyclohexyl, (pyridin-2-yl)methyl or (1-methylpyrazol-4-yl)methyl; or R 8 and R 9 combine together with the N atom to which they are attached to form a pyrrolidinyl, piperidinyl, 4-methylsulfonyl-piperidinyl, 4,4-difluoro-piperidinyl or morpholinyl group; R 10 is hydrogen, methyl or ethyl; R 11 is hydrogen or methyl; R 12 is hydrogen, methyl, cyanomethyl, cyclopropylmethyl, benzyl, (pyridin-2-yl)methyl, (pyridin-3-yl)methyl, (N-t-Boc-pyrrolidin-2-yl)methyl, 2-hydroxyethyl, 2-methoxyethyl, 2,2,2-trifluoroethyl, 2-methylsulfonylethyl, 1-cyclohexylethyl, 2-(pyridin-2-yl)ethyl, 2-(1H-pyrazol-1-yl)ethyl, 2-(4,4-difluoropiperidin-1-yl)ethyl, propyl, isopropyl, 3-(N,N-dimethylamino)propyl, 3-(morpholin-1-yl)propyl, butyl, cyclopropyl, 1-cyanocyclopropyl, cyclobutyl, cyclopentyl, 2-hydroxycyclopentyl, 2-hydroxymethylcyclopentyl, 2-oxocyclopentyl, cyclohexyl, 2-hydroxycyclohexyl, 4-hydroxycyclohexyl, cyano, methylsulfonyl, CH 2 COOEt, tetrahydrofuran-3-yl, 2-oxotetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, (1,1-dioxido)tetrahydrothiopyran-4-yl, 1,3,4-thiadiazol-2-yl, pyridin-2-yl, pyridin-3-yl, CH 2 CH(NH 2 )(COOH), CH(CH 3 )CONH 2 , oxazol-2-yl, (pyrazine-2-yl)methyl, oxetan-3-yl, (tetrahydrofuran-2-yl)methyl, (1-methylpyrazol-4-yl)methyl, thiazol-2-yl, 2-oxopyrrolidin-3-yl, 2-cyanocyclopentyl, isoxazol-4-yl, 3-methyl-1,2,4-oxadiazol-5-yl, (tetrahydropyran-4-yl)methyl, 2-oxopiperidin-3-yl, 1-methylpyrazol-4-yl, isothiazol-4-yl, 1-methyl-2-oxopiperidin-5-yl, 1-methyl-2-oxopyrrolidin-3-yl, 1-methyl-5-oxopyrrolidin-3-yl or 1-methyl-2-oxopyrrolidin-4-yl; or R 11 and R 12 combine together with the N atom to which they are attached to form a pyrrolidinyl, 2-hydroxymethyl-pyrrolidinyl, 2-methoxymethyl-pyrrolidinyl, 2-trifluoromethyl-pyrrolidinyl, 3-(fluoromethyl)pyrrolidinyl, 3-methylsulfonyl-pyrrolidinyl, N,N-dimethylpyrrolidinyl-3-carboxamide, isoxazolidin-2-yl, piperidinyl, 3-hydroxy-piperidinyl, 4-hydroxy-piperidinyl, 4-methyl-piperidinyl, 4-hydroxymethyl-piperidinyl, 4-amido-piperidinyl, 4-methylsulfonyl-piperidinyl, 4,4-difluoro-piperidinyl, N,N-dimethylpiperidinyl-4-carboxamide, N4-methyl-piperazinyl, N4-(N,N-dimethyl)acetamide-piperazinyl, N4-(pyridine-2-yl)piperazinyl, morpholinyl, thiomorpholinyl, 1-oxidothiomorpholinyl, 1,1-dioxidothiomorpholinyl, 2-oxa-7-azaspiro[4.4]nonanyl, 2-oxa-8-azaspiro[4.5]decanyl, 1,4-dioxa-8-azaspiro[4.5]decanyl group, 6,6-dimethyl-3-azabicyclo[3.1.0]hexanyl, piperazinyl, 3-oxopiperazinyl, 4-methyl-3-oxopiperazinyl, 2-cyanopyrrolidinyl, 3-cyanopyrrolidinyl, 3-fluoromethylpyrrolidinyl or 3-(N,N-dimethylacetamide)pyrrolidinyl; R 13 is hydrogen or methyl; and R 14 is cyclopropyl, cyclopentyl, pyrrolidin-1-yl, tetrahydropyran-4-yl or pyridin-3-yl. R 6 is preferably —(CH 2 ) m —X wherein m is 1, 2 or 3 and one —CH 2 — moiety within —(CH 2 ) m — may optionally be replaced by

and X is hydroxy, ethoxy, cyano, —N═C(NHCN)(NH 2 ), 1-methylimidazol-2-yl, 3-methyl-1,2,4-oxadiazol-5-yl, tetrazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, phenyl, —SO 2 —R 7 , —NR 8 R 9 , —COOR 10 , —CH(COOR 10 ) 2 , —CONR 11 R 12 or —NR 3 COR 14 ;

wherein: R 7 is methyl; R 8 is hydrogen or methyl; R 9 is hydrogen, methyl, cyclopropylmethyl, benzyl, 2-hydroxyethyl, 2,2,2-trifluoroethyl, 2-methylsulfonylethyl, 1-cyclohexylethyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, tetrahydrofuran-3-yl, (1,1-dioxido)tetrahydrothiopyran-4-yl, pyridin-2-yl, pyridin-3-yl, tetrahydropyran-3-yl, cyclohexyl, (pyridin-2-yl)methyl or (1-methylpyrazol-4-yl)methyl; or R 8 and R 9 combine together with the N atom to which they are attached to form a pyrrolidinyl, piperidinyl, 4-methylsulfonyl-piperidinyl, 4,4-difluoro-piperidinyl or morpholinyl group; R 10 is hydrogen, methyl or ethyl; R 11 is hydrogen or methyl; R 12 is hydrogen, methyl, cyanomethyl, cyclopropylmethyl, benzyl, (pyridin-2-yl)methyl, (pyridin-3-yl)methyl, (N-t-Boc-pyrrolidin-2-yl)methyl, 2-hydroxyethyl, 2-methoxyethyl, 2,2,2-trifluoroethyl, 2-methylsulfonylethyl, 1-cyclohexylethyl, 2-(pyridin-2-yl)ethyl, 2-(1H-pyrazol-1-yl)ethyl, 2-(4,4-difluoropiperidin-1-yl)ethyl, propyl, isopropyl, 3-(N,N-dimethylamino)propyl, 3-(morpholin-1-yl)propyl, butyl, cyclopropyl, 1-cyanocyclopropyl, cyclobutyl, cyclopentyl, 2-hydroxycyclopentyl, 2-hydroxymethylcyclopentyl, 2-oxocyclopentyl, cyclohexyl, 2-hydroxycyclohexyl, 4-hydroxycyclohexyl, cyano, methylsulfonyl, CH 2 COOEt, tetrahydrofuran-3-yl, 2-oxotetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, (1,1-dioxido)tetrahydrothiopyran-4-yl, 1,3,4-thiadiazol-2-yl, pyridin-2-yl, pyridin-3-yl, CH 2 CH(NH 2 )(COOH), CH(CH 3 )CONH 2 , oxazol-2-yl, (pyrazine-2-yl)methyl, oxetan-3-yl, (tetrahydrofuran-2-yl)methyl, (1-methylpyrazol-4-yl)methyl, thiazol-2-yl, 2-oxopyrrolidin-3-yl, 2-cyanocyclopentyl, isoxazol-4-yl, 3-methyl-1,2,4-oxadiazol-5-yl, (tetrahydropyran-4-yl)methyl, 2-oxopiperidin-3-yl, 1-methylpyrazol-4-yl, isothiazol-4-yl, 1-methyl-2-oxopiperidin-5-yl, 1-methyl-2-oxopyrrolidin-3-yl or 1-methyl-2-oxopyrrolidin-4-yl; or R 11 and R 12 combine together with the N atom to which they are attached to form a pyrrolidinyl, 2-hydroxymethyl-pyrrolidinyl, 2-methoxymethyl-pyrrolidinyl, 2-trifluoromethyl-pyrrolidinyl, 3-methylsulfonyl-pyrrolidinyl, piperidinyl, 3-hydroxy-piperidinyl, 4-hydroxy-piperidinyl, 4-methyl-piperidinyl, 4-hydroxymethyl-piperidinyl, 4-amido-piperidinyl, 4-methylsulfonyl-piperidinyl, 4,4-difluoro-piperidinyl, N4-methyl-piperazinyl, N4-(N,N-dimethyl)acetamide-piperazinyl, N4-(pyridine-2-yl)piperazinyl, morpholinyl, thiomorpholinyl, 1-oxidothiomorpholinyl, 1,1-dioxidothiomorpholinyl, 2-oxa-7-azaspiro[4.4]nonanyl, 2-oxa-8-azaspiro[4.5]decanyl, 1,4-dioxa-8-azaspiro[4.5]decanyl group, 6,6-dimethyl-3-azabicyclo[3.1.0]hexanyl, piperazinyl, 3-oxopiperazinyl, 4-methyl-3-oxopiperazinyl, 2-cyanopyrrolidinyl, 3-cyanopyrrolidinyl, 3-fluoromethylpyrrolidinyl or 3-(N,N-dimethylacetamide)pyrrolidinyl; R 13 is hydrogen or methyl; and R 14 is cyclopropyl, cyclopentyl, pyrrolidin-1-yl, tetrahydropyran-4-yl or pyridin-3-yl. R 6 is preferably —(CH 2 ) m —X wherein m is 1, 2 or 3 and one —CH 2 — moiety within —(CH 2 ) m may optionally be replaced by

and X is hydroxy, ethoxy, cyano, —N═C(NHCN)(NH 2 ), 1-methylimidazol-2-yl, 3-methyl-1,2,4-oxadiazol-5-yl, tetrazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, phenyl, —SO 2 —R 7 , —NR 8 R 9 , —COOR 10 , —CH(COOR 10 ) 2 , —CONR 11 R 12 or —NR 13 COR 14 ;

wherein: R 7 is methyl; R 8 is hydrogen or methyl; R 9 is hydrogen, methyl, cyclopropylmethyl, benzyl, 2-hydroxyethyl, 2,2,2-trifluoroethyl, 2-methylsulfonylethyl, 1-cyclohexylethyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, tetrahydrofuran-3-yl, (1,1-dioxido)tetrahydrothiopyran-4-yl, pyridin-2-yl or pyridin-3-yl; or R 8 and R 9 combine together with the N atom to which they are attached to form a pyrrolidinyl, piperidinyl, 4-methylsulfonyl-piperidinyl, 4,4-difluoro-piperidinyl or morpholinyl group; R 10 is hydrogen, methyl or ethyl; R 11 is hydrogen or methyl; R 12 is hydrogen, methyl, cyanomethyl, cyclopropylmethyl, benzyl, (pyridin-2-yl)methyl, (pyridin-3-yl)methyl, (N-t-Boc-pyrrolidin-2-yl)methyl, 2-hydroxyethyl, 2-methoxyethyl, 2,2,2-trifluoroethyl, 2-methylsulfonylethyl, 1-cyclohexylethyl, 2-(pyridin-2-yl)ethyl, 2-(1H-pyrazol-1-yl)ethyl, 2-(4,4-difluoropiperidin-1-yl)ethyl, propyl, isopropyl, 3-(N,N-dimethylamino)propyl, 3-(morpholin-1-yl)propyl, butyl, cyclopropyl, 1-cyanocyclopropyl, cyclobutyl, cyclopentyl, 2-hydroxycyclopentyl, 2-hydroxymethylcyclopentyl, 2-oxocyclopentyl, cyclohexyl, 2-hydroxycyclohexyl, 4-hydroxycyclohexyl, cyano, methylsulfonyl, CH 2 COOEt, tetrahydrofuran-3-yl, 2-oxotetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, (1,1-dioxido)tetrahydrothiopyran-4-yl, 1,3,4-thiadiazol-2-yl, pyridin-2-yl, pyridin-3-yl, CH 2 CH(NH 2 )(COOH) or CH(CH 3 )CONH 2 ; or R 11 and R 12 combine together with the N atom to which they are attached to form a pyrrolidinyl, 2-hydroxymethyl-pyrrolidinyl, 2-methoxymethyl-pyrrolidinyl, 2-trifluoromethyl-pyrrolidinyl, 3-methylsulfonyl-pyrrolidinyl, piperidinyl, 3-hydroxy-piperidinyl, 4-hydroxy-piperidinyl, 4-methyl-piperidinyl, 4-hydroxymethyl-piperidinyl, 4-amido-piperidinyl, 4-methylsulfonyl-piperidinyl, 4,4-difluoro-piperidinyl, N4-methyl-piperazinyl, N4-(N,N-dimethyl)acetamide-piperazinyl, N4-(pyridine-2-yl)piperazinyl, morpholinyl, thiomorpholinyl, 1-oxidothiomorpholinyl, 1,1-dioxidothiomorpholinyl, 2-oxa-7-azaspiro[4.4]nonanyl, 2-oxa-8-azaspiro[4.5]decanyl or 1,4-dioxa-8-azaspiro[4.5]decanyl group; R 13 is hydrogen or methyl; and R 14 is cyclopropyl, cyclopentyl, pyrrolidin-1-yl, tetrahydropyran-4-yl or pyridin-3-yl. R 6 is preferably —(CH 2 ) m —X wherein m is 1 or 2 and X is —NR 8 R 9 , or —CONR 11 R 12 ; wherein: R 8 is hydrogen or methyl; R 9 is 5- or 6-membered heterocyclyl optionally substituted with one or two oxo substituents; or R 8 and R 9 combine together with the N atom to which they are attached to form a 5- or 6-membered N-heterocyclyl group optionally substituted with one substituent selected from methyl, trifluoromethyl, hydroxy, hydroxymethyl, methoxymethyl, methylsulfonyl, amido, (N,N-dimethyl)acetamide and pyridyl or with one or two substituents selected from fluoro and oxo; Rn is hydrogen or methyl; R 12 is 4-, 5- or 6-membered heterocyclyl optionally substituted with one or two substituents selected from oxo and methyl; or R 11 and R 12 combine together with the N atom to which they are attached to form a 5- or 6-membered N-heterocyclyl group optionally substituted with one substituent selected from monofluoromethyl, trifluoromethyl, hydroxy, hydroxymethyl, methoxymethyl, methylsulfonyl, cyano, amido, (N,N-dimethyl)acetamide and pyridyl, or with one or two substituents selected from fluoro, methyl and oxo. R 6 is most preferably —(CH 2 ) m —X wherein m is 2 or 3 and X is —NR 8 R 9 ; wherein: R 8 is hydrogen; and R 9 is 5- or 6-membered heterocyclyl; or R 8 and R 9 combine together with the N atom to which they are attached to form a 5- or 6-membered N-heterocyclyl group.

B5. Substituent A

A is selected from the group consisting of C 5 -C 7 cycloalkyl, furanyl, thiophenyl, methylthiophenyl and

wherein:

X 1 is hydrogen, halo or methyl; X 1 ′ is hydrogen or halo; X 2 is hydrogen, halo or methyl; X 2 ′ is hydrogen or halo; and X 3 is hydrogen or fluoro.

Preferably A is

wherein X 1 , X 1 ′, X 2 , X 2 ′ and X 3 are as defined above.

More preferably A is

wherein:

X 1 is hydrogen, fluoro or chloro; X 1 ′ is hydrogen, fluoro or chloro; X 2 is hydrogen, fluoro, chloro or bromo; X 2 ′ is hydrogen, fluoro, chloro or bromo; and X 3 is hydrogen or fluoro. In one preferred embodiment not all of X 1 , X 1 ′, X 2 , X 2 ′ and X 3 are hydrogen.

Preferably A is selected from the group consisting of

More preferably A is selected from the group consisting of

Even more preferably A is selected from the group consisting of

Most preferably A is selected from the group consisting of

B6. Specific Embodiments of Compounds of Formula I

Various embodiments of substituents R 1 , R 4 , R 5 , R 6 , A, X, X 1 , X 1 ′, X 2 , X 2 ′ and X 3 have been discussed in B1 to B5 above. These “substituent” embodiments can be combined with any of the “core structure” embodiments, discussed in B0 above, to form further embodiments of compounds of formula Ia. All embodiments of compounds of formula Ia formed by combining the “substituent” embodiments and “core structure” embodiments, discussed above, are within the scope of Applicants' invention, and some preferred further embodiments of the compounds of formula Ia are provided below.

In some embodiments of formula Ia structures of formula If, Ii, and Ij are highly preferred

wherein:

R 1 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl and partially or fully deuterated C 1 -C 6 alkyl; R 4 (if present) is selected from the group consisting of hydrogen and methyl; R 5 (if present) is hydrogen; R 6 is selected from the group consisting of —COOH, —CHO, or —(CH 2 ) m —X wherein m is 1, 2 or 3 and one —CH 2 — moiety within —(CH 2 ) m — may optionally be replaced by

and X is hydroxy, ethoxy, cyano, —N═C(NHCN)(NH 2 ), —NH—C(pyrrolidin-1-yl)=NCN, 1-methylimidazol-2-yl, 3-methyl-1,2,4-oxadiazol-5-yl, tetrazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, phenyl,

—SO 2 —R 7 , —NR 8 R 9 , —COOR 10 , —CH(COOR 10 ) 2 , —CONR 11 R 12 or —NR 3 COR 14 ;

wherein: R 7 is methyl; R 8 is hydrogen or methyl; R 9 is hydrogen, methyl, cyclopropylmethyl, benzyl, 2-hydroxyethyl, 2,2,2-trifluoroethyl, 2-methylsulfonylethyl, 1-cyclohexylethyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, tetrahydrofuran-3-yl, (tetrahydrofuran-2-yl)methyl, (1,1-dioxido)tetrahydrothiopyran-4-yl, (tetrahydro-2H-pyran-4-yl)methyl, pyridin-2-yl, pyridin-3-yl, tetrahydropyran-3-yl, cyclohexyl, (pyridine-2-yl)methyl or (1-methylpyrazol-4-yl)methyl; or R 8 and R 9 combine together with the N atom to which they are attached to form a pyrrolidinyl, piperidinyl, 4-methylsulfonyl-piperidinyl, 4,4-difluoro-piperidinyl or morpholinyl group; R 10 is hydrogen, methyl or ethyl; R 11 is hydrogen or methyl; R 12 is hydrogen, methyl, cyanomethyl, cyclopropylmethyl, benzyl, (pyridin-2-yl)methyl, (pyridin-3-yl)methyl, (N-t-Boc-pyrrolidin-2-yl)methyl, 2-hydroxyethyl, 2-methoxyethyl, 2,2,2-trifluoroethyl, 2-methylsulfonylethyl, 1-cyclohexylethyl, 2-(pyridin-2-yl)ethyl, 2-(1H-pyrazol-1-yl)ethyl, 2-(4,4-difluoropiperidin-1-yl)ethyl, propyl, isopropyl, 3-(N,N-dimethylamino)propyl, 3-(morpholin-1-yl)propyl, butyl, cyclopropyl, 1-cyanocyclopropyl, cyclobutyl, cyclopentyl, 2-hydroxycyclopentyl, 2-hydroxymethylcyclopentyl, 2-oxocyclopentyl, cyclohexyl, 2-hydroxycyclohexyl, 4-hydroxycyclohexyl, cyano, methylsulfonyl, CH 2 COOEt, tetrahydrofuran-3-yl, 2-oxotetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, (1,1-dioxido)tetrahydrothiopyran-4-yl, 1,3,4-thiadiazol-2-yl, pyridin-2-yl, pyridin-3-yl, CH 2 CH(NH 2 )(COOH), CH(CH 3 )CONH 2 , oxazol-2-yl, (pyrazine-2-yl)methyl, oxetan-3-yl, (tetrahydrofuran-2-yl)methyl, (1-methylpyrazol-4-yl)methyl, thiazol-2-yl, 2-oxopyrrolidin-3-yl, 2-cyanocyclopentyl, isoxazol-4-yl, 3-methyl-1,2,4-oxadiazol-5-yl, (tetrahydropyran-4-yl)methyl, 2-oxopiperidin-3-yl, 1-methylpyrazol-4-yl, isothiazol-4-yl, 1-methyl-2-oxopiperidin-5-yl, 1-methyl-2-oxopyrrolidin-3-yl, 1-methyl-5-oxopyrrolidin-3-yl or 1-methyl-2-oxopyrrolidin-4-yl; or R 11 and R 12 combine together with the N atom to which they are attached to form a pyrrolidinyl, 2-hydroxymethyl-pyrrolidinyl, 2-methoxymethyl-pyrrolidinyl, 2-trifluoromethyl-pyrrolidinyl, 3-(fluoromethyl)pyrrolidinyl, 3-methylsulfonyl-pyrrolidinyl, N,N-dimethylpyrrolidinyl-3-carboxamide, isoxazolidin-2-yl, piperidinyl, 3-hydroxy-piperidinyl, 4-hydroxy-piperidinyl, 4-methyl-piperidinyl, 4-hydroxymethyl-piperidinyl, 4-amido-piperidinyl, 4-methylsulfonyl-piperidinyl, 4,4-difluoro-piperidinyl, N,N-dimethylpiperidinyl-4-carboxamide, N4-methyl-piperazinyl, N4-(N,N-dimethyl)acetamide-piperazinyl, N4-(pyridine-2-yl)piperazinyl, morpholinyl, thiomorpholinyl, 1-oxidothiomorpholinyl, 1,1-dioxidothiomorpholinyl, 2-oxa-7-azaspiro[4.4]nonanyl, 2-oxa-8-azaspiro[4.5]decanyl, 1,4-dioxa-8-azaspiro[4.5]decanyl group, 6,6-dimethyl-3-azabicyclo[3.1.0]hexanyl, piperazinyl, 3-oxopiperazinyl, 4-methyl-3-oxopiperazinyl, 2-cyanopyrrolidinyl, 3-cyanopyrrolidinyl, 3-fluoromethylpyrrolidinyl or 3-(N,N-dimethylacetamide)pyrrolidinyl; R 13 is hydrogen or methyl; and R 14 is cyclopropyl, cyclopentyl, pyrrolidin-1-yl, tetrahydropyran-4-yl or pyridin-3-yl; and

A is

wherein:

X 1 is hydrogen, halo or methyl; X 1 ′ is hydrogen or halo; X 2 is hydrogen, halo or methyl; X 2 ′ is hydrogen or halo; and X 3 is hydrogen or fluoro.

In some embodiments of formula Ia structures of formula If, Ii, and Ij are highly preferred

wherein:

R 1 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl and partially or fully deuterated C 1 -C 6 alkyl; R 4 (if present) is selected from the group consisting of hydrogen and methyl; R 5 (if present) is hydrogen; R 6 is selected from the group consisting of —COOH, —CHO, or —(CH 2 ) m —X wherein m is 1, 2 or 3 and one —CH 2 — moiety within —(CH 2 ) m may optionally be replaced by

and X is hydroxy, ethoxy, cyano, —N═C(NHCN)(NH 2 ), —NH—C(pyrrolidin-1-yl)=NCN, 1-methylimidazol-2-yl, 3-methyl-1,2,4-oxadiazol-5-yl, tetrazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, phenyl,

—SO 2 —R 7 , —NR 8 R 9 , —COOR 10 , —CH(COOR 10 ) 2 , —CONR 11 R 12 or —NR 13 COR 14 ;

wherein: R 7 is methyl; R 8 is hydrogen or methyl; R 9 is hydrogen, methyl, cyclopropylmethyl, benzyl, 2-hydroxyethyl, 2,2,2-trifluoroethyl, 2-methylsulfonylethyl, 1-cyclohexylethyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, tetrahydrofuran-3-yl, (1,1-dioxido)tetrahydrothiopyran-4-yl, pyridin-2-yl, pyridin-3-yl, tetrahydropyran-3-yl, cyclohexyl, (pyridine-2-yl)methyl or (1-methylpyrazol-4-yl)methyl; or R 8 and R 9 combine together with the N atom to which they are attached to form a pyrrolidinyl, piperidinyl, 4-methylsulfonyl-piperidinyl, 4,4-difluoro-piperidinyl or morpholinyl group; R 10 is hydrogen, methyl or ethyl; R 11 is hydrogen or methyl; R 12 is hydrogen, methyl, cyanomethyl, cyclopropylmethyl, benzyl, (pyridin-2-yl)methyl, (pyridin-3-yl)methyl, (N-t-Boc-pyrrolidin-2-yl)methyl, 2-hydroxyethyl, 2-methoxyethyl, 2,2,2-trifluoroethyl, 2-methylsulfonylethyl, 1-cyclohexylethyl, 2-(pyridin-2-yl)ethyl, 2-(1H-pyrazol-1-yl)ethyl, 2-(4,4-difluoropiperidin-1-yl)ethyl, propyl, isopropyl, 3-(N,N-dimethylamino)propyl, 3-(morpholin-1-yl)propyl, butyl, cyclopropyl, 1-cyanocyclopropyl, cyclobutyl, cyclopentyl, 2-hydroxycyclopentyl, 2-hydroxymethylcyclopentyl, 2-oxocyclopentyl, cyclohexyl, 2-hydroxycyclohexyl, 4-hydroxycyclohexyl, cyano, methylsulfonyl, CH 2 COOEt, tetrahydrofuran-3-yl, 2-oxotetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, (1,1-dioxido)tetrahydrothiopyran-4-yl, 1,3,4-thiadiazol-2-yl, pyridin-2-yl, pyridin-3-yl, CH 2 CH(NH 2 )(COOH), CH(CH 3 )CONH 2 , oxazol-2-yl, (pyrazine-2-yl)methyl, oxetan-3-yl, (tetrahydrofuran-2-yl)methyl, (1-methylpyrazol-4-yl)methyl, thiazol-2-yl, 2-oxopyrrolidin-3-yl, 2-cyanocyclopentyl, isoxazol-4-yl, 3-methyl-1,2,4-oxadiazol-5-yl, (tetrahydropyran-4-yl)methyl, 2-oxopiperidin-3-yl, 1-methylpyrazol-4-yl, isothiazol-4-yl, 1-methyl-2-oxopiperidin-5-yl, 1-methyl-2-oxopyrrolidin-3-yl or 1-methyl-2-oxopyrrolidin-4-yl; or R 1 and R 12 combine together with the N atom to which they are attached to form a pyrrolidinyl, 2-hydroxymethyl-pyrrolidinyl, 2-methoxymethyl-pyrrolidinyl, 2-trifluoromethyl-pyrrolidinyl, 3-methylsulfonyl-pyrrolidinyl, piperidinyl, 3-hydroxy-piperidinyl, 4-hydroxy-piperidinyl, 4-methyl-piperidinyl, 4-hydroxymethyl-piperidinyl, 4-amido-piperidinyl, 4-methylsulfonyl-piperidinyl, 4,4-difluoro-piperidinyl, N4-methyl-piperazinyl, N4-(N,N-dimethyl)acetamide-piperazinyl, N4-(pyridine-2-yl)piperazinyl, morpholinyl, thiomorpholinyl, 1-oxidothiomorpholinyl, 1,1-dioxidothiomorpholinyl, 2-oxa-7-azaspiro[4.4]nonanyl, 2-oxa-8-azaspiro[4.5]decanyl, 1,4-dioxa-8-azaspiro[4.5]decanyl group, 6,6-dimethyl-3-azabicyclo[3.1.0]hexanyl, piperazinyl, 3-oxopiperazinyl, 4-methyl-3-oxopiperazinyl, 2-cyanopyrrolidinyl, 3-cyanopyrrolidinyl, 3-fluoromethylpyrrolidinyl or 3-(N,N-dimethylacetamide)pyrrolidinyl; R 13 is hydrogen or methyl; and R 14 is cyclopropyl, cyclopentyl, pyrrolidin-1-yl, tetrahydropyran-4-yl or pyridin-3-yl; and

A is

wherein:

X 1 is hydrogen, halo or methyl; X 1 ′ is hydrogen or halo; X 2 is hydrogen, halo or methyl; X 2 ′ is hydrogen or halo; and X 3 is hydrogen or fluoro.

In some embodiments of formula Ia structures of formula If, Ii, and Ij are highly preferred

wherein:

R 1 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl and partially or fully deuterated C 1 -C 6 alkyl. R 4 (if present) is selected from the group consisting of hydrogen and methyl. R 5 (if present) is hydrogen. R 6 is selected from the group consisting of —COOH, —CHO, or —(CH 2 ) m —X wherein m is 1, 2 or 3 and one —CH 2 — moiety within —(CH 2 ) m may optionally be replaced by

and X is hydroxy, ethoxy, cyano, —N═C(NHCN)(NH 2 ), —NH—C(pyrrolidin-1-yl)=NCN, 1-methylimidazol-2-yl, 3-methyl-1,2,4-oxadiazol-5-yl, tetrazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, phenyl,

—SO 2 —R 7 , —NR 8 R 9 , —COOR 10 , —CH(COOR 10 ) 2 , —CONR 11 R 12 or —NR 13 COR 14 ;

wherein: R 7 is methyl; R 8 is hydrogen or methyl; R 9 is hydrogen, methyl, cyclopropylmethyl, benzyl, 2-hydroxyethyl, 2,2,2-trifluoroethyl, 2-methylsulfonylethyl, 1-cyclohexylethyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, tetrahydrofuran-3-yl, (1,1-dioxido)tetrahydrothiopyran-4-yl, pyridin-2-yl or pyridin-3-yl; or R 8 and R 9 combine together with the N atom to which they are attached to form a pyrrolidinyl, piperidinyl, 4-methylsulfonyl-piperidinyl, 4,4-difluoro-piperidinyl or morpholinyl group; R 10 is hydrogen, methyl or ethyl; R 11 is hydrogen or methyl; R 12 is hydrogen, methyl, cyanomethyl, cyclopropylmethyl, benzyl, (pyridin-2-yl)methyl, (pyridin-3-yl)methyl, (N-t-Boc-pyrrolidin-2-yl)methyl, 2-hydroxyethyl, 2-methoxyethyl, 2,2,2-trifluoroethyl, 2-methylsulfonylethyl, 1-cyclohexylethyl, 2-(pyridin-2-yl)ethyl, 2-(1H-pyrazol-1-yl)ethyl, 2-(4,4-difluoropiperidin-1-yl)ethyl, propyl, isopropyl, 3-(N,N-dimethylamino)propyl, 3-(morpholin-1-yl)propyl, butyl, cyclopropyl, 1-cyanocyclopropyl, cyclobutyl, cyclopentyl, 2-hydroxycyclopentyl, 2-hydroxymethylcyclopentyl, 2-oxocyclopentyl, cyclohexyl, 2-hydroxycyclohexyl, 4-hydroxycyclohexyl, cyano, methylsulfonyl, CH 2 COOEt, tetrahydrofuran-3-yl, 2-oxotetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, (1,1-dioxido)tetrahydrothiopyran-4-yl, 1,3,4-thiadiazol-2-yl, pyridin-2-yl, pyridin-3-yl, CH 2 CH(NH 2 )(COOH) or CH(CH 3 )CONH 2 ; or R 11 and R 12 combine together with the N atom to which they are attached to form a pyrrolidinyl, 2-hydroxymethyl-pyrrolidinyl, 2-methoxymethyl-pyrrolidinyl, 2-trifluoromethyl-pyrrolidinyl, 3-methylsulfonyl-pyrrolidinyl, piperidinyl, 3-hydroxy-piperidinyl, 4-hydroxy-piperidinyl, 4-methyl-piperidinyl, 4-hydroxymethyl-piperidinyl, 4-amido-piperidinyl, 4-methylsulfonyl-piperidinyl, 4,4-difluoro-piperidinyl, N4-methyl-piperazinyl, N4-(N,N-dimethyl)acetamide-piperazinyl, N4-(pyridine-2-yl)piperazinyl, morpholinyl, thiomorpholinyl, 1-oxidothiomorpholinyl, 1,1-dioxidothiomorpholinyl, 2-oxa-7-azaspiro[4.4]nonanyl, 2-oxa-8-azaspiro[4.5]decanyl or 1,4-dioxa-8-azaspiro[4.5]decanyl group; R 13 is hydrogen or methyl; and R 14 is cyclopropyl, cyclopentyl, pyrrolidin-1-yl, tetrahydropyran-4-yl or pyridin-3-yl

A is

wherein:

X 1 is hydrogen, halo or methyl; X 1 ′ is hydrogen or halo; X 2 is hydrogen, halo or methyl; X 2 ′ is hydrogen or halo; and X 3 is hydrogen or fluoro.

In other embodiments of formula Ia structures of formula If, Ii, and Ij are highly preferred

wherein:

R 1 is selected from the group consisting of hydrogen and methyl; R 4 (if present) is hydrogen; R 5 (if present) is hydrogen; R 6 is —(CH 2 ) m —X wherein m is 1 or 2 and X is —NR 8 R 9 , or —CONR 11 R 12 ;

wherein: R 8 is hydrogen or methyl; R 9 is 5- or 6-membered heterocyclyl optionally substituted with one or two oxo substituents; or R 8 and R 9 combine together with the N atom to which they are attached to form a 5- or 6-membered N-heterocyclyl group optionally substituted with one substituent selected from methyl, trifluoromethyl, hydroxy, hydroxymethyl, methoxymethyl, methylsulfonyl, amido, (N,N-dimethyl)acetamide and pyridyl or with one or two substituents selected from fluoro and oxo; R 11 is hydrogen or methyl; R 12 is 4-, 5- or 6-membered heterocyclyl optionally substituted with one or two substituents selected from oxo and methyl; or R 11 and R 12 combine together with the N atom to which they are attached to form a 5- or 6-membered N-heterocyclyl group optionally substituted with one substituent selected from monofluoromethyl, trifluoromethyl, hydroxy, hydroxymethyl, methoxymethyl, methylsulfonyl, cyano, amido, (N,N-dimethyl)acetamide and pyridyl, or with one or two substituents selected from fluoro, methyl and oxo; and

A is selected from the group consisting of

In other embodiments of formula Ia structures of formula If are highly preferred

wherein:

R 1 is selected from the group consisting of hydrogen and methyl;

R 4 is hydrogen;

R 5 is hydrogen;

R 6 is —(CH 2 ) m —X wherein m is 2 or 3 and X is —NR 8 R 9 ;

wherein: R 8 is hydrogen; and R 9 is 5- or 6-membered heterocyclyl; or R 8 and R 9 combine together with the N atom to which they are attached to form a 5- or 6-membered N-heterocyclyl group; and

A is selected from the group consisting of

Especially preferred embodiments of compounds of formula Ia are described in Examples 1 to 478 below. Where these examples describe the preparation of a compound of formula Ia in the form of a pharmaceutically acceptable salt or solvate, it will be appreciated that the present invention also relates to said compound in the form of the corresponding free acid or free base. Similarly, where these examples describe the preparation of a compound of formula Ia in the form of a free acid or free base, it will be appreciated that the present invention also relates to said compound in the form of a pharmaceutically acceptable salt or solvate thereof.

The non-salt, non-solvated forms of Examples 1 to 478 are listed below. The invention also relates to the pharmaceutically acceptable salts or solvates of each of these individual compounds. Should any of these compounds exist as tautomers, each tautomeric form, and mixtures thereof, are contemplated as included in the present invention.

Example 1: (S)-ethyl 2-(6-(3,5-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetate Example 2: (S)-ethyl 2-(6-(2,5-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetate Example 3: (S)-2-(6-(2,5-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid Example 4: Methyl 2-((5aS,6aR)-5a-(2,5-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetate Example 5: methyl 2-((5aS,6aR)-5a-(3,5-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetate Example 6: 2-((5aS,6aR)-5a-(2,5-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic acid Example 7: 2-((5aS,6aR)-5a-(3,5-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic acid. Example 8: (5aS,6aR)-5a-(3,5-difluorophenyl)-1-(2-hydroxyethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione Example 9: (S)-2-(6-(3,5-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethanone Example 10: (S)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid Example 11: (S)-2-(6-(3,5-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid Example 12: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid Example 13: (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid Example 14: (R)-2-(6-(2,5-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid Example 15: (R)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid Example 16: (S)-2-(6-(5-bromo-2-fluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid Example 17: (R)-2-(6-(5-chloro-2-fluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid Example 18: (R)-2-(6-(2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid Example 19: (S)—N-cyano-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetamide Example 20: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(methylsulfonyl)acetamide Example 21: (S)-2-(6-(5-bromo-2-fluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(methylsulfonyl)acetamide Example 22: 2-((R)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2-oxotetrahydrofuran-3-yl)acetamide Example 23: (R)—N-(methylsulfonyl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetamide Example 24: (R)-2-(6-(2,5-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(methylsulfonyl)acetamide Example 25: Ethyl (R)-(2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetyl)glycinate Example 26: (S)-2-(2-((R)-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamido)propanamide Example 27: (R)—N-(cyanomethyl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide Example 28: N-((1r,4R)-4-hydroxycyclohexyl)-2-((R)-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide Example 29: N-(2-hydroxycyclohexyl)-2-((R)-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide Example 30: (R)—N,N-dimethyl-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide Example 31: (S)-2-amino-3-(2-((R)-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetamido)propanoic acid Example 32: ((R)—N-cyclopentyl-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetamide Example 33: 2-((5aS,6aR)-5a-(3,5-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetamide Example 34: 2-((S)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2-oxocyclopentyl)acetamide Example 35: (5aS,6aR)-1-(2-aminoethyl)-5a-(3,5-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione Example 36: 2-((5aS,6aR)-5a-(2,5-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetonitrile Example 37: N-benzyl-2-((5aS,6aR)-5a-(2,5-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-methylacetamide Example 38: N-butyl-2-((5aS,6aR)-5a-(2,5-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-methylacetamide Example 39: (5aS,6aR)-1-(2-(butyl(methyl)amino)ethyl)-5a-(2,5-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione Example 40: (5aS,6aR)-1-(2-(benzyl(methyl)amino)ethyl)-5a-(2,5-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione Example 41: (5aS,6aR)-1-((1H-tetrazol-5-yl)methyl)-5a-(2,5-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione Example 42: (5aS,6aR)-5a-(2,5-difluorophenyl)-1-(2-hydroxyethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione Example 43: (S)-6-(3,5-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazole-1-carboxylic acid Example 44: ethyl 2-(5a-(thiophen-2-yl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetate Example 45: (S)-6-(3,5-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazole-1-carbaldehyde Example 46: (S)-1-(hydroxymethyl)-6-(2,3,5,6-tetrafluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione Example 47: (S)-1-(methylsulfonylmethyl)-6-(2,3,5,6-tetrafluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione Example 48: (5aS,6aR)-5a-(2,5-difluorophenyl)-1-phenethyl-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione Example 49: (5aS,6aR)-5a-(2,5-difluorophenyl)-1-(3-phenylpropyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione Example 50: (5aS,6aR)-5a-(3,5-difluorophenyl)-1-(hydroxymethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione Example 51: 2-((5aS,6aR)-5a-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic acid Example 52: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic acid Example 53: 2-((5aS,6aR)-5a-(3-chloro-5-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic acid Example 54: ethyl 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetate Example 55: ethyl 2-((5aS,6aR)-5a-(3-chloro-5-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetate Example 56: (2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetamide Example 57: 2-((5aS,6aR)-5a-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetamide Example 58: 2-((5aS,6aR)-5a-(3-chloro-5-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetamide Example 59: ethyl (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetate Example 60: ethyl (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetate Example 61: ethyl (R)-2-(6-(2,5-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetate Example 62: ethyl (S)-2-(6-(5-bromo-2-fluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetate Example 63: ethyl (R)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetate Example 64: ethyl (R)-2-(6-(5-chloro-2-fluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetate Example 65: ethyl (R)-2-(6-(2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetate Example 66: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one Example 67: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-isopropylacetamide Example 68: 2-((5aS,6aR)-5a-(3-chloro-5-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-methylacetamide Example 69: 2-((5aS,6aR)-5a-(3-chloro-5-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N,N-dimethylacetamide Example 70: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(pyrrolidin-1-yl)ethan-1-one Example 71: (R)—N-(3-(dimethylamino)propyl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide Example 72: (R)—N-(2-hydroxyethyl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide Example 73: (R)—N-(2-methoxyethyl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide Example 74: (S)-2-(6-(5-bromo-2-fluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-cyclopentylacetamide Example 75: 2-((R)-6-(5-chloro-2-fluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydrofuran-3-yl)acetamide Example 76: (R)—N-cyclopentyl-2-(6-(2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide Example 77: 2-((R)-6-(2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydrofuran-3-yl)acetamide Example 78: (R)—N-cyclopropyl-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide Example 79: (R)—N-(cyclopropylmethyl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide Example 80: (R)—N-cyclobutyl-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide Example 81: (R)-1-(4-methylpiperazin-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one Example 82: (R)-1-(4-hydroxypiperidin-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one Example 83: (R)-1-(4-(hydroxymethyl)piperidin-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one Example 84: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-cyclopentylacetamide Example 85: (R)—N,N-dimethyl-2-(4-(2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetyl)piperazin-1-yl)acetamide Example 86: (R)-1-(2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetyl)piperidine-4-carboxamide Example 87: (R)-1-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one Example 88: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-isopropylacetamide Example 89: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(3-morpholinopropyl)acetamide Example 90: 2-((S)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydrofuran-3-yl)acetamide Example 91: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(4-methylpiperazin-1-yl)ethan-1-one Example 92: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-butyl-N-methylacetamide Example 93: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2-hydroxyethyl)acetamide Example 94: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-cyclopropylacetamide Example 95: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(cyclopropylmethyl)acetamide Example 96: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide Example 97: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-propylacetamide Example 98: 1-((S)-2-(hydroxymethyl)pyrrolidin-1-yl)-2-((R)-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one Example 99: (S)—N-cyclobutyl-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide Example 100: 2-((S)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-((S)-2-(hydroxymethyl)pyrrolidin-1-yl)ethan-1-one Example 101: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(pyrrolidin-1-yl)ethan-1-one Example 102: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-cyclobutylacetamide Example 103: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2-methoxyethyl)acetamide Example 104: (R)-1-(pyrrolidin-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one Example 105: (S)-1-(pyrrolidin-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one Example 106: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2-(pyridin-2-yl)ethyl)acetamide Example 107: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2-methoxyethyl)acetamide Example 108: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide Example 109: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(pyridin-3-ylmethyl)acetamide Example 110: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(pyrrolidin-1-yl)ethan-1-one Example 111: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(4,4-difluoropiperidin-1-yl)ethan-1-one Example 112: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)acetamide Example 113: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide Example 114: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2-(methylsulfonyl)ethyl)acetamide Example 115: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2-(4,4-difluoropiperidin-1-yl)ethyl)acetamide Example 116: 2-((R)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydrofuran-3-yl)acetamide Example 117: (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(4,4-difluoropiperidin-1-yl)ethan-1-one Example 118: (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2-(methylsulfonyl)ethyl)acetamide Example 119: (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2-hydroxyethyl)acetamide Example 120: 2-((R)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2-(hydroxymethyl)cyclopentyl)acetamide Example 121: 2-((R)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(3-hydroxypiperidin-1-yl)ethan-1-one Example 122: tert-butyl (R)-2-((2-((S)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamido)methyl)pyrrolidine-1-carboxylate Example 123: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(4-(methylsulfonyl)piperidin-1-yl)ethan-1-one Example 124: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(pyridin-3-ylmethyl)acetamide Example 125: (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(1,1-dioxidothiomorpholino)ethan-1-one Example 126: (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(4-(methylsulfonyl)piperidin-1-yl)ethan-1-one Example 127: 2-((R)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-1-cyclohexylethyl)acetamide Example 128: (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(tetrahydro-2H-pyran-4-yl)acetamide Example 129: (R)—N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide Example 130: (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)acetamide Example 131: (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2-hydroxyethyl)-N-methylacetamide Example 132: (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-cyclohexyl-N-methylacetamide Example 133: (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-isopropylacetamide Example 134: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(pyridin-3-ylmethyl)acetamide Example 135: 2-((R)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(3-(methylsulfonyl)pyrrolidin-1-yl)ethan-1-one Example 136: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(1,1-dioxidothiomorpholino)ethan-1-one Example 137: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-thiomorpholinoethan-1-one Example 138: 2-((S)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(2-oxa-7-azaspiro[4.4]nonan-7-yl)ethan-1-one Example 139: (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(pyridin-2-ylmethyl)acetamide Example 140: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one Example 141: (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one Example 142: N-(2-(1H-pyrazol-1-yl)ethyl)-2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetamide Example 143:2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(cyclopropylmethyl)acetamide Example 144:2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(cyanomethyl)acetamide Example 145: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(2-(pyridin-2-yl)ethyl)acetamide Example 146: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(3-(dimethylamino)propyl)acetamide Example 147: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(4-(pyridin-2-yl)piperazin-1-yl)ethan-1-one Example 148: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(tetrahydrofuran-3-yl)acetamide Example 149: 2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(4,4-difluoropiperidin-1-yl)ethan-1-one Example 150: 2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide Example 151: 2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(pyridin-3-ylmethyl)acetamide Example 152: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide Example 153: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-cyclobutylacetamide Example 154: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-cyclopropylacetamide Example 155: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-cyclopentyl-N-methylacetamide Example 156: N-benzyl-2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetamide Example 157: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one Example 158: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(piperidin-1-yl)ethan-1-one Example 159: (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(cyanomethyl)acetamide Example 160: 2-((R)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((1R,2R)-2-hydroxycyclohexyl)acetamide Example 161: 2-((R)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((1S,2S)-2-hydroxycyclopentyl)acetamide Example 162: (S)—N-(2-(1H-pyrazol-1-yl)ethyl)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide Example 163: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-N-methylacetamide Example 164: 2-((S)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(3-(methylsulfonyl)pyrrolidin-1-yl)ethan-1-one Example 165: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(2-oxa-8-azaspiro[4.5]decan-8-yl)ethan-1-one Example 166: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(1-oxidothiomorpholino)ethan-1-one Example 167: 2-((S)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(tetrahydrofuran-3-yl)acetamide Example 168: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(1,3,4-thiadiazol-2-yl)acetamide Example 169: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(pyridin-2-yl)acetamide Example 170: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(pyridin-2-yl)acetamide Example 171: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(pyridin-3-yl)acetamide Example 172: (R)-1-(2-hydroxyethyl)-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione Example 173: (R)-6-(3-bromo-2,6-difluorophenyl)-1-(2-hydroxyethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione Example 174: (5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-1-(2-morpholinoethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione Example 175: (5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-1-(2-(isopropylamino)ethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione Example 176: (R)-6-(3-bromo-2,6-difluorophenyl)-1-(2-(((R)-tetrahydrofuran-3-yl)amino)ethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione Example 177: (R)-6-(3-bromo-2,6-difluorophenyl)-1-(2-(4,4-difluoropiperidin-1-yl)ethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione Example 178: (R)-6-(3-bromo-2,6-difluorophenyl)-1-(2-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino)ethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione Example 179: (R)-6-(3-bromo-2,6-difluorophenyl)-1-(2-(4-(methylsulfonyl)piperidin-1-yl)ethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione Example 180: (5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-1-(2-((2,2,2-trifluoroethyl)amino)ethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione Example 181: (S)-6-(3-bromo-2,6-difluorophenyl)-1-(2-(cyclobutylamino)ethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione Example 182: (R)-6-(3-bromo-2,6-difluorophenyl)-1-(2-((2-(methylsulfonyl)ethyl)amino)ethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione Example 183: (R)-6-(3-bromo-2,6-difluorophenyl)-1-(2-((2-hydroxyethyl)(methyl)amino)ethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione Example 184: (R)-6-(3-bromo-2,6-difluorophenyl)-1-(2-(((R)-1-cyclohexylethyl)amino)ethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione Example 185: (5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-1-(2-(pyrrolidin-1-yl)ethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione Example 186: (5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-1-(2-((cyclopropylmethyl)amino)ethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione Example 187: (5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-1-(2-(cyclopropylamino)ethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione Example 188: (5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-1-(2-(cyclobutylamino)ethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione Example 189: (5aS,6aR)-1-(2-(benzylamino)ethyl)-5a-(5-chloro-2-fluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione Example 190: (5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-1-(2-(cyclopentyl(methyl)amino)ethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione Example 191: (5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-1-(2-morpholinoethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione Example 192: (5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-1-(2-(pyridin-2-ylamino)ethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione Example 193: (S)-6-(3-chloro-2,6-difluorophenyl)-1-(2-(methylamino)ethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione Example 194: (5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-1-(2-(piperidin-1-yl)ethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione Example 195: (S)-6-(3-bromo-2,6-difluorophenyl)-1-(2-morpholinoethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione Example 196: (S)-6-(3-chloro-2,6-difluorophenyl)-1-(2-morpholinoethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione Example 197: (5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-1-(2-(pyridin-3-ylamino)ethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione Example 198: (R)-1-(2-(pyrrolidin-1-yl)ethyl)-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione Example 199: (R)-1-(2-morpholinoethyl)-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione Example 200: (R)-diethyl 2-((6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)methyl)malonate Example 201: (R)-2-((6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)methyl)malonic acid Example 202: (R)-3-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propanoic acid Example 203: (R)—N-(cyclopropylmethyl)-3-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propanamide Example 204: (R)-1-(pyrrolidin-1-yl)-3-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propan-1-one Example 205: (R)-1-morpholino-3-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propan-1-one Example 206: (R)-1-(4,4-difluoropiperidin-1-yl)-3-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propan-1-one Example 207: (R)-1-(piperidin-1-yl)-3-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propan-1-one Example 208: (R)-1-(4-methylpiperidin-1-yl)-3-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propan-1-one Example 209: (R)-1-(morpholinomethyl)-6-(2,3,5,6-tetrafluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione Example 210: (R)-1-(pyrrolidin-1-ylmethyl)-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione Example 211: (R)-1-(((2-hydroxyethyl)(methyl)amino)methyl)-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione Example 212: (R)-1-(2-(pyridin-3-yl)ethyl)-6-(2,3,5,6-tetrafluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione Example 213: (R)-1-(2-(pyridin-2-yl)ethyl)-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione Example 214: (R)-6-(3-bromo-2,6-difluorophenyl)-1-(2-(pyridin-3-yl)ethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione Example 215: (S)-6-(3-chloro-2,6-difluorophenyl)-1-(2-(pyridin-3-yl)ethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione Example 216: (R)-1-(3-ethoxypropyl)-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione Example 217: (R)-1-(2-(1-methyl-1H-imidazol-2-yl)ethyl)-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione Example 218: (R)-1-(2-(pyridin-4-yl)ethyl)-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione Example 219: (R)-1-(3-(pyrrolidin-1-yl)propyl)-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione Example 220: (S)—N-((6-(3-chloro-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)methyl)cyclopropanecarboxamide Example 221: (S)—N-((6-(3-chloro-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)methyl)cyclopropanecarboxamide Example 222: (S)—N-((6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)methyl)tetrahydro-2H-pyran-4-carboxamide Example 223: (S)—N-((6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)methyl)nicotinamide Example 224: 2-{[(6S)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl]methyl}-1-cyanoguanidine Example 225: (S,Z)—N-((6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)methyl)-N′-cyanopyrrolidine-1-carboximidamide Example 226: (S)—N-(2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethyl)-N-methylnicotinamide Example 227: (S)—N-(2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethyl)-N-methylpyrrolidine-1-carboxamide Example 228: (S)-6-(3-chloro-2,6-difluorophenyl)-1-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione Example 229: (R)-2-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid Example 230: (S)-2-(6-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid Example 231: 2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic acid Example 232: 2-((S)-6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydrofuran-3-yl)acetamide Example 233: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one Example 234: 1-((S)-6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydrofuran-3-yl)cyclopropane-1-carboxamide Example 235: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(1,1-dioxidothiomorpholino)ethan-1-one Example 236: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-isopropylacetamide Example 237: (R)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one Example 238: (S)-1-(6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2-(methylsulfonyl)ethyl)cyclopropane-1-carboxamide Example 239: (R)—N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide Example 240: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide Example 241: 2-((S)-6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-((S)-2-(hydroxymethyl)pyrrolidin-1-yl)ethan-1-one Example 242: (R)-2-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one Example 243: 2-((R)-2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydrofuran-3-yl)acetamide Example 244: 2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydrofuran-3-yl)acetamide Example 245: (R)-2-(6-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-cyclopentylacetamide Example 246: 2-((R)-6-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydrofuran-3-yl)acetamide Example 247: 1-((S)-2-(methoxymethyl)pyrrolidin-1-yl)-2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one Example 248: 2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-((S)-2-(trifluoromethyl)pyrrolidin-1-yl)ethan-1-one Example 249: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide Example 250: 2-((S)-6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydrofuran-3-yl)acetamide Example 251: 2-((S)-6-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydrofuran-3-yl)acetamide Example 252: 2-((S)-6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(tetrahydrofuran-3-yl)acetamide Example 253: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(cyanomethyl)acetamide Example 254: (R)—N-(1-cyanocyclopropyl)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide Example 255: 2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydro-2H-pyran-3-yl)acetamide Example 256: (S)-6-(3-bromo-2,6-difluorophenyl)-2-methyl-1-(2-(((R)-tetrahydrofuran-3-yl)amino)ethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione Example 257: (R)-2-methyl-1-(2-morpholinoethyl)-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione Example 258: (S)-2-amino-3-(2-((R)-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamido)propanoic acid Example 259: (R)-2-methyl-1-(2-(pyridin-3-yl)ethyl)-6-(2,3,5,6-tetrafluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione Example 260: (R)-3-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propanoic acid Example 261: (R)-3-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(pyrrolidin-1-yl)propan-1-one Example 262: (S)-3-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propanamide Example 263: (R)-3-(6-(2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propanamide Example 264: (R)-3-(6-(2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(pyrrolidin-1-yl)propan-1-one Example 265: 3-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydrofuran-3-yl)propanamide Example 266: (R)-3-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinopropan-1-one Example 267: 1-((S)-2-(hydroxymethyl)pyrrolidin-1-yl)-3-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propan-1-one Example 268: (S)-3-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(pyridin-2-yl)propanamide Example 269: (R)-3-(6-(2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(pyridin-2-yl)propanamide Example 270: (R)—N-(cyanomethyl)-3-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propanamide Example 271: 2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-cyclopentylacetamide Example 272: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-cyclopentylacetamide Example 273: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-cyclopentylacetamide Example 274: 2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydrofuran-3-yl)acetamide Example 275: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic acid Example 276: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic acid Example 277: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydro-2H-pyran-3-yl)acetamide Example 278: 2-((R)-2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydro-2H-pyran-3-yl)acetamide Example 279: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydrofuran-3-yl)acetamide Example 280: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetamide Example 281: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydrofuran-3-yl)acetamide Example 282: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetamide Example 283: 1-((S)-2-(methoxymethyl)pyrrolidin-1-yl)-2-((R)-2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one Example 284: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-isopropylacetamide Example 285: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(1,3,4-thiadiazol-2-yl)acetamide Example 286: (R)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(oxazol-2-yl)acetamide Example 287: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(pyridin-4-yl)acetamide Example 288: 3-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydro-2H-pyran-3-yl)propanamide Example 289: 2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((S)-tetrahydrofuran-3-yl)acetamide Example 290: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(pyridin-3-ylmethyl)acetamide Example 291: (S)—N-(benzo[d][1,3]dioxol-5-ylmethyl)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide Example 292: 1-((R)-3-fluoropyrrolidin-1-yl)-2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one Example 293: (R)—N-(2-hydroxyethyl)-N-methyl-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide Example 294: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-cyclohexylacetamide Example 295: 2-((R)-2-methyl-3-thioxo-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((S)-tetrahydrofuran-3-yl)acetamide Example 296: 1-((S)-2-(fluoromethyl)pyrrolidin-1-yl)-2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one Example 297: (R)-2-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)acetamide Example 298: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide Example 299: (R)-2-(2-methyl-6-(2,3,6-trifluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)acetamide Example 300: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide Example 301:2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydro-2H-pyran-3-yl)acetamide Example 302:2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-cyclohexylacetamide Example 303:2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-isopropylacetamide Example 304:2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(cyanomethyl)acetamide Example 305:2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(cyanomethyl)acetamide Example 306:2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N—((S)-tetrahydrofuran-3-yl)acetamide Example 307:2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydrofuran-3-yl)acetamide Example 308:2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N—((S)-tetrahydrofuran-3-yl)acetamide Example 309:2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(pyrrolidin-1-yl)ethan-1-one Example 310:2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(pyrrolidin-1-yl)ethan-1-one Example 311:2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(piperidin-1-yl)ethan-1-one Example 312:2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(piperidin-1-yl)ethan-1-one Example 313:2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)acetamide Example 314:2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)acetamide Example 315: (R)-2-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide Example 316: (R)-2-(2-methyl-3-thioxo-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(oxazol-2-yl)acetamide Example 317: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(oxazol-2-yl)acetamide Example 318: (R)-3-(2-methyl-3-thioxo-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinopropan-1-one Example 319: 1-(6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-3-((R)-2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propan-1-one Example 320: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(piperazin-1-yl)ethan-1-one Example 321: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(piperazin-1-yl)ethan-1-one Example 322: (5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-1-(2-(cyclopentylamino)ethyl)-2-methyl-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione Example 323: (R)-4-(2-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetyl)piperazin-2-one Example 324: (R)-1-methyl-4-(2-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetyl)piperazin-2-one Example 325: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-((1r,4R)-4-hydroxycyclohexyl)acetamide Example 326: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(4-methylpiperazin-1-yl)ethan-1-one Example 327: 2-((S)-6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydro-2H-pyran-3-yl)acetamide Example 328: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(pyrazin-2-ylmethyl)acetamide Example 329: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one Example 330: (5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-1-(2-(cyclopentylamino)ethyl)-2-methyl-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione Example 331: (5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-1-(2-(((R)-tetrahydro-2H-pyran-3-yl)amino)ethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione Example 332:2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(pyridin-2-ylmethyl)acetamide Example 333: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(oxetan-3-yl)acetamide Example 334: (5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-1-(2-((2,2,2-trifluoroethyl)amino)ethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione Example 335:2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(pyrazin-2-ylmethyl)acetamide Example 336:2-((S)-6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—(((S)-tetrahydrofuran-2-yl)methyl)acetamide Example 337:2-((S)-6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—(((R)-tetrahydrofuran-2-yl)methyl)acetamide Example 338: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((1-methyl-1H-pyrazol-4-yl)methyl)acetamide Example 339:2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-((1-methyl-1H-pyrazol-4-yl)methyl)acetamide Example 340: (R)-2-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide Example 341: (5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-1-(2-(cyclohexylamino)ethyl)-2-methyl-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione Example 342:2-((S)-6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-2-oxopyrrolidin-3-yl)acetamide Example 343: (5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-1-(2-((pyridin-2-ylmethyl)amino)ethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione Example 344:2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-((R)-2-(trifluoromethyl)pyrrolidin-1-yl)ethan-1-one Example 345: N-(2-cyanocyclopentyl)-2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide Example 346: (5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-1-(2-(((1-methyl-1H-pyrazol-4-yl)methyl)amino)ethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione Example 347: (R)—N-(isoxazol-4-yl)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide Example 348: (S)-1-(2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetyl)pyrrolidine-3-carbonitrile Example 349: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(5-methyl-1,3,4-oxadiazol-2-yl)acetamide Example 350: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(1-methyl-1H-pyrazol-4-yl)acetamide Example 351: (R)—N-(isothiazol-4-yl)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide Example 352: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide Example 353: 1-(3-(fluoromethyl)pyrrolidin-1-yl)-2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one Example 354: 2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-2-oxopiperidin-3-yl)acetamide Example 355: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-((1r,4R)-4-hydroxycyclohexyl)acetamide Example 356: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-cyclohexylacetamide Example 357: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-cyclopropylacetamide Example 358: N,N-dimethyl-1-(2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetyl)pyrrolidine-3-carboxamide Example 359: (5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-1-(2-(((R)-tetrahydrofuran-3-yl)amino)ethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione Example 360: 2-((R)-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydrofuran-3-yl)acetamide Example 361: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic acid Example 362: 2-((S)-6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydrofuran-3-yl)acetamide Example 363: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one Example 364: N-methyl-N-(tetrahydrofuran-3-yl)-2-((R)-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide Example 365: N—((R)-tetrahydro-2H-pyran-3-yl)-2-((R)-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide Example 366: (R)-2-(6-(2,3,6-trifluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one Example 367: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)acetamide Example 368: 2-((R)-6-(2,3,6-trifluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydrofuran-3-yl)acetamide Example 369: 2-((R)-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((S)-tetrahydrofuran-3-yl)acetamide Example 370: 2-((R)-6-(2,3,6-trifluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((S)-tetrahydrofuran-3-yl)acetamide Example 371: 2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(1-methyl-6-oxopiperidin-3-yl)acetamide Example 372: (R)—N-methyl-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)acetamide Example 373: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(tetrahydro-2H-pyran-4-yl)acetamide Example 374: N-methyl-2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(tetrahydrofuran-3-yl)acetamide Example 375: N-methyl-2-((R)-2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(tetrahydrofuran-3-yl)acetamide Example 376: (R)—N-(tetrahydro-2H-pyran-4-yl)-2-(3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide Example 377: (R)—N-(tetrahydro-2H-pyran-4-yl)-2-(3-thioxo-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide Example 378: (R)—N-methyl-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)acetamide Example 379: (R)—N-methyl-2-(6-(2,3,6-trifluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)acetamide Example 380: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(tetrahydro-2H-pyran-4-yl)acetamide Example 381:2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(tetrahydro-2H-pyran-4-yl)acetamide Example 382:2-((S)-6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydro-2H-pyran-3-yl)acetamide Example 383:2-((S)-6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(tetrahydrofuran-3-yl)acetamide Example 384:2-((S)-6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(tetrahydrofuran-3-yl)acetamide Example 385:2-((S)-6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((S)-tetrahydrofuran-3-yl)acetamide Example 386: N—((R)-tetrahydro-2H-pyran-3-yl)-2-((R)-3-thioxo-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide Example 387:2-((R)-2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—(((S)-tetrahydrofuran-2-yl)methyl)acetamide Example 388: N-(1-methyl-2-oxopyrrolidin-3-yl)-2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide Example 389:2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((S)-1-methyl-5-oxopyrrolidin-3-yl)acetamide Example 390: (R)-1-(2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetyl)pyrrolidine-3-carbonitrile Example 391:2-((R)-2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—(((R)-tetrahydrofuran-2-yl)methyl)acetamide Example 392:2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydrofuran-3-yl)acetamide Example 393: (R)—N-(oxetan-3-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide Example 394: (R)-2-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(oxetan-3-yl)acetamide Example 395:2-((R)-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—(((S)-tetrahydrofuran-2-yl)methyl)acetamide Example 396:2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(tetrahydrofuran-3-yl)acetamide Example 397: (R)-2-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide Example 398: (R)—N-methyl-2-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(oxetan-3-yl)acetamide Example 399:2-((S)-6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N—((R)-tetrahydrofuran-3-yl)acetamide Example 400:2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(oxetan-3-yl)acetamide Example 401:2-((S)-6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydro-2H-pyran-3-yl)acetamide Example 402:2-((S)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydro-2H-pyran-3-yl)acetamide Example 403:2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(oxetan-3-yl)acetamide Example 404:2-((S)-6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((S)-tetrahydrofuran-3-yl)acetamide Example 405: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(tetrahydro-2H-pyran-4-yl)acetamide Example 406: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)acetamide Example 407: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid Example 408: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(oxetan-3-yl)acetamide Example 409: (S)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid Example 410: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)acetamide Example 411: (S)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one Example 412:2-((S)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydrofuran-3-yl)acetamide Example 413: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(oxetan-3-yl)acetamide Example 414: (R)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(oxetan-3-yl)acetamide Example 415:2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydro-2H-pyran-3-yl)acetamide Example 416: (S)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)acetamide Example 417:2-((S)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((S)-tetrahydrofuran-3-yl)acetamide Example 418:2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N—((S)-tetrahydrofuran-3-yl)acetamide Example 419: (S)-2-(6-(3,5-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one Example 420: (R)—N-methyl-N-(oxetan-3-yl)-2-(3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide Example 421:2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one Example 422:2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one Example 423:2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)acetamide Example 424: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid Example 425: 2-((S)-6-(3,5-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydrofuran-3-yl)acetamide Example 426: 2-((S)-6-(3,5-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((S)-tetrahydrofuran-3-yl)acetamide Example 427 (S)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide Example 428: (S)-2-(6-(3,5-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide Example 429: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(oxetan-3-yl)acetamide Example 430: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)acetamide Example 431: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(oxetan-3-yl)acetamide Example 432: (S)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(oxetan-3-yl)acetamide Example 433: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(oxetan-3-yl)acetamide Example 434: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(tetrahydro-2H-pyran-4-yl)acetamide Example 435: (S)—N-methyl-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(oxetan-3-yl)acetamide Example 436: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one Example 437: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(oxetan-3-yl)acetamide Example 438: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(oxetan-3-yl)acetamide Example 439: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(tetrahydro-2H-pyran-4-yl)acetamide Example 440: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(tetrahydrofuran-3-yl)acetamide Example 441: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(tetrahydrofuran-3-yl)acetamide Example 442: 2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(tetrahydrofuran-3-yl)acetamide Example 443: 2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(tetrahydro-2H-pyran-4-yl)acetamide Example 444: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(isoxazolidin-2-yl)ethan-1-one Example 445: (R)-2-(6-(2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one Example 446: 2-((R)-6-(2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydrofuran-3-yl)acetamide Example 447 (R)-2-(6-(2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)acetamide Example 448: (R)-2-(6-(2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(oxetan-3-yl)acetamide Example 449: 2-((S)-6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((S)-1-methyl-5-oxopyrrolidin-3-yl)acetamide Example 450: (S)-1-(2-((S)-6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetyl)pyrrolidine-3-carbonitrile Example 451: 2-((S)-6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N—((R)-tetrahydrofuran-3-yl)acetamide Example 452: (S)-1-(2-(6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetyl)-N,N-dimethylpiperidine-4-carboxamide Example 453: 1-(2-((S)-6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetyl)-N,N-dimethylpyrrolidine-3-carboxamide Example 454: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(oxetan-3-yl)acetamide Example 455: N-methyl-2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydrofuran-3-yl)acetamide Example 456: (S)-6-(3-bromo-2,6-difluorophenyl)-1-(2-hydroxyethyl)-2-methyl-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione Example 457:2-((S)-6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(1-methyl-6-oxopiperidin-3-yl)acetamide Example 458:2-((S)-6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(3-(fluoromethyl)pyrrolidin-1-yl)ethan-1-one Example 459:2-((S)-6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((S)-tetrahydrofuran-3-yl)acetamide Example 460: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-(methyl-d)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one Example 461:2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-(methyl-d)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N—((S)-tetrahydrofuran-3-yl)acetamide Example 462:2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-(methyl-d)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic acid Example 463:2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-(methyl-d)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)acetamide Example 464:2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-(methyl-d)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydro-2H-pyran-3-yl)acetamide Example 465:2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-(methyl-d)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydrofuran-3-yl)acetamide Example 466:2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N—((R)-tetrahydrofuran-3-yl)acetamide Example 467:2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N—((R)-tetrahydrofuran-3-yl)acetamide Example 468: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N—((R)-tetrahydrofuran-3-yl)acetamide Example 469: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-(methyl-d)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)acetamide Example 470: R)-6-(2,3,6-trifluorophenyl)-1-(2-(((R)-tetrahydrofuran-3-yl)amino)ethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione Example 471: (R)-1-(3-(pyrrolidin-1-yl)propyl)-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione Example 472: (R)-1-(3-(isopropylamino)propyl)-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione Example 473: (R)-1-(2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)ethyl)-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione Example 474: (R)-2-methyl-1-(2-(pyrrolidin-1-yl)ethyl)-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione Example 475: (R)-1-(2-((((S)-tetrahydrofuran-2-yl)methyl)amino)ethyl)-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione Example 476: (R)-1-(2-(tert-butylamino)ethyl)-2-methyl-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione Example 477: (R)-2-methyl-1-(2-(((tetrahydro-2H-pyran-4-yl)methyl)amino)ethyl)-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione Example 478: (R)-1-(3-(pyrrolidin-1-yl)propyl)-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione

C. Compositions

The compounds of the invention intended for pharmaceutical use may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or as any combination thereof). Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients. Accordingly, the present invention is also directed to a pharmaceutical composition comprising (i) a therapeutically effective amount of a compound of formula Ia, as defined above, or a pharmaceutically acceptable salt or solvate thereof; and (ii) a pharmaceutically acceptable excipient.

Pharmaceutical compositions suitable for the delivery of compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in “Remington's Pharmaceutical Sciences”, 19th Edition (Mack Publishing Company, 1995).

D. Methods of Use

This invention is also directed to compounds of formula Ia, as defined above, or a pharmaceutically acceptable salt or solvate thereof, for use in therapy, in particular for the treatment of conditions ameliorated by inhibition of DβH outside the CNS.

This invention is also directed to the use of compounds of formula Ia, as defined above, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for treatment of conditions ameliorated by inhibition of DβH outside the CNS.

This invention is also directed to a method for treating conditions ameliorated by inhibition of dopamine-beta-hydroxylase outside the CNS comprising administering a therapeutically effective amount of a compound of formula Ia, as defined in claim 1 , or a pharmaceutically acceptable salt or solvate thereof, to a patient in need thereof.

Conditions ameliorated by inhibition of DβH outside the CNS can include, but are not limited to: cardiovascular disorders such as Angina, Hypertension, Chronic or Congestive Heart Failure, Pulmonary Hypertension (PH) and Pulmonary Arterial Hypertension (PAH).

Reference is made to the “Guidelines for the diagnosis and treatment of pulmonary hypertension” (European Heart Journal (2009) 30, 2493-2537) for details on the definition, classification and pathology and pathobiological features of PH.

Typically, pulmonary hypertension is a group of diseases characterized by a progressive increase of pulmonary vascular resistance leading to right ventricular failure and premature death. It may be defined by a mean pulmonary artery pressure equal or greater than 25 mmHg at rest.

PH has been clinically classified by the WHO into 5 groups, according to the cause of the disease, and symptoms may differ, depending on the ‘group’ that caused the disease. However, ‘common’ symptoms are as follows:

Difficulty in breathing or shortness of breath (main symptom) Fatigue Dizziness Swelling in the ankles or legs (edema) Bluish lips and skin (cyanosis) Chest pain Racing pulse and palpitations

A clinical classification of pulmonary hypertension (PH) has been undertaken and reported by McLaughlin et al in “ACCF/AHA 2009 Expert Consensus Document on Pulmonary Hypertension”, J Am Coll Cardiol 53, 1573-1619, 2009. PH was classified as follows:

1. Pulmonary arterial hypertension (PAH)

1.1. Idiopathic (IPAH) 1.2. Familial (FPAH) 1.3. Associated with (APAH):

1.3.1. Connective tissue disorder 1.3.2. Congenital systemic-to-pulmonary shunts 1.3.3. Portal hypertension 1.3.4. HIV infection 1.3.5. Drugs and toxins 1.3.6. Other (thyroid disorders, glycogen storage disease, Gaucher's disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, chronic myeloproliferative disorders, splenectomy) 1.4. Associated with significant venous or capillary involvement

1.4.1. Pulmonary veno-occlusive disease (PVOD) 1.4.2. Pulmonary capillary hemangiomatosis (PCH)

1.5. Persistent pulmonary hypertension of the newborn

2. Pulmonary hypertension with left heart disease

2.1. Left-sided atrial or ventricular heart disease 2.2. Left-sided valvular heart disease

3. Pulmonary hypertension associated with lung diseases and/or hypoxemia

3.1. Chronic obstructive pulmonary disease 3.2. Interstitial lung disease 3.3. Sleep disordered breathing 3.4. Alveolar hypoventilation disorders 3.5. Chronic exposure to high altitude 3.6. Developmental abnormalities

4. Pulmonary hypertension due to chronic thrombotic and/or embolic disease (CTEPH)

4.1. Thromboembolic obstruction of proximal pulmonary arteries 4.2. Thromboembolic obstruction of distal pulmonary arteries 4.3. Nonthrombotic pulmonary embolism (tumor, parasites, foreign material)

5. Miscellaneous

Sarcoidosis, histiocytosis X, lymphangiomatosis, compression of pulmonary vessels (adenopathy, tumor, fibrosing mediastinitis)

The WHO has also provided the following functional assessment classification:

Functional Symptomatic profile

Class

I Patients with pulmonary hypertension but without resulting limitation of physical activity. Ordinary physical activity does not cause dyspnoea or fatigue, chest pain, or near syncope II Patients with pulmonary hypertension resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity causes undue dyspnoea or fatigue, chest pain, or near syncope III Patients with pulmonary hypertension resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes undue dyspnoea or fatigue, chest pain, or near syncope IV Patients with pulmonary hypertension with inability to carry out any physical activity without symptoms. These patients manifest signs of right heart failure. Dyspnoea and/or fatigue may even be present at rest. Discomfort is increased by any physical activity.

E. General Synthetic Methodology

The methods used for the synthesis of the compounds of the invention are illustrated by the schemes below. The starting materials and reagents used in preparing these compounds are available from commercial suppliers or can be prepared by methods obvious to those skilled in the art. To make the schemes easier to read, the option to incorporate deuterium at certain positions is not shown. Specifically, deuterated products can be produced using specifically deuterated starting materials, including, but not limited to, those used in Examples 1-478.

The starting material for compounds of formula If, when R 1 ═H can generally be synthesised by the method outlined in Scheme 1 as either enriched enantiomers or racemates:

The starting material for compounds of formula Ii, when R 1 ═H can generally be synthesised by the method outlined in Scheme 2 as either enriched enantiomers or racemates:

Compounds of formula If or Ii, with various identities for R 6 , can generally be synthesised by the methods outlined in Schemes 3-15 as either enriched enantiomers or racemates:

Compounds wherein R 1 is C 1 -C 6 alkyl, partially or fully deuterated C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl can be synthesised using an alkyl isothiocyanate as shown in Scheme 16 below:

F. Examples

All compounds and intermediates were characterised by NMR. The spectra were recorded on a Bruker Avance III 600 MHz spectrometer with solvent used as internal standard. 13 C spectra were recorded at 150 MHz and 1 H spectra were recorded at 600 MHz. Data are reported in the following order: approximate chemical shift (ppm), number of protons, multiplicity (br, broad; d, doublet; m, multiplet; s, singlet; t, triplet) and coupling constant (Hz).

Room temperature in the following protocols means the temperature ranging from 20° C. to 25° C.

Example 1: (S)-ethyl 2-(6-(3,5-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetate

To a solution of methanol (72 mL), water (36 mL), and 2.5 M sodium hydroxide (32.4 mL, 81 mmol) was added a solution of 3,5-difluorobenzaldehyde (10 g, 70.4 mmol) and nitromethane (4.36 mL, 81 mmol) in methanol (12.00 mL) dropwise over 30 min at 5° C., while the internal temperature was maintained between 5 and 10° C. with external cooling. The reaction was then agitated in the cold for an additional 0.5, and then a solution of cc. HCl (11.73 mL, 141 mmol) in water (36 mL) was added in one portion at 0-10° C. with stirring. The resulting crystals were collected, washed with water and dried to give the product as a light yellow powder. (Yield: 7.0 g, 54%).

To a stirred solution of (E)-1,3-difluoro-5-(2-nitrovinyl)benzene (7.4 g, 40.0 mmol) in dry tetrahydrofuran (75 mL) was added 4-((1R)-hydroxy((4S,8R)-8-vinylquinuclidin-2-yl)methyl)quinolin-6-ol (0.620 g, 1.999 mmol) at room temperature with stirring followed by addition of diethyl malonate (9.15 mL, 60.0 mmol). The mixture was cooled to −15 to −17° C. under inert atmosphere and stirred for 20 h in the cold. Thereupon, the mixture was evaporated to dryness under vacuum and the residue was taken up in dichloromethane (100 mL), washed with 1 M HCl, brine, dried over MgSO 4 and filtered on a silica pad. The filtrate was concentrated to 20 mL, and the residue was crystallized on dilution with petroleum ether (ca. 50 mL). The mixture was further diluted with petroleum ether (120 mL), and aged at 5-10° C. The resulting solid was collected, washed with petroleum ether, and dried to give the product as an off-white powder. (Yield: 11.46 g, 83%).

To a suspension of (S)-diethyl 2-(1-(3,5-difluorophenyl)-2-nitroethyl)malonate (11 g, 31.9 mmol) in methanol (170 mL) was added nickel(II) chloride hexahydrate (7.57 g, 31.9 mmol) followed by addition of sodium borohydride (9.64 g, 255 mmol) in portions with ice cooling. The mixture was stirred for 6 h at room temperature, then quenched with ammonium chloride solution (300 mL), diluted with dichloromethane (150 mL), acidified with 6 M HCl to pH=2, and stirred for 16 h. Thereupon, the mixture was extracted with dichloromethane, the organic phase was dried over MgSO 4 and evaporated to dryness to give the product as a light yellow crystalline. (Yield: 8.31 g, 97%).

To a stirred solution of (4S)-ethyl 4-(3,5-difluorophenyl)-2-oxopyrrolidine-3-carboxylate (8.3 g, 30.8 mmol) in ethanol (130 mL) was added 1 M sodium hydroxide (37.0 mL, 37.0 mmol). The resulting suspension was stirred for 1 h, the organics were then removed under vacuum, and the residue was dissolved in water (300 mL). The product was crystallized on acidification with 6 M HCl. The resulting crystals were collected, washed with cold water and dried under vacuum at 50° C. to give the product as a beige powder Yield: 6.0 g, 81%.

A solution of (4S)-4-(3,5-difluorophenyl)-2-oxopyrrolidine-3-carboxylic acid (6.0 g, 24.88 mmol) in toluene (350 mL) was stirred under reflux for 3 h, whereupon the mixture was evaporated to 30 mL, and then diluted with petroleum ether. The resulting crystals were collected, washed with petroleum ether and dried under vacuum to give an off-white powder. Yield: 4.83 g, 98%.

To a stirred solution of (S)-4-(3,5-difluorophenyl)pyrrolidin-2-one (4.8 g, 24.34 mmol) in dry dichloromethane (15 mL) was added at room temperature di-tert-butyl dicarbonate (7.80 g, 36.5 mmol) followed by addition of N,N-dimethylpyridin-4-amine (2.97 g, 24.34 mmol) and triethyl amine (3.32 ml, 23.84 mmol). The mixture was then stirred at room temperature for 3 h, and then concentrated under vacuum. Chromatography (petroleum ether-ethyl acetate; 4:1) gave an oil which was crystallized from petroleum ether (60 mL). The product was isolated as a white powder. Yield: 6.24 g, 88%.

To a stirred solution of (S)-tert-butyl 4-(3,5-difluorophenyl)-2-oxopyrrolidine-1-carboxylate (2.5 g, 8.41 mmol) in dry diethyl ether (37 mL) was added dropwise 65% RED-Al (bis(2-methoxyethoxy)aluminum(III) sodium hydride) (1.51 ml, 5.05 mmol) in toluene at 0-5° C. under nitrogen and the mixture was stirred for 1 h in the cold. Thereupon, the mixture was quenched with sodium bicarbonate solution and stirred for 30 min. The organic phase was dried over MgSO 4 , and evaporated to dryness to give the product as a yellowish oil. (Yield: 2.56 g, 92%).

To a stirred solution of (4S)-tert-butyl 4-(3,5-difluorophenyl)-2-hydroxypyrrolidine-1-carboxylate (3.5 g, 11.69 mmol) in dry dichloromethane (75 mL) was added trimethylsilanecarbonitrile (3.14 ml, 23.39 mmol) followed by addition of boron trifluoride etherate (3.26 ml, 25.7 mmol) at −70° C. The mixture was stirred for 4 h in the cold, thereupon quenched with sodium bicarbonate solution, and then allowed to warm up with stirring to room temperature. The organic phase was dried over MgSO 4 , filtered and evaporated to dryness under vacuum. Chromatography (petroleum ether-ethyl acetate; 9:1) afforded the compound as a colourless oil. (Yield: 2.43 g, 67%).

To a stirred solution of (4S)-tert-butyl 2-cyano-4-(3,5-difluorophenyl)pyrrolidine-1-carboxylate (2.25 g, 7.30 mmol) in ethanol (25 mL) was added 3 M sodium hydroxide (12.16 mL, 36.5 mmol) and the solution was gently refluxed (oil bath at 80° C.) for 3 h. Thereupon, ethanol was removed under vacuum and the residue was diluted with water (30 mL), and then acidified with 2 M HCl to pH=2 at 10-15° C. The mixture was extracted with dichloromethane (50 mL), the insoluble materials in both phases was filtered off, whereupon the organic phase was washed with brine, dried over MgSO 4 and evaporated to dryness to give 0.90 g of yellowish foam. (Yield: 37%).

Step 10: (4S)-tert-butyl 4-(3,5-difluorophenyl)-2-(2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-carbonyl)pyrrolidine-1-carboxylate

To a solution of (4S)-1-(tert-butoxycarbonyl)-4-(3,5-difluorophenyl)pyrrolidine-2-carboxylic acid (0.35 g, 1.069 mmol), 2,2-dimethyl-1,3-dioxane-4,6-dione (0.154 g, 1.069 mmol) and N,N-dimethylpyridin-4-amine (0.131 g, 1.069 mmol) was added dicyclohexylmethanediimine (0.221 g, 1.069 mmol) dropwise at 0-5° C. and the mixture was stirred in the cold for 2 h. The mixture was then filtered through a celite, plug, the filtrate was washed with 1 M HCl, brine, dried over MgSO 4 , and then evaporated to dryness to give the product as oil. (Yield: 0.42 g, 87

A solution of (4S)-tert-butyl 4-(3,5-difluorophenyl)-2-(2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-carbonyl)pyrrolidine-1-carboxylate (0.41 g, 0.904 mmol) in abs. ethanol (5 mL) was stirred under reflux for 3 h. The solvent was then removed under vacuum and the residue was subjected to chromatography (petroleum ether-ethyl acetate; 9:1). The product was isolated as a colourless oil. (Yield: 0.124 g, 34%).

Step 12: ((S)-ethyl 2-(6-(3,5-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetate

A solution (4S)-tert-butyl 4-(3,5-difluorophenyl-2-(3-ethoxy-3-oxopropanoyl)pyrroline-1-carboxylate (0.11 g, 0.277 mmol) in 2 M HCl (1.107 mL, 2.214 mmol) in diethyl ether was stirred at room temperature for 5 h. and then the solvent was removed under vacuum. The residue was dissolved in a mixture of ethanol (1.5 mL) and water (1.5 mL), treated with potassium thiocyanate (0.030 g, 0.304 mmol) followed by addition of 6N HCl (0.023 mL, 0.138 mmol) and then the mixture was stirred at 90° C. for 3 h. Thereupon, ethanol was removed under vacuum, and the residue was extracted with a mixture of ethyl acetate-petroleum ether (2:1). The organic phase was dried over MgSO 4 , evaporated to dryness and the residue was subjected to chromatography (petroleum ether-EtOAc; 1:1, then 1:2). The product was isolated as a light yellow powder. (Yield: 0.038 g, 40%).

1 H NMR (DMSO d6 ): 1.78 (1H, s), 7.13 (3H, m), 4.17 (1H, dd, J=11.1, 7.8 Hz), 4.09 (2H, q, J=7.0 Hz), 4.09 (1H, m), 3.70 (1H, dd, J=11.2, 7.8 Hz), 3.52 (2H, m, J=3.1 Hz), 3.20 (1H, dd, J=15.4, 7.9 Hz), 2.84 (1H, dd, J=15.4, 8.4 Hz), 1.19 (3H, t, J=7.1 Hz).

13 C NMR (DMSO d6 ): 169.2, 163.3, 163.2, 161.7, 161.6, 155.6, 145.8, 145.8, 145.7, 129.9, 113, 110.7, 110.7, 110.6, 110.6, 102.7, 102.5, 102.3, 60.7, 50.3, 46.4, 30.4, 29.8, 14.1.

Example 2: (S)-ethyl 2-(6-(2,5-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetate and

Example 3: (S)-2-(6-(2,5-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetic Acid

A mixture of potassium 3-ethoxy-3-oxopropanoate (0.741 g, 4.35 mmol) and magnesium bromide diethyletherate (0.749 g, 2.90 mmol) in dry tetrahydrofuran (10 ml) was stirred under inert atmosphere at 50° C. for 6 h. In parallel, di(1H-imidazol-1-yl)methanone (0.706 g, 4.35 mmol) was added portionwise to a solution of (4S)-1-(tert-butoxycarbonyl)-4-(2,5-difluorophenyl)pyrrolidine-2-carboxylic acid (prepared analogous manner to Example 1 step 9) (0.95 g, 2.90 mmol) in dry tetrahydrofuran (8.00 mL) at 0-5° C. and the mixture was stirred for 2 h at room temperature. The solution was then added to the first suspension dropwise and the mixture was stirred for 16 h at ambient temperature. Thereupon, the mixture was quenched with aq. NaHSO 4 solution and then extracted with a mixture of ethyl acetate-petroleum ether (2:1). The organic phase was washed with sodium bicarbonate, dried over MgSO 4 and evaporated to dryness. Chromatography in a mixture of petroleumether-ethyl acetate (9:1) afforded (4S)-tert-butyl 4-(2,5-difluorophenyl)-2-(3-ethoxy-3-oxopropanoyl)pyrrolidine-1-carboxylate. (Yield: 0.56 g, 48.6%).

Step 2: (S)-ethyl 2-(6-(2,5-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetate and (S)-2-(6-(2,5-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetic Acid

A solution of (4S)-tert-butyl 4-(2,5-difluorophenyl)-2-(3-ethoxy-3-oxopropanoyl)pyrrolidine-1-carboxylate (0.56 g, 1.409 mmol) in 2 M HCl (5.64 mL, 11.27 mmol) in diethyl ether was stirred at room temperature for 16 h, whereupon the solvent was removed under vacuum, and the residue was dissolved in a mixture of ethanol (6 mL) and water (6 mL). The reaction mixture was treated with potassium thiocyanate (0.151 g, 1.550 mmol) followed by addition of 6 M HCl (0.117 mL, 0.705 mmol) and then stirred for 2 h Thereupon, ethanol was removed under vacuum, were upon the resulting solid was collected and washed with water. The precipitate was dissolved in ethyl acetate, dried over MgSO 4 , filtered through a silica pad, and then evaporated to dryness. Crystallization from petroleum ether afforded (S)-ethyl 2-(6-(2,5-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetate as an off-white powder. (Yield: 0.19 g, 39%).

1 H NMR (DMSO d6 ): 11.79 (1H, br s), 7.27 (2H, m), 7.18 (1H, m), 4.23 (1H, quin, J=7.7 Hz), 4.15 (1H, dd, J=11.2, 8.0 Hz), 4.09 (2H, q, J=7.1 Hz), 3.75 (1H, dd, J=11.2, 7.5 Hz), 3.52 (2H, m), 3.22 (1H, dd, J=15.5, 8.0 Hz), 2.87 (1H, br dd, J=15.6, 7.8 Hz), 1.19 (3H, t, J=7.0 Hz).

13 C NMR (DMSO d6 ): 169.2, 159, 157.5, 157.1, 155.6, 155.5, 130.1, 130, 130, 129.9, 129.8, 117.2, 117.1, 117, 116.9, 115.5, 115.4, 115.3, 115.3, 115.2, 115.2, 115.1, 115, 113, 60.7, 49.4, 40.3, 29.8, 29.6, 14.1.

The aqueous mother liqueur of the above procedure was extracted with dichloromethane. The organic phase was extracted with aq. NaOH, then the aqueous phase was acidified and extracted with dichloromethane, The organic phase was dried over MgSO 4 , evaporated to dryness to give 67 mg (15% yield) of (S)-2-(6-(2,5-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid as an off-white powder.

1 H NMR (DMSO d6 ): 12.58 (1H, br s), 11.75 (1H, s), 7.28 (2H, m), 7.18 (1H, m), 4.22 (1H, quin, J=7.8 Hz), 4.14 (1H, dd, J=11.2, 7.9 Hz), 3.73 (1H, dd, J=11.3, 7.3 Hz), 3.43 (2H, m), 3.21 (1H, dd, J=15.5, 8.0 Hz), 2.87 (1H, dd, J=15.4, 7.8 Hz).

13 C NMR (DMSO d6 ): 170.8, 159.1, 157.5, 157.1, 155.5, 155.5, 130.1, 130, 130, 129.9, 129.5, 117.1, 117.1, 117, 116.9, 115.5, 115.4, 115.3, 115.3, 115.2, 115.1, 115.1, 113.8, 49.4, 40.3, 30, 29.5.

Example 4: Methyl 2-((5aS,6aR)-5a-(2,5-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetate

To a stirred solution of 2-(2,5-difluorophenyl)acetonitrile (10.0 g, 65.3 mmol) in dry terahydrofuran (100 mL), was added (R)-2-(chloromethyl)oxirane (6.13 mL, 78.0 mmol) at room temperature, under nitrogen. The reaction was then cooled to 15° C. and 2 M sodium bis(trimethylsilyl)amide in terahydrofuran (57.1 mL, 114.0 mmol) was added, dropwise at 15° C. over a period of 2 h. Thereupon, the thus obtained red mixture was allowed to warm up to room temperature and stirred for 3 h. The reaction was diluted with dry terahydrofuran (100 mL), cooled to 0° C., and then sodium borohydride (9.88 g, 261 mmol) was added followed by dropwise addition of boron trifluoride etherate (33.10 ml, 261 mmol). The mixture was allowed to warm up to room temperature and stirred overnight. The resulting pale yellow suspension was cooled to 0° C. and carefully quenched with 2 M HCl (196 mL, 392 mmol). The terahydrofuran was then evaporated off and the aqueous phase was washed with diethyl ether. The pH of the aqueous phase was set to pH=10 by adding 3 M sodium hydroxide and then extracted with dichloromethane. The organic phase was dried over MgSO 4 , filtered and evaporated to dryness under vacuum to leave a yellow oil. (Yield: 12.91 g, 74%).

To an ice-cold solution of ((1R,2S)-2-(aminomethyl)-2-(2,5-difluorophenyl)cyclopropyl)methanol (12.91 g, 60.5 mmol) in ethanol (207 mL) was added di-tert-butyl dicarbonate (13.21 g, 60.5 mmol). The solution was stirred at room temperature for 3 h and then the solvent was evaporated off under vacuum. The resulting yellow oil was purified by chromatography (petroleum ether-ethyl acetate). The product was isolated as a white powder. (Yield: 14.28 g, 64%).

To a stirred solution of oxalyl dichloride (4.39 mL, 50.10 mmol) in dry dichloromethane (120 mL), was added dropwise a solution of dimethylsulfoxide (4.12 mL, 100.0 mmol) in dry dichloromethane (22 mL) at −78° C. The reaction mixture was stirred in the cold for 15 min, and then a solution of tert-butyl tert-butyl (((1S,2R)-1-(2,5-difluorophenyl)-2-(hydroxymethyl)cyclopropyl)methyl)carbamate (14.28 g, 45.60 mmol) in dry dichloromethane (44 mL) was added dropwise. The mixture was stirred at −78° C. for 1 h and then triethylamine (31.8 mL, 228.0 mmol) was added. The reaction was allowed to warm up gradually to room temperature and stirred at room temperature for 2 h. Thereupon, the mixture was washed three times with water, dried over MgSO 4 , filtered and evaporated to dryness to give a yellow oil. (Yield: 14.5 g, ≈100%).

To a stirred solution of tert-butyl (1S,5R)-1-(2,5-difluorophenyl)-4-hydroxy-3-azabicyclo[3.1.0]hexane-3-carboxylate (14.2 g, 45.60 mmol) in dry dichloromethane (230 mL) was added trimethylsilanecarbonitrile (16.33 ml, 122.0 mmol) at room temperature under nitrogen. The solution was then cooled to −78° C. and boron trifluoride etherate (16.83 mL, 134.0 mmol) was added dropwise. The reaction mixture was stirred in the cold for 4 h., and then saturated solution of sodium bicarbonate was added and allowed to warm up to room temperature. The organic phase was separated and aqueous phase was extracted with dichloromethane. The combined organic phases were dried over MgSO 4 , filtered and evaporated to dryness to leave a yellow oil. (Yield: 14.9 g, 92%).

Step 5: (1R,5S)-3-(tert-butoxycarbonyl)-5-(2,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic Acid

To a stirred solution of tert-butyl (1S,5R)-4-cyano-1-(2,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (14.61 g, 45.6 mmol) in ethanol (145 mL), was added a solution of 3 M sodium hydroxide (76 mL, 228.0 mmol) at room temperature. The solution was heated at 80° C. for 4 h. and then was cooled to room temperature. Thereupon, ethanol was evaporated off and the aqueous phase was acidified with 2 M HCl solution and then extracted with a mixture of dichloromethane-isopropanol (7:3). The organic phase was dried over MgSO 4 , filtered and evaporated to dryness to leave a yellow oil, which solidified on standing. (Yield: 17.0 g, 93%).

Step 6: (1S,5R)-tert-butyl 1-(2,5-difluorophenyl)-4-(2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-carbonyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a stirred solution of (1R,5S)-3-(tert-butoxycarbonyl)-5-(2,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (2.5 g, 7.37 mmol) in dichloromethane (50 mL) was added 2,2-dimethyl-1,3-dioxane-4,6-dione (1.062 g, 7.37 mmol) at room temperature followed by addition of N,N-dimethylpyridin-4-amine (0.900 g, 7.37 mmol). The thus obtained solution was cooled to 0° C. and a solution of N,N-dicyclohexylcarbodiimide (1.520 g, 7.37 mmol) in dichloromethane was added dropwise. The mixture was stirred in the cold for 2 h, and then filtered through a celite plug. The filtrate was washed with 1 M HCl and brine, dried over MgSO 4 , filtered and evaporated to dryness to give a yellow semisolid. Yield: 3.45 g, 100%.

Step 7 (1S,5R)-tert-butyl 1-(2,5-difluorophenyl)-4-(3-methoxy-3-oxopropanoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

A solution of (1S,5R)-tert-butyl 1-(2,5-difluorophenyl)-4-(2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-carbonyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (3.43 g, 7.37 mmol) in dry methanol (40 mL), was heated at reflux for 3.5 h under inert atmosphere. The solution was then cooled to room temperature and the solvent was evaporated off. The resulting yellow oil was purified by chromatography (petroleum ether-ethyl acetate; 9/1, 4/1, 2/1, then 1/1). The product was isolated as a colourless oil. (Yield: 1.84 g, 53%).

Step 8: methyl 3-((1R,5S)-5-(2,5-difluorophenyl)-3-azabicyclo[3.1.0]hexan-2-yl)-3-oxopropanoate Hydrochloride

(1S,5R)-tert-butyl 1-(2,5-difluorophenyl)-4-(3-methoxy-3-oxopropanoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.79 g, 4.53 mmol) was stirred in 2 M ethereal HCl solution (18.11 mL, 36.2 mmol) for 8 h. Thereupon, the reaction mixture was evaporated to dryness to leave the product as a white foam. (Yield: 1.14 g, 76%).

Step 9: Methyl 2-((5aS,6aR)-5a-(2,5-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetate

To a stirred solution of methyl 3-((1R,5S)-5-(2,5-difluorophenyl)-3-azabicyclo[3.1.0]hexan-2-yl)-3-oxopropanoate hydrochloride (1.14 g, 3.44 mmol) in a mixture of ethanol (14 mL) and water (14 mL) was added potassium thiocyanate (0.367 g, 3.78 mmol) followed by addition of cc. HCl (0.14 mL, 1.718 mmol). The solution was heated at reflux for 5 h, then cooled to room temperature and evaporated to dryness. The resulting oil was extracted from the aqueous phase with dichloromethane. The organic phase was dried over MgSO 4 , filtered and evaporated to dryness. The thus obtained yellow oil was separated by chromatography (dichloromethane-methanol; 98:2, then 95:5), then chromatographed again (petroleum ether-ethyl acetate; 1:1, then 1:2). The product was isolated as a yellow solid. (Yield: 90 mg, 7%).

1 H NMR (DMSO d6 ): 11.73 (1H, s), 7.29 (1H, m), 7.26 (1H, m), 7.21 (1H, m), 4.10 (1H, br d, J=12.3 Hz), 3.82 (1H, d, J=12.0 Hz), 3.66 (3H, s), 3.59 (2H, m), 2.87 (1H, dd, J=8.2, 4.3 Hz), 1.67 (1H, dd, J=8.2, 5.4 Hz), 1.14 (1H, br t, J=4.7 Hz).

13 C NMR (DMSO d6 ): 169.7, 158.8, 158.6, 157.2, 157, 156.3, 132.3, 128.6, 128.5, 128.4, 117.2, 117.1, 117, 117, 116.8, 116.8, 116, 115.9, 115.8, 115.7, 112.2, 52, 51.6, 51.5, 32.5, 29.6, 22.2, 20.7.

Example 5: Methyl 2-((5aS,6aR)-5a-(3,5-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetate

(1R,5S)-3-(tert-butoxycarbonyl)-5-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid was converted to methyl 2-((5aS,6aR)-5a-(3,5-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetate by a similar procedure as described for Example 4 and the product was isolated as a yellow solid.

1 H NMR (DMSO d6 ): 1.72 (1H, s), 7.11 (3H, m), 4.20 (1H, d, J=12.0 Hz), 4.06 (1H, d, J=12.2 Hz), 3.65 (3H, s), 3.57 (2H, m), 2.97 (1H, dd, J=8.2, 4.4 Hz), 1.70 (1H, dd, J=8.2, 5.3 Hz), 1.16 (1H, t, J=4.8 Hz).

13 C NMR (DMSO d6 ): 169.7, 163.4, 163.3, 161.8, 161.7, 156.5, 144.8, 144.7, 144.7, 132.3, 112, 110, 110, 109.9, 109.8, 102.3, 102.1, 102, 52, 50.7, 36.2, 29.6, 25.2, 22.9.

Example 6: 2-((5aS,6aR)-5a-(2,5-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic Acid

To a stirred solution of ethyl 2-((5aS,6aR)-5a-(2,5-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetate (prepared analogous manner to Example 4) (275 mg, 0.785 mmol) in ethanol (3 mL) was added 1M sodium hydroxide (0.942 ml, 0.942 mmol) at room temperature and the solution was stirred for 2 h. Thereupon, a second crop of 1 M sodium hydroxide was added (0.942 ml, 0.942 mmol) and the reaction was allowed to stir for additional 1 h. Ethanol was then removed under vacuum and the aqueous phase was extracted dichloromethane. The aqueous phase was acidified to pH=1 by adding aqueous HCL solution and then extracted with dichloromethane. The organic phase was evaporated to dryness to give the product as a yellow foam. (Yield: 0.206 g, 76%).

1 H NMR (DMSO d6 ): 12.57 (1H, br s), 11.70 (1H, s), 7.29 (1H, td, J=9.4, 4.6 Hz), 7.25 (1H, ddd, J=9.1, 5.9, 3.2 Hz), 7.21 (1H, m), 4.09 (1H, d, J=11.9 Hz), 3.81 (1H, d, J=12.0 Hz), 3.47 (2H, m), 2.87 (1H, dd, J=8.4, 4.3 Hz), 1.66 (1H, dd, J=8.4, 5.3 Hz), 1.13 (1H, t, J=4.8 Hz).

13 C NMR (DMSO d6 ): 170.7, 158.8, 158.6, 157.2, 157, 157, 156.1, 132.1, 128.6, 128.6, 128.5, 128.5, 117.2, 117.1, 117, 117, 116.9, 116.8, 116.8, 115.9, 115.9, 115.8, 115.7, 113, 51.6, 51.5, 32.5, 29.9, 22.3, 20.7.

Example 7: 2-((5aS,6aR)-5a-(3,5-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic Acid

Compound was prepared by a similar procedure as described for Example 6 and the product was isolated as a yellow solid.

1 H NMR (DMSO d6 ): 12.60 (1H, br s), 11.69 (1H, s), 7.10 (3H, m), 4.20 (1H, d, J=12.2 Hz), 4.05 (1H, d, J=12.2 Hz), 3.45 (2H, m), 2.98 (1H, dd, J=8.3, 4.3 Hz), 1.70 (1H, dd, J=8.3, 5.4 Hz), 1.16 (1H, t, J=4.8 Hz).

13 C NMR (DMSO d6 ): 170.7, 163.4, 163.3, 161.8, 161.7, 156.3, 144.9, 144.8, 144.7, 132, 112.8, 110, 110, 109.8, 109.8, 102.3, 102.1, 101.9, 50.7, 36.2, 29.9, 25.3, 22.9.

Example 8: (5aS,6aR)-5a-(3,5-difluorophenyl)-1-(2-hydroxyethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione

To a stirred solution of ethyl 2-((5aS,6aR)-5a-(3,5-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetate (300 mg, 0.856 mmol) (analogous to Example 5) in a mixture of abs. methanol (2.3 mL) and dry tetrahydrofuran (2.3 mL) was added lithium chloride (0.061 ml, 3.00 mmol). The reaction mixture was then cooled to 0° C. and sodium borohydride (113 mg, 3.00 mmol) was added portionwise. The thus obtained white suspension was allowed to warm up to room temperature and stirred for 24 h. Thereupon, water was added and the mixture was extracted with dichloromethane. The organic phase was dried over MgSO 4 , filtered and evaporated to dryness to leave a yellow oil. Chromatography (petroleum ether-ethyl acetate; 1:1, 1:4, then 5% methanol in dichloromethane) followed by trituration with heptane afforded the product as a light yellow solid. (Yield: 0.065 g, 23%).

1 H NMR (DMSO d6 ): 1.64 (1H, s), 7.10 (3H, m), 4.74 (1H, t, J=5.4 Hz), 4.17 (1H, d, J=12.0 Hz), 4.02 (1H, d, J=12.0 Hz), 3.59 (2H, m), 2.98 (1H, dd, J=8.2, 4.3 Hz), 2.53 (2H, td, J=6.8, 2.9 Hz), 1.65 (1H, dd, J=8.1, 5.2 Hz), 1.16 (1H, t, J=4.8 Hz).

13 C NMR (DMSO d6 ): 163.4, 163.3, 161.8, 161.7, 155.9, 145.1, 145.1, 145, 130.9, 116.8, 109.9, 109.9, 109.8, 109.8, 102.2, 102, 101.9, 59.4, 50.5, 36, 28, 25.6, 22.9.

Example 9: (S)-2-(6-(3,5-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethanone

Step 1: (4S)-tert-butyl 4-(3,5-difluorophenyl)-2-(3-morpholino-3-oxopropanoyl)pyrrolidine-1-carboxylate

A mixture of (4S)-tert-butyl 4-(3,5-difluorophenyl)-2-(3-ethoxy-3-oxopropanoyl)pyrrolidine-1-carboxylate (prepared according to protocol of Example 2 Step 1) (0.74 g, 1.862 mmol), morpholine (0.324 ml, 3.72 mmol) and N,N-dimethylpyridin-4-amine (0.068 g, 0.559 mmol) in toluene (3 mL) was stirred at 100° C. for 20 h. The reaction was then diluted with a mixture of ethyl acetate-petroleum ether (1:1) and washed with 1 M HCl. The organic phase was dried over MgSO 4 , stripped down to dryness and purified by chromatography in a mixture of ethyl acetate-petroleum ether (1:1) to give (4S)-tert-butyl 4-(3,5-difluorophenyl)-2-(3-morpholino-3-oxopropanoyl)pyrrolidine-1-carboxylate. Yield: 0.634 g, 78%.

A solution of (4S)-tert-butyl 4-(2,5-difluorophenyl)-2-(3-morpholino-3-oxopropanoyl)pyrrolidine-1-carboxylate (0.66 g, 1.505 mmol) in 4 M HCl (7.53 mL, 30.1 mmol) in dioxane was stirred for 4 h at room temperature. Thereupon, the reaction mixture was diluted with diethyl ether, the resulting solid was collected, washed with diethyl ether and petroleum ether, respectively and then dried in vacuum at 50° C. to give 1-((4S)-4-(3,5-difluorophenyl)pyrrolidin-2-yl)-3-morpholinopropane-1,3-dione hydrochloride as a white powder. Yield: 0.52 g, 92%.

Step 3: (S)-2-(6-(3,5-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one

A solution of 1-((4S)-4-(3,5-difluorophenyl)pyrrolidin-2-yl)-3-morpholinopropane-1,3-dione hydrochloride (0.52 g, 1.387 mmol), potassium thiocyanate (0.148 g, 1.526 mmol) and 6 M HCl (0.12 ml, 0.69 mmol) in a mixture of ethanol (7 mL) and water (7.00 mL) was stirred under reflux for 1 h. Ethanol was evaporated under vacuum. The aqueous phase was extracted with ethyl acetate, the organic phase was diluted with petroleum ether without drying until crystallization occurred. The resultant solid was collected and recrystallized from a mixture of DCM-petroleum ether to give (S)-2-(6-(3,5-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethanone as a white powder. (Yield: 0.051 g, 9%.)

1 H NMR (DMSO d6 ): 1.66 (1H, s), 7.12 (3H, br d, J=8.2 Hz), 4.16 (1H, dd, J=11.1, 7.8 Hz), 4.07 (1H, quin, J=7.8 Hz), 3.69 (1H, dd, J=11.1, 7.8 Hz), 3.56 (4H, m), 3.52 (2H, s), 3.46 (4H, m), 3.15 (1H, br dd, J=15.2, 7.8 Hz), 2.80 (1H, br dd, J=15.3, 8.2 Hz).

13 C NMR (DMSO d6 ): 166.9, 163.3, 163.2, 161.7, 161.6, 155.4, 145.9, 145.8, 145.8, 129.4, 114.4, 110.7, 110.7, 110.6, 110.6, 102.6, 102.5, 102.3, 66, 50.2, 46.4, 45.7, 41.7, 30.5, 28.8.

Example 10: (S)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetic Acid

Compound was prepared analogous manner to Example 3 from (4S)-1-(tert-butoxycarbonyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-2-carboxylic acid and isolated as an off-white powder.

1 H NMR (DMSO d6 ): 12.58 (1H, m), 11.79 (1H, s), 7.85 (1H, m), 4.50 (1H, quin, J=8.5 Hz), 4.18 (1H, dd, J=11.6, 9.2 Hz), 3.78 (1H, dd, J=11.7, 7.8 Hz), 3.41 (2H, s), 3.30 (1H, br dd, J=15.9, 9.3 Hz), 2.91 (1H, dd, J=15.9, 8.0 Hz).

13 C NMR (DMSO d6 ): 170.7, 155.3, 146.4, 145.3, 144.7, 143.7, 129.4, 120.5, 120.4, 120.3, 113.5, 105.9, 105.7, 105.6, 48.5, 35.7, 30, 29.1.

Example 11: (S)-2-(6-(3,5-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetic Acid

Compound was prepared analogous manner to Example 3 from (4S)-tert-butyl 4-(3,5-difluorophenyl)-2-(3-ethoxy-3-oxopropanoyl)pyrrolidine-1-carboxylate and isolated as an off-white powder.

1 H NMR (DMSO d6 ): 12.58 (1H, br s), 11.74 (1H, br s), 7.13 (3H, m), 4.16 (1H, dd, J=11.2, 7.9 Hz), 4.08 (1H, quin, J=8.0 Hz), 3.70 (1H, dd, J=11.2, 7.8 Hz), 3.42 (2H, m), 3.20 (1H, dd, J=15.4, 7.8 Hz), 2.85 (1H, dd, J=15.4, 8.4 Hz).

13 C NMR (DMSO d6 ): 170.7, 163.3, 163.2, 161.7, 161.6, 155.5, 145.9, 145.8, 145.7, 129.7, 113.6, 110.8, 110.7, 110.6, 110.6, 102.7, 102.5, 102.3, 50.3, 46.4, 30.4, 29.9.

Example 12: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic Acid

Compound was prepared analogous manner to Example 3 from (4S)-tert-butyl 4-(3-bromo-2,6-difluorophenyl)-2-(3-ethoxy-3-oxopropanoyl)pyrrolidine-1-carboxylate and isolated as a yellowish solid.

1 H NMR (DMSO d6 ): 12.56 (2H, m), 11.78 (1H, s), 7.72 (1H, ddd, J=5.8, 8.1, 8.8 Hz), 7.16 (1H, dt, J=1.4, 9.4 Hz), 4.46 (1H, quin, J=8.6 Hz), 4.16 (1H, dd, J=11.5, 9.3 Hz), 3.73 (1H, dd, J=11.6, 7.9 Hz), 3.41 (2H, s), 3.26 (1H, dd, J=15.8, 9.3 Hz), 2.86 (1H, dd, J=15.8, 8.1 Hz).

13 C NMR (DMSO d6 ): 170.7, 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 155.9, 155.9, 155.3, 132.5, 132.4, 129.6, 118.8, 118.7, 118.5, 113.8, 113.8, 113.7, 113.6, 113.4, 104.1, 104.1, 103.9, 103.9, 48.7, 35.6, 29.9, 29.2.

Example 13: (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic Acid

Compound was prepared analogous manner to Example 3 from (4R)-tert-butyl 4-(3-bromo-2,6-difluorophenyl)-2-(3-ethoxy-3-oxopropanoyl)pyrrolidine-1-carboxylate and isolated as a yellowish solid.

1 H NMR (DMSO d6 ): 12.56 (1H, br s), 11.78 (1H, s), 7.72 (1H, ddd, J=5.8, 8.1, 8.8 Hz), 7.17 (1H, dt, J=1.4, 9.6 Hz), 4.46 (1H, quin, J=8.6 Hz), 4.16 (1H, dd, J=11.4, 9.3 Hz), 3.73 (1H, dd, J=11.7, 8.0 Hz), 3.41 (2H, m), 3.26 (1H, dd, J=15.8, 9.4 Hz), 2.86 (1H, dd, J=15.8, 8.2 Hz).

13 C NMR (DMSO d6 ): 170.7, 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 155.9, 155.9, 155.3, 132.5, 132.4, 129.6, 118.8, 118.7, 118.5, 113.8, 113.8, 113.7, 113.6, 113.3, 104.1, 104.1, 103.9, 103.9, 48.7, 35.6, 29.9, 29.2.

Example 14: (R)-2-(6-(2,5-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic Acid

Compound was prepared analogous manner to Example 3 from (4R)-tert-butyl 4-(2,5-difluorophenyl)-2-(3-ethoxy-3-oxopropanoyl)pyrrolidine-1-carboxylate and isolated as a pale yellow solid.

1 H NMR (DMSO d6 ): 12.60 (1H, s br), 11.78 (1H, s), 7.32-7.26 (2H, m), 7.18 (1H, m), 4.22 (1H, quin, J=7.8 Hz), 4.14 (1H, dd, J=11.3, 7.9 Hz), 3.73 (1H, dd, J=11.3, 7.5 Hz), 3.40 (2H, m), 3.21 (1H, dd, J=15.5, 8.0 Hz), 2.86 (1H, dd, J=15.5, 7.8 Hz).

13 C NMR (DMSO d6 ): 170.8, 159.1, 159.1, 157.5, 157.5, 157.1, 157.1, 155.5, 155.5, 155.5, 130.1, 130.1, 130, 130, 129.5, 117.2, 117.1, 117, 116.9, 115.5, 115.4, 115.3, 115.3, 115.2, 115.1, 115.1, 113.8, 49.4, 40.3, 30, 29.5.

Example 15: (R)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic Acid

Compound was prepared analogous manner to Example 3 from (4R)-tert-butyl 4-(2,3,5,6-tetrafluorophenyl)-2-(3-ethoxy-3-oxopropanoyl)pyrrolidine-1-carboxylate and isolated as a light cream powder.

1 H NMR (DMSO d6 ): 12.58 (1H, br s), 11.80 (1H, s), 7.86 (1H, m), 4.50 (1H, quin, J=8.5 Hz), 4.18 (1H, dd, J=11.6, 9.2 Hz), 3.78 (1H, dd, J=11.7, 7.8 Hz), 3.41 (2H, s), 3.30 (1H, dd, J=15.9, 9.3 Hz), 2.91 (1H, dd, J=15.8, 8.1 Hz).

13 C NMR (DMSO d6 ): 170.7, 155.3, 146.4, 146.4, 146.4, 146.3, 146.3, 146.3, 146.2, 145.4, 145.3, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 144.8, 144.8, 144.7, 144.6, 144.6, 143.7, 143.7, 143.7, 143.7, 143.6, 143.6, 129.4, 120.5, 120.3, 120.2, 113.4, 105.9, 105.7, 105.6, 48.5, 35.7, 29.9, 29.1.

Example 16: (S)-2-(6-(5-bromo-2-fluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic Acid

Compound was prepared analogous manner to Example 3 from (4S)-tert-butyl 4-(5-bromo-2-fluorophenyl)-2-(3-ethoxy-3-oxopropanoyl)pyrrolidine-1-carboxylate and isolated as a yellow solid.

1 H NMR (DMSO d6 ): 12.58 (1H, br s), 11.76 (1H, br s), 7.59 (1H, dd, J=6.6, 2.5 Hz), 7.53 (1H, ddd, J=8.8, 4.5, 2.6 Hz), 7.23 (1H, dd, J=10.3, 8.8 Hz), 4.22 (1H, quin, J=7.9 Hz), 4.14 (1H, dd, J=11.2, 8.1 Hz), 3.74 (1H, dd, J=11.2, 7.5 Hz), 3.43 (2H, m), 3.21 (1H, dd, J=15.5, 8.1 Hz), 2.88 (1H, dd, J=15.4, 7.9 Hz).

13 C NMR (DMSO d6 ): 170.7, 160.3, 158.7, 155.5, 131.9, 131.8, 131.4, 131.4, 130.7, 130.6, 129.5, 118, 117.9, 116.5, 116.5, 113.7, 49.3, 40.4, 29.9, 29.4.

Example 17: (R)-2-(6-(5-chloro-2-fluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic Acid

Compound was prepared analogous manner to Example 3 from (4R)-tert-butyl 4-(5-chloro-2-fluorophenyl)-2-(3-ethoxy-3-oxopropanoyl)pyrrolidine-1-carboxylate and isolated as a pale yellow solid.

1 H NMR (DMSO d6 ): 12.54 (1H, m), 11.75 (1H, s), 7.47 (1H, dd, J=6.5, 2.6 Hz), 7.40 (1H, ddd, J=8.7, 4.3, 2.8 Hz), 7.29 (1H, dd, J=9.9, 8.9 Hz), 4.22 (1H, quin, J=7.8 Hz), 4.14 (1H, dd, J=11.2, 8.0 Hz), 3.74 (1H, dd, J=11.3, 7.5 Hz), 3.42 (2H, m), 3.22 (1H, dd, J=15.5, 8.1 Hz), 2.88 (1H, dd, J=15.6, 7.8 Hz).

13 C NMR (DMSO d6 ): 170.7, 159.8, 158.2, 155.5, 130.3, 130.2, 129.5, 128.9, 128.9, 128.6, 128.5, 128.5, 128.5, 117.6, 117.4, 113.7, 49.3, 40.4, 29.9, 29.4.

Example 18: (R)-2-(6-(2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic Acid

Compound was prepared analogous manner to Example 3 from (4R)-tert-butyl 4-(2,6-difluorophenyl)-2-(3-ethoxy-3-oxopropanoyl)pyrrolidine-1-carboxylate and isolated as a pale pink solid.

1 H NMR (DMSO d6 ): 12.55 (1H, br s), 11.76 (1H, s), 7.41 (1H, m), 7.13 (2H, m), 4.43 (1H, quin, J=8.8 Hz), 4.15 (1H, dd, J=10.6, 9.9 Hz), 3.72 (1H, dd, J=11.3, 8.4 Hz), 3.41 (2H, m), 3.24 (1H, dd, J=15.7, 9.2 Hz), 2.86 (1H, dd, J=15.7, 8.7 Hz).

13 C NMR (DMSO d6 ): 170.7, 161.6, 161.6, 160, 159.9, 155.3, 129.8, 129.7, 129.7, 116.5, 116.4, 113.3, 112.3, 112.2, 112.1, 112.1, 48.7, 35.3, 29.9, 29.3.

Example 19: (S)—N-cyano-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetamide

To a stirred suspension of (S)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid (Example 10) (0.035 g, 0.1 mmol) in acetonitrile (1 ml) was added 1-hydroxypyrrolidine-2,5-dione (0.012 g, 0.100 mmol) followed by addition of N,N′-methanediylidenedicyclohexanamine (0.021 g, 0.100 mmol). The reaction was stirred at room temperature for 1 h. The mixture was diluted with N,N-dimethylformamide (1 mL), whereupon cyanamide (4.20 mg, 0.100 mmol) was added followed by addition of N-ethyl-N-isopropylpropan-2-amine (0.017 ml, 0.100 mmol) and the mixture was stirred for 16 h at room temperature. Thereupon, the insoluble materials were filtered off, the filtrate was diluted with brine, acidified, and then extracted with dichloromethane. The organic phase was dried over MgSO 4 and then concentrated under reduced pressure. The product was crystallized on trituration with petroleum ether as a beige powder. (Yield: 0.015 g, 40%.)

1 H NMR (DMSO d6 ): 11.94 (1H, br), 11.79 (1H, s), 7.86 (1H, m), 4.50 (1H, quin, J=8.6 Hz), 4.19 (1H, dd, J=11.4, 9.4 Hz), 3.79 (1H, dd, J=11.7, 7.9 Hz), 3.56 (2H, br s), 3.30 (1H, br dd, J=16.0, 9.2 Hz), 2.92 (1H, dd, J=16.0, 8.1 Hz).

13 C NMR (DMSO d6 ): 169.8, 155.8, 146.4, 146.4, 146.4, 146.4, 146.3, 146.3, 146.3, 146.2, 145.4, 145.4, 145.3, 145.3, 145.3, 145.3, 145.2, 145.2, 144.8, 144.8, 144.7, 144.7, 144.6, 144.6, 143.8, 143.7, 143.7, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 130.4, 120.3, 120.2, 120.1, 111.7, 108.3, 105.9, 105.8, 105.6, 48.5, 35.8, 30.8, 29.1.

Example 20: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(methylsulfonyl)acetamide

To a stirred suspension of (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid (Example 12) (100 mg, 0.257 mmol)) in dry dichloromethane (3 mL) was added portionwise di(1H-imidazol-1-yl)methanone (45.8 mg, 0.283 mmol) at room temperature to give a clear solution. The mixture was stirred for 30 min, and then methanesulfonamide (26.9 mg, 0.283 mmol) was added followed by addition of 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (0.039 mL, 0.257 mmol) and the mixture was stirred at room temperature for 16 h. The mixture was poured onto 1 N HCl and extracted with ethyl acetate. The organic phase was washed with water and dried over MgSO 4 . The solvent was concentrated in vacuum, and then purified by chromatography in a mixture of dichloromethane-methanol (9:1). Recrystallization from a mixture of diethyl ether-isopropanol afforded (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)-N-(methylsulfonyl)acetamide as a brown solid. Yield: 30 mg, 22%.

1 H NMR (DMSO d6 ): 11.67 (1H, s), 7.72 (1H, ddd, J=5.8, 8.1, 8.8 Hz), 7.17 (1H, dt, J=1.4, 9.4 Hz), 4.43 (1H, quin, J=8.7 Hz), 4.14 (1H, dd, J=11.4, 9.3 Hz), 3.72 (1H, dd, J=11.6, 8.1 Hz), 3.25 (2H, s), 3.25 (1H, dd, J=9.5, 15.6 Hz), 2.95 (3H, s), 2.86 (1H, dd, J=15.9, 8.4 Hz).

13 C NMR (DMSO d6 ): 171, 160.9, 160.8, 159.2, 159.2, 157.6, 157.5, 155.9, 155.9, 154.8, 132.5, 132.4, 129.2, 118.8, 118.7, 118.5, 114.6, 113.8, 113.8, 113.7, 113.6, 104.1, 103.9, 48.5, 40.5, 35.7, 33.5, 29.5.

Example 21: (S)-2-(6-(5-bromo-2-fluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(methylsulfonyl)acetamide

Compound was prepare analogous manner to Example 20 from (S)-2-(6-(5-bromo-2-fluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as a yellow solid.

1 H NMR (DMSO d6 ): 1.90 (1H, br), 11.72 (1H, s), 7.60 (1H, dd, J=6.6, 2.2 Hz), 7.53 (1H, ddd, J=8.6, 4.4, 2.5 Hz), 7.23 (1H, dd, J=10.1, 9.0 Hz), 4.21 (1H, quin, J=7.9 Hz), 4.13 (1H, dd, J=11.1, 8.3 Hz), 3.73 (1H, dd, J=11.2, 7.7 Hz), 3.40 (2H, m), 3.21 (1H, br dd, J=15.4, 8.1 Hz), 3.12 (3H, s), 2.88 (1H, br dd, J=15.4, 8.1 Hz).

13 C NMR (DMSO d6 ): 169.5, 160.3, 158.7, 155.4, 131.9, 131.8, 131.4, 131.4, 130.7, 130.6, 129.7, 118, 117.9, 116.5, 113.5, 49.2, 40.8, 40.4, 32.4, 29.6.

Example 22: 2-((R)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2-oxotetrahydrofuran-3-yl)acetamide

A mixture of (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid (Example 13) (70 mg, 0.180 mmol), 3-aminodihydrofuran-2(3H)-one hydrobromide (32.7 mg, 0.180 mmol), 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine hydrochloride (34.5 mg, 0.180 mmol), N,N-dimethylpyridin-4-amine (24.17 mg, 0.198 mmol), N-ethyl-N-isopropylpropan-2-amine (0.041 mL, 0.234 mmol) in dry N,N dimethyl formamide (3 mL) was stirred for 3 h at room temperature. Thereupon, solvent was removed under reduced pressure and the residue was diluted with ethyl acetate. The mixture was washed with saturated aq. NaHCO 3 solution and brine, respectively. The organic phase was dried over MgSO 4 and then evaporated. Chromatography in a mixture of dichloromethane methanol (9:1) afforded the titled product as a yellow solid. Yield: 50 mg, 53%.

1 H NMR (DMSO d6 ): 11.80 (1H, s), 8.49 (1H, dd, J=7.8, 4.5 Hz), 7.73 (1H, ddd, J=5.8, 8.1, 8.8 Hz), 7.17 (1H, dt, J=1.4, 9.6 Hz), 4.57 (1H, dtd, J=10.6, 8.7, 8.7, 2.4 Hz), 4.44 (1H, d quin, J=8.7, 3.9 Hz), 4.34 (1H, dt, J=1.3, 9.0 Hz), 4.20 (1H, ddd, J=10.5, 8.7, 6.6 Hz), 4.15 (1H, dd, J=9.5, 11.3 Hz), 3.73 (1H, dd, J=11.5, 8.1 Hz), 3.31 (2H, t, J=5.9 Hz), 3.23 (1H, td, J=15.6, 9.4 Hz), 2.87 (1H, ddd, J=15.7, 10.7, 9.1 Hz), 2.39 (1H, m), 2.15 (1H, m).

13 C NMR (DMSO d6 ): 175.2, 167.8, 160.8, 160.8, 159.2, 159.2, 157.6, 157.5, 155.9, 155.9, 155.2, 132.5, 132.4, 129.5, 129.5, 118.7, 118.6, 118.6, 118.5, 118.4, 118.4, 113.8, 113.8, 113.7, 113.6, 113.6, 113.6, 104.1, 104.1, 103.9, 103.9, 65.3, 48.6, 48.5, 48.1, 35.7, 35.7, 31.2, 29.3, 28.2, 28.2.

Example 23: (R)—N-(methylsulfonyl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetamide

Step 1: (R)-1-(H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one

To a stirred suspension of (R)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid (Example 15) (1.8 g, 5.20 mmol) in dry dichloromethane (35 mL) was added di(1H-imidazol-1-yl)methanone (1.011 g, 6.24 mmol) portionwise at room temperature. The mixture was stirred for additional 30 min, the resulting solid was collected, washed with petroleum ether and dried on air to give (R)-1-(1H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone as a beige powder. Yield: 1.70 g, 83%.

Step 2: (R)—N-(methylsulfonyl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide

To a stirred suspension of methanesulfonamide (0.132 g, 1.388 mmol) and potassium tert-butoxide (0.142 g, 1.261 mmol) was added dry N,N-dimethyl formamide (1. mL) at room temperature. Thereupon, (R)-1-(H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone (0.5 g, 1.261 mmol) was added, and the stirring was continued for 30 min. The reaction mixture was evaporated to dryness and the residue was partitioned between ethyl acetate (50 mL) and 1M HCl (25 mL). The organic phase was dried over MgSO 4 , and then evaporated to dryness. The solid residue was slurried in ethyl acetate. The obtained solid was filtered, washed with ethyl acetate and diethyl ether, respectively, and then dried to, ether, dried to give (R)—N-(methylsulfonyl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetamide as a light brown powder. Yield: 0.28 g, 52%.

1 H NMR (DMSO d6 ): 1.93 (1H, br s), 11.83 (1H, s), 7.86 (1H, m), 4.50 (1H, quin, J=8.5 Hz), 4.19 (1H, dd, J=11.5, 9.3 Hz), 3.79 (1H, dd, J=11.6, 7.8 Hz), 3.49 (2H, m), 3.29 (1H, dd, J=15.9, 9.3 Hz), 3.24 (3H, m), 2.92 (1H, dd, J=8.2, 16.0 Hz).

13 C NMR (DMSO d6 ): 168.3, 155.6, 146.4, 146.4, 146.3, 146.3, 146.3, 146.2, 145.3, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 144.8, 144.8, 144.8, 144.7, 144.7, 144.6, 144.6, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 130, 120.4, 120.3, 120.2, 112.2, 105.9, 105.7, 105.6, 48.5, 41.1, 35.7, 31.5, 29.1.

Example 24: (R)-2-(6-(2,5-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(methylsulfonyl)acetamide

Compound was prepared analogous manner to Example 23 from (R)-2-(6-(2,5-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid (Example 14) and isolated as a yellow solid.

1 H NMR (DMSO d6 ): 1.93 (1H, br s), 11.78 (1H, s), 7.28 (2H, m), 7.18 (1H, m), 4.23 (1H, quin, J=7.8 Hz), 4.14 (1H, dd, J=11.2, 8.0 Hz), 3.74 (1H, dd, J=11.2, 7.6 Hz), 3.50 (2H, s), 3.25 (3H, s), 3.22 (1H, dd, J=15.6, 8.1 Hz), 2.87 (1H, br dd, J=15.6, 7.9 Hz).

13 C NMR (DMSO d6 ): 168.3, 159, 157.4, 157.1, 155.7, 155.5, 130.2, 130, 129.9, 129.9, 129.8, 117.1, 117.1, 117, 116.9, 115.5, 115.4, 115.3, 115.3, 115.3, 115.1, 115.1, 112.4, 49.3, 41.1, 40.2, 40, 31.5, 29.6.

Example 25: Ethyl (R)-(2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetyl)glycinate

To a stirred mixture of aminoacetic acid ethyl ester hydrochloride (0.070 g, 0.505 mmol) and triethylamine (0.07 mL, 0.505 mmol) in a mixture of dry tetrahydrofuran (2 mL) and dry N,N-dimethyl formamide (0.2 mL) was added (R)-1-(1H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone (Example 23 step 1) (0.1 g, 0.252 mmol). The reaction mixture was stirred for 30 min, and then diluted with ethyl acetate. The organic phase was washed with sodium bicarbonate solution and 1N HCl, respectively. After drying over MgSO 4 the solvent was removed under vacuum. Crystallization from diethyl ether afforded the titled compound as a light beige powder. Yield: 0.053 g, 49%.

1 H NMR (DMSO d6 ): 1.77 (1H, s), 8.38 (1H, t, J=5.9 Hz), 7.85 (1H, m), 4.48 (1H, quin, J=8.6 Hz), 4.17 (1H, dd, J=11.5, 9.2 Hz), 4.07 (2H, q, J=7.0 Hz), 3.82 (2H, d, J=5.9 Hz), 3.78 (1H, dd, J=11.6, 7.9 Hz), 3.32 (2H, m), 3.26 (1H, dd, J=15.9, 9.3 Hz), 2.90 (1H, dd, J=15.8, 8.2 Hz), 1.16 (3H, t, J=7.1 Hz).

13 C NMR (DMSO d6 ): 169.7, 168.2, 155.3, 146.4, 146.4, 146.4, 146.3, 146.3, 146.3, 146.2, 145.3, 145.3, 145.3, 145.2, 145.2, 144.8, 144.8, 144.7, 144.7, 144.6, 144.6, 143.7, 143.7, 143.7, 143.7, 143.7, 143.6, 143.6, 129.2, 120.3, 120.2, 120.1, 113.9, 105.9, 105.7, 105.6, 60.4, 48.4, 40.9, 35.8, 31.1, 29.2, 14.

Example 26: (S)-2-(2-((R)-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamido)propanamide

Compound was prepared analogous manner to Example 25 from (R)-1-(H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone (Example 23 step 1) and isolated as a beige powder.

1 H NMR (DMSO d6 ): 1.75 (1H, s), 8.14 (1H, d, J=7.5 Hz), 7.85 (1H, m), 7.34 (1H, br s), 7.02 (1H, br s), 4.48 (1H, quin, J=8.6 Hz), 4.17 (2H, m), 3.77 (1H, dd, J=11.6, 7.9 Hz), 3.30 (2H, s), 3.26 (1H, dd, J=15.9, 9.3 Hz), 2.88 (1H, dd, J=8.2, 15.9 Hz), 1.19 (3H, d, J=7.2 Hz).

13 C NMR (DMSO d6 ): 174.1, 167.3, 155.2, 146.4, 146.4, 146.4, 146.4, 146.3, 146.3, 146.3, 146.3, 146.2, 145.3, 145.3, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 144.8, 144.7, 144.7, 144.7, 144.7, 144.6, 144.6, 143.7, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 143.6, 129, 120.4, 120.3, 120.2, 114.4, 105.9, 105.7, 105.6, 48.4, 48.2, 35.8, 31.3, 29.2, 18.3.

Example 27: (R)—N-(cyanomethyl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 25 from (R)-1-(1H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone (Example 23 step 1) and isolated as a beige powder.

1 H NMR (DMSO d6 ): 1.82 (1H, s), 8.66 (1H, br t, J=5.4 Hz), 7.86 (1H, m), 4.49 (1H, quin, J=8.6 Hz), 4.18 (1H, dd, J=11.4, 9.3 Hz), 4.14 (2H, d, J=5.6 Hz), 3.79 (1H, dd, J=11.6, 7.9 Hz), 3.35 (2H, m), 3.26 (1H, br dd, J=15.8, 9.2 Hz), 2.90 (1H, m).

13 C NMR (DMSO d6 ): 168.5, 155.5, 146.4, 146.4, 146.3, 146.3, 146.3, 146.2, 145.4, 145.3, 145.3, 145.2, 145.2, 144.8, 144.8, 144.7, 144.7, 144.6, 144.6, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 129.5, 120.3, 120.2, 120.1, 117.6, 113.4, 105.9, 105.7, 105.6, 48.4, 35.8, 30.9, 29.1, 27.2.

Example 28: N-((1r,4R)-4-hydroxycyclohexyl)-2-((R)-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 25 from (R)-1-(1H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone (Example 23 step 1) and isolated as a brown powder.

1 H NMR (DMSO d6 ): 1.74 (1H, s), 7.85 (1H, m), 7.82 (1H, d, J=7.7 Hz), 4.48 (1H, quin, J=8.4 Hz), 4.17 (1H, dd, J=9.4, 11.6 Hz), 3.77 (1H, dd, J=7.8, 11.6 Hz), 3.43 (1H, m), 3.34 (1H, m), 3.24 (1H, br dd, J=15.9, 9.3 Hz), 3.20 (2H, s), 2.87 (1H, dd, J=7.8, 15.8 Hz), 1.77 (2H, m), 1.73 (2H, br m), 1.16 (4H, m).

13 C NMR (DMSO d6 ): 166.7, 155.1, 146.4, 146.3, 146.3, 146.3, 146.3, 146.2, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 144.8, 144.8, 144.7, 144.7, 144.7, 144.7, 144.6, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 143.5, 143.5, 128.7, 120.5, 120.4, 120.3, 114.5, 105.8, 105.7, 105.5, 68.1, 48.4, 47.4, 35.7, 33.9, 31.5, 30.2, 29.3.

Example 29: N-(2-hydroxycyclohexyl)-2-((R)-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 25 from (R)-1-(H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone (Example 23 step 1) and isolated as a brown powder.

1 H NMR (DMSO d6 ): 1.73 (1H, m), 7.84 (2H, m), 4.47 (1H, m), 4.17 (1H, m), 3.77 (1H, m), 3.36 (1H, m), 3.32-3.16 (4H, m), 2.89 (1H, m), 2.07-1.0 (8H, several multiplets).

13 C NMR (DMSO d6 ): 167.2, 167.2, 155.1, 146.4, 146.3, 146.2, 145.3, 145.2, 145.2, 145.2, 144.8, 144.8, 144.7, 144.6, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 128.8, 120.5, 120.4, 120.3, 120.3, 120.2, 114.7, 105.9, 105.7, 105.5, 71.1, 54.5, 48.4, 35.7, 33.9, 31.8, 31.7, 30.9, 29.3, 29.2, 24.1, 23.8.

Example 30: (R)—N,N-dimethyl-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 25 from (R)-1-(H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone (Example 23 step 1) and isolated as a light khaki powder.

1 H NMR (DMSO d6 ): 1.70 (1H, s), 7.84 (1H, m), 4.49 (1H, quin, J=8.5 Hz), 4.18 (1H, dd, J=11.6, 9.2 Hz), 3.77 (1H, dd, J=11.7, 7.8 Hz), 3.48 (2H, s), 3.23 (1H, dd, J=15.8, 9.4 Hz), 2.98 (3H, s), 2.86 (1H, dd, J=15.8, 8.1 Hz), 2.82 (3H, s).

13 C NMR (DMSO d6 ): 167.9, 155.1, 146.4, 146.4, 146.4, 146.3, 146.3, 146.3, 146.3, 146.2, 145.4, 145.3, 145.3, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 144.8, 144.8, 144.8, 144.7, 144.7, 144.7, 144.6, 143.7, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 129, 120.5, 120.4, 120.3, 114.4, 105.9, 105.7, 105.6, 48.5, 37, 35.8, 35.1, 29.2, 29.1.

Example 31: (S)-2-amino-3-(2-((R)-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetamido)propanoic acid

To a solution of (S)-2-((tert-butoxycarbonyl)amino)-3-(2-((R)-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetamido)propanoic acid (prepared analogous manner to Example 25 from (R)-1-(H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone (Example 23 step 1)) (0.3 g, 0.563 mmol) in tetrahydrofuran (4 mL) was added cc. HCl (1.17 ml, 14.08 mmol) at room temperature and the solution was stirred for 4 h. Thereupon, the solvent was removed under vacuum, the residue was taken up in water (ca. 10 mL) and then the resultant dark insoluble material was filtered off. The filtrate was neutralized to pH 7 by addition of 5 M NaOH, and then aged in ice for 30 min. The precipitate was collected, washed with minimum volume of water and dried in vacuum at 50° C. The crude product was re-slurried in acetone, and then dried to give (S)-2-amino-3-(2-((R)-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetamido)propanoic acid as a beige powder. Yield: 0.11 g, 45%.

1 H NMR (DMSO d6 ): 10.4-6.5 (4H, br), 8.31 (1H, br s), 7.84 (1H, m), 4.48 (1H, quin, J=8.6 Hz), 4.17 (1H, br dd, J=11.1, 9.5 Hz), 3.77 (1H, br dd, J=11.7, 8.0 Hz), 3.54 (1H, m), 3.35 (1H, m), 3.32 (1H, m), 3.31 (2H, m), 3.29 (1H, m), 2.91 (1H, br dd, J=15.7, 8.2 Hz).

13 C NMR (DMSO d6 ): 168.8, 168.5, 155.2, 146.4, 146.4, 146.3, 146.3, 146.2, 146.2, 145.4, 145.3, 145.3, 145.3, 145.3, 145.2, 145.2, 144.8, 144.8, 144.7, 144.7, 144.7, 144.6, 143.7, 143.7, 143.7, 143.7, 143.6, 143.6, 129.2, 120.3, 120.2, 120.1, 114.3, 105.9, 105.7, 105.6, 54.1, 48.4, 40.3, 35.8, 31.5, 29.1.

Example 32: ((R)—N-cyclopentyl-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetamide

To a stirred solution of aminocyclopentane (0.05 mL, 0.505 mmol) in dry tetrahydrofuran (2 mL) was added (R)-1-(H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone (Example 23 step 1) (0.1 g, 0.252 mmol). The reaction was stirred 30 min. at room temperature. Thereupon, the mixture was diluted with ethyl acetate (ca. 10 mL), washed with a solution of sodium bicarbonate, 1 M HCl, respectively. The organic phase was dried over MgSO 4 , filtered and evaporated to dryness. Crystallization from a mixture of diethyl ether-petroleum ether afforded (R)—N-cyclopentyl-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetamide as a beige powder. Yield: 0.064 g, 61%.

1 H NMR (DMSO d6 ): 1.74 (1H, br s), 7.93 (1H, br d, J=7.0 Hz), 7.85 (1H, m), 4.48 (1H, quin, J=8.5 Hz), 4.17 (1H, dd, J=11.4, 9.3 Hz), 3.96 (1H, sxt, J=6.8 Hz), 3.77 (1H, dd, J=11.7, 7.8 Hz), 3.25 (1H, br dd, J=15.8, 9.2 Hz), 3.21 (2H, s), 2.87 (1H, dd, J=15.8, 7.9 Hz), 1.77 (2H, m), 1.61 (2H, m), 1.48 (2H, m), 1.35 (2H, dq, J=12.7, 6.6 Hz).

13 C NMR (DMSO d6 ): 166.9, 155.1, 146.4, 146.3, 146.3, 145.3, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 144.8, 144.8, 144.7, 144.7, 144.6, 144.6, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 143.6, 128.8, 120.5, 120.4, 120.3, 114.6, 105.9, 105.7, 105.5, 50.5, 48.4, 35.7, 32.2, 32.2, 31.5, 29.3, 23.4.

Example 33: 2-((5aS,6aR)-5a-(3,5-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetamide

Step 1: tert-butyl (1S,5R)-4-(3-((tert-butoxycarbonyl)amino)-3-oxopropanoyl)-1-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

A solution of tert-butyl (1S,5R)-1-(3,5-difluorophenyl)-4-((2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)(hydroxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.0 g, 2.148 mmol) (Example 1 Step 10) and tert-butyl carbamate (0.252 g, 2.148 mmol) in acetonitrile (20 mL) was stirred under reflux for 3 h. The mixture was then evaporated to dryness and chromatographed twice (dichloromethane-methanol, and then petroleum ether-ethyl acetate). The product was isolated as a light yellow oil. (Yield: 0.33 g, 27%).

Step 2:3-((1R,5S)-5-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hexan-2-yl)-3-oxopropanamide hydrochloride

A solution of tert-butyl (1S,5R)-4-(3-((tert-butoxycarbonyl)amino)-3-oxopropanoyl)-1-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.33 g, 0.687 mmol) in 4 M HCl (1.37 mL, 5.49 mmol) in dioxane was stirred at room temperature for 4 h. The resulting precipitate was filtered off, washed with diethyl ether and dried under vacuum to give the product as a white solid. (Yield: 0.125 g, 52%).

Step 3: 2-((5aS,6aR)-5a-(3,5-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetamide)

A solution of 3-((1R,5S)-5-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hexan-2-yl)-3-oxopropanamide hydrochloride (0.117 g, 0.369 mmol), potassium thiocyanate (0.0395 g, 0.406 mmol) and 6 M HCl (0.015 mL, 0.185 mmol) in a mixture of ethanol (1.5 mL) and water (1.5 mL) was stirred under reflux for 2 h. Thereupon, the mixture was cooled to room temperature and ethanol was evaporated. The residue was partitioned between water and dichloromethane and then the organic phase was dried over MgSO 4 , filtered and evaporated. Chromatography in a mixture of dichloromethane-methanol afforded the titled product as a light yellow solid.

Yield: 0.031 g, 25%.

1 H NMR (DMSO d6 ): 1.63 (1H, s), 7.36 (1H, br s), 7.10 (3H, m), 7.05 (1H, br s), 4.18 (1H, d, J=12.2 Hz), 4.03 (1H, d, J=12.2 Hz), 3.25 (2H, m), 2.93 (1H, dd, J=8.4, 4.3 Hz), 1.67 (1H, dd, J=8.2, 5.3 Hz), 1.20 (1H, t, J=4.8 Hz).

13 C NMR (DMSO d6 ): 169.9, 163.4, 163.3, 161.8, 161.7, 156.1, 145, 144.9, 144.9, 131.9, 113.7, 110, 110, 109.9, 109.8, 102.3, 102.1, 101.9, 50.8, 36.1, 31.2, 25.1, 23.

Example 34: 2-((S)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2-oxocyclopentyl)acetamide

To a stirred suspension of (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid (Example 12) (100 mg, 0.257 mmol) in dry tetrahydrofuran (2 mL) was added di(1H-imidazol-1-yl)methanone (50 mg, 0.308 mmol) and the mixture was stirred for 1 h. Thereupon, 2-aminocyclopentanone hydrochloride (77 mg, 0.565 mmol) and the reaction mixture was stirred for additional 1 h. The mixture was then diluted with ethyl acetate (5 mL), washed with 1 M HCl solution. The organic phase was dried (MgSO 4 ), filtered and stripped down to dryness under vacuum. The crude product was purified by chromatography in a mixture of dichloromethane-methanol (9:1). The thus obtained oil was crystalized by trituration in n-heptane (light brown powder). Yield: 68 mg, 56%.

1 H NMR (DMSO d6 ): 11.78 (1H, s), 8.18, 8.17 (1H, 2 d, J=3.4 Hz), 7.73 (1H, m), 7.17 (1H, m), 4.43 (1H, m), 4.15 (1H, dd, J=9.5, 11.3 Hz), 4.03 (1H, m), 3.73 (1H, dd, J=11.5, 8.1 Hz), 3.28 (2H, t, J=5.1 Hz), 3.22 (1H, m), 2.86 (1H, m), 2.24 (1H, 2 m), 2.18-2.04 (2H, m), 1.91 (1H, m), 1.81-1.66 (2H, m).

13 C NMR (DMSO d6 ): 214.8, 214.8, 167.5, 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 155.9, 155.9, 155.1, 132.5, 132.4, 129.3, 129.2, 118.7, 118.7, 118.6, 118.5, 118.5, 118.4, 113.9, 113.9, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 56.3, 48.5, 35.7, 35.6, 35.5, 31.2, 29.3, 28.7, 28.7, 17.9.

Example 35: (5aS,6aR)-1-(2-aminoethyl)-5a-(3,5-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione Hydrochloride

To a stirred solution of 2-((5aS,6aR)-5a-(3,5-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetamide (Example 33) (52 mg, 0.162 mmol) in dry tetrahydrofuran (1 mL), was added sodium borohydride (0.032 g, 0.809 mmol) at room temperature, and then the mixture was cooled to 0° C. A solution of boron trifluoride diethyl etherate (0.103 ml, 0.809 mmol) in dry tetrahydrofuran (0.5 ml) was added dropwise to the above mixture, whereupon the reaction was allowed to warm up to room temperature and stirred for 2 h. Thereupon, the reaction was cooled again to 0° C. and quenched with 1 M HCl (˜0.3 mL), followed by addition of 2 M HCl (˜0.2 mL, to pH=1). The mixture was then allowed to warm up to room temperature and heated at reflux for 30 min. Thereupon, the mixture was cooled to room temperature, diluted with water, and then tetrahydrofuran was evaporated off. The aqueous phase was extracted with dichloromethane, whereupon, the organic phase was dried over MgSO 4 , filtered and evaporated to dryness to give the product as a yellow solid. Yield: 0.037 g, 60%).

1 H NMR (DMSO d6 ): 11.78 (1H, s), 7.77 (3H, br s), 7.13 (1H, tt, J=2.3, 9.3 Hz), 7.11 (2H, m), 4.19 (1H, d, J=12.2 Hz), 4.00 (1H, d, J=12.2 Hz), 3.05 (2H, m), 2.97 (1H, dd, J=8.2, 4.4 Hz), 2.71 (2H, m), 1.69 (1H, dd, J=8.3, 5.2 Hz), 1.24 (1H, t, J=4.8 Hz).

13 C NMR (DMSO d6 ): 163.4, 163.3, 161.8, 161.7, 156.8, 144.9, 144.8, 144.8, 132.1, 114.1, 110.2, 110.1, 110, 110, 102.4, 102.2, 102, 50.8, 37.5, 36.3, 24.9, 22.5, 22.4.

Example 36: 2-((5aS,6aR)-5a-(2,5-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetonitrile

Step 1: (1S,5R)-tert-butyl 4-(2-cyanoacetyl)-1-(2,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a cooled mixture (−78° C.) of acetonitrile (0.357 ml, 6.79 mmol) and dry tetrahydrofuran (10 mL) was added 1.6 N n-butyllithium (6.19 ml, 9.90 mmol) dropwise. The mixture was stirred in the cold for 30 min., and then a solution of (1R,5S)-3-tert-butyl 2-methyl 5-(2,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (2 g, 5.66 mmol) (Example 4, step 1) in anhydrous tetrahydrofuran (5 mL) was added, dropwise. The reaction mixture was stirred in the cold for 3 h, and then quenched by addition of 1 M HCl (9.90 ml, 9.90 mmol. Thereupon, the mixture was and allowed to warm up to room temperature and the pH of the mixture was adjusted to 3 by addition of 1 M HCl. The mixture was then partitioned between diethyl ether and brine, the organic phase was separated, dried over MgSO 4 , filtered and evaporated to dryness. The resulting yellow oil was purified by chromatography (petroleum ether-ethyl acetate; 9:1, 4:1, then 2:1). (Yield: 1.31 g, 57%).

Step 2:3-((1R,5S)-5-(2,5-difluorophenyl)-3-azabicyclo[3.1.0]hexan-2-yl)-3-oxopropanenitrile hydrochloride

A mixture of (1S,5R)-tert-butyl 4-(2-cyanoacetyl)-1-(2,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.3 g, 3.59 mmol) and a solution of 4 M HCl in dioxane (17.94 mL, 71.7 mmol) was stirred at room temperature for 4 h. Diethyl ether was then added and the mixture was stirred for 15 min. The resulting yellow solid was filtered off and dried under vacuum. (Yield: 0.96 g, 81%).

Step 3: 2-((5aS,6aR)-5a-(2,5-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetonitrile

To a solution of 3-((1R,5S)-5-(2,5-difluorophenyl)-3-azabicyclo[3.1.0]hexan-2-yl)-3-oxopropanenitrile hydrochloride (950 mg, 3.18 mmol) in a mixture of ethanol (13 mL) and water (13 mL) was added potassium thiocyanate (340 mg, 3.50 mmol) followed by addition of cc HCl (0.131 ml, 1.590 mmol). The solution was heated at reflux for 1 h. and then cooled to room temperature. Thereupon, ethanol was evaporated off, and the aqueous phase was extracted with dichloromethane. The organic phase was separated and evaporated to dryness. Chromatography (dichloromethane-methanol (98:2, then 95:5) afforded the product as a yellow foam. (Yield: 0.35 g, 32%).

1 H NMR (DMSO d6 ): 12.06 (1H, s), 7.29 (2H, m), 7.22 (1H, m), 4.10 (1H, d, J=12.0 Hz), 3.91 (2H, m), 3.82 (1H, d, J=12.0 Hz), 2.90 (1H, dd, J=8.4, 4.3 Hz), 1.72 (1H, dd, J=8.4, 5.5 Hz), 1.23 (1H, t, J=4.8 Hz).

13 C NMR (DMSO d6 ): 158.8, 158.6, 157.4, 157.2, 157, 132.5, 128.3, 128.3, 128.2, 128.2, 117.2, 117.1, 117.1, 117, 117, 117, 116.1, 116, 115.9, 115.9, 108.8, 51.6, 51.6, 32.7, 21.9, 20.5, 13.4.

Example 37: N-benzyl-2-((5aS,6aR)-5a-(2,5-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-methylacetamide

Step 1: (1S,5R)-tert-butyl 1-(2,5-difluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a stirred mixture of ethyl potassium malonate (3.39 g, 19.89 mmol) in dry tetrahydrofuran (43 mL) was added magnesium bromide diethyl etherate (3.42 g, 13.26 mmol), at room temperature under inert atmosphere, and then the thus obtained white suspension was heated at 50° C. for 3 h (1 st mixture).

In parallel, 1,1′-carbonyldiimidazole (3.66 g, 22.54 mmol) was added, in portions to a light yellow solution of (1R,5S)-3-(tert-butoxycarbonyl)-5-(2,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (Example 4 step 1) (4.5 g, 13.26 mmol) in dry tetrahydrofuran (35 mL) at 0° C., under nitrogen. The thus obtained yellow solution was allowed to warm up to room temperature, stirred for 2 h, and then added to the 1 st suspension at room temperature dropwise. Thereupon, the reaction was stirred at room temperature for 24 h, and the mixture was quenched with sodium hydrogen sulfate. The aqueous phase was extracted with a mixture of ethyl acetate-petroleum ether (2:1). The combined organic phases were washed with saturated solution of sodium bicarbonate, dried over MgSO 4 , filtered and evaporated to dryness. Chromatography (ethyl acetate-petroleum ether; 9:1, then 4:1) gave the product as a light oil. (Yield: 3.52 g, 61%).

Step 2: (1S,5R)-tert-butyl 4-(3-(benzyl(methyl)amino)-3-oxopropanoyl)-1-(2,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a stirred solution of (1S,5R)-tert-butyl 1-(2,5-difluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (1 g, 2.442 mmol) in toluene (4 mL) was added N-methylbenzylamine (0.63 ml, 4.88 mmol) followed by addition of N,N-dimethylpyridin-4-amine (0.090 g, 0.733 mmol) at room temperature. The solution was heated at 100° C. for 20 h, whereupon cooled to room temperature, diluted with a mixture of ethyl acetate-petroleum ether (1:1) and washed with 1M HCl. The organic phase was dried over MgSO 4 , filtered and evaporated to dryness. The thus obtained yellow oil was purified by chromatography (petroleum ether-ethyl acetate; 4:1, then 2:1) to leave the product as a yellow oil. (Yield: 0.88 g, 67%).

Step 3: N-benzyl-3-((1R,5S)-5-(2,5-difluorophenyl)-3-azabicyclo[3.1.0]hexan-2-yl)-N-methyl-3-oxopropanamide Hydrochloride

A mixture of (1S,5R)-tert-butyl 4-(3-(benzyl(methyl)amino)-3-oxopropanoyl)-1-(2,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (870 mg, 1.796 mmol) and 4 M HCl in dioxane (6.7 mL, 26.9 mmol) was stirred at room temperature for 2 h. Diethyl ether was then added and the suspension was stirred for 15 min. The resulting off-white precipitate was filtered and dried under vacuum. (Yield: 0.57 g, 67%).

Step 4: N-benzyl-2-((5aS,6aR)-5a-(2,5-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-methylacetamide

To a stirred solution of N-benzyl-3-((1R,5S)-5-(2,5-difluorophenyl)-3-azabicyclo[3.1.0]hexan-2-yl)-N-methyl-3-oxopropanamide hydrochloride (556 mg, 1.321 mmol) in a mixture of ethanol (5.4 mL) and water (5.4 mL) was added potassium thiocyanate (0.141 mg, 1.453 mmol) followed by addition of cc. HCl (0.054 mL, 0.661 mmol). The solution was heated at reflux for 1 h, and then cooled to room temperature. Thereupon, ethanol was evaporated off and the aqueous phase was extracted with dichloromethane. The organic phase was then dried over MgSO 4 , filtered and evaporated to dryness to give the product as a light yellow semi-solid. (Yield: 0.17 g, 29%).

1 H NMR (DMSO d6 ): 11.70 (0.65H, s), 1.68 (0.35H, s), 7.38 (0.7H, t, J=7.8 Hz), 7.34-7.17 (7.3H, m), 4.64 (0.7H, s), 4.53 (1.3H, m), 4.09, 4.08 (1H, 2 d, J=12 Hz), 3.81, 3.79 (1H, 2 d, J=12 Hz), 3.69-3.58 (2H, m), 2.98 (1.95H, s), 2.81 (1.05H, s), 2.76 (0.35H, dd, J=8.4, 4.3 Hz), 2.72 (0.65H, dd, J=8.3, 4.2 Hz), 1.63 (1H, m), 1.11 (0.65H, t, J=4.8 Hz), 1.09 (0.35H, t, J=4.8 Hz).

13 C NMR (DMSO d6 ): 168.3, 158.8, 158.6, 157.2, 157, 155.9, 137.5, 137.1, 131.8, 131.7, 128.7, 128.7, 128.6, 128.5, 128.5, 128.4, 127.7, 127.3, 127.1, 126.8, 117.2, 117.1, 117, 117, 117, 116.9, 116.8, 116.8, 116.8, 115.9, 115.9, 115.8, 115.7, 113.9, 52.6, 51.5, 50.2, 35, 33.

Example 38: N-butyl-2-((5aS,6aR)-5a-(2,5-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-methylacetamide

Compound was prepare analogous manner to Example 37 from (1R,5S)-3-(tert-butoxycarbonyl)-5-(2,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid and isolated as a light yellow foam.

1 H NMR (DMSO d6 ): 11.62 (1H, 2 s), 7.29 (1H, td, J=9.4, 4.6 Hz), 7.25 (1H, ddd, J=9.1, 5.9, 3.2 Hz), 7.20 (1H, m), 4.08 (1H, d, J=11.9 Hz), 3.81 (1H, d, J=12.2 Hz), 3.53 (2H, m), 3.29 (2H, m), 2.99 (1.65H, s), 2.82 (1.35H, s), 2.79, 2.78 (1H, 2 dd, J=8.3, 4.1 Hz), 1.65 (1H, dd, J=8.4, 5.3 Hz), 1.52 (0.9H, m), 1.43 (1.1H, m), 1.30 (0.9H, m), 1.24 (1.1H, m), 1.11 (1H, m), 0.92 (1.35H, t, J=7.4 Hz), 0.87 (1.65H, t, J=7.3 Hz).

13 C NMR (DMSO d6 ): 167.7, 167.6, 158.8, 158.6, 157.2, 157, 155.8, 131.7, 131.6, 128.7, 128.6, 128.6, 128.5, 117.2, 117.1, 117, 117, 116.8, 115.9, 115.9, 115.8, 115.7, 114.1, 114, 51.5, 49.1, 46.8, 35.1, 33.2, 32.4, 30, 29.5, 28.9, 28.9, 22.3, 22.2, 20.9, 20.8, 19.5, 19.4, 1.

Example 39: (5aS,6aR)-1-(2-(butyl(methyl)amino)ethyl)-5a-(2,5-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione Hydrochloride

Compound was prepared analogous manner to Example 35 from N-butyl-2-((5aS,6aR)-5a-(2,5-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-methylacetamide (Example 37) and isolated as a light yellow solid.

1 H NMR (DMSO d6 ): 11.81 (1H, br s), 9.25 (1H, br s), 7.30 (1H, m), 7.27 (1H, m), 7.22 (1H, m), 4.08 (1H, br d, J=12.2 Hz), 3.81 (1H, d, J=12.0 Hz), 3.17 (2H, br m), 2.95 (2H, m), 2.93 (1H, dd, J=8.2, 4.2 Hz), 2.81 (2H, br m), 2.69 (3H, br s), 1.67 (1H, br dd, J=8.2, 5.3 Hz), 1.57 (2H, br m), 1.31 (2H, dq, J=14.9, 7.4 Hz), 1.18 (1H, br t, J=4.7 Hz), 0.91 (3H, t, J=7.3 Hz).

13 C NMR (DMSO d6 ): 158.8, 158.7, 157.2, 157.1, 156.5, 131.6, 128.6, 128.5, 128.5, 128.4, 117.2, 117.2, 117.1, 117, 117, 116.8, 116, 116, 115.9, 115.8, 55.1, 53.5, 51.5, 39.8, 32.6, 26, 22.2, 20.5, 19.8, 19.5, 13.6.

Example 40: (5aS,6aR)-1-(2-(benzyl(methyl)amino)ethyl)-5a-(2,5-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione

Compound was prepared analogous manner to Example 35 from N-benzyl-2-((5aS,6aR)-5a-(2,5-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-methylacetamide (Example 37) and isolated as a white foam.

1 H NMR (CDCl 3 ): 10.33 (1H, br s), 7.37 (2H, t, J=7.3 Hz), 7.33 (2H, t, J=8.5 Hz), 7.29 (1H, t, J=7.3 Hz), 7.05 (1H, td, J=9.1, 4.5 Hz), 7.00-6.93 (2H, m), 4.25 (1H, d, J=12.2 Hz), 4.03 (1H, d, J=12.3 Hz), 3.57 (2H, m), 2.67 (4H, m), 2.51 (1H, dd, J=8.2, 4.1 Hz), 2.28 (3H, s), 1.58 (1H, dd, J=8.2, 5.5 Hz), 1.12 (1H, m).

13 C NMR (CDCl 3 ): 159.3, 158.9, 157.6, 157.2, 155.8, 137.5, 130.3, 129.4, 128.6, 128.1, 128.1, 128, 128, 127.5, 119.3, 117.1, 117, 116.9, 116.8, 116.7, 116.7, 116.5, 116.5, 116, 115.9, 115.8, 115.8, 62.8, 55.8, 52.1, 52.1, 41.5, 32.7, 22.3, 21.2, 20.9.

Example 41: (5aS,6aR)-1-((1H-tetrazol-5-yl)methyl)-5a-(2,5-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione

To a stirred solution of 2-((5aS,6aR)-5a-(2,5-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetonitrile (Example 36) (50 mg, 0.165 mmol) in dry toluene (1 mL) was added dibutyltin oxide (41.0 mg, 0.165 mmol) followed by addition of azidotrimethylsilane (0.044 mL, 0.330 mmol). The reaction mixture was heated at 100° C. for 24 h. The mixture was then cooled to room temperature, partitioned between diethyl ether and 1 M sodium hydroxide (1.6 mL) and the aqueous phase was washed with diethyl ether. The ethereal phase was discarded and the aqueous phase was acidified with 2 M HCl to pH=1. The resulting solid was collected by filtration, washed with water and dried under vacuum. (Yield: 25 mg, 37%).

1 H NMR (DMSO d6 ): 11.85 (1H, s), 7.29 (1H, td, J=9.4, 4.5 Hz), 7.25 (1H, ddd, J=9.0, 5.9, 3.2 Hz), 7.21 (1H, m), 4.18 (2H, m), 4.10 (1H, br d, J=12.0 Hz), 3.80 (1H, br d, J=5.7 Hz), 2.69 (1H, dd, J=8.3, 4.2 Hz), 1.63 (1H, dd, J=8.4, 5.3 Hz), 1.20 (1H, t, J=4.8 Hz).

13 C NMR (DMSO d6 ): 158.8, 158.6, 157.2, 157, 156.8, 153.1, 132.4, 128.5, 117.2, 116.9, 115.9, 51.6, 32.6, 22, 20.5, 19.3.

Example 42: (5aS,6aR)-5a-(2,5-difluorophenyl)-1-(2-hydroxyethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione

Compound was prepared analogous manner to Example 8 from ethyl 2-((5aS,6aR)-5a-(2,5-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetate and isolated as a yellow solid.

1 H NMR (DMSO d6 ): 11.65 (1H, br s), 7.28 (2H, m), 7.20 (1H, m), 4.75 (1H, t, J=5.3 Hz), 4.06 (1H, br d, J=12.0 Hz), 3.79 (1H, d, J=12.0 Hz), 3.60 (2H, m), 2.88 (1H, dd, J=8.2, 4.1 Hz), 2.55 (2H, m), 1.61 (1H, dd, J=8.1, 5.4 Hz), 1.14 (1H, t, J=4.7 Hz).

13 C NMR (DMSO d6 ): 158.8, 158.6, 157.2, 157, 155.7, 130.9, 128.9, 128.8, 128.7, 128.7, 117.2, 117.1, 117, 117, 116.9, 116.9, 116.8, 116.7, 116.7, 115.9, 115.8, 115.7, 115.6, 59.4, 51.4, 51.4, 32.4, 28, 22.5, 20.6.

Example 43: (S)-6-(3,5-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazole-1-carboxylic Acid

To a stirred solution of (4S)-1-(tert-butoxycarbonyl)-4-(3,5-difluorophenyl)pyrrolidine-2-carboxylic acid (Example 44, step 9) (1.4 g, 4.28 mmol) in isopropyl acetate (7 mL) was added sodium borohydride (0.259 g, 6.84 mmol) at 0-5° C. followed by addition of boron trifluoride etharate (1.084 mL, 8.55 mmol. The mixture was stirred for 2 h in the cold, then quenched with 0.5 M sodium hydroxide (30.8 mL, 15.4 mmol), and allowed to stir at room temperature for 30 min. The organic phase was separated, dried over MgSO 4 , evaporated to dryness to leave a yellowish oil. Yield: 1.37 g, 97%).

To a stirred solution of (4S)-tert-butyl 4-(3,5-difluorophenyl)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (0.46 g, 1.468 mmol) in dry dichloromethane (14 mL) was added Dess-Martin periodinane (3-oxo-1-benzo[d][1,2]iodaoxole-1,1,1(3H)-triyl triacetate) (0.623 g, 1.468 mmol) in one portion to give a clear solution. Thereupon, the mixture was stirred at room temperature for 3 h, concentrated to approximately one third and subjected to chromatography (petroleum ether-ethyl acetate 9:1, then 4:1). The product was isolated as yellowish oil. (Yield: 1.21 g, 94%).

To a stirred solution of (4S)-tert-butyl 4-(3,5-difluorophenyl)-2-formylpyrrolidine-1-carboxylate (1.2 g, 3.85 mmol) in a mixture of tetrahydrofuran (10 mL) and water (5 mL) was added potassium cyanide (0.301 g, 4.63 mmol) followed by addition of cc HCl (0.319 ml, 3.85 mmol). The mixture was stirred for 8 h, then extracted with dichloromethane. The organic phase was washed with brine, dried over MgSO 4 and evaporated to dryness to give (4S)-tert-butyl 2-(cyano(hydroxy)methyl)-4-(3,5-difluorophenyl)pyrrolidine-1-carboxylate as a yellowish oil. (Yield: 1.44 g, 99%).

Step 4: (4S)-tert-butyl 4-(3,5-difluorophenyl)-2-(2-ethoxy-1-hydroxy-2-oxoethyl)pyrrolidine-1-carboxylate

A mixture of (4S)-tert-butyl 2-(cyano(hydroxy)methyl)-4-(3,5-difluorophenyl)pyrrolidine-1-carboxylate (1.43 g, 3.80 mmol) and 2 M HCl (28.5 ml, 57.1 mmol) was stirred under reflux for 16 h. After cooling to room temperature the mixture was filtered through a celite plug to remove insoluble coloured stuff and then the filtrate was evaporated to dryness under vacuum. The residue was azeotroped twice with dry ethanol and the residue was taken up in abs. ethanol (20 mL). The thus obtained solution was treated with 4 M HCl (9.51 ml, 38.0 mmol) in dioxane and stirred under reflux for 2 h. The mixture was evaporated to dryness, and then azeotroped with abs. ethanol. The resulting semisolid was taken up in abs. ethanol (30 mL), neutralized by addition of triethylamine to pH=6-7, then a second crop of triethylamine (0.530 ml, 3.80 mmol) was added followed by addition of di-tert-butyl dicarbonate (0.830 g, 3.80 mmol). The reaction was allowed to stir at room temperature for 2 h, and then evaporated to dryness at 40° C. The residue was partitioned between dichloromethane and water, the organic phase was dried over MgSO 4 and concentrated under reduced pressure. Chromatography (petroleum ether-ethyl acetate; 9:1, then 4:1) gave the product as a yellow oil. (Yield: 1.16 g, 79%).

To a stirred solution of (4S)-tert-butyl 4-(3,5-difluorophenyl)-2-(2-ethoxy-1-hydroxy-2-oxoethyl)pyrrolidine-1-carboxylate (1.15 g, 2.98 mmol) in dry dichloromethane (25 mL) was added Dess-Martin periodinane (3-oxo-1λ 5 -benzo[d][1,2]iodaoxole-1,1,1(3H)-triyl triacetate) (1.266 g, 2.98 mmol) at room temperature in one portion and the mixture was stirred for 2 h. The reaction mixture was concentrated under vacuum, whereupon the reside was purified by chromatography (petroleum ether-ethyl acetate; 4:1). The product was isolated as a yellowish oil. (1.08 g, 94% yield).

To a stirred solution of (4S)-tert-butyl 4-(3,5-difluorophenyl)-2-(2-ethoxy-2-oxoacetyl)pyrrolidine-1-carboxylate (0.4 g, 1.043 mmol) in 4 M HCl (5.22 mL, 20.87 mmol) in dioxane was stirred at room temperature for 4 h. The reaction mixture was diluted with a mixture of diethyl ether (20 mL) and petroleum ether (5 mL) and stirred for 30 min, Thereupon, the resulting precipitate was collected, washed with diethyl ether, petroleum ether and dried under vacuum at 50° C. to give ethyl 2-((4S)-4-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-oxoacetate hydrochloride as a white powder. (Yield: 0.34 g, 92%).

Step 7: (S)-ethyl 6-(3,5-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazole-1-carboxylate

A solution of ethyl 2-((4S)-4-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-oxoacetate hydrochloride (0.33 g, 1.032 mmol), 6 M HCl (0.086 ml, 0.516 mmol) and potassium thiocyanate (0.110 g, 1.135 mmol) in a mixture of ethanol (5 mL) and water (5 mL) was stirred under reflux for 30 min. The reaction was then cooled to room temperature, and the resulting solid was collected, washed with a mixture of ethanol and water (1:1), and dried under vacuum at 50° C. to give (S)-ethyl 6-(3,5-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazole-1-carboxylate as a white solid. (Yield: 0.28 g, 84%).

Step 8: (S)-6-(3,5-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazole-1-carboxylic Acid

To a stirred solution of (S)-ethyl 6-(3,5-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazole-1-carboxylate (0.08 g, 0.247 mmol) in methanol (2 ml) was added 5 M sodium hydroxide (0.148 ml, 0.740 mmol) at room temperature and the solution was stirred for 24 h. The mixture was then diluted with water (2 mL) and a second crop of 5 M sodium hydroxide (0.148 ml, 0.740 mmol) was added and the mixture was stirred for 48 h, Methanol was removed under vacuum, the residue was diluted with water (ca. 5 mL), and then acidified to pH=2 by adding 6 M HCl. The precipitate was collected, washed with water and dried under vacuum at 50° C. to give (S)-6-(3,5-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazole-1-carboxylic acid as white powder. (Yield: 0.052 g, 71%).

1 H NMR (DMSO d6 ): 12.95 (1H, br s), 12.49 (1H, s), 7.16 (3H, m), 4.28 (1H, dd, J=11.1, 8.3 Hz), 4.20 (1H, quin, J=8.6 Hz), 3.76 (1H, dd, J=11.0, 8.8 Hz), 3.47 (1H, dd, J=16.7, 8.1 Hz), 3.10 (1H, dd, J=16.7, 9.3 Hz).

13 C NMR (DMSO d6 ): 163.3, 163.2, 161.7, 161.6, 159.5, 158.9, 145, 145, 144.9, 140.4, 112.6, 110.9, 110.9, 110.8, 110.8, 102.8, 102.6, 102.4, 50.8, 45.7, 32.3.

Example 44: Ethyl 2-(5a-(thiophen-2-yl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetate

Compound was prepared analogous manner to Example 4 from 3-(tert-butoxycarbonyl)-5-(thiophen-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid and isolated as an orange foam.

1 H NMR (DMSO d6 ): 11.74 (1H, s), 7.44 (1H, dd, J=5.1, 1.3 Hz), 7.11 (1H, dd, J=3.6, 1.2 Hz), 7.00 (1H, dd, J=5.1, 3.6 Hz), 4.16 (1H, d, J=12.0 Hz), 4.10 (2H, q, J=7.2 Hz), 4.00 (1H, d, J=12.0 Hz), 3.55 (2H, m), 2.68 (1H, dd, J=8.4, 4.0 Hz), 1.83 (1H, dd, J=8.4, 5.6 Hz), 1.24 (1H, dd, J=5.4, 4.5 Hz), 1.20 (3H, t, J=7.1 Hz).

13 C NMR (DMSO d6 ): 169.2, 156.4, 143.6, 132.2, 127.5, 125.1, 124.7, 112.3, 60.7, 52.2, 32.7, 29.7, 24.9, 24.3, 14.1.

Example 45: (S)-6-(3,5-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazole-1-carbaldehyde

To a solution of dimethyl sulfoxide (0.543 mL, 7.64 mmol) in dry tetrahydrofuran (5 mL) was added 1.6 M methyllithium (4.77 mL, 7.64 mmol) in diethyl ether with external ice-water bath cooling. The mixture was allowed to warm up to room temperature and stirred for 40 min. Thereupon, a solution of (4S)-1-(tert-butoxycarbonyl)-4-(3,5-difluorophenyl)pyrrolidine-2-carboxylic acid (Example 1 step 9) (0.5 g, 1.528 mmol) and di(1H-imidazol-1-yl)methanone (0.248 g, 1.528 mmol) in dry tetrahydrofuran (5 mL) was added dropwise with external ice-water bath cooling and the mixture was allowed to warm up to room temperature and stir under nitrogen for 30 min. The mixture was then cooled 0° C. and neutralized by adding 2 M HCl (3.82 ml, 7.64 mmol) to pH=4-5. Followed by addition of brine. The mixture was extracted with a mixture of ethyl acetate-petroleum ether (2:1) and the organic phase was dried over MgSO 4 and evaporated to dryness to give the product as a yellowish oil. (Yield: 0.44 g, 74%).

A stirred mixture of (4S)-tert-butyl 4-(3,5-difluorophenyl)-2-(2-(methylsulfinyl)acetyl)pyrrolidine-1-carboxylate (0.43 g, 1.110 mmol) and 4 M HCl (5.55 mL, 22.20 mmol) in dioxane was stirred at room temperature for 2 h. The mixture was then diluted with a mixture of diethyl ether-petroleum ether, aged for 30 min, the supernatant liquid was decanted from the separated oil which solidified on standing under high vacuum to give 1-((4S)-4-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-(methylsulfinyl)ethanone hydrochloride. (Yield: 0.32 g, 89%).

Step 3: (S)-6-(3,5-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazole-1-carbaldehyde

A solution of 1-((4S)-4-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-(methylsulfinyl)ethanone hydrochloride (0.31 g, 0.957 mmol), 6 M HCl (0.080 ml, 0.479 mmol) and potassium thiocyanate (0.099 g, 1.019 mmol) in a mixture of ethanol (4 mL) and water (4 mL) was stirred under reflux for 30 min. Thereupon, the reaction was cooled to room temperature, diluted with water, the resultant solid was filtered off and the mother liqueur was extracted with dichloromethane. The organic phase was dried over MgSO 4 , and evaporated to dryness. The residue was combined with the first precipitate and then recrystallised from ethyl acetate to give (S)-6-(3,5-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazole-1-carbaldehyde as a beige powder. (Yield: 0.035 g, 13%).

1 H NMR (DMSO d6 ): 12.76 (1H, br s), 9.36 (1H, s), 7.18 (3H, m), 4.31 (1H, dd, J=8.4, 10.8 Hz), 4.26 (1H, q, J=8.4 Hz), 3.81 (1H, dd, J=10.8, 8.1 Hz), 3.63 (1H, dd, J=16.8, 8.0 Hz), 3.25 (1H, dd, J=16.8, 8.9 Hz).

13 C NMR (DMSO d6 ): 175.9, 163.4, 163.3, 161.7, 161.6, 160.8, 145.8, 144.9, 144.8, 144.8, 121.2, 111, 111, 110.9, 110.8, 102.9, 102.8, 102.6, 51, 45.7, 31.4.

Example 46: (S)-1-(hydroxymethyl)-6-(2,3,5,6-tetrafluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione

To a stirred solution of (S)-ethyl 6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazole-1-carboxylate (analogous to Example 43, step 7) (0.08 g, 0.222 mmol) in dry diethyl ether (2 mL) and dry tetrahydrofuran (1 mL) was added dropwise 2.4 M suspension of lithium aluminumhydride (0.102 ml, 0.244 mmol) in tetrahydrofuran with external ice-water bath cooling. The reaction was stirred in the cold for 30 min, then quenched with 2 M HCl to pH=1-2. Thereupon, the mixture was diluted with dichloromethane (ca. 5 mL), the insoluble material was collected, washed with water and dichloromethane, respectively. The wet filter cake was dissolved in a mixture of ethanol and dichloromethane with heating, and then filtered. The filtrate was evaporated to dryness to give (S)-1-(hydroxymethyl)-6-(2,3,5,6-tetrafluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione as an off-white solid. (Yield: 0.026 g, 36%).

1 H NMR (DMSO d6 ): 11.85 (1H, br s), 7.86 (1H, m), 5.07 (1H, br t, J=5.1 Hz), 4.50 (1H, quin, J=8.5 Hz), 4.21 (2H, br d, J=4.7 Hz), 4.18 (1H, br dd, J=11.4, 9.4 Hz), 3.78 (1H, dd, J=11.6, 7.6 Hz), 3.33 (1H, m), 2.96 (1H, br dd, J=15.8, 8.0 Hz).

13 C NMR (DMSO d6 ): 155.6, 146.4, 146.3, 146.3, 145.3, 145.2, 144.7, 143.7, 143.6, 128.8, 120.5, 120.4, 120.4, 120.3, 105.9, 105.7, 105.6, 53.1, 48.4, 35.7, 29.

Example 47: (S)-1-(methylsulfonylmethyl)-6-(2,3,5,6-tetrafluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione

Step 1: (4S)-tert-butyl 2-(2-(methylsulfonyl)acetyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-1-carboxylate

To a solution of (4S)-1-(tert-butoxycarbonyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-2-carboxylic acid (0.5 g, 1.376 mmol) (analogous to Example 44, step 9) in dry tetrahydrofuran (5 mL) was added di(1H-imidazol-1-yl)methanone (0.223 g, 1.376 mmol) at room temperature and the mixture was stirred for 30 min. Thereupon, a solution of 1.6 M methyllithium (4.30 ml, 6.88 mmol) in diethyl ether was added to a solution of dimethyl sulfone (0.648 g, 6.88 mmol) in dry tetrahydrofuran (5 mL) at room temperature and the mixture was stirred for 15 min before addition of the previously prepared imidazolide solution with stirring and ice-water bath cooling. The mixture was stirred for 30 min in the cold, then quenched with 2 M HCl (3.44 ml, 6.88 mmol) and extracted with diethyl ether (ca. 15 mL). The organic phase was dried over MgSO 4 ) concentrated under reduced pressure and chromatographed (ethyl acetate-petroleum ether; 4:1, then 2:1) to give (4S)-tert-butyl 2-(2-(methylsulfonyl)acetyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-1-carboxylate as a colourless oil. (Yield: 0.45 g, 74%).

Step 2: 2-(methylsulfonyl)-1-((4S)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidin-2-yl)ethanone Hydrochloride

To a stirred solution of (4S)-tert-butyl 2-(2-(methylsulfonyl)acetyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-1-carboxylate (0.41 g, 0.933 mmol) in 4 M HCl (4.67 mL, 18.66 mmol) in dioxane was stirred at room temperature for 3 h. The mixture was then diluted with a mixture of diethyl ether (20 mL) and petroleum ether (5 mL), and aged for 30 min. The thus obtained precipitate was collected, washed with diethyl ether and petroleum ether, and then dried under vacuum at 50° C. to give 2-(methylsulfonyl)-1-((4S)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidin-2-yl)ethanone hydrochloride as a white powder. (Yield: 0.28 g, 80%).

Step 3: (S)-1-((methylsulfonyl)methyl)-6-(2,3,5,6-tetrafluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione

A solution of 2-(methylsulfonyl)-1-((4S)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidin-2-yl)ethanone hydrochloride (0.27 g, 0.719 mmol), 6 M HCl (0.060 ml, 0.359 mmol) and potassium thiocyanate (0.077 g, 0.790 mmol) in a mixture of ethanol (4 mL) and water (4 mL) was stirred under reflux for 30 min. The mixture was then cooled to room temperature, the resulting solid was collected, washed with water and dried under vacuum at 50° C. to give (S)-1-(methylsulfonylmethyl)-6-(2,3,5,6-tetrafluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione as a white powder. (Yield: 0.21 g, 77%).

1 H NMR (DMSO d6 ): 12.08 (1H, s), 7.86 (1H, m), 4.57 (1H, quin, J=8.4 Hz), 4.30 (2H, m), 4.23 (1H, dd, J=11.6, 9.2 Hz), 3.83 (1H, dd, J=11.7, 7.5 Hz), 3.38 (1H, dd, J=16.3, 9.4 Hz), 2.99 (1H, dd, J=7.7, 16.4 Hz), 2.97 (3H, s).

13 C NMR (DMSO d6 ): 156.6, 146.4, 146.3, 146.3, 145.2, 144.8, 144.7, 144.6, 143.6, 132.9, 120.5, 120.4, 120.3, 108, 105.9, 105.8, 105.6, 50.1, 49, 39.6, 35.6, 29.5.

Example 48: (5aS,6aR)-5a-(2,5-difluorophenyl)-1-phenethyl-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione

Step 1 (1S,5R)-tert-butyl 1-(2,5-difluorophenyl)-4-(methoxy(methyl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a stirred solution of (1R,5S)-3-(tert-butoxycarbonyl)-5-(2,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (3 g, 8.84 mmol) (analogous to Example 44, step 9) in dry dichloromethane (30 mL) was added 1,1′-carbonyldiimidazole (1.720 g, 10.61 mmol) in portions at room temperature under nitrogen and the mixture was stirred for 1 h. Thereupon, N,O-dimethylhydroxylamine hydrochloride (1.035 g, 10.61 mmol) was added in one portion and the resulting suspension was stirred overnight. The mixture was then washed with water, the organic phase was dried over MgSO 4 , filtered and evaporated to dryness. The thus obtained light yellow oil was purified by chromatography (petroleum ether-ethyl acetate; 4:1, then 2:1). The product was isolated as a light yellow foam. (Yield: 2.21 g, 59%).

Step 2 (1S,5R)-tert-butyl 1-(2,5-difluorophenyl)-4-(3-phenylpropanoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a stirred ice-cooled mixture of phenethylmagnesium bromide in dry diethyl ether (8 mL) (prepared from (2-Bromoethyl)benzene (0.446 ml, 3.27 mmol) and magnesium turnings (0.165 g, 6.80 mmol)) was added a solution of (1S,5R)-tert-butyl 1-(2,5-difluorophenyl)-4-(methoxy(methyl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (1 g, 2.62 mmol) in dry tetrahydrofuran (5 mL) dropwise below 10° C. The reaction mixture was stirred at room temperature for 24 h. The mixture was then cooled to 0° C. and 2 M HCl was added carefully.

The phases were separated and organic phase was dried over MgSO 4 , filtered and evaporated to dryness. The resulting light yellow oil purified by chromatography (petroleum ether-ethyl acetate; 9:1, 4:1, then 2:1). (Yield: 0.34 g, 30%).

Step 31-((1R,5S)-5-(2,5-difluorophenyl)-3-azabicyclo[3.1.0]hexan-2-yl)-3-phenylpropan-1-one Hydrochloride

A solution of (1S,5R)-tert-butyl 1-(2,5-difluorophenyl)-4-(3-phenylpropanoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (340 mg, 0.795 mmol) in 4 M HCl in dioxane (1.59 mL, 6.36 mmol) was stirred at room temperature for 2 h. The solvent was evaporated off and the thus obtained oil was used without purification. (Yield: 0.289 g, 100%).

Step 4 (5aS,6aR)-5a-(2,5-difluorophenyl)-1-phenethyl-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione

To a stirred solution of 1-((1R,5S)-5-(2,5-difluorophenyl)-3-azabicyclo[3.1.0]hexan-2-yl)-3-phenylpropan-1-one hydrochloride (289 mg, 0.794 mmol) in a mixture of ethanol (3 mL) and water (3 ml) was added potassium thiocyanate (0.085 mL, 0.874 mmol) followed by addition of cc. HCl (0.033 ml, 0.397 mmol). The solution was heated at reflux and for 30 min. The mixture was then cooled to room temperature and ethanol was evaporated off. The precipitated oil was extracted from the aqueous phase with dichloromethane. The organic phase was dried over MgSO 4 , filtered and evaporated to dryness. The thus obtained light yellow foam was purified by chromatography (petroleum ether-ethyl acetate; 1:1), then 1:2) to leave a yellow foam. (Yield: 0.11 g, 34%).

1 H NMR (DMSO d6 ): 11.78 (1H, s), 7.29 (3H, m), 7.20 (5H, m), 4.03 (1H, d, J=12.2 Hz), 3.76 (1H, d, J=12.2 Hz), 2.88 (2H, m), 2.70 (3H, m), 1.53 (1H, dd, J=8.2, 5.3 Hz), 0.96 (1H, t, J=4.8 Hz).

13 C NMR (DMSO d6 ): 158.8, 158.8, 158.6, 158.6, 157.2, 157, 157, 155.7, 140.8, 130.5, 128.8, 128.7, 128.6, 128.6, 128.5, 128.4, 128.3, 128.3, 128.2, 128.2, 126, 118.7, 117.2, 117.1, 117, 117, 116.8, 116.8, 116.7, 116.7, 115.9, 115.8, 115.7, 115.7, 51.3, 51.3, 33.9, 32.4, 25.9, 22.4, 20.5.

Example 49: (5aS,6aR)-5a-(2,5-difluorophenyl)-1-(3-phenylpropyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione

Compound was prepared analogous manner to Example 48 from (1S,5R)-tert-butyl 1-(2,5-difluorophenyl)-4-(methoxy(methyl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate and (3-phenylpropyl)magnesium bromide. The product was isolated as a yellow foam.

1 H NMR (DMSO d6 ): 11.71 (1H, s), 7.28 (3H, br t, J=6.9 Hz), 7.24-7.14 (4H, m), 4.07 (1H, br d, J=11.9 Hz), 3.79 (1H, d, J=12.0 Hz), 2.85 (1H, dd, J=8.1, 4.2 Hz), 2.61 (2H, br t, J=7.6 Hz), 2.42 (2H, m), 1.91 (2H, m), 1.64 (1H, dd, J=8.1, 5.4 Hz), 1.17 (1H, br t, J=4.7 Hz).

13 C NMR (DMSO d6 ): 158.8, 158.7, 158.7, 157.2, 157.1, 157.1, 155.8, 141.5, 130.2, 128.8, 128.8, 128.7, 128.7, 128.4, 128.3, 125.8, 119.1, 117.2, 117.1, 117, 116.9, 116.9, 116.8, 116.7, 115.9, 115.8, 115.7, 115.6, 51.3, 51.3, 34.4, 32.5, 29.2, 23.6, 22.5, 20.6.

Example 50: (5aS,6aR)-5a-(3,5-difluorophenyl)-1-(hydroxymethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione

Step 1 (1S,5R)-tert-butyl 4-(cyano(hydroxy)methyl)-1-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a stirred solution of (1S,5R)-tert-butyl 1-(3,5-difluorophenyl)-4-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.500 g, 1.546 mmol) (analogous to Example 39 step 8) in a mixture of tetrahydrofuran (3.4 mL) and water (1.72 mL) was added potassium cyanide (0.121 g, 1.856 mmol) followed by the addition of cc. HCl (0.127 mL, 1.546 mmol). The reaction was stirred at room temperature overnight. The mixture was then extracted with dichloromethane, washed with brine, dried over MgSO 4 , filtered and concentrated under reduced pressure to give the product as a yellow oil. (Yield: 0.554 g, 87%).

Step 2 (1S,5R)-tert-butyl 1-(3,5-difluorophenyl)-4-(2-ethoxy-1-hydroxy-2-oxoethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

A solution of (1S)-tert-butyl 4-(cyano(hydroxy)methyl)-1-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (0,554 g, 1,581 mmol) in 2 M HCl (11.86 mL, 23.72 mmol) was refluxed for 20 h. The mixture was then cooled to room temperature and precipitated brown solid was removed by filtration. The filtrate was evaporated to dryness, and then azeotroped twice with ethanol. The thus obtained residue was dissolved in ethanol (9 mL), and then treated with 4 M HCl in dioxane (3.95 mL, 15.81 mmol). The reaction mixture was refluxed for 2 h, whereupon cooled to room temperature and evaporated twice with ethanol. The resulting residue was dissolved in ethanol (11 mL), neutralized to pH=6-7 by addition of triethylamine (0.22 mL, 1,581 mmol) followed by addition of di-tert-butyl dicarbonate (0,345 g, 1,581 mmol). The reaction was stirred at room temperature overnight. Thereupon, the mixture was concentrated under reduced pressure (water bath <40° C.). The residue was quenched with water and extracted with dichloromethane. The organic phase was dried over MgSO 4 , filtrated and concentrated. The crude material was purified by chromatography (8% ethyl acetate in petroleum Ether). The product was isolated as a pale yellow oil. (Yield: 0.21 g, 33%).

Step 3 Ethyl 2-((1R,5S)-5-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hexan-2-yl)-2,2-dihydroxyacetate Hydrochloride

To a stirred solution of (1S)-tert-butyl 1-(3,5-difluorophenyl)-4-(2-ethoxy-1-hydroxy-2-oxoethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (0,210 g, 0,528 mmol) in dichloromethane (5.3 mL) was added Dess-Martin periodinane (3-oxo-1l-benzo[d][1,2]iodaoxole-1,1,1(3H)-triyl triacetate) (0,224 g, 0,528 mmol) at room temperature. The reaction was stirred at room temperature for 4 h. The solvent was then removed under reduced pressure to give a light pink pastel. Chromatography (dichloromethane-methanol-aq. Ammonia) gave the product as a pale yellow oil. (Yield: 142 g, 68%).

Step 4 ethyl 2-((1R,5S)-5-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hexan-2-yl)-2,2-dihydroxyacetate hydrochloride

A solution of (1S)-tert-butyl 1-(3,5-difluorophenyl)-4-(2-ethoxy-2-oxoacetyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (0,142 g, 0,359 mmol) in 4 M HCl in dioxane (1,796 mL, 7.18 mmol) was stirred at room temperature for 2.5 h. The mixture was then diluted with a mixture of diethyl Ether (4 mL) and petroleum ether (1 mL), stirred for 30 min, whereupon the volatiles were evaporated off to give the product as a brown oil. (Yield: 0.126 g, 100%).

Step 5 (5aS,6aR)-ethyl 5a-(3,5-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-1-carboxylate

To a stirred solution of ethyl 2-((5S)-5-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hexan-2-yl)-2,2-dihydroxyacetate hydrochloride (0,126 g, 0,360 mmol) in a mixture of ethanol (1.5 mL) and water (1.5 mL) was added cc. HCl (0.03 mL, 0,180 mmol) and potassium thiocyanate (0,039 g, 0,396 mmol) at room temperature. The reaction mixture was refluxed for 30 min, and then cooled to room temperature. The stirring was continued overnight, and then the resultant off-white precipitate was filtered off, washed with cold water and dried under vacuum. (Yield: 0.79 mg, 65%).

Step 6 (5aS,6aR)-5a-(3,5-difluorophenyl)-1-(hydroxymethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione

To a stirred solution (5aS,6aR)-ethyl 5a-(3,5-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-1-carboxylate (0,188 g, 0,559 mmol) in a mixture of dry diethyl ether (3.2 mL) and dry tetrahydrofuran (1.6 mL) was added dropwise 2.4 M suspension of lithium aluminum hydride (0,256 mL, 0,615 mmol) in terahydrofuran with ice-water bath cooling. The reaction was stirred for 30 min at 0-5° C., quenched with 0.5 M HCl to pH=1-2 (ca. 5 mL), and then diluted with diethyl ether (ca. 10 mL). The resulting solid was collected, washed with water and dried under vacuum at 50° C. to give a light yellow powder. (Yield: 0.038 g, 22%).

1 H NMR (DMSO d6 ): 1.75 (1H, br s), 7.11 (3H, m), 5.10 (1H, br s), 4.25 (2H, m), 4.20 (1H, d, J=12.2 Hz), 4.03 (1H, d, J=12.0 Hz), 3.02 (1H, dd, J=8.3, 4.3 Hz), 1.69 (1H, dd, J=8.4, 5.3 Hz), 1.17 (1H, t, J=4.8 Hz).

13 C NMR (DMSO d6 ): 163.4, 163.3, 161.8, 161.7, 156.7, 144.9, 144.8, 144.8, 131.4, 119.8, 110, 110, 109.9, 109.8, 102.3, 102.1, 101.9, 53.1, 50.7, 36.3, 25.4, 22.9.

Example 51: 2-((5aS,6aR)-5a-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic Acid

Compound was prepared analogous manner to Example 2 from (1R,5S)-3-(tert-butoxycarbonyl)-5-(3-bromo-2,6-difluorophenyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid. The product was isolated as a yellow solid.

1 H NMR (DMSO d6 ): 12.63 (1H, br s), 11.72 (1H, br s), 7.75 (1H, td, J=8.5, 5.8 Hz), 7.16 (1H, td, J=9.2, 1.0 Hz), 4.04 (1H, d, J=12.2 Hz), 3.74 (1H, br d, J=12.0 Hz), 3.49 (2H, m), 2.77 (1H, dd, J=8.4, 4.3 Hz), 1.67 (1H, dd, J=8.4, 5.4 Hz), 1.24 (1H, t, J=5.0 Hz).

13 C NMR (DMSO d6 ): 170.8, 161.9, 161.9, 160.2, 160.2, 158.8, 158.8, 158.8, 157.2, 157.1, 133.1, 133, 131.9, 117.1, 117, 116.9, 113.5, 113.5, 113.4, 113.3, 113.3, 103.7, 103.7, 103.6, 103.6, 51.5, 29.9, 26.5, 21.8, 21.2.

Example 52: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic Acid

Compound was prepared analogous manner to Example 2 from (1R,5S)-3-(tert-butoxycarbonyl)-5-(5-chloro-2-fluorophenyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid. The product was isolated as a light yellow solid.

1 H NMR (DMSO d6 ): 12.60 (1H, br s), 11.70 (1H, s), 7.45 (1H, dd, J=6.5, 2.5 Hz), 7.42 (1H, ddd, J=8.6, 4.3, 2.8 Hz), 7.30 (1H, t, J=9.4 Hz), 4.09 (1H, br d, J=12.0 Hz), 3.80 (1H, d, J=12.0 Hz), 3.47 (2H, m), 2.88 (1H, dd, J=8.2, 4.1 Hz), 1.67 (1H, dd, J=8.2, 5.4 Hz), 1.12 (1H, t, J=4.8 Hz).

13 C NMR (DMSO d6 ): 170.8, 161.3, 159.6, 156.1, 132.1, 130.1, 130.1, 129.4, 129.3, 128.9, 128.8, 128.3, 128.3, 117.6, 117.4, 113, 51.6, 32.4, 29.9, 22.2, 20.6.

Example 53: 2-((5aS,6aR)-5a-(3-chloro-5-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic Acid

Compound was prepared analogous manner to Example 2 from (1R,5S)-3-(tert-butoxycarbonyl)-5-(3-chloro-5-fluorophenyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid. The product was isolated as a light yellow solid.

1 H NMR (DMSO d6 ): 12.60 (1H, br s), 11.68 (1H, s), 7.31 (1H, dt, J=8.7, 2.0 Hz), 7.27 (1H, t, J=1.5 Hz), 7.22 (1H, dt, J=9.9, 1.9 Hz), 4.21 (1H, d, J=12.0 Hz), 4.03 (1H, d, J=12.2 Hz), 3.45 (2H, m), 3.00 (1H, dd, J=8.4, 4.3 Hz), 1.69 (1H, dd, J=8.2, 5.3 Hz), 1.14 (1H, t, J=4.8 Hz).

13 C NMR (DMSO d6 ): 170.7, 163.1, 161.5, 156.3, 144.8, 144.7, 134.2, 134.1, 132, 123, 122.9, 114.3, 114.2, 112.9, 112.8, 112.8, 50.8, 36.1, 36.1, 29.9, 25.1, 22.6.

Example 54: Ethyl 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetate

Compound was prepared analogous manner to Example 2 from (1R,5S)-3-(tert-butoxycarbonyl)-5-(5-chloro-2-fluorophenyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid. The product was isolated as an off-white foam.

1 H NMR (DMSO d6 ): 1.73 (1H, s), 7.46 (1H, dd, J=6.5, 2.6 Hz), 7.43 (1H, ddd, J=8.6, 4.3, 2.8 Hz), 7.30 (1H, t, J=9.4 Hz), 4.11 (2H, q, J=7.1 Hz), 4.09 (1H, d, J=12.2 Hz), 3.81 (1H, d, J=12.2 Hz), 3.57 (2H, m), 2.87 (1H, dd, J=8.3, 4.2 Hz), 1.68 (1H, dd, J=8.4, 5.4 Hz), 1.21 (3H, t, J=7.1 Hz), 1.13 (1H, t, J=4.8 Hz).

13 C NMR (DMSO d6 ): 169.2, 161.3, 159.6, 156.2, 132.3, 130.2, 130.1, 129.4, 129.3, 128.8, 128.7, 128.3, 128.3, 117.6, 117.4, 112.3, 60.7, 51.6, 51.6, 32.4, 29.8, 22.1, 20.6, 14.1.

Example 55: Ethyl 2-((5aS,6aR)-5a-(3-chloro-5-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetate

Compound was prepared analogous manner to Example 2 from (1R,5S)-3-(tert-butoxycarbonyl)-5-(3-chloro-5-fluorophenyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid. The product was isolated as a white solid.

1 H NMR (DMSO d6 ): 1.72 (1H, s), 7.32 (1H, dt, J=8.7, 2.0 Hz), 7.28 (1H, t, J=1.5 Hz), 7.23 (1H, dt, J=9.9, 2.0 Hz), 4.21 (1H, d, J=12.2 Hz), 4.11 (2H, q, J=7.0 Hz), 4.04 (1H, d, J=12.2 Hz), 3.54 (2H, m), 2.99 (1H, dd, J=8.4, 4.4 Hz), 1.70 (1H, dd, J=8.4, 5.3 Hz), 1.21 (3H, t, J=7.0 Hz), 1.15 (1H, t, J=4.8 Hz).

13 C NMR (DMSO d6 ): 169.2, 163.1, 161.5, 156.4, 144.7, 144.7, 134.2, 134.1, 132.3, 123, 123, 114.4, 114.2, 112.9, 112.8, 112.1, 60.7, 50.9, 36.1, 36.1, 29.8, 25, 22.7, 14.1.

Example 56: (2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetamide

To a stirred solution of 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic acid (Example 52) (630 mg, 1.860 mmol) in anhydrous dichloromethane (11 mL) was added 1,1′-Carbonyldiimidazole (362 mg, 2.232 mmol) and the reaction was stirred for 30 min. at room temperature. Thereupon, ammonia (0.53 mL, 3.72 mL) 7 M in methanol was added and the mixture was stirred for 3 h at room temperature. The solvent was then evaporated and the obtained brown oil was separated by column chromatography (dichloromethane-methanol). Trituration in a mixture of dichloromethane-diethyl ether-petroleum ether afforded the titled product as a dark yellow solid.

1 H NMR (DMSO d6 ): 11.64 (1H, s), 7.46 (1H, dd, J=6.6, 2.6 Hz), 7.43 (1H, ddd, J=8.7, 4.3, 2.7 Hz), 7.37 (1H, br s), 7.30 (1H, t, J=9.5 Hz), 7.03 (1H, m), 4.07 (1H, d, J=12.0 Hz), 3.79 (1H, d, J=12.0 Hz), 3.27 (2H, m), 2.85 (1H, dd, J=8.4, 4.3 Hz), 1.64 (1H, dd, J=8.4, 5.3 Hz), 1.17 (1H, t, J=4.8 Hz).

13 C NMR (DMSO d6 ): 169.9, 161.2, 159.6, 155.9, 131.8, 130.1, 130.1, 129.3, 129.3, 129, 128.9, 128.3, 128.3, 117.6, 117.4, 114, 51.6, 32.3, 31.2, 22.1, 20.7.

Example 57: 2-((5aS,6aR)-5a-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 56 from 2-((5aS,6aR)-5a-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic acid (Example 51). The product was isolated as a yellow solid.

1 H NMR (DMSO d6 ): 1.67 (1H, m), 7.74 (1H, td, J=8.4, 5.9 Hz), 7.39 (1H, br s), 7.15 (1H, td, J=9.2, 1.2 Hz), 7.04 (1H, br s), 4.02 (1H, d, J=12.2 Hz), 3.72 (1H, d, J=12.2 Hz), 3.29 (2H, m), 2.74 (1H, dd, J=8.4, 4.4 Hz), 1.64 (1H, dd, J=8.2, 5.4 Hz), 1.28 (1H, br t, J=4.9 Hz).

13 C NMR (DMSO d6 ): 169.9, 161.9, 161.9, 160.2, 160.2, 158.8, 158.8, 157.2, 157.1, 155.8, 133, 133, 131.5, 117.2, 117.1, 117, 114.4, 113.5, 113.5, 113.4, 113.3, 103.7, 103.7, 103.6, 103.6, 51.4, 31.2, 26.4, 21.7, 21.3.

Example 58: 2-((5aS,6aR)-5a-(3-chloro-5-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 56 from 2-((5aS,6aR)-5a-(3-chloro-5-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic acid (Example 53). The product was isolated as a beige solid.

1 H NMR (DMSO d6 ): 1.62 (1H, s), 7.35 (1H, br s), 7.31 (1H, dt, J=8.7, 2.1 Hz), 7.28 (1H, t, J=1.6 Hz), 7.23 (1H, dt, J=10.0, 1.9 Hz), 7.05 (1H, br s), 4.19 (1H, d, J=12.0 Hz), 4.01 (1H, d, J=12.0 Hz), 3.25 (2H, m), 2.95 (1H, dd, J=8.4, 4.3 Hz), 1.67 (1H, dd, J=8.4, 5.3 Hz), 1.19 (1H, t, J=4.8 Hz).

13 C NMR (DMSO d6 ): 169.9, 163.1, 161.5, 156.1, 144.9, 144.9, 134.2, 134.1, 131.9, 123, 123, 114.3, 114.1, 113.7, 112.9, 112.8, 50.9, 36.1, 36.1, 31.2, 24.9, 22.8

Example 59: ethyl (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetate

Compound was prepared analogous manner to Example 2 from (4S)-1-(tert-butoxycarbonyl)-4-(3-bromo-2,6-difluorophenyl)pyrrolidine-2-carboxylic acid and isolated as a yellow solid.

1 H NMR (DMSO d6 ): 11.81 (1H, s), 7.72 (1H, ddd, J=5.8, 8.1, 8.8 Hz), 7.16 (1H, dt, J=1.4, 9.4 Hz), 4.47 (1H, quin, J=8.5 Hz), 4.17 (1H, dd, J=11.2, 9.5 Hz), 4.09 (2H, q, J=7.1 Hz), 3.73 (1H, dd, J=11.6, 7.8 Hz), 3.50 (2H, s), 3.27 (1H, dd, J=15.8, 9.4 Hz), 2.86 (1H, dd, J=15.8, 7.9 Hz), 1.19 (3H, t, J=7.1 Hz).

13 C NMR (DMSO d6 ): 169.1, 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 155.9, 155.9, 155.4, 132.5, 132.4, 129.9, 118.9, 118.7, 118.6, 113.8, 113.8, 113.6, 113.6, 112.6, 104.1, 104.1, 103.9, 103.9, 60.7, 48.7, 35.6, 29.8, 29.3, 14.1.

Example 60: Ethyl (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetate

Compound was prepared analogous manner to Example 2 from (4R)-1-(tert-butoxycarbonyl)-4-(3-bromo-2,6-difluorophenyl)pyrrolidine-2-carboxylic acid and isolated as a yellow solid.

1 H NMR (DMSO d6 ): 11.81 (1H, s), 7.72 (1H, ddd, J=5.8, 8.1, 8.8 Hz), 7.16 (1H, dt, J=1.4, 9.6 Hz), 4.47 (1H, quin, J=8.5 Hz), 4.17 (1H, dd, J=11.4, 9.2 Hz), 4.09 (2H, q, J=7.0 Hz), 3.73 (1H, dd, J=11.6, 7.8 Hz), 3.50 (2H, s), 3.27 (1H, dd, J=16.0, 9.4 Hz), 2.86 (1H, dd, J=15.9, 8.0 Hz), 1.19 (3H, t, J=7.1 Hz).

13 C NMR (DMSO d6 ): 169.1, 160.8, 160.7, 159.2, 159.1, 157.5, 157.5, 155.9, 155.9, 155.4, 132.5, 132.4, 129.9, 118.9, 118.7, 118.6, 113.8, 113.8, 113.6, 113.6, 112.6, 104.1, 104.1, 103.9, 103.9, 60.7, 48.7, 35.6, 29.8, 29.2, 14.1.

Example 61: Ethyl (R)-2-(6-(2,5-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetate

Compound was prepared analogous manner to Example 2 from (4R)-1-(tert-butoxycarbonyl)-4-(2,5-difluorophenyl)pyrrolidine-2-carboxylic acid and isolated as a white solid.

1 H NMR (DMSO d6 ): 1.82 (1H, s), 7.29 (1H, dt, J=4.7, 9.5 Hz), 7.26 (1H, m), 7.19 (1H, m), 4.22 (1H, quin, J=7.8 Hz), 4.14 (1H, dd, J=11.3, 7.9 Hz), 4.09 (2H, q, J=7.0 Hz), 3.74 (1H, dd, J=11.3, 7.5 Hz), 3.53 (2H, m), 3.22 (1H, dd, J=15.5, 8.0 Hz), 2.86 (1H, dd, J=15.5, 7.8 Hz), 1.19 (3H, t, J=7.1 Hz).

13 C NMR (DMSO d6 ): 169.2, 159.1, 159, 157.5, 157.5, 157.1, 157.1, 155.6, 155.5, 155.5, 130.1, 130, 130, 129.9, 129.8, 117.2, 117.1, 117, 116.9, 115.5, 115.4, 115.3, 115.3, 115.2, 115.2, 115.1, 115, 113.1, 60.7, 49.4, 40.3, 29.8, 29.6, 14.1.

Example 62: Ethyl (S)-2-(6-(5-bromo-2-fluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetate

Compound was prepared analogous manner to Example 2 from (4S)-1-(tert-butoxycarbonyl)-4-(5-bromo-2-fluorophenyl)pyrrolidine-2-carboxylic acid and isolated as an orange solid.

1 H NMR (DMSO d6 ): 11.80 (1H, s), 7.58 (1H, dd, J=6.6, 2.5 Hz), 7.53 (1H, ddd, J=8.7, 4.5, 2.6 Hz), 7.23 (1H, dd, J=10.1, 8.8 Hz), 4.22 (1H, quin, J=7.9 Hz), 4.14 (1H, dd, J=11.2, 8.1 Hz), 4.09 (2H, q, J=7.2 Hz), 3.75 (1H, dd, J=11.3, 7.5 Hz), 3.52 (2H, m), 3.22 (1H, dd, J=15.6, 8.2 Hz), 2.87 (1H, dd, J=15.6, 7.9 Hz), 1.19 (3H, t, J=7.1 Hz).

13 C NMR (DMSO d6 ): 169.2, 160.3, 158.7, 155.6, 131.9, 131.8, 131.4, 131.3, 130.7, 130.6, 129.7, 118, 117.9, 116.5, 116.5, 113, 60.7, 49.3, 40.4, 29.8, 29.5, 14.1.

Example 63: Ethyl (R)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetate

Compound was prepared analogous manner to Example 2 from (4R)-1-(tert-butoxycarbonyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-2-carboxylic acid and isolated as a light cream powder.

1 H NMR (DMSO d6 ): 11.83 (1H, s), 7.86 (1H, m), 4.51 (1H, quin, J=8.5 Hz), 4.19 (1H, dd, J=11.6, 9.1 Hz), 4.09 (2H, q, J=7.2 Hz), 3.79 (1H, dd, J=11.7, 7.6 Hz), 3.51 (2H, s), 3.30 (1H, dd, J=16.0, 9.4 Hz), 2.91 (1H, dd, J=15.9, 7.8 Hz), 1.19 (3H, t, J=7.1 Hz).

13 C NMR (DMSO d6 ): 169.1, 155.5, 146.4, 146.3, 146.2, 145.3, 145.2, 144.7, 144.6, 143.7, 143.6, 129.6, 120.5, 120.4, 120.3, 112.7, 105.9, 105.7, 105.6, 60.6, 48.6, 35.7, 29.8, 29.1, 14.

Example 64: Ethyl (R)-2-(6-(5-chloro-2-fluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetate

Compound was prepared analogous manner to Example 2 from (4R)-1-(tert-butoxycarbonyl)-4-(5-chloro-2-fluorophenyl)pyrrolidine-2-carboxylic acid and isolated as a pale yellow solid.

1 H NMR (DMSO d6 ): 11.78 (1H, s), 7.45 (1H, dd, J=6.5, 2.6 Hz), 7.40 (1H, ddd, J=8.8, 4.4, 2.7 Hz), 7.29 (1H, dd, J=10.1, 8.9 Hz), 4.22 (1H, quin, J=7.8 Hz), 4.15 (1H, dd, J=11.3, 8.1 Hz), 4.10 (2H, q, J=7.2 Hz), 3.75 (1H, dd, J=11.3, 7.5 Hz), 3.52 (2H, m), 3.22 (1H, dd, J=15.5, 8.1 Hz), 2.88 (1H, dd, J=15.6, 7.8 Hz), 1.19 (3H, t, J=7.0 Hz).

13 C NMR (DMSO d6 ): 169.1, 159.8, 158.1, 155.6, 130.3, 130.2, 129.7, 128.9, 128.8, 128.5, 128.5, 128.4, 128.4, 117.6, 117.4, 113, 60.7, 49.3, 40.3, 29.8, 29.5, 14.

Example 65: Ethyl (R)-2-(6-(2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetate

Compound was prepared analogous manner to Example 2 from (4R)-1-(tert-butoxycarbonyl)-4-(2,6-difluorophenyl)pyrrolidine-2-carboxylic acid and isolated as an orange solid.

1 H NMR (DMSO d6 ): 1.80 (1H, s), 7.41 (1H, tt, J=8.4, 6.6 Hz), 7.13 (2H, m), 4.43 (1H, quin, J=8.7 Hz), 4.16 (1H, dd, J=9.2, 11.3 Hz), 4.09 (2H, q, J=7.0 Hz), 3.73 (1H, dd, J=11.4, 8.2 Hz), 3.50 (2H, s), 3.25 (1H, dd, J=15.7, 9.2 Hz), 2.86 (1H, dd, J=15.7, 8.5 Hz), 1.19 (3H, t, J=7.1 Hz).

13 C NMR (DMSO d6 ): 169.1, 161.6, 161.5, 160, 159.9, 155.4, 130, 129.8, 129.8, 129.7, 116.6, 116.5, 116.4, 112.6, 112.2, 112.2, 112.1, 112.1, 60.6, 48.7, 35.2, 29.8, 29.3, 14.

Example 66: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one

Compound was prepared analogous manner to Example 37 from (1R,5S)-3-(tert-butoxycarbonyl)-5-(5-chloro-2-fluorophenyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid and isolated as a greenish solid.

1 H NMR (DMSO d6 ): 11.64 (1H, s), 7.45 (1H, dd, J=2.7, 6.5 Hz), 7.43 (1H, ddd, J=8.6, 4.4, 2.7 Hz), 7.30 (1H, dd, J=9.9, 8.7 Hz), 4.08 (1H, d, J=12.0 Hz), 3.79 (1H, d, J=12.2 Hz), 3.57 (6H, m), 3.49 (2H, m), 3.46 (2H, m), 2.78 (1H, dd, J=8.4, 4.3 Hz), 1.69 (1H, dd, J=8.3, 5.4 Hz), 1.11 (1H, t, J=4.8 Hz).

13 C NMR (DMSO d6 ): 166.9, 161.3, 159.6, 156, 131.8, 130.2, 130.2, 129.4, 129.3, 128.8, 128.7, 128.3, 128.3, 117.6, 117.4, 113.7, 66, 54.9, 51.6, 45.7, 41.8, 32.4, 29, 22.1, 20.7.

Example 67: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-isopropylacetamide

Compound was prepared analogous manner to Example 37 from (1R,5S)-3-(tert-butoxycarbonyl)-5-(5-chloro-2-fluorophenyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid and isolated as a light yellow solid.

1 H NMR (DMSO d6 ): 1.69 (1H, s), 7.88 (1H, d, J=7.6 Hz), 7.45 (1H, dd, J=2.6, 6.5 Hz), 7.43 (1H, ddd, J=8.5, 4.3, 2.8 Hz), 7.30 (1H, dd, J=9.8, 8.8 Hz), 4.07 (1H, d, J=12.0 Hz), 3.83 (1H, oct, J=7.3 Hz), 3.79 (1H, d, J=12.2 Hz), 3.25 (2H, m), 2.80 (1H, dd, J=8.4, 4.3 Hz), 1.66 (1H, dd, J=8.4, 5.3 Hz), 1.13 (1H, t, J=4.8 Hz), 1.06 (6H, d, J=6.6 Hz).

13 C NMR (DMSO d6 ): 166.7, 161.2, 159.6, 155.8, 131.6, 130.2, 130.1, 129.3, 129.3, 128.9, 128.8, 128.3, 128.3, 117.6, 117.4, 114.1, 51.5, 51.5, 40.7, 32.3, 31.5, 22.4, 22.3, 22, 20.8.

Example 68: 2-((5aS,6aR)-5a-(3-chloro-5-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-methylacetamide

Compound was prepared analogous manner to Example 37 from (1R,5S)-3-(tert-butoxycarbonyl)-5-(3-chloro-5-fluorophenyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid and isolated as a light yellow solid.

1 H NMR (DMSO d6 ): 1.62 (1H, s), 7.78 (1H, q, J=4.5 Hz), 7.31 (1H, dt, J=8.7, 1.9 Hz), 7.28 (1H, t, J=1.5 Hz), 7.23 (1H, dt, J=10.0, 1.8 Hz), 4.19 (1H, d, J=12.2 Hz), 4.02 (1H, d, J=12.0 Hz), 3.27 (2H, m), 2.93 (1H, dd, J=8.3, 4.3 Hz), 2.60 (3H, d, J=4.5 Hz), 1.67 (1H, dd, J=8.4, 5.3 Hz), 1.20 (1H, t, J=4.8 Hz).

13 C NMR (DMSO d6 ): 168.2, 163.1, 161.4, 156.2, 144.9, 144.8, 134.2, 134.1, 132, 123, 123, 114.3, 114.1, 113.4, 112.9, 112.8, 50.9, 36, 36, 31.3, 24.9, 22.8.

Example 69: 2-((5aS,6aR)-5a-(3-chloro-5-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N,N-dimethylacetamide

Compound was prepared analogous manner to Example 37 from (1R,5S)-3-(tert-butoxycarbonyl)-5-(3-chloro-5-fluorophenyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid and isolated as a yellow solid.

1 H NMR (DMSO d6 ): 11.58 (1H, s), 7.31 (1H, dt, J=8.7, 2.1 Hz), 7.27 (1H, t, J=1.6 Hz), 7.22 (1H, dt, J=10.0, 2.0 Hz), 4.20 (1H, d, J=12.0 Hz), 4.03 (1H, d, J=12.0 Hz), 3.52 (2 H, s), 3.02 (3H, s), 2.90 (1H, dd, J=8.4, 4.4 Hz), 2.85 (3H, s), 1.68 (1H, dd, J=8.3, 5.2 Hz), 1.13 (1H, t, J=4.8 Hz).

13 C NMR (DMSO d6 ): 167.9, 163.1, 161.5, 156.1, 144.8, 144.8, 134.2, 134.1, 131.6, 122.9, 122.9, 114.3, 114.1, 113.8, 112.9, 112.7, 50.8, 37, 36, 36, 35.1, 29.2, 25.1, 22.8.

Example 70: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(pyrrolidin-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 37 from (1R,5S)-3-(tert-butoxycarbonyl)-5-(5-bromo-2-fluorophenyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid and isolated as a light yellow solid.

1 H NMR (DMSO d6 ): 11.61 (1H, s), 7.59-7.53 (2H, m), 7.24 (1H, dd, J=10.1, 8.7 Hz), 4.07 (1H, d, J=12.0 Hz), 3.79 (1H, d, J=12.0 Hz), 3.48 (2H, m), 3.46 (2H, t, 6.9 Hz), 3.31 (2H, t, J=6.9 Hz), 2.79 (1H, dd, J=8.4, 4.3 Hz), 1.90 (2H, quin, J=6.9 Hz), 1.78 (2H, quin, J=6.9 Hz), 1.67 (1H, dd, J=8.4, 5.3 Hz), 1.10 (1H, t br, J=4.8 Hz).

13 C NMR (DMSO d6 ): 166.2, 161.8, 160.1, 155.9, 133, 133, 132.3, 132.2, 131.7, 129.3, 129.2, 118, 117.8, 116.2, 116.2, 113.8, 51.6, 51.6, 46.1, 45.6, 32.2, 30.5, 25.6, 24, 22.1, 20.7.

Example 71: (R)—N-(3-(dimethylamino)propyl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide Hydrochloride

Compound was prepared analogous manner to Example 32 from (R)-1-(H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a yellowish powder.

1 H NMR (DMSO d6 ): 1.78 (1H, m), 10.33 (1H, br s), 8.22 (1H, br t, J=5.5 Hz), 7.85 (1H, m), 4.50 (1H, quin, J=8.5 Hz), 4.19 (1H, br t, J=10.3 Hz), 3.80 (1H, m), 3.29 (3H, m), 3.11 (2H, q, J=6.4 Hz), 3.01 (2H, m), 2.91 (1H, br dd, J=15.7, 8.2 Hz), 2.71 (6H, d, J=4.5 Hz), 1.79 (2H, m).

13 C NMR (DMSO d6 ): 168.1, 146.4, 146.4, 146.3, 145.4, 145.4, 145.3, 145.3, 145.2, 144.8, 144.8, 144.8, 144.7, 144.7, 144.7, 144.7, 144.6, 143.8, 143.7, 143.7, 143.7, 143.6, 143.6, 129.5, 120.3, 120.2, 119.2, 114.7, 105.9, 105.8, 105.6, 54.4, 48.5, 42, 42, 35.9, 35.8, 31.5, 29.2, 24.1.

Example 72: (R)—N-(2-hydroxyethyl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light cream powder.

1 H NMR (DMSO d6 ): 10.98 (1H, m), 7.98 (1H, br t, J=5.2 Hz), 7.84 (1H, m), 4.68 (1H, br s), 4.48 (1H, quin, J=8.5 Hz), 4.17 (1H, br dd, J=11.2, 9.5 Hz), 3.77 (1H, dd, J=11.5, 8.0 Hz), 3.39 (2H, br t, J=5.9 Hz), 3.25 (3H, m), 3.11 (2H, q, J=5.9 Hz), 2.89 (1H, br dd, J=15.8, 8.1 Hz).

13 C NMR (DMSO d6 ): 167.7, 155.2, 146.4, 146.3, 146.3, 145.4, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 144.8, 144.7, 144.7, 144.7, 144.6, 144.6, 143.7, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 143.6, 128.9, 120.4, 120.3, 120.2, 114.4, 105.9, 105.7, 105.6, 59.7, 48.4, 41.7, 35.8, 31.5, 29.1.

Example 73: (R)—N-(2-methoxyethyl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light beige powder.

1 H NMR (DMSO d6 ): 1.74 (1H, br s), 8.04 (1H, br t, J=5.1 Hz), 7.85 (1H, m), 4.48 (1H, quin, J=8.5 Hz), 4.17 (1H, dd, J=9.5, 11.3 Hz), 3.77 (1H, dd, J=11.5, 8.0 Hz), 3.33 (2H, t, J=5.4 Hz), 3.29-3.16 (8H, m), 2.88 (1H, br dd, J=15.9, 8.1 Hz).

13 C NMR (DMSO d6 ): 167.7, 155.2, 146.4, 146.4, 146.4, 146.3, 146.3, 146.3, 146.2, 145.3, 145.3, 145.3, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 144.8, 144.8, 144.7, 144.6, 144.6, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 128.9, 120.4, 120.3, 120.2, 114.3, 105.9, 105.7, 105.6, 70.5, 57.8, 48.4, 38.6, 35.7, 31.4, 29.2.

Example 74: (S)-2-(6-(5-bromo-2-fluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-cyclopentylacetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(5-bromo-2-fluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a pale brown solid.

1 H NMR (DMSO d6 ): 11.71 (1H, s), 7.93 (1H, br d, J=7.0 Hz), 7.57 (1H, dd, J=6.7, 2.4 Hz), 7.53 (1H, ddd, J=8.7, 4.5, 2.5 Hz), 7.23 (1H, dd, J=10.3, 8.8 Hz), 4.20 (1H, quin, J=7.8 Hz), 4.12 (1H, dd, J=11.2, 8.1 Hz), 3.97 (1H, sxt, J=6.9 Hz), 3.73 (1H, dd, J=11.3, 7.5 Hz), 3.21 (2H, s), 3.17 (1H, br dd, J=15.5, 8.1 Hz), 2.83 (1H, dd, J=15.5, 7.8 Hz), 1.77 (2H, m), 1.61 (2H, m), 1.48 (2H, m), 1.35 (2H, m).

13 C NMR (DMSO d6 ): 167, 160.3, 158.7, 155.2, 131.9, 131.8, 131.4, 131.3, 130.8, 130.7, 128.8, 118, 117.9, 116.5, 116.5, 114.8, 50.5, 49.2, 40.3, 32.2, 31.5, 29.7, 23.4.

Example 75: 2-((R)-6-(5-chloro-2-fluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(H-imidazol-1-yl)-2-(6-(5-chloro-2-fluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a green solid.

1 H NMR (DMSO d6 ): 11.72 (1H, s), 8.22 (1H, br d, J=6.5 Hz), 7.45 (1H, dd, J=6.5, 2.6 Hz), 7.40 (1H, ddd, J=8.7, 4.3, 2.8 Hz), 7.29 (1H, dd, J=10.1, 8.9 Hz), 4.21 (2H, m), 4.13 (1H, dd, J=11.3, 8.1 Hz), 3.77 (1H, m), 3.72 (2H, m), 3.66 (1H, td, J=8.2, 5.6 Hz), 3.46 (1H, dd, J=8.9, 3.7 Hz), 3.25 (2H, s), 3.18 (1H, dd, J=15.4, 8.1 Hz), 2.84 (1H, dd, J=15.4, 7.8 Hz), 2.07 (1H, dq, J=12.7, 7.6 Hz), 1.71 (1H, m).

13 C NMR (DMSO d6 ): 167.6, 159.8, 158.2, 155.3, 130.4, 130.3, 129, 128.9, 128.8, 128.5, 128.5, 128.5, 128.4, 117.6, 117.4, 114.6, 72.4, 66.3, 49.8, 49.2, 40.3, 32, 31.3, 29.6.

Example 76: (R)—N-cyclopentyl-2-(6-(2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(H-imidazol-1-yl)-2-(6-(2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a pale grey solid.

1 H NMR (DMSO d6 ): 1.72 (1H, s), 7.92 (1H, br d, J=7.2 Hz), 7.40 (1H, m), 7.13 (2H, m), 4.41 (1H, quin, J=8.8 Hz), 4.14 (1H, dd, J=9.3, 11.3 Hz), 3.96 (1H, sxt, J=6.8 Hz), 3.71 (1H, dd, J=11.4, 8.4 Hz), 3.20 (2H, s), 3.18 (1H, dd, J=9.2, 15.6 Hz), 2.84 (1H, dd, J=15.6, 8.6 Hz), 1.77 (2H, m), 1.61 (2H, m), 1.48 (2H, m), 1.35 (2H, m).

13 C NMR (DMSO d6 ): 167, 161.6, 161.6, 160, 159.9, 155.1, 129.8, 129.7, 129.7, 129, 116.6, 116.4, 116.3, 114.5, 112.2, 112.2, 112.1, 112.1, 50.5, 48.6, 35.3, 32.2, 32.2, 31.5, 29.4, 23.4.

Example 77: 2-((R)-6-(2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example from (R)-1-(1H-imidazol-1-yl)-2-(6-(2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a pale grey solid.

1 H NMR (DMSO d6 ): 1.73 (1H, s), 8.21 (1H, br d, J=6.5 Hz), 7.40 (1H, m), 7.13 (2H, t, J=8.1 Hz), 4.41 (1H, quin, J=8.8 Hz), 4.21 (1H, m), 4.14 (1H, dd, J=10.8, 9.8 Hz), 3.76 (1H, m), 3.71 (2H, m), 3.65 (1H, td, J=8.2, 5.6 Hz), 3.45 (1H, dd, J=8.9, 3.7 Hz), 3.24 (2H, s), 3.19 (1H, dd, J=15.6, 9.2 Hz), 2.84 (1H, dd, J=15.7, 8.7 Hz), 2.06 (1H, dq, J=12.7, 7.6 Hz), 1.71 (1H, m).

13 C NMR (DMSO d6 ): 167.5, 161.6, 161.6, 160, 159.9, 155.1, 129.8, 129.7, 129.7, 129.2, 116.5, 116.4, 116.3, 114.2, 112.2, 112.2, 112.1, 112.1, 72.4, 66.3, 49.8, 48.6, 35.3, 32, 31.3, 29.4.

Example 78: (R)—N-cyclopropyl-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a beige powder.

1 H NMR (DMSO d6 ): 1.74 (1H, s), 8.04 (1H, br d, J=3.7 Hz), 7.85 (1H, m), 4.48 (1H, quin, J=8.6 Hz), 4.17 (1H, dd, J=11.5, 9.3 Hz), 3.77 (1H, dd, J=11.7, 7.9 Hz), 3.25 (1H, dd, J=15.8, 9.4 Hz), 3.19 (2H, m), 2.88 (1H, dd, J=15.9, 8.2 Hz), 2.59 (1H, tq, J=7.4, 3.8 Hz), 0.60 (2H, m), 0.38 (2H, m).

13 C NMR (DMSO d6 ): 168.7, 155.2, 146.4, 146.4, 146.4, 146.3, 146.3, 146.2, 145.3, 145.3, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 144.8, 144.8, 144.7, 144.7, 144.7, 144.6, 144.6, 143.7, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 128.9, 120.4, 120.3, 120.2, 114.3, 105.9, 105.7, 105.5, 48.4, 35.7, 31.3, 29.2, 22.4, 5.6, 5.6.

Example 79: (R)—N-(cyclopropylmethyl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a cream powder.

1 H NMR (DMSO d6 ): 1.76 (1H, s), 8.05 (1H, br t, J=5.4 Hz), 7.85 (1H, m), 4.48 (1H, quin, J=8.6 Hz), 4.17 (1H, dd, J=11.6, 9.1 Hz), 3.77 (1H, dd, J=11.6, 7.9 Hz), 3.25 (1H, dd, J=9.3, 11.7 Hz), 3.24 (2H, s), 2.92 (2H, t, J=6.2 Hz), 2.89 (1H, dd, J=16.1, 8.3 Hz), 0.87 (1H, m), 0.38 (2H, m), 0.13 (2H, m).

13 C NMR (DMSO d6 ): 167.4, 155.2, 146.4, 146.4, 146.4, 146.4, 146.4, 146.3, 146.3, 146.3, 146.2, 145.3, 145.3, 145.3, 145.3, 145.2, 145.2, 144.8, 144.8, 144.8, 144.7, 144.7, 144.7, 144.7, 144.6, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 128.9, 120.4, 120.3, 120.2, 114.4, 105.9, 105.7, 105.6, 48.4, 43.1, 35.8, 31.5, 29.2, 10.7, 3.2.

Example 80: (R)—N-cyclobutyl-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a beige powder.

1 H NMR (DMSO d6 ): 1.74 (1H, s), 8.20 (1H, br d, J=7.6 Hz), 7.85 (1H, m), 4.48 (1H, quin, J=8.5 Hz), 4.16 (2H, m), 3.77 (1H, dd, J=11.6, 7.9 Hz), 3.24 (1H, br dd, J=15.8, 9.2 Hz), 3.20 (2H, s), 2.87 (1H, br dd, J=15.8, 8.1 Hz), 2.12 (2H, m), 1.86 (2H, m), 1.60 (2H, m).

13 C NMR (DMSO d6 ): 166.5, 155.2, 146.4, 146.4, 146.3, 146.3, 146.3, 146.2, 145.3, 145.3, 145.2, 145.2, 145.2, 145.2, 144.8, 144.7, 144.7, 144.7, 144.6, 144.6, 143.7, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 128.9, 120.4, 120.3, 120.2, 114.3, 105.9, 105.7, 105.5, 48.4, 44, 35.7, 31.4, 30.2, 30.2, 29.2, 14.6.

Example 81: (R)-1-(4-methylpiperazin-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from (R)-1-(H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a cream powder.

1 H NMR (DMSO d6 ): 1.70 (1H, br s), 7.85 (1H, m), 4.49 (1H, quin, J=8.5 Hz), 4.18 (1H, dd, J=11.4, 9.3 Hz), 3.78 (1H, dd, J=11.7, 7.7 Hz), 3.50 (2H, m), 3.48-3.38 (4H, m), 3.24 (1H, br dd, J=15.8, 9.4 Hz), 2.85 (1H, dd, J=15.8, 7.9 Hz), 2.26 (4H, m), 2.17 (3H, s).

13 C NMR (DMSO d6 ): 166.5, 155.2, 146.4, 146.4, 146.3, 146.3, 146.3, 146.2, 145.3, 145.2, 144.8, 144.8, 144.7, 144.7, 144.7, 144.6, 144.6, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 143.6, 143.5, 129, 120.5, 120.4, 120.3, 114.2, 105.8, 105.7, 105.5, 54.6, 54.2, 48.5, 45.6, 45.1, 41.2, 35.8, 29.2, 29.1.

Example 82: (R)-1-(4-hydroxypiperidin-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from (R)-1-(H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a cream powder.

1 H NMR (DMSO d6 ): 1.70 (1H, br s), 7.85 (1H, m), 4.75 (1H, s br), 4.48 (1H, quin, J=8.5 Hz), 4.18 (1H, m), 3.86 (1H, m), 3.77 (1H, dd, J=11.6, 7.9 Hz), 3.67 (2H, m), 3.49 (2H, m), 3.24 (1H, br dd, J=15.8, 9.2 Hz), 3.16 (1H, m), 3.01 (1H, m), 2.86 (1H, dd, J=15.8, 7.9 Hz), 1.69 (2H, m), 1.32 (1H, br d, J=9.1 Hz), 1.24 (1H, m).

13 C NMR (DMSO d6 ): 66.2, 155.2, 146.4, 146.4, 146.4, 146.3, 146.3, 146.2, 145.3, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 144.8, 144.8, 144.7, 144.7, 144.6, 144.6, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 129, 120.5, 120.4, 120.2, 114.4, 105.9, 105.7, 105.5, 65.4, 65.4, 48.4, 42.8, 39, 35.8, 34.5, 34.4, 33.8, 29.2, 29.1, 29.1.

Example 83: (R)-1-(4-(hydroxymethyl)piperidin-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from (R)-1-(H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a beige powder.

1 H NMR (DMSO d6 ): 1.71 (1H, br d, J=5.1 Hz), 7.85 (1H, m), 4.48 (1H, m), 4.48 (1H, br), 4.34 (1H, br d, J=11.6 Hz), 4.17 (1H, m), 3.84 (1H, br d, J=12.5 Hz), 3.77 (1H, m), 3.48 (2H, m), 3.23 (3H, m), 2.98 (1H, m), 2.86 (1H, m), 2.52 (1H, m), 1.74-1.51 (3H, m), 0.98 (2H, m).

13 C NMR (DMSO d6 ): 166.1, 166.1, 155.2, 155.1, 146.4, 146.4, 146.4, 146.4, 146.4, 146.3, 146.3, 146.3, 146.2, 145.4, 145.4, 145.3, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 145.2, 144.8, 144.7, 144.7, 144.7, 144.6, 144.6, 143.7, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 143.5, 128.9, 120.4, 120.3, 120.2, 114.5, 114.4, 105.9, 105.7, 105.5, 65.5, 65.5, 48.5, 45.3, 45.3, 41.3, 38.3, 38.3, 35.8, 35.7, 29.2, 29.2, 29, 28.3, 28.3.

Example 84: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-cyclopentylacetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a white solid.

1 H NMR (DMSO d6 ): 1.55 (1H, br s), 7.93 (1H, br d, J=7.2 Hz), 7.61 (1H, m), 7.22 (1H, m), 4.44 (1H, quin, J=8.6 Hz), 4.15 (1H, dd, J=9.6, 10.5 Hz), 3.96 (1H, sxt, J=6.8 Hz), 3.73 (1H, dd, J=11.5, 8.0 Hz), 3.21 (1H, m), 3.20 (2H, s), 2.83 (1H, br dd, J=15.8, 8.1 Hz), 1.76 (2H, m), 1.61 (2H, m), 1.48 (2H, m), 1.35 (2H, m).

13 C NMR (DMSO d6 ): 166.9, 160.1, 158.5, 158.5, 156.6, 156.5, 155.1, 154.9, 154.9, 129.7, 129.6, 128.9, 118.8, 118.7, 118.6, 116, 115.9, 114.5, 113.2, 113.2, 113.1, 113.1, 50.5, 48.5, 35.6, 32.2, 32.2, 31.5, 29.3, 23.4.

Example 85: (R)—N,N-dimethyl-2-(4-(2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetyl)piperazin-1-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light beige powder.

1 H NMR (DMSO d6 ): 1.71 (1H, m), 7.85 (1H, m), 4.50 (1H, quin, J=8.5 Hz), 4.18 (1H, dd, J=11.2, 9.5 Hz), 3.77 (1H, dd, J=11.6, 7.8 Hz), 3.50 (2H, s), 3.44 (4H, m), 3.24 (1H, br dd, J=15.8, 9.5 Hz), 3.16 (2H, s), 2.99 (3H, s), 2.86 (1H, dd, J=7.8, 15.7 Hz), 2.80 (3H, s), 2.41 (4H, m).

13 C NMR (DMSO d6 ): 168.7, 166.4, 155.2, 146.4, 146.4, 146.4, 146.4, 146.3, 146.3, 146.2, 146.2, 145.3, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 145.2, 144.8, 144.8, 144.7, 144.7, 144.7, 144.6, 144.6, 143.7, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 129, 120.5, 120.4, 120.3, 114.2, 105.8, 105.7, 105.5, 59.5, 52.5, 52.1, 48.5, 45.2, 41.3, 36.6, 35.8, 34.9, 29.2, 29.

Example 86: (R)-1-(2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetyl)piperidine-4-carboxamide

Compound was prepared analogous manner to Example 32 from (R)-1-(H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a beige powder.

1 H NMR (DMSO d6 ): 1.70 (1H, br d, J=4.5 Hz), 7.85 (1H, quin, J=8.7 Hz), 7.28 (1H, br s), 6.80 (1H, br s), 4.49 (1H, quin, J=8.4 Hz), 4.30 (1H, br d, J=13.1 Hz), 4.18 (1H, dd, J=9.7, 11.3 Hz), 3.86 (1H, br d, J=11.9 Hz), 3.77 (1H, dd, J=11.7, 7.8 Hz), 3.50 (2H, m), 3.24 (1H, ddd, J=15.7, 9.1, 6.5 Hz), 3.02 (1H, m), 2.87 (1H, dd, J=7.9, 15.7 Hz), 2.60 (1H, m), 2.32 (1H, tt, J=11.4, 3.8 Hz), 1.69 (2H, m), 1.47 (1H, m), 1.35 (1H, m).

13 C NMR (DMSO d6 ): 175.9, 175.9, 166.3, 166.2, 155.2, 146.4, 146.4, 146.4, 146.3, 146.3, 146.3, 146.2, 145.3, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 145.2, 144.8, 144.8, 144.7, 144.7, 144.6, 144.6, 143.7, 143.7, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 143.6, 143.6, 129, 120.4, 120.3, 120.2, 114.4, 105.9, 105.7, 105.5, 48.4, 44.8, 41.2, 41, 35.8, 29.1, 29.1, 29, 28.7, 28.1.

Example 87: (R)-1-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from (R)-1-(H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a white powder.

1 H NMR (DMSO d6 ): 1.68 (1H, m), 7.85 (1H, m), 4.49 (1H, quin, J=8.5 Hz), 4.17 (1H, dd, J=11.4, 9.2 Hz), 3.90 (4H, s), 3.78 (1H, dd, J=11.7, 7.7 Hz), 3.53 (2H, s), 3.49 (4H, m), 3.24 (1H, dd, J=15.8, 9.4 Hz), 2.85 (1H, dd, J=15.8, 7.9 Hz), 1.63 (2H, m), 1.55 (2H, br s).

13 C NMR (DMSO d6 ): 166.4, 155.2, 146.4, 146.4, 146.4, 146.3, 146.3, 146.2, 145.3, 145.3, 145.3, 145.2, 145.2, 144.8, 144.8, 144.7, 144.7, 144.6, 144.6, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 143.6, 129.1, 120.5, 120.4, 120.3, 114.3, 106.3, 105.8, 105.7, 105.5, 63.8, 48.4, 43.4, 35.8, 34.9, 34.3, 29.2, 29.

Example 88: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-isopropylacetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a white solid.

1 H NMR (DMSO d6 ): 1.75 (1H, br s), 7.86 (1H, br d, J=7.5 Hz), 7.61 (1H, m), 7.22 (1H, m), 4.44 (1H, quin, J=8.6 Hz), 4.14 (1H, dd, J=11.4, 9.3 Hz), 3.80 (1H, m), 3.72 (1H, dd, J=11.6, 8.1 Hz), 3.21 (1H, dd, J=9.2, 15.8 Hz), 3.19 (2H, s), 2.84 (1H, dd, J=15.8, 8.3 Hz), 1.03 (6H, d, J=6.6 Hz).

13 C NMR (DMSO d6 ): 166.5, 160.1, 160.1, 158.5, 158.5, 156.6, 156.5, 155.1, 154.9, 154.9, 129.7, 129.6, 128.9, 118.8, 118.7, 118.6, 116.1, 116, 115.9, 115.9, 114.5, 113.2, 113.2, 113.1, 113.1, 48.5, 40.6, 35.6, 31.5, 29.3, 22.3.

Example 89: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(3-morpholinopropyl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a white solid.

1 H NMR (DMSO d6 ): 11.75 (1H, s), 7.93 (1H, br t, J=5.5 Hz), 7.62 (1H, m), 7.22 (1H, m), 4.44 (1H, quin, J=8.7 Hz), 4.15 (1H, dd, J=11.2, 9.4 Hz), 3.73 (1H, dd, J=11.5, 8.1 Hz), 3.53 (4H, br t, J=4.5 Hz), 3.22 (2H, s), 3.21 (1H, m), 3.06 (2H, m), 2.84 (1H, dd, J=15.8, 8.4 Hz), 2.29 (4H, br s), 2.24 (2H, br t, J=7.2 Hz), 1.53 (2H, quin, J=7.1 Hz).

13 C NMR (DMSO d6 ): 167.5, 160.2, 160.1, 158.5, 158.5, 156.6, 156.5, 155.2, 154.9, 154.9, 129.7, 129.7, 129, 118.7, 118.6, 118.5, 116.1, 116.1, 116, 115.9, 114.3, 113.3, 113.2, 113.1, 113.1, 66.2, 55.8, 53.3, 48.5, 37.1, 35.6, 31.5, 29.3, 25.9.

Example 90: 2-((S)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light cream powder.

1 H NMR (DMSO d6 ): 1.75 (1H, s), 8.22 (1H, d, J=6.6 Hz), 7.72 (1H, td, J=8.4, 5.7 Hz), 7.16 (1H, m), 4.44 (1H, quin, J=8.6 Hz), 4.20 (1H, m), 4.14 (1H, dd, J=11.4, 9.2 Hz), 3.76 (1H, m), 3.72 (2H, m), 3.65 (1H, td, J=8.2, 5.6 Hz), 3.45 (1H, dd, J=8.9, 3.6 Hz), 3.24 (2H, s), 3.21 (1H, dd, J=9.3, 15.7 Hz), 2.83 (1H, dd, J=15.6, 8.1 Hz), 2.06 (1H, m), 1.71 (1H, m).

13 C NMR (DMSO d6 ): 167.5, 160.8, 160.8, 159.2, 159.1, 157.5, 157.5, 155.9, 155.9, 155.1, 132.5, 132.4, 129.1, 118.8, 118.7, 118.5, 114.2, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 72.4, 66.3, 49.8, 48.6, 35.6, 32, 31.3, 29.3.

Example 91: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(4-methylpiperazin-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light cream solid.

1 H NMR (DMSO d6 ): 1.70 (1H, s), 7.72 (1H, m), 7.16 (1H, m), 4.45 (1H, quin, J=8.5 Hz), 4.15 (1H, dd, J=11.4, 9.4 Hz), 3.72 (1H, dd, J=11.7, 7.8 Hz), 3.49 (2H, m), 3.43 (4H, m), 3.20 (1H, dd, J=15.8, 9.3 Hz), 2.81 (1H, dd, J=15.8, 8.0 Hz), 2.26 (4H, m), 2.17 (3H, s).

13 C NMR (DMSO d6 ): 166.5, 160.8, 160.7, 159.1, 159.1, 157.5, 157.5, 155.9, 155.8, 155.2, 132.5, 132.4, 129.2, 118.9, 118.7, 118.6, 114.1, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 54.6, 54.2, 48.6, 45.6, 45.1, 41.2, 35.7, 29.3, 29.1.

Example 92: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-butyl-N-methylacetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light beige solid.

1 H NMR (DMSO d6 ): 1.71 (1H, br s), 7.72 (1H, m), 7.17 (1H, m), 4.44 (1H, m), 4.15 (1H, dd, J=9.4, 11.3 Hz), 3.72 (1H, dd, J=11.5, 7.8 Hz), 3.47 (2H, m), 3.24 (3H, m), 2.95 (1.6H, s), 2.82 (1H, m), 2.79 (1.4H, s), 1.49 (1H, quin, J=7.6 Hz), 1.40 (1H, m), 1.31-1.15 (2H, m), 0.90, 0.85 (3H, 2 t, J=7.2 Hz).

13 C NMR (DMSO d6 ): 167.6, 167.5, 160.8, 160.7, 159.1, 159.1, 157.5, 157.5, 155.9, 155.8, 155, 132.5, 132.4, 129.2, 129.1, 118.8, 118.8, 118.7, 118.7, 118.6, 118.6, 114.4, 114.3, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 49.1, 48.6, 46.7, 35.7, 35, 33.1, 30, 29.4, 29.3, 29.3, 28.9, 28.8, 19.5, 19.3, 13.7.

Example 93: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2-hydroxyethyl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light beige powder.

1 H NMR (DMSO d6 ): 11.73 (1H, s), 7.96 (1H, br t, J=5.5 Hz), 7.72 (1H, m), 7.17 (1H, m), 4.67 (1H, br s), 4.44 (1H, quin, J=8.7 Hz), 4.14 (1H, dd, J=9.5, 11.4 Hz), 3.72 (1H, dd, J=11.5, 8.1 Hz), 3.39 (2H, br t, J=5.7 Hz), 3.24 (2H, m), 3.21 (1H, dd, J=15.7, 9.5 Hz), 3.11 (2H, q, J=6.0 Hz), 2.84 (1H, dd, J=15.8, 8.4 Hz).

13 C NMR (DMSO d6 ): 167.7, 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 155.9, 155.9, 155.1, 132.5, 132.4, 129.1, 118.7, 118.6, 118.4, 114.3, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 59.7, 48.5, 41.7, 35.7, 31.5, 29.2.

Example 94: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-cyclopropylacetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a brown powder.

1 H NMR (DMSO d6 ): 11.73 (1H, s), 8.03 (1H, br d, J=3.5 Hz), 7.72 (1H, td, J=8.4, 5.9 Hz), 7.16 (1H, t, J=9.5 Hz), 4.44 (1H, quin, J=8.7 Hz), 4.14 (1H, dd, J=9.6, 11.2 Hz), 3.72 (1H, dd, J=11.4, 8.1 Hz), 3.21 (1H, dd, J=9.7, 15.9 Hz), 3.18 (2H, s), 2.83 (1H, dd, J=15.6, 8.3 Hz), 2.59 (1H, m), 0.59 (2H, m), 0.38 (2H, m).

13 C NMR (DMSO d6 ): 168.7, 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 155.9, 155.9, 155.1, 132.5, 132.4, 129.1, 118.7, 118.6, 118.5, 114.2, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 48.5, 35.6, 31.3, 29.3, 22.4, 5.6, 5.6.

Example 95: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(cyclopropylmethyl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light cream powder.

1 H NMR (DMSO d6 ): 1.75 (1H, s), 8.04 (1H, t, J=5.5 Hz), 7.72 (1H, ddd, J=8.9, 8.1, 5.8 Hz), 7.16 (1H, m), 4.44 (1H, quin, J=8.7 Hz), 4.15 (1H, dd, J=11.4, 9.3 Hz), 3.72 (1H, dd, J=11.6, 8.1 Hz), 3.24 (2H, s), 3.22 (1H, dd, J=9.5, 15.7 Hz), 2.92 (2H, t, J=6.2 Hz), 2.84 (1H, dd, J=15.7, 8.2 Hz), 0.87 (1H, m), 0.37 (2H, m), 0.13 (2H, m).

13 C NMR (DMSO d6 ): 167.4, 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 155.9, 155.9, 155.1, 132.5, 132.4, 129.1, 118.7, 118.6, 118.5, 114.3, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 48.5, 43.1, 35.6, 31.5, 29.3, 10.7, 3.2.

Example 96: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light beige powder.

1 H NMR (DMSO d6 ): 11.73 (1H, s), 7.72 (1H, td, J=8.4, 5.7 Hz), 7.37 (1H, br s), 7.17 (1H, m), 7.02 (1H, br s), 4.45 (1H, quin, J=8.8 Hz), 4.14 (1H, dd, J=9.5, 11.2 Hz), 3.73 (1H, dd, J=11.5, 8.1 Hz), 3.23 (1H, dd, J=9.3, 16.0 Hz), 3.21 (2H, d, J=4.8 Hz), 2.85 (1H, dd, J=15.7, 8.4 Hz).

13 C NMR (DMSO d6 ): 169.8, 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 155.9, 155.9, 155.1, 132.5, 132.4, 129.2, 118.7, 118.5, 118.4, 114.3, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 48.5, 35.7, 31.2, 29.2.

Example 97: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-propylacetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light cream powder.

1 H NMR (DMSO d6 ): 1.74 (1H, s), 7.91 (1H, br t, J=5.5 Hz), 7.72 (1H, ddd, J=8.8, 8.1, 5.8 Hz), 7.16 (1H, m), 4.44 (1H, quin, J=8.7 Hz), 4.14 (1H, dd, J=11.4, 9.3 Hz), 3.72 (1H, dd, J=11.5, 8.0 Hz), 3.23 (2H, s), 3.20 (1H, dd, J=9.0, 15.8 Hz), 2.99 (2H, m), 2.83 (1H, dd, J=15.8, 8.3 Hz), 1.39 (2H, sxt, J=7.2 Hz), 0.82 (3H, t, J=7.4 Hz).

13 C NMR (DMSO d6 ): 167.4, 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 155.9, 155.9, 155.1, 132.5, 132.4, 129.2, 129.1, 118.7, 118.6, 118.5, 114.3, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 48.5, 40.5, 35.7, 31.5, 29.3, 22.3, 11.4.

Example 98: 1-((S)-2-(hydroxymethyl)pyrrolidin-1-yl)-2-((R)-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from (R)-1-(H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light beige powder.

1 H NMR (DMSO d6 ): 1.72 (1H, br s), 7.85 (1H, m), 5.18-4.57 (1H, 2 br s), 4.48 (1H, quin, J=8.5 Hz), 4.18 (1H, br t, J=10.3 Hz), 4.0-3.86 (1H, 2 m), 3.78 (1H, br dd, J=11.5, 7.8 Hz), 3.67-3.18 (7H, multiplets), 2.87 (1H, br dd, J=15.7, 7.9 Hz), 2.01-1.68 (4H, m).

13 C NMR (DMSO d6 ): 166.8, 166.7, 155.1, 155, 146.4, 146.4, 146.4, 146.3, 146.3, 146.3, 146.2, 145.3, 145.3, 145.2, 145.2, 144.8, 144.8, 144.7, 144.7, 144.6, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 143.6, 129, 129, 120.5, 120.4, 120.3, 114.6, 114.1, 105.8, 105.7, 105.5, 62.6, 60.9, 58.8, 58.8, 48.4, 47, 45.5, 35.8, 35.7, 30.7, 30, 29.2, 27.8, 26.7, 23.4, 21.4.

Example 99: (S)—N-cyclobutyl-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a beige powder.

1 H NMR (DMSO d6 ): 11.74 (1H, s), 8.20 (1H, br d, J=7.6 Hz), 7.85 (1H, m), 4.48 (1H, quin, J=8.6 Hz), 4.16 (2H, m), 3.77 (1H, dd, J=11.7, 7.8 Hz), 3.24 (1H, dd, J=15.8, 9.4 Hz), 3.20 (2H, s), 2.87 (1H, dd, J=15.8, 8.1 Hz), 2.12 (2H, m), 1.86 (2H, m), 1.60 (2H, m).

13 C NMR (DMSO d6 ): 166.5, 155.2, 146.4, 146.3, 146.3, 146.2, 145.3, 145.3, 145.3, 145.2, 145.2, 144.8, 144.8, 144.7, 144.7, 144.7, 144.6, 144.6, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 128.9, 120.3, 114.3, 105.9, 105.7, 105.6, 48.4, 44, 35.7, 31.4, 30.2, 30.2, 29.2, 14.6.

Example 100: 2-((S)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-((S)-2-(hydroxymethyl)pyrrolidin-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a brown solid.

1 H NMR (DMSO d6 ): 1.70 (1H, s), 7.72 (1H, m), 7.16 (1H, m), 4.97 (0.35H, br s), 4.71 (0.65H, br s), 4.45 (1H, m), 4.15 (1H, dd, J=9.0, 11.2 Hz), 3.95 (0.35H, m), 3.91 (0.65H, m), 3.72 (1H, dd, J=11.6, 7.9 Hz), 3.57 (0.35H, m), 3.52-3.36 (3.65H, m), 3.31-3.14 (3H, m), 2.83 (1H, m), 1.84 (4H, m).

13 C NMR (DMSO d6 ): 166.8, 160.8, 160.7, 159.2, 159.1, 157.5, 157.5, 155.9, 155.9, 155, 155, 132.5, 132.4, 129.3, 129.1, 118.9, 118.8, 118.7, 118.7, 114.5, 114, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 62.7, 60.9, 58.8, 58.8, 48.6, 48.6, 47, 45.5, 35.6, 30.7, 30.1, 29.4, 29.3, 27.8, 26.7, 23.4, 21.4.

Example 101: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(pyrrolidin-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light brown powder.

1 H NMR (DMSO d6 ): 1.71 (1H, s), 7.72 (1H, m), 7.17 (1H, m), 4.45 (1H, quin, J=8.6 Hz), 4.15 (1H, dd, J=11.4, 9.3 Hz), 3.72 (1H, dd, J=11.7, 7.8 Hz), 3.42 (2H, m), 3.41 (2H, s), 3.27 (2H, t, J=6.9 Hz), 3.21 (1H, dd, J=15.7, 9.4 Hz), 2.81 (1H, dd, J=15.7, 8.1 Hz), 1.87 (2H, m), 1.76 (2H, m).

13 C NMR (DMSO d6 ): 166.1, 160.8, 160.8, 159.2, 159.1, 157.5, 157.5, 155.9, 155.9, 155.1, 132.5, 132.4, 129.2, 118.9, 118.8, 118.6, 114.1, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 48.6, 46.2, 45.5, 35.6, 30.5, 29.3, 25.6, 24.

Example 102: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-cyclobutylacetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light beige powder.

1 H NMR (DMSO d6 ): 1.73 (1H, s), 8.20 (1H, br d, J=7.6 Hz), 7.72 (1H, m), 7.17 (1H, m), 4.44 (1H, quin, J=8.7 Hz), 4.15 (2H, m), 3.72 (1H, dd, J=11.6, 7.9 Hz), 3.20 (1H, dd, J=9.3, 15.5 Hz), 3.19 (2H, s), 2.82 (1H, dd, J=15.6, 8.3 Hz), 2.12 (2H, m), 1.86 (2H, m), 1.60 (2H, m).

13 C NMR (DMSO d6 ): 166.5, 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 155.9, 155.9, 155.1, 132.5, 132.4, 129.1, 118.8, 118.6, 118.5, 114.2, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 48.6, 44, 35.6, 31.4, 30.2, 30.2, 29.3, 14.7.

Example 103: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2-methoxyethyl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a beige powder.

1 H NMR (DMSO d6 ): 1.74 (1H, s), 8.04 (1H, br t, J=5.4 Hz), 7.72 (1H, m), 7.16 (1H, m), 4.44 (1H, quin, J=8.7 Hz), 4.14 (1H, dd, J=m), 3.72 (1H, dd, J=11.5, 8.0 Hz), 3.32 (2H, t, J=5.6 Hz), 3.24 (2H, m), 3.22-3.17 (3H, m), 3.20 (3H, s), 2.83 (1H, dd, J=15.8, 8.3 Hz).

13 C NMR (DMSO d6 ): 167.7, 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 155.9, 155.9, 155.1, 132.5, 132.4, 129.1, 118.7, 118.6, 118.5, 114.3, 113.8, 113.8, 113.6, 104.1, 104, 103.9, 103.9, 70.5, 57.8, 48.5, 38.6, 35.6, 31.5, 29.3.

Example 104: (R)-1-(pyrrolidin-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light beige powder.

1 H NMR (DMSO d6 ): 1.71 (1H, br s), 7.85 (1H, m), 4.49 (1H, quin, J=8.5 Hz), 4.18 (1H, dd, J=11.6, 9.1 Hz), 3.78 (1H, dd, J=11.7, 7.7 Hz), 3.42 (4H, m), 3.27 (2H, t, J=7 Hz), 3.25 (1H, dd, J=9.3, 15.8 Hz), 2.87 (1H, dd, J=15.8, 7.9 Hz), 1.88 (2H, m), 1.76 (2H, m).

13 C NMR (DMSO d6 ): 166.1, 155.1, 146.4, 146.4, 146.3, 146.3, 146.3, 146.3, 146.3, 146.2, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 144.8, 144.8, 144.7, 144.7, 144.7, 144.6, 144.6, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 129, 120.5, 120.4, 120.3, 114.2, 105.8, 105.7, 105.5, 48.5, 46.1, 45.5, 35.7, 30.4, 29.2, 25.6, 24.

Example 105: (S)-1-(pyrrolidin-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light beige powder.

1 H NMR (DMSO d6 ): 1.72 (1H, br s), 7.85 (1H, m), 4.49 (1H, quin, J=8.5 Hz), 4.18 (1H, dd, J=11.5, 9.2 Hz), 3.77 (1H, dd, J=11.6, 7.8 Hz), 3.42 (4H, m), 3.27 (2H, t, J=7 Hz), 3.25 (1H, dd, J=9.3, 15.8 Hz), 2.87 (1H, dd, J=15.8, 7.9 Hz), 1.87 (2H, m), 1.76 (2H, m).

13 C NMR (DMSO d6 ): 166.1, 155.1, 146.4, 146.4, 146.3, 146.3, 146.3, 146.3, 146.2, 145.3, 145.3, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 144.8, 144.8, 144.7, 144.7, 144.6, 144.6, 144.6, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 143.6, 129, 120.5, 120.4, 120.3, 114.2, 105.8, 105.7, 105.5, 48.5, 46.1, 45.5, 35.7, 30.4, 29.2, 25.6, 24.

Example 106: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2-(pyridin-2-yl)ethyl)acetamide hydrochloride

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as an off-white solid.

1 H NMR (DMSO d6 ): 11.72 (1H, br s), 8.70 (1H, br d, J=5.1 Hz), 8.25 (1H, br s), 8.12 (1H, br t, J=5.6 Hz), 7.71 (2H, m), 7.62 (1H, m), 7.23 (1H, m), 4.41 (1H, quin, J=8.7 Hz), 4.14 (1H, dd, J=9.4, 11.4 Hz), 3.73 (1H, dd, J=11.4, 8.2 Hz), 3.47 (2H, m), 3.21 (2H, m), 3.15 (1H, dd, J=15.8, 9.2 Hz), 3.07 (2H, t, J=6.6 Hz), 2.79 (1H, dd, J=15.8, 8.4 Hz).

13 C NMR (DMSO d6 ): 168, 160.2, 160.1, 158.6, 158.5, 156.6, 156.6, 155.9, 155.8, 155.2, 155.2, 155, 154.9, 143.7, 143.2, 129.8, 129.7, 129.4, 126.3, 123.9, 118.7, 118.5, 118.4, 116.1, 116, 114.1, 114, 113.3, 113.1, 48.5, 38.1, 35.6, 34.3, 31.5, 29.2.

Example 107: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2-methoxyethyl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as an off-white solid.

1 H NMR (DMSO d6 ): 1.74 (1H, s), 8.04 (1H, br t, J=5.6 Hz), 7.61 (1H, m), 7.22 (1H, m), 4.44 (1H, quin, J=8.7 Hz), 4.15 (1H, dd, J=11.4, 9.2 Hz), 3.73 (1H, dd, J=11.6, 8.1 Hz), 3.32 (2H, t, J=5.5 Hz), 3.26-3.15 (5H, m), 3.20 (3H, s), 2.84 (1H, dd, J=15.8, 8.2 Hz).

13 C NMR (DMSO d6 ): 167.7, 155.1, 129.7, 129.6, 129.1, 118.7, 118.6, 118.5, 116.1, 116, 115.9, 115.9, 114.2, 113.2, 113.2, 113.1, 113.1, 70.5, 57.8, 48.5, 38.6, 35.6, 31.5, 29.2.

Example 108: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as an off-white solid.

1 H NMR (DMSO d6 ): 11.73 (1H, br s), 7.62 (1H, m), 7.37 (1H, br s), 7.22 (1H, m), 7.01 (1H, br s), 4.45 (1H, quin, J=8.7 Hz), 4.14 (1H, dd, J=9.4, 11.2 Hz), 3.74 (1H, dd, J=11.5, 8.1 Hz), 3.23 (1H, dd, J=9.3, 15.7 Hz), 3.21 (2H, m), 2.86 (1H, dd, J=15.7, 8.5 Hz).

13 C NMR (DMSO d6 ): 169.8, 160.2, 160.1, 158.5, 158.5, 156.6, 156.5, 155.1, 155, 154.9, 129.7, 129.6, 129.2, 118.7, 118.6, 118.4, 116.1, 116, 115.9, 115.9, 114.4, 113.2, 113.2, 113.1, 113.1, 48.5, 35.6, 31.2, 29.2.

Example 109: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(pyridin-3-ylmethyl)acetamide Hydrochloride

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as an off-white solid.

1 H NMR (DMSO d6 ): 11.81 (1H, s), 8.51 (1H, t, J=5.9 Hz), 8.48 (1H, dd, J=0.6, 2.4 Hz), 8.41 (1H, dd, J=4.7, 1.6 Hz), 7.65 (1H, m), 7.62 (1H, m), 7.31 (1H, ddd, J=0.8, 4.8, 7.8 Hz), 7.22 (1H, m), 4.42 (1H, quin, J=8.7 Hz), 4.29 (2H, m), 4.14 (1H, dd, J=9.4, 11.3 Hz), 3.73 (1H, dd, J=11.5, 8.1 Hz), 3.32 (2H, m), 3.14 (1H, dd, J=15.7, 9.2 Hz), 2.76 (1H, dd, J=15.8, 8.4 Hz).

13 C NMR (DMSO d6 ): 167.9, 160.2, 160.1, 158.5, 158.5, 156.6, 156.5, 155.3, 154.9, 154.9, 148.8, 148.1, 135.2, 134.7, 129.7, 129.7, 129.3, 123.3, 118.6, 118.5, 118.4, 116.1, 116, 115.9, 115.9, 114, 113.3, 113.2, 113.1, 113.1, 48.5, 39.8, 35.6, 31.4, 29.2.

Example 110: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(pyrrolidin-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as an off-white solid.

1 H NMR (DMSO d6 ): 1.71 (1H, br s), 7.61 (1H, m), 7.21 (1H, m), 4.44 (1H, quin, J=8.5 Hz), 4.16 (1H, dd, J=11.2, 9.5 Hz), 3.73 (1H, dd, J=11.6, 7.9 Hz), 3.42 (2H, m), 3.41 (2 H, s), 3.27 (2H, t, J=6.9 Hz), 3.22 (1H, dd, J=15.8, 9.3 Hz), 2.82 (1H, dd, J=15.8, 8.1 Hz), 1.87 (2H, m), 1.76 (2H, m).

13 C NMR (DMSO d6 ): 166.1, 160.1, 160.1, 158.5, 158.5, 156.6, 156.5, 155.1, 154.9, 154.9, 129.7, 129.6, 129.2, 118.9, 118.8, 118.6, 116.1, 116, 115.9, 115.9, 114.1, 113.2, 113.2, 113.1, 113.1, 48.6, 46.1, 45.5, 35.6, 30.4, 29.3, 25.6, 24.

Example 111: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(4,4-difluoropiperidin-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as an off-white solid.

1 H NMR (DMSO d6 ): 1.68 (1H, s), 7.61 (1H, m), 7.21 (1H, m), 4.45 (1H, quin, J=8.6 Hz), 4.16 (1H, dd, J=11.5, 9.2 Hz), 3.74 (1H, dd, J=11.7, 7.8 Hz), 3.57 (2H, s), 3.56 (4H, m), 3.23 (1H, dd, J=15.8, 9.3 Hz), 2.83 (1H, dd, J=15.7, 8.1 Hz), 2.02 (2H, m), 1.91 (2H, m).

13 C NMR (DMSO d6 ): 166.8, 160.1, 160.1, 158.5, 158.5, 156.6, 156.5, 155.2, 154.9, 154.9, 129.7, 129.6, 129.4, 124.3, 122.7, 121.1, 118.9, 118.7, 118.6, 116.1, 116, 115.9, 115.9, 114, 113.2, 113.2, 113.1, 113.1, 48.6, 42.1, 42.1, 42.1, 38.5, 38.4, 38.4, 35.6, 33.9, 33.8, 33.6, 33.3, 33.2, 33, 29.2, 28.9.

Example 112: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as an off-white solid.

1 H NMR (DMSO d6 ): 1.77 (1H, s), 8.09 (1H, d, J=7.6 Hz), 7.61 (1H, m), 7.22 (1H, m), 4.44 (1H, quin, J=8.6 Hz), 4.15 (1H, dd, J=11.4, 9.2 Hz), 3.93 (1H, m), 3.73 (1H, dd, J=11.7, 8.0 Hz), 3.27-3.17 (5H, m), 3.08 (2H, m), 2.85 (1H, dd, J=15.8, 8.2 Hz), 2.04 (2H, m), 1.90 (2H, m).

13 C NMR (DMSO d6 ): 167.1, 160.2, 160.1, 158.5, 158.5, 156.6, 156.5, 155.2, 154.9, 154.9, 129.7, 129.6, 129.2, 118.8, 118.7, 118.6, 116.1, 116, 115.9, 115.9, 114.1, 113.3, 113.2, 113.1, 113.1, 48.5, 48.3, 43.9, 35.6, 31.4, 29.3, 29.1.

Example 113: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as an off-white solid.

1 H NMR (DMSO d6 ): 1.79 (1H, s), 8.64 (1H, br t, J=6.3 Hz), 7.61 (1H, m), 7.21 (1H, m), 4.44 (1H, quin, J=8.7 Hz), 4.16 (1H, dd, J=11.2, 9.3 Hz), 3.90 (2H, qd, J=9.8, 6.5 Hz), 3.74 (1H, dd, J=11.5, 8.0 Hz), 3.36 (2H, m), 3.21 (1H, dd, J=15.8, 9.3 Hz), 2.84 (1H, dd, J=15.8, 8.3 Hz).

13 C NMR (DMSO d6 ): 168.6, 160.2, 160.1, 158.5, 158.5, 156.6, 156.5, 155.3, 154.9, 154.9, 129.7, 129.7, 129.4, 127.5, 125.6, 123.8, 121.9, 118.7, 118.6, 118.5, 116.1, 116, 115.9, 115.9, 113.5, 113.2, 113.2, 113.1, 113.1, 48.5, 35.6, 31.1, 29.2.

Example 114: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2-(methylsulfonyl)ethyl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as an off-white solid.

1 H NMR (DMSO d6 ): 11.74 (1H, s), 8.20 (1H, t, J=5.6 Hz), 7.62 (1H, m), 7.22 (1H, m), 4.44 (1H, quin, J=8.7 Hz), 4.15 (1H, dd, J=11.4, 9.2 Hz), 3.74 (1H, dd, J=11.7, 8.1 Hz), 3.46 (2H, m), 3.27 (2H, m), 3.24 (2H, t, J=6.9 Hz), 3.23 (1H, m), 2.99 (3H, s), 2.87 (1H, dd, J=15.8, 8.4 Hz).

13 C NMR (DMSO d6 ): 168.1, 160.2, 160.1, 158.5, 158.5, 156.6, 156.5, 155.3, 154.9, 154.9, 129.7, 129.6, 129.5, 118.6, 118.5, 118.4, 116.1, 115.9, 113.8, 113.2, 113.1, 53, 48.5, 40.8, 35.6, 33, 31.3, 29.2.

Example 115: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2-(4,4-difluoropiperidin-1-yl)ethyl)acetamide Hydrochloride

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as an off-white solid.

1 H NMR (DMSO d6 ): 1.75 (1H, s), 10.88 (1H, br s), 8.28 (1H, br t, J=5.3 Hz), 7.62 (1H, m), 7.22 (1H, m), 4.45 (1H, quin, J=8.7 Hz), 4.15 (1H, dd, J=9.4, 11.4 Hz), 3.75 (1H, dd, J=8.2, 11.5 Hz), 3.64 (2H, br s), 3.46 (2H, q, J=5.9 Hz), 3.33 (2H, m), 3.24 (1H, dd, J=9.2, 15.8 Hz), 3.20 (2H, br s), 3.15 (2H, br s), 2.88 (1H, dd, J=15.8, 8.5 Hz), 2.46-2.24 (4H, 2 br s).

13 C NMR (DMSO d6 ): 168.5, 160.2, 160.1, 158.5, 158.5, 156.6, 155.3, 155, 129.8, 129.7, 129.6, 118.6, 118.5, 118.4, 116.2, 116.1, 116.1, 116, 113.8, 113.3, 113.3, 113.1, 113.1, 54.2, 48.7, 48.5, 35.6, 33.9, 31.5, 30.4, 29.3.

Example 116: 2-((R)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light cream powder.

1 H NMR (DMSO d6 ): 1.74 (1H, s), 8.22 (1H, d, J=6.6 Hz), 7.72 (1H, m), 7.16 (1H, m), 4.44 (1H, quin, J=8.6 Hz), 4.21 (1H, m), 4.14 (1H, dd, J=11.4, 9.2 Hz), 3.76 (1H, m), 3.71 (2H, m), 3.65 (1H, td, J=8.2, 5.6 Hz), 3.45 (1H, dd, J=8.9, 3.7 Hz), 3.24 (2H, s), 3.22 (1H, dd, J=9.4, 15.8 Hz), 2.83 (1H, dd, J=15.8, 8.1 Hz), 2.06 (1H, m), 1.71 (1H, m).

13 C NMR (DMSO d6 ): 167.5, 160.8, 160.8, 159.2, 159.1, 157.5, 157.5, 155.9, 155.9, 155.1, 132.5, 132.4, 129.1, 118.8, 118.7, 118.5, 114.2, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 72.4, 66.3, 49.7, 48.6, 35.6, 32, 31.3, 29.3.

Example 117: (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(4,4-difluoropiperidin-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from (R)-1-(H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a cream powder.

1 H NMR (DMSO d6 ): 11.68 (1H, s), 7.72 (1H, ddd, J=9.0, 8.0, 5.7 Hz), 7.16 (1H, m), 4.45 (1H, quin, J=8.5 Hz), 4.16 (1H, dd, J=11.5, 9.2 Hz), 3.73 (1H, dd, J=11.6, 7.8 Hz), 3.56 (6H, m), 3.22 (1H, dd, J=15.8, 9.3 Hz), 2.82 (1H, dd, J=15.8, 8.1 Hz), 2.02 (2H, m), 1.91 (2H, m).

13 C NMR (DMSO d6 ): 166.8, 160.8, 160.7, 159.2, 159.1, 157.5, 157.5, 155.9, 155.8, 155.2, 132.5, 132.4, 129.4, 124.2, 122.6, 121, 118.8, 118.7, 118.6, 114, 113.8, 113.7, 113.6, 113.6, 104, 104, 103.9, 103.9, 48.6, 42.1, 42.1, 42.1, 38.5, 38.4, 38.4, 35.7, 33.9, 33.8, 33.6, 33.3, 33.2, 33, 29.3, 28.9.

Example 118: (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2-(methylsulfonyl)ethyl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light brown powder.

1 H NMR (DMSO d6 ): 11.74 (1H, s), 8.19 (1H, t, J=5.7 Hz), 7.72 (1H, ddd, J=8.9, 8.1, 5.8 Hz), 7.17 (1H, m), 4.44 (1H, quin, J=8.7 Hz), 4.15 (1H, dd, J=11.4, 9.2 Hz), 3.73 (1H, dd, J=11.6, 8.2 Hz), 3.46 (2H, m), 3.30-3.18 (5H, m), 2.99 (3H, s), 2.86 (1H, dd, J=15.8, 8.4 Hz).

13 C NMR (DMSO d6 ): 168.1, 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 155.9, 155.9, 155.3, 132.5, 132.4, 129.5, 118.6, 118.5, 118.4, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 53, 48.5, 40.8, 35.7, 33, 31.3, 29.2.

Example 119: (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2-hydroxyethyl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light cream powder.

1 H NMR (DMSO d6 ): 11.72 (1H, s), 7.95 (1H, t, J=5.5 Hz), 7.72 (1H, m), 7.16 (1H, m), 4.66 (1H, t, J=5.4 Hz), 4.44 (1H, quin, J=8.7 Hz), 4.14 (1H, dd, J=11.4, 9.3 Hz), 3.72 (1H, dd, J=11.6, 8.1 Hz), 3.39 (2H, q, J=5.9 Hz), 3.24 (2H, m), 3.21 (1H, dd, J=15.8, 9.5 Hz), 3.11 (2H, q, J=6.0 Hz), 2.84 (1H, dd, J=15.8, 8.4 Hz).

13 C NMR (DMSO d6 ): 167.7, 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 155.9, 155.9, 155.1, 132.5, 132.4, 129.1, 118.7, 118.6, 118.4, 114.3, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 59.7, 48.5, 41.7, 35.7, 31.5, 29.3.

Example 120: 2-((R)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2-(hydroxymethyl)cyclopentyl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light brown powder.

1 H NMR (DMSO d6 ): 1.76 (1H, br s), 7.80 (0.5H, d, J=4.5 Hz), 7.80 (0.5H, d, J=4.5 Hz), 7.72 (1H, m), 7.16 (1H, m), 4.44 (1H, m), 4.32 (1H, m), 4.15 (1H, dd, J=11.1, 9.8 Hz), 4.08 (1H, m), 3.72 (1H, dd, J=11.0, 8.2 Hz), 3.33 (1H, m), 3.27 (2H, s), 3.25 (1H, m), 3.24 (1H, m), 2.84 (1H, m), 1.98 (1H, m), 1.80 (1H, m), 1.65 (2H, m), 1.47 (2H, m), 1.33 (1H, m).

13 C NMR (DMSO d6 ): 167.8, 160.8, 160.8, 159.2, 159.1, 157.5, 157.5, 155.9, 155.9, 155.1, 132.5, 132.4, 129, 129, 118.8, 118.7, 118.5, 114.4, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 60.9, 51.5, 51.5, 48.6, 45, 45, 35.7, 35.6, 31.4, 31.3, 31.3, 29.3, 26.2, 26.2, 21.5.

Example 121: 2-((R)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(3-hydroxypiperidin-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from (R)-1-(H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light brown powder.

1 H NMR (DMSO d6 ): 11.68 (1H, m), 7.72 (1H, ddd, J=8.7, 8.1, 5.8 Hz), 7.16 (1H, m), 4.89 (1H, m), 4.44 (1H, quin, J=8.6 Hz), 4.15 (1H, m), 4.08 (0.5H, m), 3.72 (1H, dd, J=11.5, 8.0 Hz), 3.64-3.43 (4H, m), 3.35 (0.5H, m), 3.26-3.13 (1.5H, m), 3.10 (0.5H, m), 3.00 (0.5H, m), 2.81 (1H, m), 2.57 (0.5H, m), 1.87-1.72 (1H, 2 m), 1.65 (1H, m), 1.44 (0.5H, m), 1.31 (1.5H, m).

13 C NMR (DMSO d6 ): 166.7, 166.7, 166.4, 166.4, 160.8, 160.8, 159.2, 159.1, 157.5, 157.5, 155.9, 155.8, 155.1, 132.5, 132.4, 129.1, 118.9, 118.8, 118.7, 118.6, 118.6, 118.5, 114.4, 114.3, 114.3, 114.2, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 65, 64.9, 54.9, 52.3, 48.6, 45.4, 45.4, 41.7, 41.7, 35.7, 32.8, 32.8, 32.3, 32.3, 29.3, 29.2, 29.1, 29, 23.4, 23.4, 21.7, 21.7.

Example 122: tert-butyl (R)-2-((2-((S)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamido)methyl)pyrrolidine-1-carboxylate

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light brown powder.

1 H NMR (DMSO d6 ): 1.74 (1H, 2 s), 8.00 (1H, m), 7.72 (1H, td, J=8.4, 5.8 Hz), 7.16 (1H, m), 4.44 (1H, quin, J=8.6 Hz), 4.15 (1H, dd, J=9.5, 11.4 Hz), 3.72 (1H, dd, J=8.0, 11.5 Hz), 3.71 (1H, m), 3.25 (2H, s), 3.20 (3H, m), 3.07, 2.96 (1H, 2 m), 2.83 (1H, m), 1.87-1.58 (5H, m), 1.38 (9H, s).

13 C NMR (DMSO d6 ): 167.8, 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 155.9, 155.9, 155.2, 153.9, 153.4, 132.5, 132.4, 129.2, 129, 118.7, 118.6, 118.5, 118.5, 114.3, 114.3, 114.2, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 78.4, 56.4, 48.5, 46.4, 46.1, 40.9, 35.7, 31.5, 29.3, 28.1, 27.6, 23.1, 22.2.

Example 123: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(4-(methylsulfonyl)piperidin-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a beige solid.

1 H NMR (DMSO d6 ): 1.69 (1H, 2 s), 7.72 (1H, m), 7.16 (1H, m), 4.48 (1H, m), 4.44 (1H, quin, J=8.5 Hz), 4.15 (1H, dd, J=11.4, 9.2 Hz), 4.01 (1H, br d, J=13.6 Hz), 3.72 (1H, dd, J=11.6, 7.9 Hz), 3.54 (2H, m), 3.36 (1H, m), 3.21 (1H, m), 3.07 (1H, m), 2.94 (3H, s), 2.82 (1H, m), 2.61 (1H, m), 2.04 (2H, br d, J=12.5 Hz), 1.56 (1H, m), 1.42 (1H, m).

13 C NMR (DMSO d6 ): 166.5, 166.5, 160.8, 160.8, 159.2, 159.1, 157.5, 157.5, 155.9, 155.8, 155.2, 132.5, 132.4, 129.3, 129.2, 118.7, 118.6, 118.5, 114.2, 113.8, 113.8, 113.6, 113.6, 104, 104, 103.9, 103.9, 58.4, 58.4, 48.6, 43.9, 37.5, 35.7, 29.2, 29, 29, 24.7, 24.1.

Example 124: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(pyridin-3-ylmethyl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a tan solid.

1 H NMR (DMSO d6 ): 1.80 (1H, br s), 8.51 (1H, t, J=5.6 Hz), 8.48 (1H, s), 8.41 (1H, d, J=3.7 Hz), 7.73 (1H, m), 7.65 (1H, d, J=7.8 Hz), 7.31 (1H, dd, J=7.6, 4.8 Hz), 7.17 (1H, t, J=9.3 Hz), 4.42 (1H, quin, J=8.7 Hz), 4.29 (2H, d, J=5.7 Hz), 4.14 (1H, t, J=10.3 Hz), 3.72 (1H, dd, J=11.3, 8.4 Hz), 3.33 (2H, m), 3.13 (1H, br dd, J=15.7, 9.2 Hz), 2.75 (1H, br dd, J=15.7, 8.4 Hz).

13 C NMR (DMSO d6 ): 167.9, 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 155.9, 155.9, 155.3, 148.8, 148.1, 135.1, 134.7, 132.5, 132.4, 129.3, 123.3, 118.6, 118.5, 118.3, 114, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 48.5, 39.8, 35.6, 31.4, 29.2.

Example 125: (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(1,1-dioxidothiomorpholino)ethan-1-one

Compound was prepared analogous manner to Example 32 from (R)-1-(H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light cream powder.

1 H NMR (DMSO d6 ): 1.63 (1H, s), 7.72 (1H, ddd, J=8.7, 8.1, 5.8 Hz), 7.17 (1H, m), 4.46 (1H, quin, J=8.6 Hz), 4.16 (1H, dd, J=11.3, 9.4 Hz), 3.87 (4H, m), 3.73 (1H, dd, J=11.6, 7.9 Hz), 3.62 (2H, s), 3.26 (2H, br m), 3.23 (1H, dd, J=15.9, 9.3 Hz), 3.10 (2H, br t, J=4.9 Hz), 2.84 (1H, dd, J=15.8, 8.1 Hz).

13 C NMR (DMSO d6 ): 167.4, 160.8, 160.8, 159.2, 159.1, 157.5, 157.5, 155.9, 155.8, 155.2, 132.5, 132.4, 129.5, 118.8, 118.7, 118.6, 113.8, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 51.3, 51.1, 48.6, 43.8, 40.3, 35.7, 29.2, 28.7.

Example 126: (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(4-(methylsulfonyl)piperidin-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from (R)-1-(H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a cream powder.

1 H NMR (DMSO d6 ): 1.69 (1H, 2 s), 7.72 (1H, m), 7.16 (1H, m), 4.48 (1H, m), 4.44 (1H, quin, J=8.5 Hz), 4.15 (1H, dd, J=11.4, 9.2 Hz), 4.01 (1H, br d, J=13.6 Hz), 3.72 (1H, dd, J=11.6, 7.9 Hz), 3.54 (2H, m), 3.36 (1H, m), 3.21 (1H, m), 3.07 (1H, m), 2.94 (3H, s), 2.82 (1H, m), 2.61 (1H, m), 2.04 (2H, br d, J=12.5 Hz), 1.56 (1H, m), 1.42 (1H, m).

13 C NMR (DMSO d6 ): 166.5, 166.5, 160.8, 160.8, 159.2, 159.1, 157.5, 157.5, 155.9, 155.8, 155.2, 132.5, 132.4, 129.3, 129.2, 118.7, 118.6, 118.5, 114.2, 113.8, 113.8, 113.6, 113.6, 104, 104, 103.9, 103.9, 58.4, 58.4, 48.6, 43.9, 37.5, 35.7, 29.2, 29, 29, 24.7, 24.1.

Example 127: 2-((R)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-1-cyclohexylethyl)acetamide

Compound was prepare analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light cream powder.

1 H NMR (DMSO d6 ): 1.76 (1H, s), 7.73 (2H, m), 7.16 (1H, m), 4.44 (1H, quin, J=8.6 Hz), 4.14 (1H, dd, J=11.4, 9.2 Hz), 3.72 (1H, dd, J=11.6, 7.9 Hz), 3.57 (1H, m), 3.22 (3H, m), 2.81 (1H, dd, J=15.7, 8.2 Hz), 1.64 (4.7H, m), 1.23 (1.3H, m), 1.09 (3H, m), 0.97 (3H, d, J=6.7 Hz), 0.88 (2H, m).

13 C NMR (DMSO d6 ): 166.7, 160.8, 160.7, 159.1, 159.1, 157.6, 157.5, 155.9, 155.9, 155, 132.5, 132.4, 128.8, 118.8, 118.7, 118.6, 114.6, 113.8, 113.7, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 48.7, 48.5, 42.3, 35.6, 31.6, 29.5, 28.8, 28.5, 26, 25.7, 25.7, 17.5.

Example 128: (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(tetrahydro-2H-pyran-4-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a green powder.

1 H NMR (DMSO d6 ): 1.69 (1H, br s), 7.72 (1H, m), 7.16 (1H, m), 4.45 (1.6H, m), 4.15 (1H, m), 3.88 (2.4H, m), 3.73 (1H, br dd, J=11.5, 7.8 Hz), 3.57, 3.48 (2H, 2 m), 3.40 (1H, m), 3.34 (1H, m), 3.21 (1H, m), 2.84, 2.71 (3H, 2 s), 2.80 (1H, dd, J=7.4, 15.3 Hz), 1.82-1.61 (2H, m), 1.52 (1H, m), 1.38 (1H, m).

13 C NMR (DMSO d6 ): 167.6, 167.6, 160.8, 160.7, 159.1, 159.1, 157.5, 157.5, 155.9, 155.8, 155.1, 155, 132.4, 132.4, 129.3, 129.2, 118.9, 118.8, 118.7, 114.4, 114.2, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 66.5, 66.5, 66.2, 49.6, 48.6, 35.7, 30.2, 30.2, 30, 29.5, 29.4, 29.3, 29.2, 27.

Example 129: (R)—N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a cream powder.

1 H NMR (DMSO d6 ): 11.78 (1H, s), 8.10 (1H, d, J=7.6 Hz), 7.85 (1H, m), 4.48 (1H, quin, J=8.6 Hz), 4.17 (1H, dd, J=11.4, 9.2 Hz), 3.93 (1H, m), 3.77 (1H, dd, J=11.6, 7.8 Hz), 3.28-3.17 (3H, m), 3.26 (2H, s), 3.08 (2H, m), 2.89 (1H, dd, J=8.0, 15.8 Hz), 2.04 (2H, br d, J=11.3 Hz), 1.90 (2H, m).

13 C NMR (DMSO d6 ): 167.1, 155.2, 146.4, 146.3, 146.2, 145.3, 145.2, 144.8, 144.7, 144.6, 143.7, 143.6, 129, 120.4, 120.3, 120.2, 114.2, 105.9, 105.7, 105.6, 48.4, 48.3, 43.9, 35.7, 31.4, 29.2, 29.1.

Example 130: (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a cream powder.

1 H NMR (DMSO d6 ): 1.77 (1H, s), 8.09 (1H, d, J=7.6 Hz), 7.72 (1H, ddd, J=8.8, 8.2, 5.9 Hz), 7.17 (1H, m), 4.44 (1H, quin, J=8.6 Hz), 4.15 (1H, dd, J=11.2, 9.5 Hz), 3.93 (1H, m), 3.72 (1H, dd, J=11.6, 7.9 Hz), 3.24 (2H, s), 3.22 (3H, m), 3.08 (2H, m), 2.84 (1H, dd, J=15.7, 8.1 Hz), 2.04 (2H, m), 1.90 (2H, m).

13 C NMR (DMSO d6 ): 167.1, 160.8, 160.8, 159.2, 159.1, 157.5, 157.5, 155.9, 155.8, 155.1, 132.5, 132.4, 129.2, 118.8, 118.7, 118.5, 114.1, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 48.6, 48.3, 43.9, 35.6, 31.4, 29.3, 29.1.

Example 131: (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2-hydroxyethyl)-N-methylacetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a pale brown powder.

1 H NMR (DMSO d6 ): 11.69 (1H, 2 s), 7.72 (1H, ddd, J=8.6, 8.1, 5.9 Hz), 7.16 (1H, m), 4.87 (0.6H, t, J=5.4 Hz), 4.64 (0.4H, t, J=5.4 Hz), 4.44 (1H, 2 quin, J=8.7 Hz), 4.15 (1H, m), 3.72 (1H, dd, J=11.5, 8.0 Hz), 3.54 (2H, m), 3.46 (2H, m), 3.40-3.29 (2H, m), 3.20 (1H, m), 3.02 (1.2H, s), 2.82 (1.8H, s), 2.81 (1H, m).

13 C NMR (DMSO d6 ): 168.2, 167.9, 160.8, 160.8, 159.2, 159.1, 157.5, 157.5, 155.9, 155.8, 155, 132.5, 132.4, 129.2, 129.1, 118.8, 118.8, 118.7, 118.6, 118.6, 118.5, 114.5, 114.2, 113.8, 113.8, 113.6, 113.6, 104, 104, 103.9, 103.9, 58.5, 58.4, 51.6, 50, 48.6, 36.4, 35.6, 33.4, 29.4, 29.3, 29.2, 29.1, 29.

Example 132: (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-cyclohexyl-N-methylacetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a brown powder.

1 H NMR (DMSO d6 ): 1.69 (1H, s), 7.72 (1H, m), 7.16 (1H, m), 4.44 (1H, quin, J=8.4 Hz), 4.20 (0.6H, tt, J=3.8, 11.8 Hz), 4.15 (1H, m), 3.72 (1H, br dd, J=11.5, 7.7 Hz), 3.58 (0.4H, tt, J=11.6, 3.5 Hz), 3.51 (0.8H, m), 3.46 (1.2H, m), 3.21 (1H, br dd, J=15.8, 9.3 Hz), 2.80 (1H, m), 2.81, 2.69 (3H, 2 s), 1.84-0.97 (10H, m).

13 C NMR (DMSO d6 ): 167.3, 167.3, 160.8, 160.7, 159.1, 159.1, 157.5, 157.5, 155.9, 155.8, 155, 155, 132.4, 132.4, 129.2, 129.1, 118.9, 118.8, 118.8, 114.5, 114.3, 113.8, 113.7, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 55.7, 52, 48.6, 35.7, 30.2, 30.2, 30, 29.4, 29.4, 29.3, 29.2, 29.2, 29.2, 26.9, 25.3, 25.1, 25.1, 25, 24.8.

Example 133: (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-isopropylacetamide

Compound was prepared analogous manner to Example 32 rom (R)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a cream powder.

1 H NMR (DMSO d6 ): 1.74 (1H, s), 7.84 (1H, br d, J=7.5 Hz), 7.72 (1H, ddd, J=5.8, 8.1, 8.8 Hz), 7.16 (1H, m), 4.44 (1H, quin, J=8.6 Hz), 4.14 (1H, dd, J=11.4, 9.2 Hz), 3.80 (1H, hep, J=6.7 Hz), 3.72 (1H, dd, J=11.6, 7.9 Hz), 3.21 (1H, dd, J=9.2, 15.8 Hz), 3.19 (2H, s), 2.83 (1H, dd, J=15.7, 8.2 Hz), 1.04 (6H, d, J=6.6 Hz).

13 C NMR (DMSO d6 ): 166.5, 160.8, 160.8, 159.2, 159.1, 157.5, 157.5, 155.9, 155.8, 155, 132.5, 132.4, 129, 118.8, 118.7, 118.5, 114.4, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 48.6, 40.6, 35.6, 31.5, 29.4, 22.3.

Example 134: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(pyridin-3-ylmethyl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a beige solid.

1 H NMR (DMSO d6 ): 1.76, 1.75 (1H, 2 br s), 8.52 (0.7H, m), 8.49 (0.7H, d, J=1.8 Hz), 8.44 (0.7H, dd, J=4.8, 1.7 Hz), 7.69-7.58 (2H, m), 7.40 (0.3H, dd, J=7.6, 4.9 Hz), 7.33 (1H, ddd, J=0.7, 4.8, 7.8 Hz), 7.22 (1H, m), 4.65 (0.6H, s), 4.53 (1.4H, m), 4.43 (1H, m), 4.16 (1H, m), 3.73 (1H, dd, J=11.6, 7.9 Hz), 3.59 (2H, m), 3.31-3.13 (1H, m), 2.98 (2H, s), 2.79 (1H, s), 2.85-2.73 (1H, m).

13 C NMR (DMSO d6 ): 168.4, 155.2, 149.1, 148.7, 148.5, 148.3, 135.4, 134.7, 133.1, 132.7, 129.7, 129.6, 129.3, 129.3, 123.7, 123.5, 118.7, 118.6, 116.1, 116, 115.9, 115.9, 114.1, 114.1, 113.2, 113.2, 113.1, 113.1, 50.2, 48.5, 48, 35.6, 35.1, 33.4, 29.6, 29.3, 29.2, 29.1.

Example 135: 2-((R)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(3-(methylsulfonyl)pyrrolidin-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from (R)-1-(H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light brown powder.

1 H NMR (DMSO d6 ): 1.73 (1H, s), 7.72 (1H, m), 7.16 (1H, m), 4.45 (1H, 2 quin, J=8.6 Hz), 4.15 (1H, m), 4.06 (0.4H, m), 3.95 (0.6H, m), 3.88 (0.4H, m), 3.83 (0.4H, m), 3.72 (1H, dd, J=11.6, 7.9 Hz), 3.70-3.61 (1.8H, m), 3.56 (0.6H, m), 3.52-3.46 (1.4H, m), 3.45 (1H, s), 3.39 (0.4H, m), 3.22 (1H, m), 3.06, 3.06, 3.04, 3.04 (3H, 4 s), 2.84 (1H, m), 2.33 (1H, m), 2.22 (1H, m).

13 C NMR (DMSO d6 ): 166.4, 166.3, 160.8, 160.8, 159.2, 159.1, 157.5, 157.5, 155.9, 155.8, 155.2, 155.2, 132.5, 132.4, 129.4, 129.4, 118.8, 118.8, 118.7, 118.6, 118.5, 118.5, 113.8, 113.8, 113.7, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 60.6, 60.6, 58.9, 58.9, 48.6, 45.4, 45.4, 45.3, 45.3, 45.1, 44.9, 35.7, 30.3, 30.2, 30.2, 30.2, 29.3, 25.7, 24.1, 24.1.

Example 136: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(1,1-dioxidothiomorpholino)ethan-1-one

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as an off-white solid.

1 H NMR (DMSO d6 ): 11.63 (1H, s), 7.72 (1H, td, J=8.4, 5.8 Hz), 7.17 (1H, m), 4.46 (1H, quin, J=8.6 Hz), 4.16 (1H, dd, J=9.3, 11.1 Hz), 3.87 (4H, m), 3.73 (1H, dd, J=11.5, 7.8 Hz), 3.62 (2H, s), 3.26 (2H, m), 3.23 (1H, dd, J=9.3, 15.8 Hz), 3.10 (2H, m), 2.84 (1H, dd, J=15.8, 8.1 Hz).

13 C NMR (DMSO d6 ): 167.4, 160.8, 160.8, 159.2, 159.1, 157.5, 157.5, 155.9, 155.8, 155.2, 132.5, 132.4, 129.5, 118.7, 113.8, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 51.3, 51.1, 48.6, 43.8, 40.3, 35.7, 29.2, 28.7.

Example 137: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-thiomorpholinoethan-1-one

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as an off-white solid.

1 H NMR (DMSO d6 ): 11.69 (1H, s), 7.72 (1H, ddd, J=5.8, 8.1, 8.8 Hz), 7.16 (1H, m), 4.45 (1H, quin, J=8.6 Hz), 4.15 (1H, dd, J=11.2, 9.3 Hz), 3.73 (1H, dd, J=8.0, 11.6 Hz), 3.71 (4H, m), 3.51 (2H, m), 3.21 (1H, dd, J=15.8, 9.3 Hz), 2.81 (1H, dd, J=15.9, 8.0 Hz), 2.61 (2H, m), 2.55-2.50 (2H, m).

13 C NMR (DMSO d6 ): 166.6, 160.8, 160.8, 159.2, 159.1, 157.5, 157.5, 155.9, 155.8, 155.1, 132.5, 132.4, 129.3, 118.9, 118.7, 118.6, 114.1, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 48.6, 48.1, 44, 35.7, 29.3, 29.1, 26.9, 26.4.

Example 138: 2-((S)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(2-oxa-7-azaspiro[4.4]nonan-7-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a white solid.

1 H NMR (DMSO d6 ): 1.71 (1H, s), 7.72 (1H, m), 7.16 (1H, m), 4.45 (1H, quin, J=8.6 Hz), 4.15 (1H, dd, J=11.3, 9.4 Hz), 3.81-3.69 (3H, m), 3.59-3.47 (3H, m), 3.44-3.40 (3H, m), 3.36 (1H, m), 3.30-3.18 (2H, m), 2.82 (1H, m), 1.96-1.73 (4H, m).

13 C NMR (DMSO d6 ): 166.4, 166.4, 160.8, 159.2, 157.5, 157.5, 155.9, 155.8, 155.1, 132.4, 132.4, 129.3, 118.9, 118.8, 118.7, 114, 114, 113.8, 113.8, 113.6, 113.6, 104, 104, 103.9, 103.9, 75.2, 75.2, 75.1, 66.9, 66.9, 55, 54.2, 49.6, 48.6, 47.8, 45.6, 45, 35.8, 35.8, 35.8, 35.6, 34.7, 33.2, 30.3, 30.3, 30, 30, 29.3.

Example 139: (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(pyridin-2-ylmethyl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a cream powder.

1 H NMR (DMSO d6 ): 11.84 (1H, s), 8.58 (1H, t, J=5.9 Hz), 8.50 (1H, m), 7.73 (2H, m), 7.30 (1H, d, J=7.8 Hz), 7.23 (1H, dd, J=6.9, 5.0 Hz), 7.17 (1H, m), 4.43 (1H, quin, J=m), 4.36 (2H, m), 4.14 (1H, dd, J=9.6, 11.3 Hz), 3.73 (1H, dd, J=11.5, 8.1 Hz), 3.36 (2H, m), 3.17 (1H, dd, J=15.8, 9.3 Hz), 2.78 (1H, dd, J=15.7, 8.4 Hz).

13 C NMR (DMSO d6 ): 167.9, 160.8, 160.7, 159.1, 159.1, 158.2, 157.5, 157.5, 155.9, 155.9, 155.3, 148.8, 136.7, 132.5, 132.4, 129.2, 122.1, 121.2, 118.6, 118.5, 118.4, 114.1, 113.8, 113.7, 113.6, 113.6, 104, 104, 103.9, 103.9, 48.5, 44.3, 35.6, 31.5, 29.2.

Example 140: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light brown powder.

1 H NMR (DMSO d6 ): 11.70 (1H, s), 7.72 (1H, ddd, J=5.8, 8.1, 8.7 Hz), 7.17 (1H, m), 4.45 (1H, quin, J=8.5 Hz), 4.15 (1H, dd, J=11.5, 9.2 Hz), 3.73 (1H, dd, J=11.7, 7.8 Hz), 3.60-3.52 (4H, m), 3.51 (2H, s), 3.48-3.40 (4H, m), 3.21 (1H, dd, J=15.8, 9.3 Hz), 2.82 (1H, dd, J=15.8, 8.1 Hz)

13 C NMR (DMSO d6 ): 166.8, 160.8, 160.8, 159.2, 159.1, 157.5, 157.5, 155.9, 155.9, 155.2, 132.5, 132.4, 129.3, 118.9, 118.7, 118.6, 114, 113.8, 113.6, 104.1, 104, 103.9, 103.9, 66, 66, 48.6, 45.7, 41.7, 35.7, 29.3, 28.9.

Example 141: (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one

Compound was prepared analogous manner to Example 32 from (R)-1-(H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light brown powder.

1 H NMR (DMSO d6 ): 11.70 (1H, s), 7.72 (1H, ddd, J=5.8, 8.1, 8.7 Hz), 7.17 (1H, m), 4.45 (1H, quin, J=8.5 Hz), 4.15 (1H, dd, J=11.5, 9.2 Hz), 3.73 (1H, dd, J=11.7, 7.8 Hz), 3.60-3.52 (4H, m), 3.51 (2H, s), 3.48-3.40 (4H, m), 3.21 (1H, dd, J=15.8, 9.3 Hz), 2.82 (1H, dd, J=15.8, 8.1 Hz).

13 C NMR (DMSO d6 ): 166.8, 160.8, 160.8, 159.2, 159.1, 157.5, 157.5, 155.9, 155.9, 155.2, 132.5, 132.4, 129.3, 118.9, 118.7, 118.6, 114, 113.8, 113.6, 104.1, 104, 103.9, 103.9, 66, 66, 48.6, 45.7, 41.7, 35.7, 29.3, 28.9.

Example 142: N-(2-(1H-pyrazol-1-yl)ethyl)-2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 25 from 2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one (prepared analogous to Example 23 step 1) and isolated as a light yellow solid. 20 1 H NMR (DMSO d6 ): 1.68 (1H, s), 8.09 (1H, t, J=5.6 Hz), 7.68 (1H, dd, J=2.2, 0.6 Hz), 7.63 (1H, td, J=8.7, 5.6 Hz), 7.43 (1H, dd, J=0.6, 1.8 Hz), 7.21 (1H, dt, J=1.4, 9.2 Hz), 6.20 (1H, m), 4.17 (2H, t, J=6.3 Hz), 4.02 (1H, d, J=12.2 Hz), 3.74 (1H, d, J=12.2 Hz), 3.44 (2H, m), 3.31 (2H, m), 2.70 (1H, dd, J=8.4, 4.4 Hz), 1.65 (1H, dd, J=8.2, 5.4 Hz), 1.26 (1H, t, J=5.0 Hz).

13 C NMR (DMSO d6 ): 168.1, 161.2, 161.2, 159.6, 159.5, 157.8, 157.8, 156.1, 156.1, 155.9, 138.8, 131.5, 130.3, 130.2, 130.1, 117.2, 117.1, 116.9, 115.7, 115.7, 115.6, 115.6, 114, 112.9, 112.9, 112.8, 112.7, 105, 51.4, 50.2, 39.4, 31.3, 26.3, 21.6, 21.2.

Example 143: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(cyclopropylmethyl)acetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a yellow solid.

1 H NMR (DMSO d6 ): 11.65 (1H, s), 8.03 (1H, br t, J=5.5 Hz), 7.58-7.53 (2H, m), 7.24 (1H, dd, J=10.1, 8.7 Hz), 4.07 (1H, d, J=12.0 Hz), 3.79 (1H, d, J=12.2 Hz), 3.30 (2H, m), 2.96 (2H, t, J=6.2 Hz), 2.82 (1H, dd, J=8.4, 4.3 Hz), 1.66 (1H, dd, J=8.4, 5.3 Hz), 1.15 (1H, t, J=4.8 Hz), 0.90 (1H, m), 0.40 (2H, m), 0.16 (2H, m).

13 C NMR (DMSO d6 ): 167.5, 161.7, 160.1, 155.9, 133, 132.9, 132.3, 132.2, 131.7, 129.3, 129.2, 118, 117.8, 116.2, 116.2, 114, 51.6, 43.2, 31.4, 22, 20.7, 10.7, 3.3, 3.2

Example 144: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(cyanomethyl)acetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a white solid.

1 H NMR (DMSO d6 ): 11.72 (1H, s), 8.66 (1H, br t, J=5.4 Hz), 7.62-7.51 (2H, m), 7.24 (1H, dd, J=10.0, 8.8 Hz), 4.16 (2H, m), 4.09 (1H, dd, J=11.8 Hz), 3.80 (1H, d, J=12.0 Hz), 3.39 (2H, m), 2.85 (1H, dd, J=8.3, 4.2 Hz), 1.64 (1H, dd, J=8.4, 5.3 Hz), 1.18 (1H, t, J=4.8 Hz).

13 C NMR (DMSO d6 ): 168.6, 161.7, 160.1, 156.2, 132.9, 132.9, 132.3, 132.3, 129.3, 129.2, 118, 117.8, 117.6, 116.2, 112.9, 51.6, 32.3, 30.9, 27.3, 22.1, 20.6.

Example 145: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(2-(pyridin-2-yl)ethyl)acetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a yellow solid.

1 H NMR (DMSO d6 ): 1.66 (1H, br s), 8.48 (1H, ddd, J=0.8, 1.8, 4.8 Hz), 8.03 (1H, t, J=5.6 Hz), 7.68 (1H, td, J=7.6, 1.9 Hz), 7.56 (2H, m), 7.24 (2H, m), 7.19 (1H, ddd, J=7.5, 4.9, 1.1 Hz), 4.07 (1H, d, J=12.2 Hz), 3.79 (1H, d, J=12.0 Hz), 3.43 (2H, m), 3.28 (2H, m), 2.88 (2H, t, J=7.3 Hz), 2.79 (1H, dd, J=8.4, 4.3 Hz), 1.64 (1H, dd, J=8.4, 5.3 Hz), 1.14 (1H, t, J=4.8 Hz).

13 C NMR (DMSO d6 ): 167.7, 161.8, 160.1, 159, 156, 149, 136.5, 133, 133, 132.3, 132.3, 131.8, 129.3, 129.2, 123.2, 121.5, 118, 117.8, 116.2, 116.2, 113.8, 51.6, 38.8, 37.2, 32.2, 31.5, 22, 20.7.

Example 146: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(3-(dimethylamino)propyl)acetamide hydrochloride

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a dark yellow solid.

1 H NMR (D 2 O): 7.52 (1H, dd, J=6.6, 2.3 Hz), 7.43 (1H, m), 7.03 (1H, t, J=9.4 Hz), 4.20 (1H, d, J=12.2 Hz), 3.92 (1H, d, J=12.2 Hz), 3.58 (2H, s), 3.30 (2H, t, J=6.7 Hz), 3.14 (2H, m), 2.87 (6H, s), 2.73 (1H, dd, J=8.4, 4.3 Hz), 1.95 (2H, m), 1.66 (1H, dd, J=8.1, 5.8 Hz), 1.19 (1H, t, J=4.8 Hz).

13 C NMR (D 2 O): 171.6, 162, 160.3, 151.4, 134.7, 133.1, 132.5, 132.4, 128.3, 128.2, 117.6, 117.4, 116.1, 114.3, 55.3, 52.2, 42.7, 36.3, 32.4, 31.3, 24.1, 21.5, 20.5.

Example 147: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(4-(pyridin-2-yl)piperazin-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a yellow solid.

1 H NMR (DMSO d6 ): 11.63 (1H, s), 8.11 (1H, dd, J=5.1, 1.2 Hz), 7.68 (1H, br d, J=18.6 Hz), 7.56 (2H, m), 7.23 (1H, dd, J=10.1, 8.8 Hz), 6.99 (1H, br s), 6.75 (1H, br s), 4.08 (1H, br d, J=12.2 Hz), 3.79 (1H, d, J=12.0 Hz), 3.69-3.51 (10H, m), 2.80 (1H, dd, J=8.3, 4.2 Hz), 1.68 (1H, dd, J=8.4, 5.3 Hz), 1.11 (1H, br t, J=4.8 Hz).

13 C NMR (DMSO d6 ): 167, 161.8, 160.1, 156, 133, 133, 132.3, 132.3, 131.8, 129.3, 129.2, 118, 117.8, 116.2, 116.2, 113.7, 113.2, 51.6, 44.9, 44.6, 44.4, 40.8, 32.3, 29.2, 22.1, 20.7.

Example 148: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a beige foam.

1 H NMR (DMSO d6 ): 11.66 (1H, s), 8.23 (1H, d, J=6.7 Hz), 7.56 (2H, m), 7.24 (1H, dd, J=10.1, 8.6 Hz), 4.24 (1H, tt, J=10.2, 3.8 Hz), 4.07 (1H, d, J=12.0 Hz), 3.78 (2H, m), 3.74 (1H, dd, J=8.9, 6.0 Hz), 3.67 (1H, td, J=8.2, 5.6 Hz), 3.49 (1H, dd, J=8.8, 3.7 Hz), 3.30 (2H, m), 2.81 (1H, dd, J=8.4, 4.2 Hz), 2.08 (1H, dq, J=12.6, 7.6 Hz), 1.75 (1H, m), 1.66 (1H, dd, J=8.4, 5.4 Hz), 1.12 (1H, t, J=4.8 Hz).

13 C NMR (DMSO d6 ): 167.6, 161.8, 160.1, 155.9, 133, 133, 132.3, 132.2, 131.7, 129.3, 129.2, 118, 117.8, 116.2, 116.2, 113.9, 72.4, 66.3, 51.6, 49.8, 32.2, 32, 31.2, 22.1, 20.7.

Example 149: 2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(4,4-difluoropiperidin-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a brown solid.

1 H NMR (DMSO d6 ): 11.63 (1H, br s), 7.63 (1H, td, J=8.7, 5.7 Hz), 7.20 (1H, dt, J=9.3 Hz, 1.3 Hz), 4.04 (1H, d, J=12.2 Hz), 3.74 (1H, d, J=12.2 Hz), 3.66 (2H, m), 3.59 (4H, m), 2.69 (1H, dd, J=8.4, 4.4 Hz), 2.04 (2H, m), 1.93 (2H, m), 1.68 (1H, dd, J=8.2, 5.4 Hz), 1.24 (1H, t, J=5.0 Hz).

13 C NMR (DMSO d6 ): 166.8, 161.2, 161.2, 159.6, 159.5, 157.8, 157.7, 156.1, 156.1, 156, 131.5, 130.3, 130.2, 124.3, 122.7, 121.1, 117.1, 117, 116.9, 115.7, 115.7, 115.6, 115.6, 114, 112.9, 112.9, 112.8, 112.7, 51.4, 42.2, 42.1, 42.1, 38.5, 38.5, 38.4, 33.9, 33.8, 33.6, 33.3, 33.2, 33, 29.1, 26.4, 21.7, 21.2.

Example 150: 2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a light brown solid.

1 H NMR (DMSO d6 ): 11.73 (1H, s), 8.67 (1H, t, J=6.3 Hz), 7.63 (1H, td, J=8.7, 5.6 Hz), 7.21 (1H, dt, J=1.4, 9.2 Hz), 4.03 (1H, d, J=12.2 Hz), 3.93 (2H, qd, J=9.8, 6.5 Hz), 3.74 (1H, d, J=12.2 Hz), 3.43 (2H, m), 2.72 (1H, dd, J=8.4, 4.4 Hz), 1.65 (1H, dd, J=8.4, 5.4 Hz), 1.26 (1H, t, J=5.0 Hz).

13 C NMR (DMSO d6 ): 169.2, 161.7, 161.6, 160, 160, 158.3, 158.2, 156.6, 156.6, 156.5, 132.2, 130.8, 130.7, 127.9, 126.1, 124.2, 122.4, 117.6, 117.5, 117.4, 116.2, 116.2, 116.1, 116.1, 114, 113.4, 113.4, 113.2, 113.2, 51.9, 40.1, 31.5, 26.8, 22.1, 21.7.

Example 151: 2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(pyridin-3-ylmethyl)acetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a white solid.

1 H NMR (DMSO d6 ): 1.75 (1H, s), 8.55-8.48 (2H, m), 8.43 (1H, dd, J=4.7, 1.6 Hz), 7.67 (1H, dt, J=7.8, 2.0 Hz), 7.64 (1H, td, J=8.7, 5.7 Hz), 7.34 (1H, ddd, J=0.7, 4.8, 7.8 Hz), 7.21 (1H, dt, J=1.0, 9.1 Hz), 4.32 (2H, m), 4.02 (1H, d, J=12.2 Hz), 3.74 (1H, d, J=12.2 Hz), 3.40 (2H, m), 2.68 (1H, dd, J=8.4, 4.4 Hz), 1.62 (1H, dd, J=8.3, 5.5 Hz), 1.27 (1H, t, J=5.0 Hz).

13 C NMR (DMSO d6 ): 168, 161.2, 161.2, 159.6, 159.5, 157.8, 157.7, 156.1, 156, 148.8, 148.1, 135.1, 134.7, 131.6, 130.3, 130.2, 123.4, 117.2, 117, 116.9, 115.7, 115.6, 114, 112.9, 112.9, 112.8, 112.8, 51.4, 39.8, 31.3, 26.3, 21.5, 21.2.

Example 152: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a light beige solid.

1 H NMR (DMSO d6 ): 1.75 (1H, s), 8.55-8.48 (2H, m), 8.43 (1H, dd, J=4.7, 1.6 Hz), 7.67 (1H, dt, J=7.8, 2.0 Hz), 7.64 (1H, td, J=8.7, 5.7 Hz), 7.34 (1H, ddd, J=0.7, 4.8, 7.8 Hz), 7.21 (1H, dt, J=1.0, 9.1 Hz), 4.32 (2H, m), 4.02 (1H, d, J=12.2 Hz), 3.74 (1H, d, J=12.2 Hz), 3.40 (2H, m), 2.68 (1H, dd, J=8.4, 4.4 Hz), 1.62 (1H, dd, J=8.3, 5.5 Hz), 1.27 (1H, t, J=5.0 Hz).

13 C NMR (DMSO d6 ): 168, 161.2, 161.2, 159.6, 159.5, 157.8, 157.7, 156.1, 156, 148.8, 148.1, 135.1, 134.7, 131.6, 130.3, 130.2, 123.4, 117.2, 117, 116.9, 115.7, 115.6, 114, 112.9, 112.9, 112.8, 112.8, 51.4, 39.8, 31.3, 26.3, 21.5, 21.2.

Example 153: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-cyclobutylacetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a yellow solid.

1 H NMR (DMSO d6 ): 1.63 (1H, s), 8.20 (1H, br d, J=7.8 Hz), 7.56 (2H, m), 7.24 (1H, dd, J=9.9, 8.7 Hz), 4.20 (1H, sxt, J=8.1 Hz), 4.07 (1H, d, J=12.0 Hz), 3.78 (1H, d, J=12.0 Hz), 3.25 (2H, m), 2.80 (1H, dd, J=8.4, 4.3 Hz), 2.14 (2H, m), 1.90 (2H, m), 1.63 (3H, m), 1.13 (1H, t, J=4.8 Hz).

13 C NMR (DMSO d6 ): 166.6, 161.7, 160.1, 155.9, 133, 132.9, 132.3, 132.2, 131.7, 129.3, 129.2, 118, 117.8, 116.2, 113.9, 51.5, 44.1, 32.2, 31.3, 30.2, 30.2, 22, 20.7, 14.6.

Example 154: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-cyclopropylacetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a yellow solid.

1 H NMR (DMSO d6 ): 1.63 (1H, s), 8.04 (1H, br d, J=3.8 Hz), 7.56 (2H, m), 7.24 (1H, dd, J=10.1, 8.7 Hz), 4.07 (1H, d, J=11.9 Hz), 3.78 (1H, d, J=12.0 Hz), 3.25 (2H, m), 2.81 (1H, dd, J=8.3, 4.2 Hz), 2.62 (1H, m), 1.65 (1H, dd, J=8.4, 5.3 Hz), 1.13 (1H, t, J=4.8 Hz), 0.62 (2H, m), 0.42 (2H, m).

13 C NMR (DMSO d6 ): 168.8, 161.7, 160.1, 155.9, 133, 132.9, 132.3, 132.2, 131.7, 129.3, 129.2, 118, 117.8, 116.2, 116.2, 113.8, 51.6, 32.2, 31.2, 22.5, 22, 20.7, 5.6, 5.6.

Example 155: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-cyclopentyl-N-methylacetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a brown solid.

1 H NMR (DMSO d6 ): 1.59 (1H, br s), 7.55 (2H, m), 7.24 (1H, t, J=9.4 Hz), 4.82, 4.28 (1H, 2 m), 4.07 (1H, d, J=12.0 Hz), 3.78 (1H, d, J=12.0 Hz), 3.61, 3.52 (2H, 2 m), 2.85, 2.70 (3H, 2 s), 2.77 (1H, m), 1.85-1.40 (9H, m), 1.10 (1H, m).

13 C NMR (DMSO d6 ): 167.9, 167.7, 161.7, 160.1, 155.9, 155.9, 133, 132.9, 132.3, 132.2, 131.6, 131.6, 129.3, 129.2, 118, 117.8, 116.2, 116.1, 114.1, 114, 57.6, 53.7, 51.5, 32.3, 32.2, 30.1, 29.5, 29.4, 28.5, 27.8, 27.7, 27.1, 23.9, 23.8, 22.1, 20.7, 20.6.

Example 156: N-benzyl-2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepare analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a brown solid.

1 H NMR (DMSO d6 ): 11.72 (1H, s), 8.45 (1H, t, J=5.9 Hz), 7.47-7.40 (2H, m), 7.35-7.25 (5H, m), 7.22 (1H, m), 4.29 (2H, m), 4.07 (1H, d, J=12.0 Hz), 3.80 (1H, d, J=12.2 Hz), 3.38 (2H, m), 2.77 (1H, dd, J=8.4, 4.3 Hz), 1.62 (1H, dd, J=8.4, 5.3 Hz), 1.16 (1H, m).

13 C NMR (DMSO d6 ): 167.8, 161.2, 159.6, 156, 139.3, 131.8, 130.1, 130, 129.3, 129.2, 128.9, 128.8, 128.2, 128.2, 128.2, 127.3, 126.8, 117.6, 117.4, 113.7, 51.5, 42.3, 32.3, 31.4, 22, 20.7.

Example 157: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl-1-morpholinoethan-1-one

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a green solid.

1 H NMR (DMSO d6 ): 11.61 (1H, s), 7.65-7.46 (2H, m), 7.24 (1H, dd, J=10.0, 8.7 Hz), 4.08 (1H, d, J=12.0 Hz), 3.79 (1H, d, J=12.0 Hz), 3.63-3.52 (6H, m), 3.49 (2H, m), 3.46 (2H, m), 2.78 (1H, dd, J=8.4, 4.3 Hz), 1.68 (1H, dd, J=8.3, 5.4 Hz), 1.11 (1H, t, J=4.8 Hz).

13 C NMR (DMSO d6 ): 166.9, 161.8, 160.1, 156, 133, 133, 132.3, 132.3, 131.7, 129.3, 129.2, 118, 117.8, 116.2, 116.2, 113.7, 66, 51.6, 51.6, 45.7, 41.7, 32.3, 29, 22.1, 20.7.

Example 158: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(piperidin-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a dark yellow solid.

1 H NMR (DMSO d6 ): 11.60 (1H, s), 7.47-7.40 (2H, m), 7.30 (1H, dd, J=9.9, 8.7 Hz), 4.08 (1H, d, J=12.2 Hz), 3.79 (1H, d, J=12.2 Hz), 3.54 (2H, m), 3.44 (4H, m), 2.78 (1H, dd, J=8.3, 4.2 Hz), 1.68 (1H, dd, J=8.4, 5.3 Hz), 1.58 (2H, m), 1.50 (2H, m), 1.44 (2H, m), 1.10 (1H, t, J=4.8 Hz).

13 C NMR (DMSO d6 ): 166.2, 161.2, 159.6, 155.9, 131.6, 130.1, 130.1, 129.3, 129.3, 128.9, 128.7, 128.3, 128.2, 117.6, 117.4, 114, 51.5, 51.5, 46.2, 42.2, 32.3, 29.3, 25.9, 25.2, 23.9, 22.1, 20.7.

Example 159: (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(cyanomethyl)acetamide

Compound was prepared analogous manner to Example 34 from (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid (Example 13) and isolated as a grey powder.

1 H NMR (DMSO d6 ): 11.80 (1H, s), 8.65 (1H, t, J=5.5 Hz), 7.72 (1H, m), 7.17 (1H, m), 4.45 (1H, quin, J=8.7 Hz), 4.15 (1H, dd, J=9.4, 11.5 Hz), 4.14 (2H, d, J=5.6 Hz), 3.74 (1H, dd, J=11.5, 8.1 Hz), 3.34 (2H, m), 3.22 (1H, dd, J=15.8, 9.3 Hz), 2.86 (1H, dd, J=15.8, 8.4 Hz).

13 C NMR (DMSO d6 ): 168.6, 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 155.9, 155.9, 155.4, 132.5, 132.4, 129.7, 118.6, 118.5, 118.3, 117.5, 113.8, 113.8, 113.6, 113.6, 113.3, 104.1, 104, 103.9, 103.9, 48.6, 35.7, 31, 29.2, 27.2.

Example 160: 2-((R)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((1R,2R)-2-hydroxycyclohexyl)acetamide

Compound was prepared analogous manner to Example 34 from (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid (Example 13) and isolated as a beige powder.

1 H NMR (DMSO d6 ): 1.71 (1H, 2 s), 7.80 (1H, 2 d, J=2.1 Hz), 7.72 (1H, m), 7.16 (1H, m), 4.52 (1H, 2 dd, J=4.8 Hz), 4.43 (1H, 2 quin, J=8.6 Hz), 4.14 (1H, dd, J=11.4, 9.5 Hz), 3.72 (1H, dd, J=11.6, 7.9 Hz), 3.37 (1H, m), 3.29-3.18 (4H, m), 2.86 (0.5H, dd, J=8.2, 16.2 Hz), 2.82 (0.5H, dd, J=8.3, 16.0 Hz), 1.83 (1H, m), 1.75 (1H, m), 1.64-1.50 (2H, 2 m), 1.22-1.01 (4H, m).

13 C NMR (DMSO d6 ): 167.2, 167.2, 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 155.9, 155.9, 155, 155, 132.5, 132.4, 129, 129, 118.8, 118.8, 118.7, 118.6, 118.6, 118.5, 114.6, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 71.1, 54.5, 48.5, 35.6, 33.9, 31.8, 31.7, 30.9, 29.4, 29.4, 24.1, 23.7.

Example 161: 2-((R)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-((1S,2S)-2-hydroxycyclopentyl)acetamide

Compound was prepared analogous manner to Example 34 from (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid (Example 13) and isolated as a light brown powder.

1 H NMR (DMSO d6 ): 1.74 (1H, s), 7.89 (1H, d, J=7.2 Hz), 7.72 (1H, m), 7.16 (1H, m), 4.70 (1H, d, J=4.3 Hz), 4.44 (1H, quin, J=8.6 Hz), 4.14 (1H, dd, J=11.4, 9.3 Hz), 3.79 (1H, m), 3.73 (2H, m), 3.22 (2H, s), 3.22 (1H, m), 2.83 (1H, dd, J=15.8, 8.2 Hz), 1.90 (1H, m), 1.76 (1H, m), 1.59 (2H, m), 1.41 (1H, m), 1.30 (1H, m).

13 C NMR (DMSO d6 ): 167.3, 160.8, 160.8, 159.2, 159.1, 157.5, 157.5, 155.9, 155.9, 155.1, 132.5, 132.4, 128.9, 118.8, 118.7, 118.5, 114.4, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 76, 57.7, 48.5, 35.6, 32.1, 31.5, 29.4, 29.3, 20.4.

Example 162: (S)—N-(2-(1H-pyrazol-1-yl)ethyl)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 34 from (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as a beige solid.

1 H NMR (DMSO d6 ): 11.74 (1H, s), 8.06 (1H, t, J=5.6 Hz), 7.66 (1H, d, J=2.1 Hz), 7.62 (1H, m), 7.40 (1H, d, J=1.3 Hz), 7.23 (1H, m), 6.17 (1H, t, J=2.1 Hz), 4.42 (1H, quin, J=8.7 Hz), 4.15 (3H, m), 3.73 (1H, dd, J=11.4, 8.2 Hz), 3.43 (2H, q, J=6.0 Hz), 3.22 (2H, m), 3.13 (1H, dd, J=15.7, 9.2 Hz), 2.79 (1H, dd, J=15.8, 8.4 Hz).

13 C NMR (DMSO d6 ): 168, 160.2, 160.1, 158.5, 158.5, 156.6, 156.5, 155.2, 155, 154.9, 138.7, 130.1, 129.7, 129.6, 129.2, 118.4, 116.1, 116, 115.9, 115.9, 114, 113.2, 113.2, 113.1, 113.1, 104.9, 50.2, 48.4, 39.8, 35.6, 31.4, 29.1.

Example 163: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-N-methylacetamide

Compound was prepare analogous manner to Example 34 from (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as an orange solid.

1 H NMR (DMSO d6 ): 1.70 (1H, s), 7.61 (1H, m), 7.22 (1H, m), 4.58 (0.65H, tt, J=12.3, 3.4 Hz), 4.45 (1H, m), 4.16 (1.35H, m), 3.74 (1H, m), 3.58 (0.7H, m), 3.49 (1.3H, m), 3.43-3.35 (2H, m), 3.22 (1H, m), 3.12 (0.7H, m), 3.04 (1.3H, m), 2.85 (1.95H, s), 2.83 (1H, m), 2.70 (1.05H, s), 2.24-2.07 (2H, m), 1.93 (0.7H, m), 1.79 (1.3H, m).

13 C NMR (DMSO d6 ): 167.8, 167.6, 160.1, 160.1, 158.5, 158.4, 156.6, 156.5, 155.1, 155.1, 154.9, 154.8, 129.7, 129.6, 129.5, 129.3, 118.9, 118.8, 118.7, 116.1, 116, 115.9, 115.9, 114.2, 114.1, 113.2, 113.2, 113.1, 113.1, 49.4, 49.3, 49.2, 48.6, 35.7, 35.6, 29.9, 29.4, 29.2, 29.1, 27.7, 27.7, 26.9, 26.6.

Example 164: 2-((S)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(3-(methylsulfonyl)pyrrolidin-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 34 from (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid (Example 12) and isolated as a beige solid.

1 H NMR (DMSO d6 ): 1.73 (1H, 2 s), 7.72 (1H, m), 7.16 (1H, m), 4.44 (1H, m), 4.15 (1H, m), 4.06, 3.94 (1H, 2 m), 3.88, 3.83, 3.70-3.61, 3.56, 3.50, 3.38 (4H, several mult.), 3.72 (1H, dd, J=11.4, 8.0 Hz), 3.48, 3.45 (2H, 2 m), 3.22 (1H, dd, J=15.6, 9.4 Hz), 3.07, 3.05 (3H, 2s), 2.84 (1H, m), 2.33 (1H, m), 2.22 (1H, m).

13 C NMR (DMSO d6 ): 166.4, 166.3, 160.8, 160.8, 159.2, 159.1, 157.5, 157.5, 155.9, 155.8, 155.2, 155.2, 132.5, 132.4, 129.4, 129.4, 118.8, 118.8, 118.7, 118.6, 118.5, 118.5, 113.8, 113.8, 113.7, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 60.6, 60.6, 58.9, 58.9, 48.6, 45.4, 45.4, 45.3, 45.3, 45.1, 44.9, 35.7, 30.3, 30.2, 30.2, 30.2, 29.3, 25.7, 24.1, 24.1.

Example 165: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(2-oxa-8-azaspiro[4.5]decan-8-yl)ethan-1-one

Compound was prepared analogous manner to Example 34 from (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid (Example 12) and isolated as a beige solid.

1 H NMR (DMSO d6 ): 1.70 (1H, s), 7.72 (1H, m), 7.16 (1H, m), 4.45 (1H, quin, J=8.3 Hz), 4.15 (1H, br t, J=10 Hz), 3.73 (3H, m), 3.60-3.27 (8H, m), 3.21 (1H, br dd, J=15.7, 9.2 Hz), 2.80 (1H, br dd, J=15.8, 7.6 Hz), 1.72 (2H, m), 1.47 (2H, m), 1.42 (2H, m).

13 C NMR (DMSO d6 ): 166.4, 166.4, 160.8, 159.2, 157.5, 157.5, 155.9, 155.8, 155.1, 132.4, 132.4, 129.1, 118.9, 118.8, 118.7, 114, 114, 113.8, 113.8, 113.6, 113.6, 104, 104, 103.9, 103.9, 76.9, 76.7, 66.4, 66.4, 48.6, 43.4, 41.6, 36.5, 36.3, 35.6, 34.7, 34, 29.3, 29.2.

Example 166: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(1-oxidothiomorpholino)ethan-1-one

Compound was prepared analogous manner to Example 34 from (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid (Example 12) and isolated as a beige solid.

1 H NMR (DMSO d6 ): 1.68 (1H, s), 7.72 (1H, m), 7.17 (1H, m), 4.46 (1H, quin, J=8.4 Hz), 4.16 (2H, m), 3.88 (1H, m), 3.82 (1H, m), 3.73 (1H, dd, J=11.3, 8.1 Hz), 3.57 (3H, m), 3.23 (1H, dd, J=15.7, 9.4 Hz), 2.90 (1H, m), 2.83 (1H, dd, J=15.8, 8.2 Hz), 2.76 (3H, m).

13 C NMR (DMSO d6 ): 167, 160.8, 160.8, 159.2, 159.1, 157.5, 157.5, 155.9, 155.8, 155.1, 132.5, 132.4, 129.4, 118.9, 118.7, 118.6, 113.9, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 48.6, 45.1, 45, 44.7, 44.6, 37, 37, 37, 35.7, 33.1, 33.1, 29.3, 29.3, 29.2, 28.8, 28.8.

Example 167: 2-((S)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 34 from (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid (Example 12) and isolated as a brown powder.

1 H NMR (DMSO d6 ): 1.68 (1H, 2 s), 7.72 (1H, m), 7.16 (1H, m), 5.08 (0.6H, m), 4.61 (0.4H, m), 4.45 (1H, quin, J=8.6 Hz), 4.15 (1H, dd, J=9.6, 11.5 Hz), 3.91 (1H, m), 3.72 (1H, dd, J=11.7, 7.8 Hz), 3.66 (0.8H, m), 3.63-3.52 (3H, m), 3.48 (1.2H, m), 3.20 (1H, m), 2.88 (1.8H, m), 2.81 (1H, m), 2.72 (1.2H, s), 2.21-2.02 (1H, m), 1.88-1.69 (1H, m).

13 C NMR (DMSO d6 ): 168.2, 168.2, 167.7, 160.8, 160.7, 159.1, 159.1, 157.5, 157.5, 155.9, 155.8, 155.1, 155.1, 132.4, 132.4, 129.3, 129.2, 118.8, 118.7, 118.6, 114.2, 114.2, 114.1, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 69.3, 69.3, 69.2, 67.1, 67, 56.5, 56.5, 52.9, 48.6, 35.7, 30, 29.8, 29.8, 29.7, 29.7, 29.5, 29.5, 29.3, 29.2, 27.6.

Example 168: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(1,3,4-thiadiazol-2-yl)acetamide

To a stirred mixture of 1,3,4-thiadiazol-2-amine (35.2 mg, 0.348 mmol) and N-ethyl-N-isopropylpropan-2-amine (DIPEA) (0.06 ml, 0.348 mmol). in dichloromethane (2 mL) was added (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid (100 mg, 0.290 mmol) followed by addition of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (0.180 ml, 0.290 mmol). The reaction was stirred at room temperature overnight. Thereupon, the organic was removed under vacuum and the residue was purified by column chromatography in a mixture of dichloromethane-methanol. Recrystallization from isopropanol afforded the titled product as an off-white solid.

Yield: 76 mg, 61%.

1 H NMR (DMSO d6 ): 12.72 (1H, s), 11.81 (1H, s), 9.17 (1H, s), 7.61 (1H, m), 7.22 (1H, m), 4.47 (1H, quin, J=8.6 Hz), 4.17 (1H, dd, J=9.5, 11.2 Hz), 3.75 (1H, dd, J=11.7, 8.1 Hz), 3.71 (2H, m), 3.26 (1H, dd, J=15.8, 9.2 Hz), 2.88 (1H, dd, J=15.8, 8.2 Hz).

13 C NMR (DMSO d6 ): 167.5, 160.2, 160.1, 158.5, 158.5, 158.5, 156.6, 156.5, 155.6, 154.9, 154.9, 148.8, 130.2, 129.7, 129.6, 118.7, 118.6, 118.5, 116.1, 116, 115.9, 115.9, 113.3, 113.2, 113.1, 113.1, 112.5, 48.6, 35.6, 31.1, 29.2.

Example 169: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(pyridin-2-yl)acetamide

Compound was prepared analogous manner to Example 168 from (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as an off-white powder.

1 H NMR (DMSO d6 ): 11.81 (1H, s), 10.61 (1H, s), 8.31 (1H, ddd, J=0.8, 1.8, 4.8 Hz), 8.04 (1H, br d, J=8.2 Hz), 7.77 (1H, m), 7.61 (1H, m), 7.21 (1H, m), 7.10 (1H, ddd, J=7.3, 4.9, 0.9 Hz), 4.46 (1H, quin, J=8.6 Hz), 4.17 (1H, dd, J=11.3, 9.4 Hz), 3.75 (1H, dd, J=11.6, 7.9 Hz), 3.58 (2H, m), 3.26 (1H, dd, J=15.8, 9.3 Hz), 2.88 (1H, dd, J=8.3, 15.8 Hz).

13 C NMR (DMSO d6 ): 167.6, 160.1, 160.1, 158.5, 158.5, 156.6, 156.5, 155.4, 154.9, 154.9, 151.9, 148, 138.2, 129.7, 129.6, 119.5, 118.8, 118.6, 118.5, 116.1, 116, 115.9, 115.9, 113.6, 113.4, 113.2, 113.2, 113.1, 113.1, 48.6, 35.6, 32.2, 29.2.

Example 170: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(pyridin-2-yl)acetamide

Compound was prepared analogous manner to Example 168 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as a brown solid.

1 H NMR (DMSO d6 ): 11.71 (1H, s), 10.62 (1H, s), 8.33 (1H, dd, J=4.7, 1.0 Hz), 8.06 (1H, br d, J=8.1 Hz), 7.79 (1H, m), 7.56 (2H, m), 7.24 (1H, dd, J=10.0, 8.8 Hz), 7.11 (1H, ddd, J=6.7, 5.6, 0.7 Hz), 4.09 (1H, d, J=12.0 Hz), 3.81 (1H, d, J=12.2 Hz), 3.65 (2H, m), 2.88 (1H, dd, J=8.4, 4.3 Hz), 1.66 (1H, dd, J=8.3, 5.4 Hz), 1.14 (1H, t, J=4.8 Hz).

13 C NMR (DMSO d6 ): 167.7, 161.7, 160.1, 156.1, 151.9, 148, 138.2, 132.9, 132.9, 132.3, 132.3, 129.3, 129.2, 119.5, 118, 117.8, 116.2, 116.2, 113.4, 113.2, 51.6, 32.3, 32.2, 22.2, 20.6.

Example 171: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(pyridin-3-yl)acetamide

Compound was prepared analogous manner to Example 168 from 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as a beige solid.

1 H NMR (DMSO d6 ): 11.75 (1H, br s), 10.33 (1H, br s), 8.75 (1H, br s), 8.27 (1H, d, J=4.1 Hz), 8.04 (1H, d, J=7.9 Hz), 7.46 (1H, dd, J=6.5, 2.6 Hz), 7.43 (1H, ddd, J=8.7, 4.3, 2.6 Hz), 7.37 (1H, dd, J=8.2, 4.7 Hz), 7.30 (1H, dd, J=9.0, 10.0 Hz), 4.10 (1H, d, J=12.0 Hz), 3.82 (1H, d, J=12.0 Hz), 3.61 (2H, br s), 2.88 (1H, dd, J=8.2, 4.1 Hz), 1.67 (1H, dd, J=8.4, 5.4 Hz), 1.16 (1H, t, J=4.8 Hz).

13 C NMR (DMSO d6 ): 167.4, 161.3, 159.6, 156.2, 144.3, 140.8, 135.7, 132.3, 130.2, 130.1, 129.4, 129.3, 128.9, 128.7, 128.3, 126.3, 123.7, 117.6, 117.4, 113.2, 51.6, 32.4, 32.1, 22.1, 20.7.

Example 172: (R)-1-(2-hydroxyethyl)-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione

Compound was prepared analogous manner to Example 8 from ethyl (R)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetate and isolated as a cream powder.

1 H NMR (DMSO d6 ): 1.73 (1H, s), 7.85 (1H, m), 4.69 (1H, t, J=5.3 Hz), 4.48 (1H, quin, J=8.6 Hz), 4.16 (1H, dd, J=11.5, 9.2 Hz), 3.76 (1H, dd, J=11.6, 8.1 Hz), 3.55 (2H, m), 3.29 (1H, dd, J=15.6, 9.2 Hz), 2.93 (1H, dd, J=15.6, 8.2 Hz), 2.49 (2H, t, J=6.8 Hz).

13 C NMR (DMSO d6 ): 155, 146.4, 146.4, 146.4, 146.3, 146.3, 146.2, 145.4, 145.3, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 144.8, 144.8, 144.7, 144.7, 144.7, 144.6, 144.6, 143.7, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 128.2, 120.4, 120.3, 120.2, 117.6, 105.9, 105.7, 105.5, 59.2, 48.3, 35.8, 29, 28.

Example 173: (R)-6-(3-bromo-2,6-difluorophenyl)-1-(2-hydroxyethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione

Compound was prepared analogous manner to Example 8 from ethyl (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetate and isolated as a light cream powder.

1 H NMR (DMSO d6 ): 11.72 (1H, s), 7.72 (1H, ddd, J=9.0, 8.0, 5.8 Hz), 7.16 (1 Hm), 4.69 (1H, br t, J=5.1 Hz), 4.43 (1H, quin, J=8.7 Hz), 4.13 (1H, dd, J=11.6, 9.1 Hz), 3.71 (1H, dd, J=11.6, 8.1 Hz), 3.54 (2H, m), 3.25 (1H, dd, J=15.6, 9.2 Hz), 2.89 (1H, dd, J=15.6, 8.4 Hz), 2.48 (2H, t, J=6.7 Hz).

13 C NMR (DMSO d6 ): 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 155.9, 155.9, 154.9, 132.5, 132.4, 128.3, 118.7, 118.6, 118.4, 117.5, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 59.2, 48.4, 35.7, 29.1, 28.

Example 174: (5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-1-(2-morpholinoethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione hydrochloride

Compound was prepared analogous manner to Example 35 from 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one (Example 66) and isolated as a beige solid.

1 H NMR (CD 3 OD): 7.44 (1H, dd, J=6.4, 2.7 Hz), 7.36 (1H, ddd, J=8.8, 4.4, 2.6 Hz), 7.17 (1H, dd, J=9.8, 8.8 Hz), 4.20 (1H, d, J=12.3 Hz), 3.93 (1H, d, J=12.2 Hz), 3.86 (4H, br), 3.28-3.0 (6H, m), 2.94 (2H, m), 2.85 (1H, dd, J=8.3, 4.0 Hz), 1.71 (1H, dd, J=8.2, 5.6 Hz), 1.18 (1H, dd, J=5.5, 4.2 Hz).

13 C NMR (CD 3 OD): 163.3, 161.6, 157.1, 134.2, 131.5, 131.4, 131, 130.9, 130.7, 130.7, 130, 129.9, 118.6, 118.4, 66.2, 57.3, 54, 53.5, 53.5, 34.2, 23.2, 22.1, 21.3.

Example 175: (5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-1-(2-(isopropylamino)ethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione hydrochloride

Compound was prepared analogous manner to Example 35 from 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-isopropylacetamide (Example 67) and isolated as a light beige solid.

1 H NMR (DMSO d6 ): 1.80 (1H, br s), 8.48 (2H, br s), 7.48 (1H, dd, J=6.5, 2.7 Hz), 7.44 (1H, ddd, J=8.7, 4.3, 2.8 Hz), 7.31 (1H, dd, J=9.9, 8.9 Hz), 4.08 (1H, d, J=12.2 Hz), 3.80 (1H, d, J=12.0 Hz), 3.31 (1H, m), 3.16 (2H, br t, J=7.5 Hz), 2.97 (1H, dd, J=8.4, 4.3 Hz), 2.80 (2H, m), 1.67 (1H, dd, J=8.2, 5.3 Hz), 1.23 (6H, d, J=6.5 Hz), 1.20 (1H, t, J=4.8 Hz).

13 C NMR (DMSO d6 ): 161.2, 159.6, 156.5, 131.7, 130.1, 130.1, 129.4, 129.3, 128.8, 128.7, 128.3, 128.3, 117.6, 117.4, 114.6, 51.5, 51.5, 49.4, 42.3, 32.5, 22.1, 21.4, 20.3, 18.8, 18.8.

Example 176: (R)-6-(3-bromo-2,6-difluorophenyl)-1-(2-(((R)-tetrahydrofuran-3-yl)amino)ethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione

Compound was prepared analogous manner to Example 35 from 2-((R)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydrofuran-3-yl)acetamide (Example 116) and isolated as a cream powder.

1 H NMR (DMSO d6 ): 1.72 (1H, br s), 7.72 (1H, m), 7.16 (1H, m), 4.45 (1H, quin, J=8.5 Hz), 4.13 (1H, dd, J=11.0, 9.7 Hz), 3.74-3.68 (2H, m), 3.66 (1H, dd, J=8.6, 5.8 Hz), 3.61 (1H, m), 3.33 (1H, m), 3.31-3.21 (2H, m), 2.88 (1H, dd, J=15.6, 8.2 Hz), 2.67 (2H, m), 2.46 (2H, t, J=7.1 Hz), 1.91 (1H, m), 1.59 (1H, m).

13 C NMR (DMSO d6 ): 160.8, 160.8, 159.2, 159.2, 159.1, 157.6, 157.5, 155.9, 155.9, 154.9, 132.4, 132.4, 128.1, 118.9, 118.7, 118.6, 118.2, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 72.5, 66.3, 57.9, 48.4, 46.3, 35.7, 32.5, 29.2, 25.

Example 177: (R)-6-(3-bromo-2,6-difluorophenyl)-1-(2-(4,4-difluoropiperidin-1-yl)ethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione

Compound was prepared analogous manner to Example 35 from 2-((R)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydrofuran-3-yl)acetamide (Example 117) and isolated as a white powder.

1 H NMR (DMSO d6 ): 1.74 (1H, s), 7.72 (1H, m), 7.16 (1H, m), 4.45 (1H, quin, J=8.5 Hz), 4.13 (1H, dd, J=11.3, 9.4 Hz), 3.71 (1H, dd, J=11.6, 7.8 Hz), 3.29 (1H, dd, J=15.6, 9.4 Hz), 2.88 (1H, dd, J=15.7, 7.9 Hz), 2.58-2.46 (8H, m), 1.91 (4H, m).

13 C NMR (DMSO d6 ): 160.8, 160.7, 159.1, 159.1, 157.5, 157.5, 155.9, 155.8, 154.9, 132.4, 132.4, 128.1, 124.4, 122.8, 121.2, 119, 118.9, 118.7, 118, 113.8, 113.7, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 54.9, 49.2, 49.2, 49.1, 48.5, 35.7, 33.5, 33.4, 33.2, 29.2, 22.1.

Example 178: (R)-6-(3-bromo-2,6-difluorophenyl)-1-(2-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino)ethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione

Compound was prepared analogous manner to Example 35 from 2-((R)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydrofuran-3-yl)acetamide (Example 130) and isolated as a cream powder.

1 H NMR (DMSO d6 ): 1.74 (1H, s), 7.72 (1H, m), 7.16 (1H, m), 4.45 (1H, quin, J=8.5 Hz), 4.13 (1H, dd, J=9.7, 11.1 Hz), 3.71 (1H, dd, J=11.4, 7.9 Hz), 3.27 (1H, dd, J=15.5, 9.2 Hz), 3.08 (2H, m), 2.98 (2H, m), 2.89 (1H, dd, J=15.6, 8.1 Hz), 2.73 (1H, m), 2.68 (2H, t, J=7.2 Hz), 2.46 (2H, t, J=7.1 Hz), 2.01 (2H, m), 1.83 (2H, m).

13 C NMR (DMSO d6 ): 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 155.9, 155.9, 155, 132.5, 132.4, 128.1, 118.9, 118.7, 118.6, 118.2, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 54.9, 50.4, 48.4, 47.7, 44.8, 35.7, 29.1, 29, 29, 25.

Example 179: (R)-6-(3-bromo-2,6-difluorophenyl)-1-(2-(4-(methylsulfonyl)piperidin-1-yl)ethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione

Compound was prepare analogous manner to Example 35 from 2-((R)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydrofuran-3-yl)acetamide (Example 126) and isolated as a white powder.

1 H NMR (DMSO d6 ): 1.74 (1H, s), 7.72 (1H, m), 7.16 (1H, m), 4.45 (1H, quin, J=8.5 Hz), 4.13 (1H, dd, J=11.3, 9.4 Hz), 3.70 (1H, dd, J=11.7, 7.8 Hz), 3.28 (1H, dd, J=15.6, 9.4 Hz), 3.01 (1H, tt, J=3.6, 12.4 Hz), 3.0-2.94 (2H, m), 2.90 (3H, s), 2.89 (1H, dd, J=8.0, 15.4 Hz), 2.50 (4H, m), 1.94 (4H, m), 1.55 (2H, m).

13 C NMR (DMSO d6 ): 160.8, 160.8, 159.2, 159.1, 157.5, 157.5, 155.9, 155.8, 154.9, 132.4, 132.4, 128.1, 118.9, 118.8, 118.7, 118.1, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 58.8, 55.7, 51.4, 51.3, 48.5, 37.4, 35.7, 29.2, 24.4, 24.4, 22.

Example 180: (5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-1-(2-((2,2,2-trifluoroethyl)amino)ethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione

Compound was prepared analogous manner to Example 35 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide (Example 152) and isolated as a yellow solid.

1 H NMR (DMSO d6 ): 11.65 (1H, s), 7.59 (1H, dd, J=6.7, 2.6 Hz), 7.55 (1H, ddd, J=8.7, 4.5, 2.5 Hz), 7.24 (1H, dd, J=10.2, 8.7 Hz), 4.06 (1H, d, J=11.4 Hz), 3.77 (1H, d, J=12.0 Hz), 3.26 (2H, m), 2.90 (1H, dd, J=8.4, 4.3 Hz), 2.84 (2H, m), 2.54 (2H, m), 1.62 (1H, dd, J=8.3, 5.4 Hz), 1.16 (1H, t, J=4.8 Hz).

13 C NMR (DMSO d6 ): 161.8, 160.1, 155.8, 132.8, 132.8, 132.3, 132.2, 130.7, 129.5, 129.4, 129, 127.2, 125.3, 123.5, 118, 117.8, 117.5, 116.2, 116.2, 51.4, 49.3, 49.1, 48.9, 48.7, 47.7, 32.2, 24.8, 22.3, 20.4.

Example 181: (S)-6-(3-bromo-2,6-difluorophenyl)-1-(2-(cyclobutylamino)ethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione

Compound was prepared analogous manner to Example 35 from (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-cyclobutylacetamide (Example 102) and isolated as a white powder.

1 H NMR (DMSO d6 ): 1.73 (1H, m), 7.72 (1H, m), 7.16 (1H, m), 4.45 (1H, t, J=8.7 Hz), 4.13 (1H, dd, J=11.3, 9.4 Hz), 3.71 (1H, dd, J=11.6, 7.9 Hz), 3.26 (1H, dd, J=15.6, 9.4 Hz), 3.18 (1H, quin, J=7.5 Hz), 2.88 (1H, dd, J=15.6, 8.1 Hz), 2.64 (2H, t, J=7.1 Hz), 2.45 (2H, t, J=7.0 Hz), 2.07 (2H, m), 1.75-1.45 (4H, m).

13 C NMR (DMSO d6 ): 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 155.9, 155.9, 155, 132.5, 132.4, 128.1, 118.8, 118.7, 118.6, 118, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 53.2, 48.4, 44.6, 35.7, 30, 29.1, 24.7, 14.5.

Example 182: (R)-6-(3-bromo-2,6-difluorophenyl)-1-(2-((2-(methylsulfonyl)ethyl)amino)ethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione

Compound was prepared analogous manner to Example 35 from (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2-(methylsulfonyl)ethyl)acetamide (Example 118) and isolated as a yellow powder.

1 H NMR (DMSO d6 ): 1.73 (1H, br s), 7.73 (1H, m), 7.17 (1H, m), 4.44 (1H, quin, J=8.7 Hz), 4.14 (1H, dd, J=9.5, 11.5 Hz), 3.71 (1H, dd, J=11.5, 8.1 Hz), 3.26 (1H, dd, J=15.5, 9.2 Hz), 3.20 (2H, t, J=6.7 Hz), 2.97 (3H, s), 2.91 (2H, t, J=6.7 Hz), 2.91 (1H, m), 2.70 (2H, t, J=7.0 Hz), 2.47 (2H, t, J=7.0 Hz).

13 C NMR (DMSO d6 ): 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 155.9, 155.9, 155, 132.5, 132.4, 128.2, 118.7, 118.6, 118.5, 118, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 53.6, 48.4, 47, 42.4, 41.4, 35.7, 29, 24.7.

Example 183: (R)-6-(3-bromo-2,6-difluorophenyl)-1-(2-((2-hydroxyethyl)(methyl)amino)ethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione

Compound was prepared analogous manner to Example 35 from (R)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2-hydroxyethyl)-N-methylacetamide (Example 131) and isolated as a brown powder.

1 H NMR (DMSO d6 ): 1.72 (1H, s), 7.72 (1H, m), 7.17 (1H, m), 4.44 (1H, quin, J=8.7 Hz), 4.41 (1H, t, br, J=5.5 Hz), 4.13 (1H, dd, J=11.2, 9.5 Hz), 3.70 (1H, dd, J=11.6, 8.1 Hz), 3.44 (2H, q, J=6.1 Hz), 3.27 (1H, dd, J=15.5, 9.3 Hz), 2.88 (1H, dd, J=15.6, 8.3 Hz), 2.52 (2H, m), 2.48 (2H, t, J=7.1 Hz), 2.41 (2H, t, J=6.2 Hz), 2.18 (3H, s).

13 C NMR (DMSO d6 ): 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 155.9, 155.9, 154.9, 132.5, 132.4, 127.9, 118.8, 118.6, 118.5, 118.3, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 58.9, 58.8, 55.8, 48.4, 42, 35.7, 29.1, 22.1.

Example 184: (R)-6-(3-bromo-2,6-difluorophenyl)-1-(2-(((R)-1-cyclohexylethyl)amino)ethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione

Compound was prepared analogous manner to Example 35 from 2-((R)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-1-cyclohexylethyl)acetamide (Example 127) and isolated as a cream powder.

1 H NMR (DMSO d6 ): 11.84 (1H, br), 7.73 (1H, m), 7.17 (1H, m), 4.45 (1H, quin, J=8.6 Hz), 4.13 (1H, dd, J=11.2, 9.4 Hz), 3.71 (1H, dd, J=11.6, 7.8 Hz), 3.28 (1H, dd, J=15.7, 9.5 Hz), 2.88 (1H, dd, J=15.6, 8.2 Hz), 2.83, 2.71 (2H, 2 br s), 2.50 (3H, m), 1.68 (2H, br d, J=12.6 Hz), 1.60 (3H, m), 1.38-1.0 (5H, m), 0.94 (4H, m).

13 C NMR (DMSO d6 ): 160.8, 160.7, 159.1, 159.1, 157.6, 157.5, 155.9, 155.9, 155.1, 132.5, 132.4, 128.2, 118.8, 118.7, 118.6, 113.8, 113.6, 104.1, 103.9, 57, 48.4, 44.8, 41.8, 35.7, 29.2, 29.2, 27.1, 26.2, 26.1, 25.9, 24.6, 15.7.

Example 185: (5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-1-(2-(pyrrolidin-1-yl)ethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione hydrochloride

Compound was prepared analogous manner to Example 35 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(pyrrolidin-1-yl)ethan-1-one (Example 70) and isolated as a beige solid.

1 H NMR (DMSO d6 ): 11.80 (1H, br s), 9.60 (1H, br s), 7.59 (1H, dd, J=6.7, 2.5 Hz), 7.56 (1H, ddd, J=8.7, 4.5, 2.6 Hz), 7.25 (1H, dd, J=10.0, 8.8 Hz), 4.08 (1H, d, J=12.0 Hz), 3.80 (1H, d, J=12.2 Hz), 3.39-3.05 (6H, m), 2.97 (1H, dd, J=8.4, 4.3 Hz), 2.83 (2H, m), 1.91 (4H, br s), 1.67 (1H, dd, J=8.2, 5.3 Hz), 1.19 (1H, t, J=4.7 Hz).

13 C NMR (DMSO d6 ): 161.8, 160.1, 156.5, 132.9, 132.9, 132.4, 132.3, 131.7, 129.2, 129.1, 118, 117.9, 116.2, 116.2, 114.6, 53.4, 52.4, 51.5, 32.4, 22.7, 22.1, 21.3, 20.3.

Example 186: (5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-1-(2-((cyclopropylmethyl)amino)ethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione hydrochloride

Compound was prepared analogous manner to Example 35 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(cyclopropylmethyl)acetamide (Example 143) and isolated as a beige solid.

1 H NMR (DMSO d6 ): 11.79 (1H, s br), 8.39 (2H, s br), 7.59 (1H, dd, J=6.7, 2.5 Hz), 7.56 (1H, ddd, J=8.6, 4.4, 2.6 Hz), 7.25 (1H, dd, J=9.9, 8.9 Hz), 4.08 (1H, br d, J=12.0 Hz), 3.79 (1H, d, J=12.0 Hz), 3.17 (2H, t, J=7.3 Hz), 2.93 (1H, dd, J=8.2, 4.3 Hz), 2.87-2.73 (4H, m), 1.67 (1H, dd, J=8.1, 5.4 Hz), 1.20 (1H, t, J=4.8 Hz), 1.02 (1H, m), 0.58 (2H, m), 0.34 (2H, m).

13 C NMR (DMSO d6 ): 161.8, 160.1, 156.5, 133, 132.9, 132.4, 132.3, 131.7, 129.3, 129.2, 118, 117.9, 116.2, 116.2, 114.7, 51.5, 51.4, 44.8, 32.4, 22.1, 21.3, 20.3, 7.3, 3.9, 3.8.

Example 187: (5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-1-(2-(cyclopropylamino)ethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione hydrofluoride

Compound was prepared analogous manner to Example 35 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-cyclopropylacetamide (Example 154) and isolated as a beige solid.

1 H NMR (DMSO d6 ): 11.76 (1H, br s), 7.59 (1H, dd, J=6.6, 2.5 Hz), 7.56 (1H, ddd, J=8.6, 4.5, 2.6 Hz), 7.25 (1H, dd, J=10.0, 8.9 Hz), 4.07 (1H, d, J=12.0 Hz), 3.78 (1H, d, J=12.0 Hz), 3.14 (2H, m), 2.93 (1H, dd, J=8.3, 4.2 Hz), 2.73 (2H, m), 2.52 (1H, m), 1.65 (1H, dd, J=8.2, 5.3 Hz), 1.19 (1H, t, J=4.8 Hz), 0.70-0.57 (4H, m).

13 C NMR (DMSO d6 ): 161.8, 160.1, 156.3, 132.9, 132.9, 132.3, 132.3, 131.4, 129.3, 129.2, 118, 117.8, 116.2, 116.2, 115.4, 51.5, 46.2, 32.4, 29.5, 22.2, 22.2, 20.4, 4.1, 4.

Example 188: (5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-1-(2-(cyclobutylamino)ethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione hydrofluoride

Compound was prepared analogous manner to Example 35 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-cyclobutylacetamide (Example 153) and isolated as a beige solid.

1 H NMR (DMSO d6 ): 1.80 (1H, s br), 8.44 (1H, s br), 7.59 (1H, dd, J=6.7, 2.5 Hz), 7.56 (1H, ddd, J=8.7, 4.4, 2.6 Hz), 7.25 (1H, dd, J=10.0, 8.9 Hz), 4.07 (1H, d, J=12.0 Hz), 3.78 (1H, d, J=12.0 Hz), 3.65 (1H, quin, J=8.0 Hz), 3.02 (2H, t, J=7.2 Hz), 2.94 (1H, dd, J=8.3, 4.2 Hz), 2.74 (2H, m), 2.18 (2H, m), 2.08 (2H, m), 1.77 (2H, m), 1.66 (1H, dd, J=8.2, 5.3 Hz), 1.20 (1H, t, J=4.7 Hz).

13 C NMR (DMSO d6 ): 161.8, 160.1, 156.5, 133, 133, 132.4, 132.3, 131.8, 129.3, 129.2, 118, 117.9, 116.2, 116.2, 114.6, 51.6, 51.6, 51.1, 42.8, 32.4, 26.4, 22.1, 21.6, 20.3, 14.5.

Example 189: (5aS,6aR)-1-(2-(benzylamino)ethyl)-5a-(5-chloro-2-fluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione hydrofluoride

Compound was prepared analogous manner to Example 35 from N-benzyl-2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetamide (Example 156) and isolated as a beige solid.

1 H NMR (DMSO d6 ): 1.79 (1H, br s), 8.28 (2H, br m), 7.50-7.41 (6H, m), 7.39 (1H, m), 7.31 (1H, dd, J=9.0, 9.9 Hz), 4.10 (2H, s), 4.08 (1H, d, J=12.3 Hz), 3.79 (1H, d, J=12.2 Hz), 3.12 (2H, t, J=6.8 Hz), 2.90 (1H, dd, J=8.4, 4.3 Hz), 2.78 (2H, m), 1.66 (1H, dd, J=8.2, 5.3 Hz), 1.19 (1H, t, J=4.7 Hz).

13 C NMR (DMSO d6 ): 161.2, 159.6, 156.4, 133.6, 131.5, 130.1, 130.1, 129.5, 129.4, 129.3, 128.9, 128.8, 128.6, 128.6, 128.3, 117.6, 117.4, 115.1, 51.5, 50.6, 45.5, 32.4, 22.1, 21.8, 20.4.

Example 190: (5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-1-(2-(cyclopentyl(methyl)amino)ethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione hydrofluoride

Compound was prepared analogous manner to Example 35 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-cyclopentyl-N-methylacetamide (Example 155) and isolated as a beige solid.

1 H NMR (DMSO d6 ): 1.81 (1H, br s), 9.42 (1H, m), 7.63-7.49 (2H, m), 7.25 (1H, t, J=9.3 Hz), 4.08 (1H, d, J=12.0 Hz), 3.79 (1H, d, J=12.2 Hz), 3.29 (2H, m), 2.95 (2H, dd, J=7.8, 3.9 Hz), 2.78 (4H, br m), 1.97 (2H, br m), 1.78-1.37 (7H, m), 1.17 (1H, m), 1H (br).

13 C NMR (DMSO d6 ): 161.7, 160.1, 156.4, 132.9, 132.8, 132.3, 132.3, 131.4, 129.2, 129.1, 118, 117.8, 116.2, 116.2, 66.1, 52.6, 51.5, 37.8, 32.4, 27.9, 23.7, 22.2, 20.3, 19.6.

Example 191: (5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-1-(2-morpholinoethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione hydrofluoride

Compound was prepared analogous manner to Example 35 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one (Example 157) and isolated as an off-white solid.

1 H NMR (DMSO d6 ): 1.85 (1H, br s), 11.05 (1H, br s), 7.64-7.52 (2H, m), 7.25 (1H, br t, J=9.3 Hz), 4.08 (1H, d, J=11.9 Hz), 3.98 (2H, br m), 3.79 (3H, m), 3.44 (2H, m), 3.35 (2H, m), 3.10 (2H, br s), 2.97 (3H, br s), 1.67 (1H, m), 1.19 (1H, br s).

13 C NMR (DMSO d6 ): 161.8, 160.1, 156.6, 132.9, 132.4, 132.3, 131.5, 129.2, 129.1, 118, 117.8, 116.2, 114.3, 63.1, 53.9, 51.5, 51.2, 50.9, 32.4, 22.1, 20.4, 18.7.

Example 192: (5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-1-(2-(pyridin-2-ylamino)ethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione hydrofluoride

Compound was prepared analogous manner to Example 35 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(pyridin-2-yl)acetamide (Example 170) and isolated as a dark beige solid.

1 H NMR (DMSO d6 ): 11.75 (1H, s), 7.95 (1H, dd, J=5.4, 1.5 Hz), 7.64-7.43 (3H, m), 7.23 (1H, t, J=9.8 Hz), 6.66 (1H, br s), 6.58 (1H, br s), 4.05 (1H, d, J=11.9 Hz), 3.76 (1H, d, J=12.1 Hz), 3.50 (2H, m), 2.73 (1H, dd, J=8.1, 4.2 Hz), 2.69 (2H, t, J=6.9 Hz), 1.54 (1H, dd, J=8.2, 5.3 Hz), 1.11 (1H, t, J=4.8 Hz).

13 C NMR (DMSO d6 ): 161.7, 160.1, 157.3, 155.9, 145.6, 137.9, 132.8, 132.8, 132.2, 132.2, 131.1, 129.4, 129.3, 118, 117.8, 117.1, 116.1, 111.6, 109.2, 51.4, 39.4, 32.2, 24, 22.4, 20.3.

Example 193: (S)-6-(3-chloro-2,6-difluorophenyl)-1-(2-(methylamino)ethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione Hydrochloride

Compound was prepared analogous manner to Example 35 from (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-methylacetamide and isolated as a white solid.

1 H NMR (DMSO d6 ): 1.89 (1H, s), 8.93 (2H, m), 7.63 (1H, m), 7.23 (1H, m), 4.44 (1H, quin, J=8.8 Hz), 4.14 (1H, dd, J=11.3, 9.4 Hz), 3.75 (1H, dd, J=11.5, 8.4 Hz), 3.31 (1H, dd, J=9.1, 15.6 Hz), 3.09 (2H, br s), 2.94 (1H, dd, J=15.6, 8.7 Hz), 2.76 (2H, m), 2.52 (3H, br s).

13 C NMR (DMSO d6 ): 160.2, 160.1, 158.5, 158.5, 156.6, 156.6, 155.9, 155, 154.9, 129.8, 129.7, 129.5, 118.4, 118.2, 118.1, 116.1, 116.1, 116, 115.9, 114.7, 113.3, 113.2, 113.1, 113.1, 48.3, 46.4, 35.8, 32.3, 29, 21.

Example 194: (5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-1-(2-(piperidin-1-yl)ethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione Hydrofluoride

Compound was prepared analogous manner to Example 35 from 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(piperidin-1-yl)ethan-1-one (Example 158) and isolated as a beige solid.

1 H NMR (DMSO d6 ): 1.80 (1H, br s), 9.08 (2H, br s), 7.47 (1H, dd, J=6.5, 2.6 Hz), 7.44 (1H, ddd, J=8.6, 4.3, 2.8 Hz), 7.31 (1H, dd, J=9.1, 9.9 Hz), 4.08 (1H, d, J=11.9 Hz), 3.80 (1H, d, J=12.0 Hz), 3.50-2.63 (8H, m), 2.94 (1H, dd, J=8.3, 4.2 Hz), 2.0-1.25 (6H, m), 1.68 (1H, dd, J=8.3, 5.4 Hz), 1.18 (1H, t, J=4.5 Hz).

13 C NMR (DMSO d6 ): 161.2, 159.6, 156.4, 131.4, 130, 129.4, 129.3, 128.8, 128.7, 128.3, 117.6, 117.4, 114.7, 54.4, 52.6, 51.5, 32.4, 23, 22.1, 21.7, 20.4, 19.6.

Example 195: (S)-6-(3-bromo-2,6-difluorophenyl)-1-(2-morpholinoethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione

Compound was prepared analogous manner to Example 35 from (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one (Example 140) and isolated as a beige powder.

1 H NMR (DMSO d6 ): 11.73 (1H, s), 7.72 (1H, ddd, J=5.8, 8.1, 8.7 Hz), 7.16 (1H, m), 4.45 (1H, quin, J=8.5 Hz), 4.13 (1H, dd, J=11.5, 9.2 Hz), 3.70 (1H, dd, J=11.6, 7.8 Hz), 3.53 (4H, br t, J=4.5 Hz), 3.28 (1H, dd, J=15.6, 9.4 Hz), 2.89 (1H, dd, J=15.6, 8.0 Hz), 2.51 (2H, m) 2.46 (2H, m), 2.34 (4H, br s).

13 C NMR (DMSO d6 ): 160.8, 160.7, 159.1, 159.1, 157.6, 157.5, 155.9, 155.9, 154.8, 132.4, 132.4, 128.1, 119, 118.8, 118.7, 118.1, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 66.2, 56.3, 53, 48.5, 35.7, 29.3, 21.5.

Example 196: (S)-6-(3-chloro-2,6-difluorophenyl)-1-(2-morpholinoethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione Hydrochloride

Compound was prepared analogous manner to Example 35 from (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one and isolated as a white solid.

1 H NMR (DMSO d6 ): 1.93 (1H, s), 11.01 (1H, br s), 7.63 (1 Hm), 7.23 (1H, m), 4.47 (1H, quin, J=8.5 Hz), 4.16 (1H, dd, J=11.4, 9.2 Hz), 3.96 (2H, br d, J=12.2 Hz), 3.76 (3H, m), 3.40 (2H, br d, J=12.0 Hz), 3.31 (2H, m), 3.05 (2H, m), 2.94 (1H, br dd, J=15.8, 8.1 Hz), 2.89 (2H, br t, J=7.5 Hz).

13 C NMR (DMSO d6 ): 160.1, 160.1, 158.5, 158.4, 156.6, 156.5, 155.8, 154.9, 154.9, 129.8, 129.7, 129.1, 118.7, 118.6, 118.5, 116.1, 116.1, 116, 115.9, 114.7, 113.3, 113.2, 113.1, 113.1, 63.1, 53.8, 51.1, 48.5, 35.7, 29.1, 18.8.

Example 197: (5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-1-(2-(pyridin-3-ylamino)ethyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione

Compound was prepared analogous manner to Example 35 from 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(pyridin-3-yl)acetamide (Example 171) and isolated as a beige solid.

1 H NMR (DMSO d6 ): 11.78 (1H, br s), 8.00 (1H, d, J=2.8 Hz), 7.75 (1H, dd, J=4.5, 1.2 Hz), 7.46 (1H, dd, J=6.5, 2.6 Hz), 7.42 (1H, ddd, J=8.7, 4.3, 2.8 Hz), 7.29 (1H, dd, J=9.0, 9.9, Hz), 7.07 (1H, dd, J=8.3, 4.6 Hz), 6.96 (1H, ddd, J=1.2, 2.7, 8.3 Hz), 5.93 (1H, t, J=5.9 Hz), 4.06 (1H, d, J=11.9 Hz), 3.77 (1H, d, J=12.2 Hz), 3.30 (2H, m), 2.81 (1H, dd, J=8.2, 4.3 Hz), 2.66 (2H, m), 1.56 (1H, dd, J=8.2, 5.3 Hz), 1.14 (1H, t, J=4.8 Hz).

13 C NMR (DMSO d6 ): 161.2, 159.6, 155.9, 144.4, 135.3, 131.1, 130, 129.9, 129.3, 129.2, 129, 128.9, 128.3, 128.2, 123.6, 117.5, 117.4, 117.4, 117, 51.4, 51.4, 41.2, 32.3, 23.9, 22.3, 20.3.

Example 198: (R)-1-(2-(pyrrolidin-1-yl)ethyl)-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione Hydrochloride

Compound was prepared analogous manner to Example 35 from (R)-1-(pyrrolidin-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one (Example 104) and isolated as a light yellow solid.

1 H NMR (DMSO d6 ): 1.92 (1H, s), 10.90 (1H, br s), 7.87 (1H, m), 4.51 (1H, quin, J=8.5 Hz), 4.17 (1H, dd, J=11.5, 9.2 Hz), 3.78 (1H, dd, J=11.6, 7.8 Hz), 3.47 (2H, m), 3.37 (1H, m), 3.32 (2H, m), 2.98 (3H, m), 2.85 (2H, br t, J=7.8 Hz), 1.98 (2H, m), 1.86 (2H, m).

13 C NMR (DMSO d6 ): 155.9, 146.4, 146.4, 146.4, 146.3, 146.3, 146.3, 146.3, 146.3, 146.2, 145.3, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 144.8, 144.7, 144.7, 144.7, 144.6, 144.6, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 143.6, 129, 120.4, 120.3, 120.2, 114.9, 105.9, 105.8, 105.6, 53, 52, 48.4, 35.8, 29, 22.7, 20.8.

Example 199: (R)-1-(2-morpholinoethyl)-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione Hydrochloride

Compound was prepared analogous manner to Example from (R)-1-morpholino-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one and isolated as a light cream powder.

1 H NMR (DMSO d6 ): 11.95 (1H, s), 11.05 (1H, br s), 7.88 (1H, m), 4.51 (1H, quin, J=8.4 Hz), 4.17 (1H, br dd, J=11.4, 9.4 Hz), 3.96 (2H, br d, J=12.2 Hz), 3.78 (3H, m), 3.41 (2H, m), 3.36 (1H, m), 3.30 (2H, m), 3.06 (2H, m), 2.98 (1H, br dd, J=15.7, 7.9 Hz), 2.89 (2H, m).

13 C NMR (DMSO d6 ): 155.9, 146.4, 146.3, 146.3, 145.3, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 144.8, 144.8, 144.8, 144.7, 144.7, 144.7, 144.6, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 128.9, 120.4, 120.3, 120.2, 114.8, 106, 105.8, 105.6, 63.1, 53.8, 51.1, 48.4, 35.8, 29, 18.8.

Example 200: (R)-diethyl 2-((6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)methyl)malonate

To a solution of (4R)-1-(tert-butoxycarbonyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-2-carboxylic acid (2 g, 5.51 mmol) and N-ethyl-N-isopropylpropan-2-amine (DIPEA) (1.68 mL, 9.63 mmol) in dry tetrahydrofuran (20 mL) was added ethyl chloroformate (0.793 mL, 8.26 mmol) at 0-5° C. The mixture was stirred for 4 h in the cold, and then diluted with acetonitrile (10 mL) followed by addition of 2 M (diazomethyl)trimethylsilane (5.51 mL 11.01 mmol) in diethyl ether. The stirring was continued for additional 3 h at 0-5° C. and the mixture was allowed to warm up naturally overnight with stirring under N 2 . Thereupon, the solvents were removed under vacuum and the residue was purified by column chromatography in a mixture of petroleumether-ethyl acetate. to give (4R)-tert-butyl 2-(2-diazoacetyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-1-carboxylate as a yellow oil. Yield: 1.99 g, 93%.

To a solution of (4R)-tert-butyl 2-(2-diazoacetyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-1-carboxylate (1.98 g, 5.11 mmol) in diethyl ether (15 mL) was added 48% HBr (0.61 mL, 5.37 mmol) at 0-5° C. with stirring. After 5 min. the mixture was diluted with ethyl acetate (20 mL) and then washed with sodium bicarbonate solution. The organic phase was dried (MgSO 4 ), filtered, evaporated to dryness to give (4R)-tert-butyl 2-(2-bromoacetyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-1-carboxylate as a yellowish oil. Yield: 1.83 g, 81%.

Step 3: diethyl 2-(2-((4R)-1-(tert-butoxycarbonyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidin-2-yl)-2-oxoethyl)malonate

To a solution of diethyl malonate (0.83 mL, 5.45 mmol) in N,N-dimethyl formamide (7 mL) was added sodium hydride (60% in minar oil) (0.174 g, 4.36 mmol) with ice cooling and the solution was stirred for 30 min. Thereupon, (4R)-tert-butyl 2-(2-bromoacetyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-1-carboxylate (1.6 g, 3.63 mmol) in dry tetrahydrofuran (3.50 mL) was added to the above reaction mixture with ice cooling and the mixture was stirred in the cold for 30 min. The reaction was then diluted with a mixture of ethyl acetate-petroleumether (2:1), washed with NaHSO 4 solution (40 mL), dried over MgSO 4 , filtered and evaporated to dryness. Chromatography in a mixture of ethyl acetate-petroleumether afforded the titled product as a white powder. Yield: 1.15 g, 60%.

Step 4: diethyl 2-(2-oxo-2-((4R)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidin-2-yl)ethyl)malonate Hydrochloride

Diethyl 2-(2-((4R)-1-(tert-butoxycarbonyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidin-2-yl)-2-oxoethyl)malonate (1.3 g, 2.502 mmol) was dissolved in 4 M HCl (9.38 mL, 37.5 mmol) in dioxane and the solution was stirred for 2 h. Thereupon, the mixture was diluted with diethyl ether (ca. 150 mL) The resulting crystals were collected, washed with diethyl ether and dried under vacuum at 50° C. to give diethyl 2-(2-oxo-2-((4R)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidin-2-yl)ethyl)malonate hydrochloride as a white powder. Yield: 1.02 g, 89%.

Step 5: diethyl (R)-2-((6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)methyl)malonate

A mixture of diethyl 2-(2-oxo-2-((4R)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidin-2-yl)ethyl)malonate hydrochloride (1.01 g, 2.216 mmol), potassium isothiocyanate (0.237 g, 2.437 mmol) and cc. HCl (0.092 mL, 1.108 mmol) in abs. ethanol (22 mL) was stirred under reflux for 30 min. The suspension was then cooled to room temperature, evaporated to dryness and the residue was partitioned between dichloromethane and water. The organic phase was dried (MgSO 4 ), filtered and evaporated to dryness to give the titled product as a yellow powder.

Yield: 0.94 g, 92% yield.

1 H NMR (DMSO d6 ): 1.80 (1H, s), 7.85 (1H, m), 4.47 (1H, quin, J=8.4 Hz), 4.20-4.05 (5H, m), 3.81 (1H, t, J=8.0 Hz), 3.74 (1H, dd, J=11.8, 7.4 Hz), 3.28 (1H, dd, J=15.8, 9.4 Hz), 2.93-2.80 (3H, m), 1.14 (6H, q, J=7.3 Hz).

13 C NMR (DMSO d6 ): 168, 167.9, 155.7, 146.4, 146.3, 146.3, 146.3, 146.2, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 145.2, 144.8, 144.8, 144.7, 144.7, 144.6, 144.6, 143.7, 143.6, 143.6, 143.6, 143.5, 143.5, 143.5, 129.1, 120.6, 120.5, 120.4, 115.6, 105.9, 105.7, 105.6, 61.3, 61.2, 50.1, 48.5, 35.7, 29, 23.5, 13.8, 13.8.

Example 201: (R)-2-((6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)methyl)malonic Acid

To a solution of (R)-diethyl 2-((6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)methyl)malonate (Example 200) (0.9 g, 1.955 mmol) in methanol (20 mL) was added 1 M sodium hydroxide solution (11.72 mL, 11.72 mmol) and the mixture was stirred at room temperature overnight. Thereupon, methanol was removed by vacuum, the residue was diluted with water (20 mL) and then acidified to pH=1 by addition of 2 M HCl solution with ice cooling. The mixture was then extracted with 50 mL of mixture of dichloromethane-isopropanol (9:1), the organic phase was dried over MgSO 4 , filtered and evaporated to 5 mL volume. The resulting precipitate was collected by filtration washed with petroleum ether and dried under vacuum at 50° C. to give (R)-2-((6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)methyl)malonic acid as a yellow powder. Yield: 0.74 g, 94%.

1 H NMR (DMSO d6 ): 12.93 (1H, br s), 11.79 (1H, s), 7.85 (1H, m), 4.45 (1H, quin, J=8.6 Hz), 4.16 (1H, dd, J=11.6, 9.2 Hz), 3.75 (1H, dd, J=8.0, 11.5 Hz), 3.56 (1H, t, J=8.0 Hz), 3.26 (1H, dd, J=15.8, 9.3 Hz), 2.89 (1H, dd, J=15.8, 8.2 Hz), 2.80 (2H, dd, J=7.9, 2.9 Hz).

13 C NMR (DMSO d6 ): 169.8, 169.8, 155.5, 146.4, 146.4, 146.4, 146.3, 146.3, 146.3, 146.2, 145.3, 145.3, 145.2, 145.2, 145.2, 144.8, 144.8, 144.8, 144.7, 144.7, 144.7, 144.6, 144.6, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 143.6, 143.6, 128.8, 120.3, 120.2, 120.1, 116.4, 105.9, 105.8, 105.6, 50.6, 48.3, 35.7, 29, 23.7.

Example 202: (R)-3-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propanoic Acid

To a solution of (R)-2-((6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)methyl)malonic acid (0.1 g, 0.247 mmol) in formic acid (0.237 mL, 6.18 mmol) was added triethylamine (0.345 mL, 2.473 mmol) dropwise with stirring (exothermic reaction), and then the resulting solution was stirred at 115° C. for 1 h. Thereupon, the mixture was diluted with water to 4 mL, the resulting oily mixture treated with 2 M HCl (0.5 mL) and then aged for 30 min. The resultant solid was collected washed with water and dried under vacuum at 50° C. to give (R)-3-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)propanoic acid as a beige powder. Yield: 0.051 g, 57%.

1 H NMR (DMSO d6 ): 12.22 (1H, br), 11.78 (1H, s), 7.85 (1H, m), 4.47 (1H, quin, J=8.6 Hz), 4.15 (1H, dd, J=11.7, 9.2 Hz), 3.75 (1H, dd, J=11.7, 7.8 Hz), 3.30 (1H, br dd, J=15.7, 9.4 Hz), 2.92 (1H, dd, J=15.7, 8.1 Hz), 2.63-2.54 (2H, m), 2.5 (2H, m).

13 C NMR (DMSO d6 ): 173.4, 155.2, 146.4, 146.4, 146.3, 146.3, 146.2, 145.3, 145.3, 145.3, 145.3, 145.2, 145.2, 144.8, 144.8, 144.7, 144.7, 144.6, 144.6, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 128, 127.7, 120.4, 120.3, 120.2, 118.7, 105.9, 105.7, 105.6, 48.3, 35.8, 32.2, 29, 19.7.

Example 203: (R)—N-(cyclopropylmethyl)-3-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propanamide

Compound was prepared analogous manner to Example 32 from (R)-3-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propanoic acid (Example 202) and isolated as an off-white powder.

1 H NMR (DMSO d6 ): 1.72 (1H, br s), 7.90 (1H, br t, J=5.5 Hz), 7.86 (1H, m), 4.46 (1H, quin, J=8.5 Hz), 4.14 (1H, dd, J=11.5, 9.2 Hz), 3.74 (1H, dd, J=11.7, 7.8 Hz), 3.29 (1H, dd, J=15.7, 9.2 Hz), 2.91 (1H, m), 2.89 (2H, br t, J=6.2 Hz), 2.57 (2H, m), 2.34 (2H, t, J=7.4 Hz), 0.83 (1H, m), 0.35 (2H, m), 0.09 (2H, m).

13 C NMR (DMSO d6 ): 170.5, 155, 146.4, 146.4, 146.3, 146.3, 146.3, 146.2, 146.2, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 145.2, 145.2, 144.8, 144.8, 144.7, 144.7, 144.7, 144.6, 144.6, 143.7, 143.6, 143.6, 143.6, 143.6, 143.6, 143.5, 127.5, 120.5, 120.4, 120.3, 119.1, 105.9, 105.7, 105.5, 48.2, 42.8, 35.8, 33.4, 29.1, 20, 10.7, 3.1.

Example 204: (R)-1-(pyrrolidin-1-yl)-3-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propan-1-one

Compound was prepared analogous manner to Example 32 from (R)-3-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propanoic acid (Example 202) and isolated as an off-white powder.

1 H NMR (DMSO d6 ): 1.73 (1H, br s), 7.85 (1H, t, J=9.0 Hz), 4.46 (1H, quin, J=8.6 Hz), 4.15 (1H, dd, J=11.5, 9.2 Hz), 3.74 (1H, dd, J=11.7, 7.8 Hz), 3.36 (2H, t, J=6.8 Hz), 3.30 (1H, br dd, J=15.7, 9.4 Hz), 3.25 (2H, t, J=6.9 Hz), 2.93 (1H, dd, J=15.7, 8.1 Hz), 2.56 (2H, m), 2.51 (2H, m), 1.84 (2H, m), 1.74 (2H, m).

13 C NMR (DMSO d6 ): 169, 155, 146.4, 146.3, 146.3, 145.3, 145.2, 144.8, 144.7, 144.6, 143.7, 143.6, 127.6, 120.5, 120.4, 120.3, 119.2, 105.8, 105.7, 105.5, 48.2, 45.7, 45.3, 35.8, 32.2, 28.9, 25.5, 23.9, 19.5.

Example 205: (R)-1-morpholino-3-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propan-1-one

Compound was prepared analogous manner to Example 32 from (R)-3-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propanoic acid (Example 202) and isolated as a beige powder.

1 H NMR (DMSO d6 ): 1.73 (1H, br s), 7.86 (1H, m), 4.47 (1H, quin, J=8.6 Hz), 4.15 (1H, dd, J=11.4, 9.3 Hz), 3.75 (1H, dd, J=11.6, 7.9 Hz), 3.52 (4H, dt, J=13.2, 4.7 Hz), 3.42 (4H, m), 3.31 (1H, dd, J=9.3, 15.7 Hz), 2.94 (1H, dd, J=15.6, 8.1 Hz), 2.58 (4H, m).

13 C NMR (DMSO d6 ): 169.6, 155.1, 146.4, 146.3, 146.2, 145.3, 145.2, 144.8, 144.7, 144.6, 143.7, 143.6, 127.6, 120.4, 120.3, 120.2, 119.1, 105.9, 105.7, 105.5, 66.1, 66.1, 48.2, 45.2, 41.5, 35.8, 30.5, 28.9, 19.8.

Example 206: (R)-1-(4,4-difluoropiperidin-1-yl)-3-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propan-1-one

Compound was prepared analogous manner to Example 32 from (R)-3-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propanoic acid (Example 202) and isolated as a light yellow powder.

1 H NMR (DMSO d6 ): 11.74 (1H, s), 7.86 (1H, m), 4.47 (1H, quin, J=8.6 Hz), 4.15 (1H, dd, J=11.5, 9.3 Hz), 3.75 (1H, dd, J=11.6, 7.9 Hz), 3.54 (4H, m), 3.31 (1H, m), 2.94 (1H, dd, J=15.7, 8.2 Hz), 2.66 (2H, m), 2.57 (2H, m), 1.98 (2H, m), 1.88 (2H, m).

13 C NMR (DMSO d6 ): 169.5, 155.1, 146.4, 146.3, 146.2, 145.3, 145.2, 144.8, 144.7, 143.7, 143.6, 127.6, 124.3, 122.7, 121.1, 120.4, 120.3, 120.2, 119, 105.9, 105.7, 105.6, 48.2, 41.6, 41.5, 41.5, 38.1, 38, 38, 35.8, 34, 33.8, 33.7, 33.3, 33.2, 33, 30.5, 28.9, 19.9.

Example 207: (R)-1-(piperidin-1-yl)-3-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propan-1-one

Compound was prepared analogous manner to Example 32 from (R)-3-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propanoic acid (Example 202) and isolated as a beige powder.

1 H NMR (DMSO d6 ): 1.72 (1H, br s), 7.86 (1H, m), 4.46 (1H, quin, J=8.6 Hz), 4.15 (1H, dd, J=11.6, 9.2 Hz), 3.75 (1H, dd, J=11.7, 7.8 Hz), 3.37 (4H, m), 3.30 (1H, dd, J=9.3, 11.8 Hz), 2.93 (1H, dd, J=15.6, 8.1 Hz), 2.57 (4H, m), 1.55 (2H, m), 1.45 (2H, m), 1.38 (2H, m).

13 C NMR (DMSO d6 ): 168.9, 155, 146.4, 146.3, 146.2, 145.3, 145.2, 145.2, 144.8, 144.7, 144.6, 143.6, 143.6, 127.6, 120.4, 120.3, 120.2, 119.2, 105.8, 105.7, 105.5, 48.2, 45.7, 41.9, 35.8, 30.7, 28.9, 26, 25.3, 24, 20.

Example 208: (R)-1-(4-methylpiperidin-1-yl)-3-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propan-1-one

Compound was prepared analogous manner to Example 32 from (R)-3-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propanoic acid (Example 202) and isolated as a beige powder.

1 H NMR (DMSO d6 ): 11.73 (1H, s), 7.86 (1H, m), 4.46 (1H, quin, J=8.6 Hz), 4.32 (1H, br d, J=13.2 Hz), 4.14 (1H, m), 3.81 (1H, br d, J=13.5 Hz), 3.74 (1H, dd, J=11.7, 8.0 Hz), 3.30 (1H, m), 2.92 (2H, br dd, J=15.1, 8.8 Hz), 2.56 (4H, m), 2.47 (1H, m), 1.57 (3H, m), 0.95 (1H, m), 0.87 (4H, m).

13 C NMR (DMSO d6 ): 168.9, 155.1, 146.4, 146.3, 146.2, 145.3, 145.2, 144.8, 144.7, 144.6, 143.7, 143.6, 127.5, 127.5, 120.4, 120.4, 120.3, 120.3, 120.2, 120.2, 119.2, 119.2, 105.9, 105.7, 105.6, 48.2, 45, 44.9, 41.3, 35.8, 34.2, 33.5, 30.7, 30.6, 30.3, 29, 29, 21.6, 20.

Example 209: (R)-1-(morpholinomethyl)-6-(2,3,5,6-tetrafluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione Hydrochloride

Step 1: tert-butyl(4R)-2-(2-morpholinoacetyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-1-carboxylate Hydrobromide

To a solution of (4R)-tert-butyl 2-(2-bromoacetyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-1-carboxylate (Example 200 step 2) (0.1 g, 0.227 mmol) in dry tetrahydrofuran (1 mL) was added morpholine (0.020 mL, 0.227 mmol) at room temperature in one portion. The reaction was stirred for 15 min. and then diluted with diethyl ether (1 mL). The resulting solid was filtered off and the filtrate was evaporated to dryness to give (4R)-tert-butyl 2-(2-morpholinoacetyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-1-carboxylate hydrobromide as viscous oil. Yield: 0.105 g, 88%.

(4R)-tert-butyl 2-(2-morpholinoacetyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-1-carboxylate hydrobromide (0.105 g, 0.199 mmol) was dissolved in 4 M HCl (0.996 mL, 3.98 mmol) in dioxane and the solution was stirred for 1 h. Thereupon, the mixture was diluted with diethyl ether (ca. 10 mL) an the resulting precipitate was aged for 30 min with stirring. The solid was collected, washed with diethyl ether and dried to give 2-morpholino-1-((4R)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidin-2-yl)ethanone dihydrochloride as a white powder. Yield: 0.083 g, 99%.

Step 3: (R)-1-(morpholinomethyl)-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione Hydrochloride

A mixture of 2-morpholino-1-((4R)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidin-2-yl)ethanone dihydrochloride (0.078 g, 0.186 mmol), potassium isothiocyanate (0.027 g, 0.279 mmol) and cc. HCl (0.022 mL, 0.130 mmol) in a mixture of ethanol (1 mL) and water (1 mL) was stirred under reflux for 30 min. Thereupon, the mixture was diluted with water (ca. 2 mL) and then ethanol was removed under vacuum. The aqueous residue was neutralized by addition of sodium bicarbonate solution and then extracted with dichloromethane. The organic phase was dried (MgSO 4 ), filtered and evaporated to dryness. The oily residue was taken up in isopropanol (ca. 1 mL), acidified by addition of 2 M HCl in diethyl ether, and then diluted with diethyl ether to 10 mL. The resulting precipitate was collected, washed with diethyl ether and dried in vacuum at 50° C. to give (R)-1-(morpholinomethyl)-6-(2,3,5,6-tetrafluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione hydrochloride as an off-white powder, Yield: 0.050 g, 63%.

1 H NMR (DMSO d6 ): 12.07 (1H, s), 11.58 (1H, br s), 7.88 (1H, m), 4.54 (1H, quin, J=8.5 Hz), 4.23 (1H, dd, J=11.7, 9.2 Hz), 4.15 (2H, m), 3.97 (2H, br d, J=12.5 Hz), 3.85 (1H, dd, J=11.7, 7.8 Hz), 3.78 (2H, br t, J=12.0 Hz), 3.52 (1H, dd, J=9.4, 16.3 Hz), 3.29 (2H, br dd, J=18.0, 13.4 Hz), 3.12 (1H, dd, J=16.4, 8.1 Hz), 3.04 (2H, m).

13 C NMR (DMSO d6 ): 157.4, 146.4, 146.4, 146.3, 145.3, 145.2, 144.8, 144.7, 144.7, 143.7, 143.6, 135.6, 120, 108.2, 106, 105.9, 105.7, 63.1, 50.2, 48.9, 48.5, 35.6, 29.6.

Example 210: (R)-1-(pyrrolidin-1-ylmethyl)-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione hydrochloride

Compound was prepared analogous manner to Example 209 and isolated as an off-white powder.

1 H NMR (DMSO d6 ): 12.11 (1H, s), 11.13 (1H, br s), 7.87 (1H, m), 4.53 (1H, quin, J=8.4 Hz), 4.23 (1H, dd, J=11.4, 9.4 Hz), 4.15 (2H, br s), 3.84 (1H, dd, J=11.7, 7.6 Hz), 3.52 (1H, br dd, J=16.2, 9.3 Hz), 3.38 (2H, m), 3.12 (1H, br dd, J=16.3, 7.8 Hz), 3.03 (2H, br s), 1.99 (2H, br s), 1.88 (2H, br s).

13 C NMR (DMSO d6 ): 157, 146.4, 146.3, 146.3, 145.3, 145.2, 144.8, 144.7, 144.6, 143.7, 143.6, 134.1, 120.3, 120.2, 111.1, 106, 105.8, 105.7, 52.2, 48.9, 46.1, 35.6, 29.5, 22.7.

Example 211: (R)-1-(((2-hydroxyethyl)(methyl)amino)methyl)-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione hydrochloride

Compound was prepared analogous manner to Example 209 and isolated as a cream powder.

1 H NMR (DMSO d6 ): 12.10 (1H, br s), 10.45 (1H, br s), 7.88 (1H, br s), 5.35 (1H, br), 4.55 (1H, m), 4.23 (1H, dd, J=11.5, 9.3 Hz), 4.17 (2H, m), 3.85 (1H, m), 3.77 (2H, br t, J=5.2 Hz), 3.49 (1H, dt, J=9.9, 16.3 Hz), 3.19 (1H, m), 3.09 (1H, m), 3.04 (1H, m), 2.81 (0.5H, br s), 2.72 (2.5H, br t, J=5.6 Hz).

13 C NMR (DMSO d6 ): 157.4, 146.4, 146.3, 146.2, 145.3, 145.2, 144.8, 144.7, 144.6, 143.7, 143.6, 135.6, 120.2, 120.1, 120.1, 108.5, 108.5, 106, 105.8, 105.7, 56, 56, 55.2, 48.9, 48.6, 48.6, 42.4, 39, 35.6, 35.6, 29.6.

Example 212: (R)-1-(2-(pyridin-3-yl)ethyl)-6-(2,3,5,6-tetrafluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione

Step 1: tert-butyl (4R)-2-(2-(dimethoxyphosphoryl)acetyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-1-carboxylate

To a solution of dimethyl methylphosphonate (0.655 mL, 6.04 mmol) in dry tetrahydrofuran (12 mL) was added N-butyllithium (4.15 mL, 6.65 mmol) (1.6 M in hexane) at −78° C., and the mixture was stirred for 30 min in the cold. Thereupon, a solution of (4R)-1-tert-butyl 2-methyl 4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-1,2-dicarboxylate (1.14 g, 3.02 mmol) in tetrahydrofuran (12 mL) was added, and the reaction mixture was stirred for 2 h in the cold. The reaction mixture was quenched with saturated ammonium chloride solution and then extracted with ethyl acetate (20 mL). The organic phase was dried over MgSO 4 , filtered and evaporated to leave a colorless oil which was purified by column chromatography in a mixture of petroleumether-ethyl acetate to give (4R)-tert-butyl 2-(2-(dimethoxyphosphoryl)acetyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-1-carboxylate as a colorless oil. (Yield: 0.86 g, 60% yield).

Step 2: tert-butyl (4R)-2-((E)-3-(pyridin-3-yl)acryloyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-1-carboxylate

To a solution of (4R)-tert-butyl 2-(2-(dimethoxyphosphoryl)acetyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-1-carboxylate (0.2 g, 0.426 mmol) in ethanol (2.5 mL) was added potassium carbonate (0.065 g, 0.469 mmol) and the mixture was stirred at room temperature for 15 min. Thereupon, 3-pyridinecarboxaldehyde (0.044 mL, 0.469 mmol) was added and the stirring was continued for 2 h. The resulting solid was filtered off, the filtrate was evaporated to dryness, and then purified by column chromatography in a mixture of petroleumether-ethyl acetate to give (4R)-tert-butyl 2-((E)-3-(pyridin-3-yl)acryloyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-1-carboxylate as an oil. Yield: 0.19 g, 99%.

Step 3: tert-butyl(4R)-2-(3-(pyridin-3-yl)propanoyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-1-carboxylate

A solution of (4R)-tert-butyl 2-((E)-3-(pyridin-3-yl)acryloyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-1-carboxylate (0.18 g, 0.400 mmol) in ethyl acetate (5 mL) was hydrogenated over 10% palladium on charcoal (0.043 g, 0.040 mmol) for 7 h with a H 2 balloon. Thereupon, the catalyst was filtered through a celite pad and the filtrate was evaporated to give (4R)-tert-butyl 2-(3-(pyridin-3-yl)propanoyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-1-carboxylate as an oil. Yield: 0.16 g, 88%.

Step 4: (R)-1-(2-(pyridin-3-yl)ethyl)-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione

(4R)-tert-butyl 2-(3-(pyridin-3-yl)propanoyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-1-carboxylate (0.16 g, 0.354 mmol) was dissolved in 4 M HCl (1.33 mL, 5.30 mmol) in dioxane and the solution was stirred for 1 h. The mixture was then diluted with diethyl ether ether (ca. 10 mL) to give a semi-solid precipitate. Thereupon, diethyl ether was decanted and the residue was dissolved in mixture of ethanol (2 mL) and water (2 mL) followed by addition of 6 M HCl (0.03 mL, 0.177 mmol) and potassium isothiocyanate (0.052 g, 0.530 mmol). The mixture was stirred under reflux for 30 min. After being cooled to room temperature, the pH was set to 7-8 by addition of 1 M sodium hydroxide solution. The aqueous mixture was extracted with dichloromethane, the organic phase was dried (MgSO 4 ), filtered and evaporated to dryness. The residue was purified by chromatography in a mixture of dichloromethane-methanol to give (R)-1-(2-(pyridin-3-yl)ethyl)-6-(2,3,5,6-tetrafluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione as an off-white powder. Yield: 0.049 g, 35%.

1 H NMR (DMSO d6 ): 11.87 (1H, s), 8.38 (2H, m), 7.84 (1H, m), 7.57 (1H, dt, J=7.8, 2.0 Hz), 7.28 (1H, dd, J=7.8, 4.8 Hz), 4.40 (1H, quin, J=8.4 Hz), 4.12 (1H, dd, J=11.6, 9.1 Hz), 3.73 (1H, dd, J=11.7, 7.6 Hz), 3.08 (1H, dd, J=15.6, 9.2 Hz), 2.85 (2H, m), 2.67 (2H, t, J=7.7 Hz), 2.65 (1H, m).

13 C NMR (DMSO d6 ): 155.3, 149.6, 147.3, 146.4, 146.4, 146.3, 146.2, 146.2, 145.3, 145.2, 145.2, 145.2, 145.1, 144.8, 144.8, 144.7, 144.7, 144.6, 144.6, 143.6, 143.6, 143.6, 143.6, 143.5, 143.5, 143.5, 143.5, 136.1, 135.8, 127.9, 123.3, 120.4, 120.3, 120.2, 118.6, 105.8, 105.7, 105.5, 48.2, 35.8, 30.8, 28.8, 25.4.

Example 213: (R)-1-(2-(pyridin-2-yl)ethyl)-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione

Compound was prepared analogous manner to Example 212 and isolated as an off-white powder.

1 H NMR (DMSO d6 ): 11.85 (1H, s), 8.45 (1H, m), 7.84 (1H, m), 7.66 (1H, td, J=7.6, 1.9 Hz), 7.20 (1H, d, J=7.8 Hz), 7.17 (1H, ddd, J=7.4, 4.9, 1.0 Hz), 4.39 (1H, quin, J=8.4 Hz), 4.11 (1H, dd, J=11.6, 9.1 Hz), 3.71 (1H, dd, J=11.7, 7.6 Hz), 3.11 (1H, dd, J=15.6, 9.3 Hz), 2.98 (2H, m), 2.78 (2H, m), 2.66 (1H, dd, J=15.6, 7.8 Hz).

13 C NMR (DMSO d6 ): 159.9, 155.1, 148.9, 146.4, 146.3, 146.2, 145.2, 145.1, 145.1, 145.1, 145.1, 144.8, 144.7, 144.7, 144.6, 144.6, 144.6, 143.6, 143.6, 143.5, 143.5, 143.5, 143.5, 136.4, 127.7, 122.8, 121.4, 120.5, 120.4, 120.3, 119, 105.8, 105.7, 105.5, 48.2, 35.8, 35.7, 28.9, 23.6.

Example 214: (R)-6-(3-bromo-2,6-difluorophenyl)-1-(2-(pyridin-3-yl)ethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione

Compound was prepared analogous manner to Example 212 and isolated as a cream powder.

1 H NMR (DMSO d6 ): 11.86 (1H, s), 8.39 (2H, m), 7.71 (1H, ddd, J=5.9, 8.1, 8.7 Hz), 7.57 (1H, dt, J=7.9, 2.0 Hz), 7.28 (1H, ddd, J=7.8, 4.8, 0.8 Hz), 7.15 (1H, m), 4.36 (1H, m), 4.10 (1H, m), 3.67 (1H, dd, J=11.6, 7.8 Hz), 3.04 (1H, dd, J=15.6, 9.2 Hz), 2.85 (2H, m), 2.67 (2H, t, J=7.7 Hz), 2.61 (1H, dd, J=15.6, 8.2 Hz).

13 C NMR (DMSO d6 ): 160.7, 160.7, 159.1, 159, 157.5, 157.4, 155.9, 155.8, 155.2, 149.6, 147.3, 136.1, 135.8, 132.4, 132.4, 128.1, 123.3, 118.7, 118.6, 118.5, 113.8, 113.7, 113.6, 113.6, 104, 104, 103.9, 103.9, 48.4, 35.7, 30.8, 28.9, 25.4.

Example 215: (S)-6-(3-chloro-2,6-difluorophenyl)-1-(2-(pyridin-3-yl)ethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione Hydrochloride

Compound was prepared analogous manner to Example 212 and isolated as an off-white solid.

1 H NMR (DMSO d6 ): 1.86 (1H, s), 8.64 (2H, m), 8.09 (1H, br d, J=7.8 Hz), 7.73 (1H, dd, J=7.7, 5.5 Hz), 7.61 (1H, m), 7.21 (1H, m), 4.38 (1H, quin, J=8.5 Hz), 4.11 (1H, dd, J=11.2, 9.4 Hz), 3.68 (1H, dd, J=11.6, 7.6 Hz), 3.11 (1H, br dd, J=15.6, 9.3 Hz), 2.99 (2H, m), 2.73 (2H, t, J=7.5 Hz), 2.67 (1H, dd, J=15.7, 7.9 Hz).

13 C NMR (DMSO d6 ): 160.1, 160, 158.4, 158.4, 156.5, 156.4, 155.3, 154.9, 154.8, 144.5, 142.7, 142, 138.8, 129.7, 129.6, 128.3, 125.5, 118.9, 118.8, 118.6, 118, 116.1, 116, 115.9, 115.9, 113.2, 113.2, 113.1, 113.1, 48.4, 35.6, 30.5, 28.9, 24.9.

Example 216: (R)-1-(3-ethoxypropyl)-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione

Compound was prepared analogous manner to Example 212 and isolated as a white powder.

1 H NMR (DMSO d6 ): 1.77 (1H, s), 7.85 (1H, m), 4.50 (1H, quin, J=8.4 Hz), 4.16 (1H, dd, J=11.5, 9.2 Hz), 3.76 (1H, dd, J=11.7, 7.6 Hz), 3.36 (2H, m), 3.31 (3H, m), 2.90 (1H, dd, J=15.7, 7.8 Hz), 2.38 (2H, t, J=7.5 Hz), 1.73 (2H, quin, J=6.9 Hz), 1.07 (3H, t, J=7.0 Hz).

13 C NMR (DMSO d6 ): 155.1, 146.4, 146.4, 146.3, 146.3, 146.2, 146.2, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 145.2, 144.8, 144.8, 144.7, 144.6, 144.6, 143.7, 143.6, 143.6, 127.5, 120.6, 120.5, 120.4, 119.2, 105.8, 105.7, 105.5, 68.5, 65.2, 48.3, 35.8, 28.9, 27.7, 20.8, 15.1.

Example 217: (R)-1-(2-(1-methyl-1H-imidazol-2-yl)ethyl)-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione

Compound was prepared analogous manner to Example 212 and isolated as a light beige powder.

1 H NMR (DMSO d6 ): 11.89 (1H, br s), 7.85 (1H, m), 6.99 (1H, s), 6.72 (1H, s), 4.43 (1H, quin, J=8.5 Hz), 4.14 (1H, dd, J=9.4, 11.3 Hz), 3.75 (1H, br dd, J=11.5, 8.0 Hz), 3.51 (3H, s), 3.18 (1H, br dd, J=15.6, 9.4 Hz), 2.85 (2H, dd, J=7.1, 8.8 Hz), 2.79 (1H, br dd, J=15.6, 8.1 Hz), 2.73 (2H, dd, J=7.1, 8.8 Hz).

13 C NMR (DMSO d6 ): 155.1, 146.4, 146.4, 146.3, 146.3, 146.2, 145.3, 145.3, 145.3, 145.2, 145.2, 144.8, 144.7, 144.6, 143.7, 143.7, 143.6, 143.6, 143.6, 143.5, 127.9, 126.1, 121, 120.3, 119, 105.9, 105.7, 105.6, 48.2, 35.8, 32, 28.7, 24.9, 22.2.

Example 218: (R)-1-(2-(pyridin-4-yl)ethyl)-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione

Compound was prepared analogous manner to Example 212 and isolated as a light yellow powder.

1 H NMR (DMSO d6 ): 11.87 (1H, s), 8.43 (2H, m), 7.84 (1H, m), 7.19 (2H, m), 4.41 (1H, quin, J=8.4 Hz), 4.13 (1H, dd, J=11.6, 9.1 Hz), 3.73 (1H, dd, J=11.7, 7.5 Hz), 3.13 (1H, dd, J=15.7, 9.4 Hz), 2.85 (2H, m), 2.68 (3H, m).

13 C NMR (DMSO d6 ): 155.3, 149.6, 149.5, 146.4, 146.4, 146.3, 146.3, 146.3, 146.2, 146.2, 145.3, 145.2, 145.2, 145.2, 145.2, 145.1, 145.1, 145.1, 144.8, 144.8, 144.7, 144.7, 144.7, 144.6, 144.6, 143.6, 143.6, 143.6, 143.5, 143.5, 143.5, 143.5, 127.9, 123.8, 120.5, 120.4, 120.3, 118.5, 105.9, 105.7, 105.6, 48.3, 35.8, 32.8, 28.9, 24.6.

Example 219: (R)-1-(3-(pyrrolidin-1-yl)propyl)-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione hydrochloride

Compound was prepared analogous manner to Example 35 from (R)-1-(pyrrolidin-1-yl)-3-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propan-1-one (Example 204) and isolated as a yellowish powder.

1 H NMR (DMSO d6 ): 1.86 (1H, br s), 10.76 (1H, br s), 7.87 (1H, m), 4.51 (1H, quin, J=8.5 Hz), 4.16 (1H, dd, J=11.4, 9.3 Hz), 3.77 (1H, br dd, J=11.6, 7.8 Hz), 3.49 (2H, m), 3.34 (1H, dd, J=6.4, 11.7 Hz), 3.05 (2H, m), 2.96 (1H, dd, J=8.0, 15.8 Hz), 2.93 (2H, m), 2.46 (2H, br t, J=7.4 Hz), 1.95 (4H, m), 1.87 (2H, m).

13 C NMR (DMSO d6 ): 155.4, 146.4, 146.4, 146.4, 146.3, 146.3, 146.3, 146.2, 145.3, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 144.8, 144.7, 144.7, 144.7, 144.6, 144.6, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 143.5, 128, 120.4, 120.3, 120.2, 118.2, 105.9, 105.7, 105.6, 53, 52.8, 48.3, 35.8, 28.9, 23.9, 22.6, 21.3.

Example 220: (S)—N-((6-(3-chloro-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)methyl)cyclopropanecarboxamide

Step 1: (S)-1-(aminomethyl)-6-(3-chloro-2,6-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione

To a stirred solution of (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid (1 g, 2.90 mmol) in a mixture of Toluene (20 mL) and ethanol (0.85 mL, 14.50 mmol) was added triethylamine (0.48 mL, 3.48 mmol) followed by dropwise addition of diphenyl phosphorazidate (0.75 mL 3.48 mmol) at room temperature. The reaction mixture was heated at reflux for 3 h. The solvent was then removed under reduced pressure and the obtained crude oil was purified by column chromatography in a mixture of dichloromethane-methanol. The obtained oil was dissolved in 2 mL of methanol and treated with 2 mL of 1 M potassium hydroxide solution and the reaction was stirred at room temperature overnight. Thereupon, the mixture was diluted with water and extracted with a mixture of dichloromethane:isopropanol (7:3). The organic phase was evaporated to dryness and the product was purified by chromatography. Yield: 74 mg, 8%.

Step 2: (S)—N-((6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)methyl)cyclopropanecarboxamide

To a stirred solution of (S)-1-(aminomethyl)-6-(3-chloro-2,6-difluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione (70 mg, 0.222 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.042 mL, 0.244 mmol) was added cyclopropanecarbonyl chloride (0.024 mL, 0.266 mmol) and the reaction was stirred for 1 h at room temperature. The reaction was then diluted with 10 mL of dichloromethane, washed with 1 M HCl and concentrated NaHCO 3 , respectively. The organic phase was dried over MgSO 4 , filtered and evaporated to dryness. The residue was dissolved in 2 mL of 4 N HCl in dioxane and stirred overnight at room temperature. Thereupon, the solvent was removed under vacuum and the crude product was purified by column chromatography in a mixture of dichloromethane-methanol. Trituration in diethyl ether afforded (S)—N-((6-(3-chloro-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)methyl)cyclopropanecarboxamide as an off-white solid. Yield: 16 mg, 18%.

1 H NMR (DMSO d6 ): 11.81 (1H, br s), 8.40 (1H, t, J=5.4 Hz), 7.62 (1H, m), 7.22 (1H, m), 4.44 (1H, quin, J=8.6 Hz), 4.14 (1H, dd, J=11.5, 9.2 Hz), 4.02 (2H, m), 3.72 (1H, dd, J=11.7, 7.8 Hz), 3.24 (1H, dd, J=15.8, 9.4 Hz), 2.87 (1H, dd, J=15.8, 8.1 Hz), 1.55 (1H, m), 0.64 (4H, m).

13 C NMR (DMSO d6 ): 172.7, 160.1, 160.1, 158.5, 158.4, 156.6, 156.5, 155.5, 154.9, 154.9, 129.7, 129.7, 128.9, 118.8, 118.7, 118.6, 117.5, 116.1, 116, 115.9, 115.9, 113.3, 113.2, 113.1, 113.1, 48.5, 35.6, 33.2, 29.2, 13.4, 6.3, 6.3.

Example 221: (S)—N-((6-(3-chloro-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)methyl)cyclopropanecarboxamide

Step 1: (S)-1-(aminomethyl)-6-(3-chloro-2,6-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione Hydrochloride

To a stirred solution of (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid (1 g, 2.90 mmol) in 1,4-Dioxane (100 ml) was added in triethylamine (0.404 ml, 2.90 mmol) followed by addition of diphenyl phosphorazidate (0.686 ml, 3.19 mmol) and the reaction was stirred at room temperature for 30 min. The above mixture was added dropwise to a pre-heated (80° C.) solution of formic acid (0.657 mL, 17.40 mmol) and hydrogen chloride (5.80 mL, 5.80 mmol) in 1,4-Dioxane (100 mL). The reaction was stirred in the warm 90 min. and then cooled to room temperature. The solvent was removed under vacuum and the residue was azeotroped with isopropanol. Recrystallization from a mixture of isopropanol-diethyl ether afforded yield (S)-1-(aminomethyl)-6-(3-chloro-2,6-difluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione hydrochloride. Yield: 395 mg, 38%.

Step 2: (S)—N-((6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)methyl)cyclopentanecarboxamide

To a stirred solution of (S)-1-(aminomethyl)-6-(3-chloro-2,6-difluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione hydrochloride (75 mg, 0.213 mmol) in dichloromethane (2 mL) was added N-ethyl-N-isopropylpropan-2-amine (DIPEA) (0.076 mL, 0.426 mmol). After being stirred for 15 min. at room temperature, cyclopentanecarboxylic acid (36.5 mg, 0.319 mmol) was added followed by addition of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (0.198 ml, 0.319 mmol). The reaction was stirred overnight at room temperature. Thereupon, the mixture was diluted with 10 mL of dichloromethane, washed with 1 M HCl, saturated NaHCO 3 and brine, respectively. The organics were dried over MgSO 4 , filtered and evaporated to dryness. Chromatography in a mixture of dichloromethane-isopropanol afforded (S)—N-((6-(3-chloro-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)methyl)cyclopentanecarboxamide as an off-white solid. Yield: 31 mg, 35%.

1 H NMR (DMSO d6 ): 11.79 (1H, s), 8.11 (1H, t, J=5.5 Hz), 7.61 (1H, m), 7.21 (1H, m), 4.44 (1H, quin, J=8.5 Hz), 4.14 (1H, dd, J=11.3, 9.4 Hz), 4.01 (2H, m), 3.71 (1H, dd, J=11.7, 7.8 Hz), 3.24 (1H, dd, J=15.8, 9.4 Hz), 2.85 (1H, dd, J=15.8, 7.9 Hz), 2.50 (1H, m), 1.70 (2H, m), 1.58 (4H, m), 1.47 (2H, m).

13 C NMR (DMSO d6 ): 175.4, 160.1, 160.1, 158.5, 158.4, 156.6, 156.5, 155.3, 154.9, 154.9, 129.7, 129.6, 128.7, 118.9, 118.7, 118.6, 117.7, 116.1, 116.1, 116, 115.9, 113.3, 113.2, 113.1, 113.1, 48.5, 44.1, 35.6, 33, 29.9, 29.9, 29.3, 25.6.

Example 222: (S)—N-((6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)methyl)tetrahydro-2H-pyran-4-carboxamide

Compound was prepared analogous manner to Example 221 from (S)-1-(aminomethyl)-6-(3-chloro-2,6-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione hydrochloride and isolated as an off-white solid.

1 H NMR (DMSO d6 ): 11.80 (1H, br s), 8.14 (1H, br t, J=5.4 Hz), 7.61 (1H, m), 7.22 (1H, m), 4.44 (1H, quin, J=8.6 Hz), 4.14 (1H, dd, J=11.5, 9.3 Hz), 4.02 (2H, m), 3.83 (2H, m), 3.71 (1H, dd, J=11.6, 7.8 Hz), 3.25 (3H, m), 2.85 (1H, dd, J=15.8, 8.1 Hz), 2.35 (1H, m), 1.54 (4H, m).

13 C NMR (DMSO d6 ): 174, 160.1, 160.1, 158.5, 158.4, 156.6, 156.5, 155.3, 154.9, 154.9, 129.7, 129.6, 128.7, 118.9, 118.8, 118.6, 117.5, 116, 115.9, 113.3, 113.2, 113.1, 113.1, 66.4, 48.5, 40.6, 35.6, 33, 29.2, 28.8.

Example 223: (S)—N-((6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)methyl)nicotinamide

Compound was prepared analogous manner to Example 221 from (S)-1-(aminomethyl)-6-(3-chloro-2,6-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione hydrochloride and isolated as an off-white solid.

1 H NMR (DMSO d6 ): 11.90 (1H, br s), 9.03 (1H, t, J=5.4 Hz), 9.00 (1H, dd, J=2.3, 0.8 Hz), 8.70 (1H, dd, J=4.8, 1.7 Hz), 8.18 (1H, dt, J=8.1, 1.9 Hz), 7.60 (1H, m), 7.50 (1H, ddd, J=7.9, 4.8, 0.7 Hz), 7.20 (1H, m), 4.44 (1H, quin, J=8.6 Hz), 4.27 (2H, m), 4.15 (1H, dd, J=11.4, 9.2 Hz), 3.72 (1H, dd, J=11.7, 7.9 Hz), 3.26 (1H, dd, J=15.8, 9.4 Hz), 2.88 (1H, dd, J=15.8, 8.1 Hz).

13 C NMR (DMSO d6 ): 165, 160.1, 160.1, 158.5, 158.4, 156.6, 156.5, 155.6, 154.9, 154.9, 152, 148.4, 135, 129.7, 129.6, 129.5, 129, 123.5, 118.7, 118.6, 118.5, 117, 116.1, 116, 115.9, 115.9, 113.2, 113.2, 113.1, 113.1, 48.5, 35.6, 33.7, 29.2.

Example 224: 2-{[(6S)-6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl]methyl}-1-cyanoguanidine

To a stirred suspension of (S)-1-(aminomethyl)-6-(3-bromo-2,6-difluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione hydrochloride (prepared analogous manner to Example 221 step 1) (0.23 g, 0.580 mmol) in tetrahydrofuran (29.0 mL) was added N-ethyl-N-isopropylpropan-2-amine (DIPEA) (0.203 mL, 1.160 mmol), followed by quick addition of diphenyl N-cyanocarbonimidate (0.276 g, 1.160 mmol), and then the reaction was stirred for 30 min. at room temperature. Thereupon, 7 M ammonia in methanol (4.14 mL, 29.0 mmol) was added and the mixture was heated at 80° C. overnight in a sealed tube. Thereupon, the reaction was cooled to room temperature and evaporated to dryness under reduced pressure. Chromatography in a mixture of dichloromethane-methanol afforded the product as a light yellow solid.

1 H NMR (DMSO d6 ): 11.83 (1H, s), 7.73 (1H, m), 7.17 (1H, m), 6.97 (1H, s br), 6.81 (2H, s br), 4.47 (1H, quin, J=8.6 Hz), 4.15 (1H, m), 4.03 (2H, m), 3.72 (1H, dd, J=11.6, 7.9 Hz), 3.25 (1H, dd, J=9.4, 15.7 Hz), 2.86 (1H, dd, J=15.8, 8.1 Hz).

13 C NMR (DMSO d6 ): 161.1, 160.8, 160.7, 159.1, 159.1, 157.5, 157.5, 155.9, 155.8, 155.7, 132.5, 132.4, 129.2, 118.8, 118.6, 118.5, 117.8, 116.9, 113.8, 113.8, 113.6, 113.6, 104.1, 103.9, 48.5, 35.6, 35, 29.3.

Example 225: (S,Z)—N-((6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)methyl)-N′-cyanopyrrolidine-1-carboximidamide

Compound was prepared analogous manner to Example 224 and isolated as a dark yellow solid.

1 H NMR (DMSO d6 ): 1.74 (1H, s), 7.73 (1H, m), 7.17 (1H, m), 7.04 (0.8H, t, J=5.6 Hz), 6.87 (0.2H, s), 4.45 (1H, quin, J=8.7 Hz), 4.24-4.09 (2.6H, m), 3.98 (0.4H, t, J=6.1 Hz), 3.71 (1H, dd, J=11.7, 8.0 Hz), 3.47 (3.2H, br s), 3.30-3.16 (1.8H, m), 2.90 (1H, m), 1.84, 1.77 (4H, m).

13 C NMR (DMSO d6 ):160.8, 160.8, 159.2, 159.1, 158.6, 157.5, 157.5, 156.3, 155.9, 155.9, 155.6, 155.5, 132.5, 132.4, 129, 119.1, 118.7, 118.6, 118.6, 118.5, 118.3, 117.4, 117.3, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 48.5, 47.8, 36.2, 35.6, 29.2, 24.8.

Example 226: (S)—N-(2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethyl)-N-methylnicotinamide

Compound was prepared analogous manner to Example 168 from (S)-6-(3-chloro-2,6-difluorophenyl)-1-(2-(methylamino)ethyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione hydrochloride (Example 193) and isolated as an off-white solid.

1 H NMR (DMSO d6 ): 1.93 (0.5H, br s), 11.64 (0.5H, br s), 8.63 (0.5H, br d, J=4.0 Hz), 8.59 (0.5H, br d, J=4.0 Hz), 8.57 (0.5H, br s), 8.43 (0.5H, s), 7.78 (05H, br d, J=7.6 Hz), 7.62 (1H, m), 7.51 (0.5H, br d, J=7.6 Hz), 7.45 (0.5H, br dd, J=7.0, 5.3 Hz), 7.42 (0.5H, m), 7.21 (1H, m), 4.46 (0.5H, m), 4.37 (0.5H, quin, J=8.5 Hz), 4.15 (1H, m), 3.73 (1H, m), 3.65 (1H, m), 3.41 (1H, m), 3.31 (0.5H, m), 3.01 (0.5H, dd, J=9.2, 15.8 Hz), 2.97 (1.5H, s), 2.91 (1H, dd, J=7.9, 15.6 Hz), 2.87 (1.5H, s), 2.70 (1H, m), 2.53 (1H, m).

13 C NMR (DMSO d6 ): 168.3, 167.8, 160.1, 160.1, 158.5, 158.4, 156.5, 156.5, 155.5, 155.5, 155.4, 154.9, 154.8, 150.3, 150, 147.5, 146.9, 134.5, 134.2, 132.2, 132.1, 129.7, 129.7, 129.6, 128.9, 128.8, 128.7, 123.5, 123.4, 118.8, 118.7, 118.6, 118.5, 118.4, 118.3, 116.9, 116.1, 116.1, 116, 115.9, 115.9, 113.2, 113.1, 49.9, 48.5, 48.3, 45.9, 37.3, 35.7, 32.5, 28.9, 28.6, 22.7, 21.9.

Example 227: (S)—N-(2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethyl)-N-methylpyrrolidine-1-carboxamide

To a stirred suspension of (S)-6-(3-chloro-2,6-difluorophenyl)-1-(2-(methylamino)ethyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione hydrochloride (Example 193) (87 mg, 0.229 mmol in pyridine (2 mL) was added pyrrolidine-1-carbonyl chloride (0.030 mL, 0.275 mmol) an the reaction was stirred at room temperature overnight. The reaction was diluted with dichloromethane (10 mL) and washed three times with 5 mL of 1 M HCl. The organic phase was dried over MgSO 4 , filtered and evaporated to dryness. The crude product was purified by chromatography in a mixture of dichloromethane-methanol. Crystallization from ethyl acetate afforded (S)—N-(2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethyl)-N-methylpyrrolidine-1-carboxamide as a white solid.

Yield: 23 mg, 22%.

1 H NMR (DMSO d6 ): 1.82 (1H, s), 7.62 (1H, m), 7.22 (1H, m), 4.42 (1H, quin, J=8.7 Hz), 4.12 (1H, dd, J=9.5, 11.2 Hz), 3.72 (1H, dd, J=11.5, 8.1 Hz), 3.30 (2H, t, J=7.0 Hz), 3.24 (1H, dd, J=15.6, 9.2 Hz), 3.16 (4H, m), 2.86 (1H, dd, J=15.6, 8.4 Hz), 2.71 (3H, s), 2.56 (2H, br t, J=7.0 Hz), 1.71 (4H, m).

13 C NMR (DMSO d6 ): 161.8, 160.1, 160.1, 158.5, 158.5, 156.6, 156.5, 155.2, 155, 154.9, 129.7, 129.7, 128.5, 118.7, 118.5, 118.4, 117.3, 116.1, 116.1, 116, 115.9, 113.3, 113.2, 113.1, 113.1, 48.3, 48.1, 47.9, 36, 35.7, 28.9, 25.1, 22.4.

Example 228: (S)-6-(3-chloro-2,6-difluorophenyl)-1-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione

To a stirred suspension of (S)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid (150 mg, 0.435 mmol) in dioxane (3 mL) was added 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine hydrochloride (113 mg, 0.592 mmol) in one portion and the reaction mixture was stirred for 30 min. at room temperature. Thereupon, the obtained solution was treated with N-hydroxyacetimidamide (32.2 mg, 0.435 mmol) and the reaction mixture was stirred for 1 h at room temperature followed by stirring at 110° C. for additional 3.5 h. The solvent was then removed under vacuum and the residue was diluted with ethyl acetate (25 mL), twice with sodium bicarbonate solution (25 mL) and water (25 mL), respectively. The organic phase was dried over MgSO 4 , filtered and evaporated to dryness. Purification by chromatography (reversed phase, acetonitrile-water mixture) followed by recrystallization from isopropanol afforded (S)-6-(3-chloro-2,6-difluorophenyl)-1-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione as an off-white solid. Yield: 0.058 g, 34%.

1 H NMR (DMSO d6 ): 11.97 (1H, s), 7.61 (1H, m), 7.21 (1H, m), 4.48 (1H, quin, J=8.5 Hz), 4.18 (1H, dd, J=9.3, 11.7 Hz), 4.15 (2H, m), 3.75 (1H, dd, J=11.6, 7.8 Hz), 3.25 (1H, dd, J=15.9, 9.3 Hz), 2.86 (1H, dd, J=15.9, 8.0 Hz), 2.31 (3H, s).

13 C NMR (DMSO d6 ): 175.9, 167.1, 160.1, 160.1, 158.5, 158.4, 156.6, 156.5, 156.1, 154.9, 154.9, 130.2, 129.7, 129.7, 118.8, 118.6, 118.5, 116.1, 116, 115.9, 115.9, 113.2, 113.2, 113.1, 113.1, 112, 48.7, 35.6, 29, 22, 11.1.

Example 229: (R)-2-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetic Acid

Step 1: ethyl (R)-2-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetate

To a solution of (4R)-tert-butyl 2-(3-ethoxy-3-oxopropanoyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-1-carboxylate (3.22 g, 5.57 mmol) in dichloromethane (50 mL) was added trifluoroacetic acid (8.59 mL, 111 mmol) in one portion and the solution was stirred for 5 h at room temperature. Thereupon, the mixture was quenched with sodium bicarbonate solution with ice cooling. The organic phase was dried over MgSO 4 , filtered and treated with methyl isothiocyanate (0.489 g, 6.69 mmol) followed by addition of triethyl amine (0.78 mL, 5.57 mmol). The solution was stirred for 64 h at room temperature, and then evaporated to dryness. The residue was dissolved in abs. ethanol (50 mL) followed by addition of cc. HCl (1.39 mL, 16.72 mmol) and the mixture was stirred under reflux for 1 h. Thereupon the solvent was removed and the residue was partitioned between dichloromethane and water. The organic phase was dried (MgSO 4 ), filtered and evaporated. Chromatography in a mixture of petroleumether-ethyl acetate followed by slurring in petroleum ether afforded (R)-ethyl 2-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetate as colorless solid. Yield: 0.25 g, 11%.

Step 2: (R)-2-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic Acid

To a solution of (R)-ethyl 2-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetate (0.25 g, 0.644 mmol) in methanol (7 mL) was added 1 N NaOH (0.97 mL, 0.966 mmol) (gentle heating and sonication to get clear solution) and the mixture was stirred for 3 h at room temperature. Methanol was then removed under vacuum, the residue was diluted with water to approx. 10 mL, acidified by addition of 6 M HCl to pH=1-2. The resulting precipitate was collected, washed with water, dried in vacuum at 50° C. to give (R)-2-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid as an off-white powder. Yield: 0.21 g, 91%.

1 H NMR (DMSO d6 ): 12.74 (1H, s br), 7.86 (1H, m), 4.49 (1H, quin, J=8.5 Hz), 4.25 (1H, dd, J=11.6, 9.2 Hz), 3.85 (1H, dd, J=11.7, 7.6 Hz), 3.65 (2H, s), 3.40 (3H, s), 3.35 (1H, m), 2.95 (1H, dd, J=16.0, 7.8 Hz).

13 C NMR (DMSO d6 ): 170.8, 156.4, 146.4, 146.3, 146.3, 146.2, 145.3, 145.2, 144.8, 144.8, 144.7, 144.7, 144.6, 144.6, 143.7, 143.6, 143.6, 143.6, 128.5, 120.5, 120.4, 120.3, 115.6, 105.9, 105.7, 105.6, 49.5, 34.8, 31.4, 29.8, 29.

Example 230: (S)-2-(6-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid

Compound was prepared in an analogous manner to Example 229 from (4S)-tert-butyl 2-(3-ethoxy-3-oxopropanoyl)-4-(5-chloro-2-fluorophenyl)pyrrolidine-1-carboxylate and isolated as a beige solid.

1 H NMR (DMSO d6 ): 12.70 (1H, br s), 7.47 (1H, dd, J=6.5, 2.6 Hz), 7.40 (1H, ddd, J=8.7, 4.4, 2.6 Hz), 7.29 (1H, dd, J=9.9, 8.9 Hz), 4.21 (2H, m), 3.81 (1H, m), 3.67 (2H, s), 3.39 (3H, m), 3.27 (1H, br dd, J=15.6, 7.5 Hz), 2.93 (1H, dd, J=15.5, 7.3 Hz).

13 C NMR (DMSO d6 ): 170.8, 159.8, 158.2, 156.6, 130.2, 130.1, 128.9, 128.9, 128.7, 128.5, 128.5, 128.5, 117.6, 117.4, 115.8, 50.2, 31.4, 29.8, 29.3.

Example 231: 2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic Acid

Compound was prepared in an analogous manner to Example 229 from tert-butyl (1S,5R)-1-(3-chloro-2,6-difluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate and isolated as a beige solid.

1 H NMR (DMSO d6 ): 12.78 (1H, br s), 7.64 (1H, m), 7.21 (1H, t, J=8.9 Hz), 4.12 (1H, d, J=12.2 Hz), 3.81 (1H, d, J=12.0 Hz), 3.74 (2H, m), 3.36 (3H, s), 2.85 (1H, dd, J=8.2, 4.4 Hz), 1.70 (1H, dd, J=8.1, 5.6 Hz), 1.27 (1H, t, J=5.0 Hz).

13 C NMR (DMSO d6 ): 170.9, 161.2, 161.2, 159.6, 159.6, 157.8, 157.8, 157, 156.2, 156.1, 117, 116.9, 116.8, 115.8, 115.7, 115.6, 115.6, 115.6, 112.9, 112.9, 112.8, 112.8, 52.3, 31.4, 29.8, 25.7, 21.7, 21.1.

Example 232: 2-((S)-6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light cream powder.

1 H NMR (DMSO d6 ): 8.38 (1H, br d, J=6.6 Hz), 7.73 (1H, m), 7.17 (1H, m), 4.44 (1H, quin, J=8.6 Hz), 4.22 (2H, m), 3.78 (2H, m), 3.72 (1H, dd, J=8.9, 6.0 Hz), 3.66 (1H, m), 3.46 (1H, dd, J=8.9, 3.5 Hz), 3.43 (2H, m), 3.40 (3H, s), 3.28 (1H, dd, J=15.8, 9.5 Hz), 2.88 (1H, dd, J=15.8, 8.1 Hz), 2.07 (1H, m), 1.71 (1H, m).

13 C NMR (DMSO d6 ): 167.6, 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 156.2, 155.9, 155.9, 132.5, 132.4, 128.4, 118.8, 118.7, 118.6, 116.4, 113.8, 113.8, 113.6, 113.6, 104.1, 104.1, 103.9, 103.9, 72.4, 66.3, 49.8, 49.6, 34.8, 32, 31.5, 31.1, 29.2.

Example 233: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light cream powder.

1 H NMR (DMSO d6 ): 7.72 (1H, m), 7.16 (1H, m), 4.44 (1H, quin, J=8.5 Hz), 4.22 (1H, dd, J=9.3, 11.2 Hz), 3.79 (1H, br dd, J=11.6, 7.6 Hz), 3.75 (2H, s), 3.59 (2H, m), 3.55 (2H, m), 3.49 (2H, m), 3.45 (2H, m), 3.36 (3H, m), 3.27 (1H, dd, J=15.8, 9.4 Hz), 2.85 (1H, dd, J=15.8, 7.8 Hz).

13 C NMR (DMSO d6 ): 166.8, 160.8, 160.7, 159.2, 159.1, 157.5, 157.5, 156.2, 155.9, 155.9, 132.5, 132.4, 128.3, 118.9, 118.8, 118.6, 116.2, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 66, 66, 49.5, 45.6, 41.7, 34.8, 31.5, 29.2, 28.8.

Example 234: 1-((S)-6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydrofuran-3-yl)cyclopropane-1-carboxamide

Compound was prepared analogous manner to Example 32 from (S)-(1-(6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)cyclopropyl)(1H-imidazol-1-yl)methanone and isolated as a white powder.

1 H NMR (DMSO d6 ): 7.74 (1H, m), 7.63 (1H, d, J=6.9 Hz), 7.18 (1H, m), 4.41 (1H, quin, J=8.9 Hz), 4.32 (1H, m), 4.21 (1H, dd, J=9.3, 11.3 Hz), 3.84-3.74 (2H, m), 3.72 (1H, dd, J=8.8, 6.7 Hz), 3.63 (1H, m), 3.46 (1H, dd, J=8.8, 4.8 Hz), 3.35 (3H, s), 3.24 (1H, dd, J=15.6, 9.0 Hz), 2.97 (1H, dd, J=15.6, 9.0 Hz), 2.04 (1H, m), 1.76 (1H, m), 1.43 (1H, m), 1.35 (1H, m), 1.02 (2H, m).

13 C NMR (DMSO d6 ): 170.4, 161, 160.9, 159.3, 159.3, 157.7, 157.6, 156.5, 156.1, 156, 132.6, 132.5, 130.9, 119.3, 118, 117.9, 117.7, 113.8, 113.8, 113.6, 113.6, 104.1, 103.9, 71.5, 66.6, 50.3, 49.2, 35.1, 32, 31.4, 29, 22.1, 15.5, 15.1.

Example 235: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(1,1-dioxidothiomorpholino)ethan-1-one

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a white solid.

1 H NMR (DMSO d6 ): 7.73 (1H, ddd, J=8.8, 8.1, 5.8 Hz), 7.17 (1H, m), 4.44 (1H, quin, J=8.5 Hz), 4.23 (1H, dd, J=11.2, 9.5 Hz), 3.90 (2H, m), 3.87 (2H, m), 3.85 (2H, s), 3.80 (1H, dd, J=11.6, 7.8 Hz), 3.36 (3H, s), 3.31 (2H, m), 3.28 (1H, dd, J=9.3, 15.8 Hz), 3.13 (2H, m), 2.86 (1H, dd, J=15.9, 8.0 Hz).

13 C NMR (DMSO d6 ): 167.2, 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 156.3, 155.9, 155.9, 132.5, 132.4, 128.5, 118.8, 118.7, 118.6, 116, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 51.1, 51, 49.6, 43.7, 40.2, 34.8, 31.6, 29.2, 28.8.

Example 236: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-isopropylacetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as an off-white solid.

1 H NMR (DMSO d6 ): 7.99 (1H, br d, J=7.5 Hz), 7.62 (1H, m), 7.22 (1H, m), 4.44 (1H, quin, J=8.6 Hz), 4.22 (1H, dd, J=11.3, 9.4 Hz), 3.81 (2H, m), 3.40 (3H, s), 3.38 (2H, m), 3.29 (1H, dd, J=15.8, 9.3 Hz), 2.89 (1H, dd, J=15.8, 8.0 Hz), 1.05 (6H, d, J=6.5 Hz).

13 C NMR (DMSO d6 ): 166.6, 160.1, 160.1, 158.5, 158.5, 156.6, 156.5, 156.2, 156.1, 154.9, 154.9, 129.7, 129.6, 128.3, 118.8, 118.7, 118.6, 116.6, 116.1, 116, 115.9, 113.2, 113.2, 113.1, 113.1, 49.5, 40.7, 34.7, 31.4, 31.3, 29.2, 22.3, 22.3.

Example 237: (R)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one

Compound was prepared analogous manner to Example 32 from (R)-1-(H-imidazol-1-yl)-2-(6-(2,3,6-trifluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a beige powder.

1 H NMR (DMSO d6 ): 7.47 (1H, qd, J=9.4, 4.9 Hz), 7.18 (1H, m), 4.44 (1H, quin, J=8.5 Hz), 4.24 (1H, dd, J=9.4, 11.2 Hz), 3.81 (1H, dd, J=11.4, 7.9 Hz), 3.75 (2H, s), 3.59 (2H, m), 3.56 (2H, m), 3.49 (2H, m), 3.45 (2H, m), 3.36 (3H, s), 3.28 (1H, dd, J=15.7, 9.2 Hz), 2.88 (1H, dd, J=15.8, 8.1 Hz).

13 C NMR (DMSO d6 ): 166.8, 157, 156.9, 156.3, 155.3, 155.3, 149, 149, 147.6, 147.5, 147.4, 147.4, 145.9, 145.9, 145.9, 145.8, 128.2, 118.9, 118.8, 118.8, 118.7, 116.5, 116.4, 116.4, 116.3, 116.3, 112, 112, 112, 111.9, 111.8, 111.8, 66, 66, 49.4, 45.6, 41.7, 34.8, 31.5, 29.2, 28.8.

Example 238: (S)-1-(6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2-(methylsulfonyl)ethyl)cyclopropane-1-carboxamide

Compound was prepared analogous manner to Example 32 from (S)-(1-(6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)cyclopropyl)(1H-imidazol-1-yl)methanone and isolated as a light cream solid.

1 H NMR (DMSO d6 ): 7.84 (1H, t, J=5.6 Hz), 7.74 (1H, m), 7.18 (1H, m), 4.41 (1H, quin, J=8.9 Hz), 4.21 (1H, dd, J=9.4, 10.9 Hz), 3.81 (1H, dd, J=11.2, 9.1 Hz), 3.45 (2H, q, J=6.5 Hz), 3.37 (3H, s), 3.24 (3H, m), 2.98 (3H, s), 2.98 (1H, dd, J=9.4, 15.4 Hz), 1.43 (1H, m), 1.34 (1H, m), 1.08 (1H, m), 1.04 (1H, m).

13 C NMR (DMSO d6 ): 170.7, 160.9, 160.9, 159.3, 159.3, 157.7, 157.6, 156.7, 156.1, 156, 132.6, 132.5, 131.2, 119.1, 117.8, 117.7, 117.6, 113.8, 113.7, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 52.7, 49.2, 40.6, 35.1, 33.4, 31.5, 28.9, 19.2, 15.4, 14.8.

Example 239: (R)—N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(H-imidazol-1-yl)-2-(6-(2,3,6-trifluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a beige powder.

1 H NMR (DMSO d6 ): 8.23 (1H, d, J=7.6 Hz), 7.48 (1H, qd, J=9.4, 4.8 Hz), 7.18 (1H, m), 4.43 (1H, quin, J=8.7 Hz), 4.23 (1H, dd, J=9.7, 11.5 Hz), 3.95 (1H, m), 3.81 (1H, dd, J=11.4, 7.9 Hz), 3.44 (2H, m), 3.39 (3H, s), 3.29 (1H, dd, J=15.8, 9.4 Hz), 3.23 (2H, m), 3.06 (2H, m), 2.90 (1H, dd, J=8.3, 15.8 Hz), 2.05 (2H, m), 1.90 (2H, m).

13 C NMR (DMSO d6 ): 167.2, 157, 156.9, 156.3, 155.4, 155.3, 149.1, 149, 149, 147.6, 147.5, 147.5, 147.4, 147.4, 147.3, 146, 145.9, 145.9, 145.8, 128.5, 118.9, 118.8, 118.7, 118.6, 116.5, 116.5, 116.4, 116.3, 116.3, 112, 112, 112, 111.8, 111.8, 111.8, 111.8, 49.5, 48.4, 44.1, 34.7, 31.5, 31.2, 29.2, 29.1.

Example 240: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a brown powder.

1 H NMR (DMSO d6 ): 7.73 (1H, m), 7.51 (1H, br s), 7.17 (1H, m), 7.10 (1H, br s), 4.44 (1H, quin, J=8.7 Hz), 4.21 (1H, dd, J=9.4, 11.4 Hz), 3.80 (1H, dd, J=11.6, 7.9 Hz), 3.40 (2H, m), 3.39 (3H, s), 3.29 (1H, dd, J=15.7, 9.4 Hz), 2.90 (1H, dd, J=15.8, 8.3 Hz).

13 C NMR (DMSO d6 ): 169.9, 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 156.2, 155.9, 155.9, 132.5, 132.4, 128.5, 118.7, 118.5, 118.4, 116.5, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 49.5, 34.8, 31.4, 31, 29.1.

Example 241: 2-((S)-6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-((S)-2-(hydroxymethyl)pyrrolidin-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from (S)-1-(1-H-imidazol-1-yl)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a brown powder.

1 H NMR (DMSO d6 ): 7.72 (1H, m), 7.16 (1H, t, J=9.4 Hz), 5.04 (0.3H, t, J=5.5 Hz), 4.72 (0.7H, t, J=5.6 Hz), 4.44 (1H, m), 4.22 (1H, dd, J=9.5, 11.1 Hz), 4.02 (0.3H, q, J=6.6 Hz), 3.93 (0.7H, m), 3.79 (1.6H, m), 3.64 (1.4H, m), 3.48 (2.1H, m), 3.43-3.36 (3.9H, m), 3.27 (2H, m), 2.86 (1H, m), 1.85 (4H, m).

13 C NMR (DMSO d6 ): 166.8, 166.7, 160.8, 160.7, 159.1, 159.1, 157.6, 157.5, 156.1, 156, 155.9, 155.9, 132.5, 132.4, 128.3, 128.2, 118.9, 118.8, 118.8, 118.7, 116.7, 116.2, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 62.8, 62.8, 60.8, 58.8, 58.7, 49.6, 49.5, 46.9, 45.5, 34.8, 31.6, 31.5, 30.6, 30, 29.2, 27.8, 26.7, 23.5, 21.4.

Example 242: (R)-2-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as an off-white powder.

1 H NMR (DMSO d6 ): 7.86 (1H, m), 4.49 (1H, quin, J=8.5 Hz), 4.25 (1H, dd, J=11.6, 9.2 Hz), 3.84 (1H, dd, J=11.6, 7.6 Hz), 3.75 (2H, s), 3.59 (2H, m), 3.55 (2H, m), 3.49 (2H, m), 3.45 (2H, m), 3.36 (3H, s), 3.30 (1H, dd, J=15.9, 9.3 Hz), 2.90 (1H, dd, J=15.8, 7.8 Hz).

13 C NMR (DMSO d6 ): 166.8, 156.3, 146.4, 146.3, 146.2, 145.4, 145.3, 145.3, 145.3, 145.2, 145.2, 144.8, 144.8, 144.7, 144.6, 144.6, 143.7, 143.7, 143.6, 143.6, 143.6, 128, 120.5, 120.4, 120.3, 116.3, 105.9, 105.7, 105.6, 66, 66, 49.4, 45.6, 41.7, 34.9, 31.5, 29.1, 28.8.

Example 243: 2-((R)-2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl-N—((R)-tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as an off-white powder.

1 H NMR (DMSO d6 ): 8.37 (1H, d, J=6.6 Hz), 7.86 (1H, m), 4.48 (1H, quin, J=8.5 Hz), 4.27-4.19 (2H, m), 3.84 (1H, dd, J=11.7, 7.6 Hz), 3.77 (1H, q, J=7.3 Hz), 3.72 (1H, dd, J=8.9, 5.9 Hz), 3.66 (1H, td, J=8.2, 5.6 Hz), 3.46 (1H, br dd, J=8.9, 3.6 Hz), 3.44 (2H, s), 3.40 (3H, s), 3.31 (1H, dd, J=9.4, 16.1 Hz), 2.93 (1H, dd, J=15.8, 7.9 Hz), 2.08 (1H, m), 1.71 (1H, m).

13 C NMR (DMSO d6 ): 167.6, 156.2, 146.4, 146.4, 146.3, 146.3, 146.2, 145.3, 145.3, 145.3, 145.3, 145.2, 145.2, 144.8, 144.7, 144.6, 144.6, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 128.2, 120.5, 120.4, 120.3, 116.4, 105.9, 105.7, 105.6, 72.4, 66.3, 49.8, 49.4, 34.9, 32, 31.5, 31, 29.1.

Example 244: 2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-2-(6-(2,3,6-trifluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light beige powder.

1 H NMR (DMSO d6 ): 8.36 (1H, br d, J=6.5 Hz), 7.47 (1H, m), 7.18 (1H, t br), 4.43 (1H, quin, J=8.6 Hz), 4.29-4.16 (2H, m), 3.81 (1H, dd, J=11.6, 8.1 Hz), 3.77 (1H, m), 3.72 (1H, dd, J=9.0, 5.9 Hz), 3.66 (1H, td, J=8.2, 5.6 Hz), 3.46 (1H, dd, J=8.9, 3.6 Hz), 3.43 (2H, s), 3.40 (3H, s), 3.29 (1H, dd, J=15.8, 9.3 Hz), 2.90 (1H, dd, J=15.8, 8.2 Hz), 2.08 (1H, m), 1.71 (1H, m).

13 C NMR (DMSO d6 ): 167.6, 157, 156.9, 156.9, 156.9, 156.2, 155.3, 155.3, 155.3, 155.3, 149, 147.5, 147.5, 147.4, 145.9, 145.8, 145.8, 128.4, 118.9, 118.8, 118.8, 118.7, 116.5, 116.4, 116.4, 116.3, 112, 112, 111.9, 111.9, 111.8, 111.8, 111.8, 111.8, 72.3, 66.2, 49.8, 49.4, 34.7, 32, 31.5, 31.1, 29.1.

Example 245: (R)-2-(6-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-cyclopentylacetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(H-imidazol-1-yl)-2-(6-(5-chloro-2-fluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a beige solid.

1 H NMR (DMSO d6 ): 8.08 (1H, br d, J=7.0 Hz), 7.46 (1H, dd, J=6.5, 2.5 Hz), 7.41 (1H, ddd, J=8.7, 4.3, 2.7 Hz), 7.30 (1H, dd, J=9.0, 10.0 Hz), 4.20 (2H, m), 3.98 (1H, m), 3.80 (1H, m), 3.41 (2H, s), 3.39 (3H, s), 3.24 (1H, br dd, J=15.6, 7.5 Hz), 2.89 (1H, br dd, J=15.4, 7.0 Hz), 1.79 (2H, m), 1.62 (2H, m), 1.49 (2H, m), 1.36 (2H, m).

13 C NMR (DMSO d6 ): 167, 159.8, 158.2, 156.3, 130.3, 130.2, 128.9, 128.9, 128.5, 128.5, 128.5, 128.2, 117.6, 117.4, 116.9, 50.5, 50.1, 39.8, 32.2, 32.2, 31.4, 31.2, 29.5, 23.4.

Example 246: 2-((R)-6-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(5-chloro-2-fluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a beige solid.

1 H NMR (DMSO d6 ): 8.37 (1H, br d, J=6.6 Hz), 7.46 (1H, dd, J=6.5, 2.6 Hz), 7.41 (1H, ddd, J=8.7, 4.3, 2.8 Hz), 7.30 (1H, dd, J=10.0, 8.9 Hz), 4.28-4.15 (3H, m), 3.78 (2H, m), 3.73 (1H, dd, J=8.9, 5.9 Hz), 3.66 (1H, td, J=8.2, 5.6 Hz), 3.47 (1H, dd, J=8.9, 3.5 Hz), 3.45 (2H, s), 3.40 (3H, s), 3.24 (1H, dd, J=15.5, 7.6 Hz), 2.90 (1H, dd, J=15.4, 7.2 Hz), 2.08 (1H, m), 1.71 (1H, m).

13 C NMR (DMSO d6 ): 167.6, 159.8, 158.2, 156.4, 130.2, 130.1, 128.9, 128.9, 128.5, 128.5, 128.4, 117.6, 117.4, 116.7, 72.4, 66.3, 50.1, 49.8, 39.8, 32, 31.5, 31, 29.4.

Example 247: 1-((S)-2-(methoxymethyl)pyrrolidin-1-yl)-2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(2,3,6-trifluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a white powder.

1 H NMR (DMSO d6 ): 7.47 (1H, m), 7.18 (1H, m), 4.43 (1H, m), 4.23 (1.35H, m), 4.04 (0.65H, m), 3.82 (1H, m), 3.79 (0.7H, m), 3.65 (1.3H, s), 3.53-3.37 (2.3H, m), 3.36, 3.35 (3H, 2 s), 3.34-3.22 (3.75H, m), 3.21 (1.95H, s), 2.92-2.84 (1H, m), 2.0-1.73 (4H, m).

13 C NMR (DMSO d6 ): 166.9, 166.6, 156.9, 156.9, 156.9, 156.9, 156.2, 156.1, 155.3, 155.3, 155.3, 149.1, 149, 149, 147.6, 147.5, 147.5, 147.4, 147.4, 147.3, 145.9, 145.9, 145.9, 145.8, 129.5, 128.2, 128.2, 118.9, 118.9, 118.8, 118.7, 116.7, 116.5, 116.4, 116.4, 116.3, 116.3, 112, 112, 112, 111.8, 111.8, 111.8, 111.8, 73.8, 71.6, 58.5, 58.3, 56.3, 56.2, 49.4, 46.8, 45.4, 34.8, 31.5, 30.6, 29.9, 29.1, 29.1, 28.2, 27.2, 23.5, 21.5.

Example 248: 2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-((S)-2-(trifluoromethyl)pyrrolidin-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from (R)-1-(H-imidazol-1-yl)-2-(6-(2,3,6-trifluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light cream powder.

1 H NMR (DMSO d6 ): 7.47 (1H, m), 7.18 (1H, m), 5.03 (0.3H, m), 4.76 (0.7H, quin, J=8.3 Hz), 4.43 (1H, quin, J=8.6 Hz), 4.25 (1H, m), 3.94 (0.3H, br d, J=17.5 Hz), 3.83 (1H, dd, J=11.5, 7.8 Hz), 3.79 (1.4H, m), 3.64 (1.7H, m), 3.35 (3H, s), 3.30 (1.6H, m), 2.90 (1H, m), 2.28-1.85 (4H, m).

13 C NMR (DMSO d6 ): 168.6, 168.1, 156.9, 156.9, 156.4, 156.3, 155.3, 155.3, 149.1, 149, 149, 148.9, 147.6, 147.5, 147.5, 147.4, 147.4, 147.3, 147.3, 145.9, 145.9, 145.9, 145.8, 128.8, 128.6, 128.5, 127, 125.1, 123.2, 118.9, 118.8, 118.7, 116.5, 116.4, 116.4, 116.3, 116, 115.8, 111.9, 111.8, 56.6, 56.4, 56.2, 56, 49.5, 47, 46.5, 34.8, 34.7, 31.4, 31.4, 30.4, 29.6, 29.2, 26.2, 24.8, 23.6, 21.3.

Example 249: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(H-imidazol-1-yl)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as an off-white solid.

1 H NMR (DMSO d6 ): 7.62 (1H, m), 7.51 (1H, br s), 7.22 (1H, m), 7.10 (1H, br s), 4.44 (1H, quin, J=8.6 Hz), 4.22 (1H, dd, J=9.3, 11.3 Hz), 3.81 (1H, dd, J=11.5, 8.0 Hz), 3.41 (2H, m), 3.40 (3H, s), 3.30 (1H, dd, J=15.9, 9.3 Hz), 2.91 (1H, dd, J=15.8, 8.3 Hz).

13 C NMR (DMSO d6 ): 169.9, 160.2, 160.1, 158.5, 158.5, 156.6, 156.6, 156.2, 155, 154.9, 129.7, 129.7, 128.5, 118.7, 118.6, 118.4, 116.5, 116.1, 116.1, 116, 115.9, 113.3, 113.2, 113.1, 113.1, 49.4, 34.8, 31.4, 31, 29.1.

Example 250: 2-((S)-6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(H-imidazol-1-yl)-2-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as an off-white solid.

1 H NMR (DMSO d6 ): 8.37 (1H, br d, J=6.6 Hz), 7.61 (1H, m), 7.21 (1H, m), 4.44 (1H, quin, J=8.5 Hz), 4.22 (2H, m), 3.78 (2H, m), 3.72 (1H, dd, J=8.9, 6.0 Hz), 3.66 (1H, td, J=8.2, 5.6 Hz), 3.45 (1H, dd, J=9.0, 3.4 Hz), 3.43 (2H, m), 3.40 (3H, s), 3.29 (1H, dd, J=15.8, 9.4 Hz), 2.89 (1H, dd, J=15.8, 8.1 Hz), 2.07 (1H, dq, J=12.7, 7.6 Hz), 1.71 (1H, m).

13 C NMR (DMSO d6 ): 167.6, 160.2, 160.1, 158.5, 158.5, 156.6, 156.5, 156.2, 154.9, 154.9, 129.7, 129.7, 128.4, 118.8, 118.7, 118.6, 116.4, 116.1, 116, 115.9, 115.9, 113.3, 113.2, 113.1, 113.1, 72.4, 66.3, 49.8, 49.5, 34.7, 32, 31.5, 31.1, 29.2.

Example 251: 2-((S)-6-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(H-imidazol-1-yl)-2-(6-(5-chloro-2-fluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as an off-white solid.

1 H NMR (DMSO d6 ): 8.37 (1H, d, J=6.6 Hz), 7.47 (1H, dd, J=6.5, 2.7 Hz), 7.41 (1H, ddd, J=8.8, 4.4, 2.7 Hz), 7.30 (1H, dd, J=10.1, 8.8 Hz), 4.22 (3H, m), 3.79 (2H, m), 3.73 (1H, dd, J=8.9, 5.9 Hz), 3.66 (1H, td, J=8.2, 5.6 Hz), 3.46 (2H, m), 3.46 (1H, dd, J=3.6, 9.0 Hz), 3.40 (3H, s), 3.24 (1H, dd, J=15.6, 7.6 Hz), 2.90 (1H, dd, J=15.5, 7.3 Hz), 2.08 (1H, m), 1.72 (1H, m).

13 C NMR (DMSO d6 ): 167.6, 159.8, 158.2, 156.4, 130.2, 130.1, 128.9, 128.9, 128.5, 128.5, 128.5, 128.3, 117.6, 117.4, 116.7, 72.4, 66.3, 50.1, 49.8, 39.8, 32, 31.5, 31, 29.4.

Example 252: 2-((S)-6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-methyl-N-(tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 34 from (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid (Example 12) and isolated as a yellow powder.

1 H NMR (DMSO d6 ): 7.72 (1H, m), 7.16 (1H, m), 5.09 (0.6H, m), 4.65 (0.4H, m), 4.44 (1H, quin, J=8.5 Hz), 4.22 (1H, dd, J=9.7, 11.2 Hz), 3.91 (1H, m), 3.81 (1H, m), 3.80 (1H, dd, J=7.7, 11.6 Hz), 3.71 (1H, m), 3.69 (1H, m), 3.62 (1H, m), 3.56 (1H, m), 3.34 (3H, m), 3.26 (1H, m), 2.93 (1.8H, m), 2.84 (1H, m), 2.74 (1.2H, s), 2.25-2.04 (1H, m), 1.90-1.72 (1H, m).

13 C NMR (DMSO d6 ): 168.2, 167.6, 160.8, 160.7, 159.1, 159.1, 157.5, 157.5, 156.2, 156.2, 155.9, 155.8, 132.5, 132.4, 128.3, 128.1, 118.9, 118.8, 118.6, 116.5, 116.4, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 69.4, 69.3, 69.3, 69.2, 67.1, 67, 56.5, 56.5, 53, 49.5, 34.8, 31.5, 31.5, 31.2, 29.9, 29.8, 29.7, 29.7, 29.4, 29.4, 29.3, 29.2, 29.2, 27.6.

Example 253: (S)-2-(6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(cyanomethyl)acetamide

Compound was prepared analogous manner to Example 34 from (S)-2-(6-(3-bromo-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid (Example 12) and isolated as a cream powder.

1 H NMR (DMSO d6 ): 8.78 (1H, t, J=5.5 Hz), 7.72 (1H, m), 7.16 (1H, m), 4.44 (1H, quin, J=8.6 Hz), 4.23 (1H, dd, J=9.7, 11.2 Hz), 4.16 (2H, d, J=5.6 Hz), 3.81 (1H, dd, J=11.4, 8.1 Hz), 3.55 (2H, m), 3.39 (3H, s), 3.29 (1H, dd, J=15.8, 9.3 Hz), 2.90 (1H, dd, J=15.8, 8.2 Hz).

13 C NMR (DMSO d6 ): 168.6, 160.8, 160.8, 159.2, 159.1, 157.6, 157.5, 156.5, 155.9, 155.9, 132.5, 132.4, 128.9, 118.6, 118.5, 118.4, 117.5, 115.5, 113.8, 113.8, 113.6, 113.6, 104.1, 104.1, 103.9, 103.9, 49.5, 34.8, 31.4, 30.8, 29.1, 27.3.

Example 254: (R)—N-(1-cyanocyclopropyl)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 34 from (R)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as a cream powder.

1 H NMR (DMSO d6 ): 9.03 (1H, s), 7.48 (1H, m), 7.18 (1H, br t, J=9.4 Hz), 4.43 (1H, quin, J=8.6 Hz), 4.24 (1H, dd, J=9.5, 11.3 Hz), 3.82 (1H, dd, J=11.4, 8.1 Hz), 3.48 (2H, m), 3.37 (3H, s), 3.30 (1H, dd, J=9.2, 11.9 Hz), 2.92 (1H, dd, J=15.8, 8.3 Hz), 1.48 (2H, m), 1.14 (2H, m).

13 C NMR (DMSO d6 ): 169.3, 156.9, 156.5, 155.3, 149, 149, 148.9, 147.5, 147.5, 147.4, 147.4, 147.4, 147.3, 145.9, 145.9, 145.8, 128.8, 120.6, 118.8, 118.7, 118.7, 118.6, 116.5, 116.5, 116.4, 116.3, 115.5, 112, 112, 112, 111.9, 111.8, 111.8, 111.8, 111.8, 49.5, 34.7, 31.4, 30.8, 29.1, 19.9, 15.6, 15.6.

Example 255: 2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydro-2H-pyran-3-yl)acetamide

Compound was prepared analogous manner to Example 34 from (R)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as a white powder.

1 H NMR (DMSO d6 ): 8.12 (1H, br d, J=7.3 Hz), 7.47 (1H, m), 7.18 (1H, br t, J=9.6 Hz), 4.43 (1H, quin, J=8.6 Hz), 4.23 (1H, dd, J=9.6, 11.3 Hz), 3.81 (1H, dd, J=11.5, 8.0 Hz), 3.72-3.59 (3H, m), 3.45 (2H, s), 3.39 (3H, s), 3.36 (1H, m), 3.29 (1H, dd, J=15.8, 9.3 Hz), 3.12 (1H, m), 2.90 (1H, dd, J=15.7, 8.2 Hz), 1.80 (1H, m), 1.66 (1H, m), 1.46 (2H, m).

13 C NMR (DMSO d6 ): 167.3, 157, 156.9, 156.9, 156.2, 155.3, 155.3, 149.1, 149, 149, 148.9, 147.5, 147.5, 147.5, 147.4, 147.4, 147.4, 147.3, 145.9, 145.9, 145.9, 145.8, 128.3, 118.9, 118.8, 118.8, 118.7, 116.5, 116.4, 116.4, 116.3, 111.9, 111.8, 70.1, 67, 49.4, 45.1, 34.7, 31.5, 31.2, 29.1, 28.5, 23.8.

Example 256: (S)-6-(3-bromo-2,6-difluorophenyl)-2-methyl-1-(2-(((R)-tetrahydrofuran-3-yl)amino)ethyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione hydrochloride

Compound was prepared analogous manner to Example 35 from 1-((S)-6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydrofuran-3-yl)acetamide (Example 234) and isolated as a light cream powder.

1 H NMR (DMSO d6 ): 9.20 (2H, m), 7.74 (1H, m), 7.18 (1H, m), 4.44 (1H, quin, J=8.7 Hz), 4.22 (1H, dd, J=9.5, 11.1 Hz), 3.91 (2H, m), 3.84 (1H, s br), 3.80 (1H, dd, J=8.1, 11.4 Hz), 3.75 (1H, dd, J=6.0, 10.2 Hz), 3.64 (1H, m), 3.47 (3H, s), 3.40 (1H, dd, J=9.6, 15.9 Hz), 3.13 (2H, br s), 3.00 (1H, dd, J=15.7, 8.4 Hz), 2.94 (2H, t, J=7.6 Hz), 2.20 (1H, m), 2.03 (1H, m).

13 C NMR (DMSO d6 ): 160.8, 160.8, 159.2, 159.1, 157.6, 157.6, 156.6, 156, 155.9, 132.6, 132.5, 128.5, 118.5, 118.4, 118.3, 116.5, 113.8, 113.8, 113.7, 113.6, 104.1, 104.1, 104, 104, 68.9, 66.4, 57.5, 49.4, 43.5, 34.9, 31.4, 29.2, 28.9, 21.1.

Example 257: (R)-2-methyl-1-(2-morpholinoethyl)-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione Hydrochloride

Compound was prepared analogous manner to Example 35 from (R)-2-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinoethan-1-one (Example 242) and isolated as a pale yellow powder.

1 H NMR (DMSO d6 ): 1.61 (1H, br s), 7.88 (1H, m), 4.51 (1H, quin, J=8.4 Hz), 4.24 (1H, dd, J=11.3, 9.5 Hz), 3.97 (2H, br d, J=11.7 Hz), 3.85 (1H, dd, J=7.7, 11.7 Hz), 3.82 (2H, m), 3.48 (3H, s), 3.47 (2H, m), 3.43 (1H, dd, J=15.6, 8.6 Hz), 3.30 (2H, m), 3.13-2.98 (5H, m).

13 C NMR (DMSO d6 ): 156.7, 146.4, 146.4, 146.3, 146.3, 146.3, 146.3, 146.2, 145.3, 145.3, 145.3, 145.3, 145.2, 144.8, 144.8, 144.7, 144.7, 144.6, 144.6, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 127.9, 120.4, 120.3, 120.2, 116.6, 105.9, 105.8, 105.6, 63.1, 52.9, 50.8, 49.3, 34.9, 31.4, 29.2, 18.6.

Example 258: (S)-2-amino-3-(2-((R)-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamido)propanoic Acid

To a solution of pyridin-2-amine (28.9 mg, 0.307 mmol) in N,N-dimethyl formamide (0.93 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.10 mL, 0.557 mmol). The reaction mixture was cooled in an ice bath and 1-(bis(dimethylamino)methylene)-1H-[1,2,3]triazolo[4,5-b]pyridine-1-ium 3-oxide hexafluorophosphate(V) (HATU) (117 mg, 0.307 mmol) and (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid (100 mg, 0.279 mmol) were added in one portion. The reaction mixture was allowed to warm up to room temperature and stirred for 2 h. The reaction mixture was then transferred to a separatory funnel, diluted with 30 mL of water and 40 mL of ethyl acetate. The aqueous layer was extracted twice with 40 mL of ethyl acetate. The organic layer was washed with brine, dried over MgSO 4 , filtered and evaporated to dryness. Chromatography afforded (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)-N-(pyridin-2-yl)acetamide as an off-white solid.

Yield: 31 mg, 25%.

1 H NMR (DMSO d6 ): 10.76 (1H, s), 8.32 (1H, dd, J=4.8, 1.0 Hz), 8.04 (1H, br d, J=8.1 Hz), 7.78 (1H, m), 7.61 (1H, m), 7.21 (1H, m), 7.11 (1H, dd, J=7.0, 5.2 Hz), 4.46 (1H, quin, J=8.5 Hz), 4.24 (1H, dd, J=9.7, 11.1 Hz), 3.81 (1H, dd, J=7.9, 11.7 Hz), 3.79 (2H, m), 3.44 (3H, m), 3.31 (1H, m), 2.92 (1H, dd, J=16.0, 8.1 Hz).

13 C NMR (DMSO d6 ): 167.7, 160.1, 160.1, 158.5, 158.4, 156.6, 156.5, 156.4, 154.9, 154.9, 151.7, 148, 138.2, 129.7, 129.6, 128.8, 119.6, 118.8, 118.7, 118.5, 116, 116, 116, 115.9, 115.9, 115.9, 115.8, 113.5, 113.2, 113.2, 113.1, 113, 49.5, 34.7, 31.9, 31.6, 29.2.

Example 259: (R)-2-methyl-1-(2-(pyridin-3-yl)ethyl)-6-(2,3,5,6-tetrafluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione

Compound was prepared analogous manner to Example 229 step 1 from tert-butyl (4R)-2-(3-(pyridin-3-yl)propanoyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-1-carboxylate (Example 212 step 3) and isolated as an off-white powder.

1 H NMR (DMSO d6 ): 8.42 (1H, d, J=1.8 Hz), 8.38 (1H, dd, J=4.7, 1.5 Hz), 7.84 (1H, m), 7.62 (1H, dt, J=7.8, 1.8 Hz), 7.28 (1H, dd, J=7.7, 4.8 Hz), 4.38 (1H, quin, J=8.4 Hz), 4.19 (1H, br dd, J=11.4, 9.2 Hz), 3.79 (1H, dd, J=11.7, 7.4 Hz), 3.45 (3H, s), 3.13 (1H, dd, J=15.7, 9.4 Hz), 2.86 (4H, m), 2.67 (1H, dd, J=15.6, 7.6 Hz).

13 C NMR (DMSO d6 ): 156.1, 149.7, 147.4, 146.4, 146.3, 146.2, 145.3, 145.2, 145.2, 145.2, 145.2, 145.1, 145.1, 145.1, 144.8, 144.7, 144.7, 144.7, 144.6, 144.6, 143.6, 143.6, 143.6, 143.6, 143.5, 143.5, 143.5, 136, 135.9, 127.1, 123.3, 120.4, 120.3, 120.2, 120.2, 105.8, 105.7, 105.5, 49.1, 34.9, 31.2, 30.1, 29.1, 25.2.

Example 260: (R)-3-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propanoic Acid

Compound was prepared analogous manner to Example 229 step 1 from ethyl oxoacetate and (4R)-tert-butyl 2-(2-(dimethoxyphosphoryl)acetyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-1-carboxylate (Example 212 step 3) and isolated as an off-white powder.

1 H NMR (DMSO d6 ): 12.33 (1H, br s), 7.86 (1H, m), 4.46 (1H, quin, J=8.5 Hz), 4.22 (1H, dd, J=11.4, 9.3 Hz), 3.81 (1H, dd, J=11.7, 7.7 Hz), 3.44 (3H, s), 3.38 (1H, dd, J=9.4, 15.2 Hz), 2.99 (1H, dd, J=15.7, 7.9 Hz), 2.73 (2H, t, J=7.3 Hz), 2.54 (2H, t, J=7.3 Hz).

13 C NMR (DMSO d6 ): 173.4, 156, 146.4, 146.3, 146.3, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 144.8, 144.8, 144.7, 144.7, 144.7, 144.6, 144.6, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 143.5, 126.8, 120.5, 120.4, 120.4, 120.3, 105.9, 105.7, 105.6, 49.1, 34.9, 31.4, 31.1, 29.3, 19.5.

Example 261: (R)-3-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(pyrrolidin-1-yl)propan-1-one

Compound was prepared analogous manner to Example 32 from (R)-1-(H-imidazol-1-yl)-3-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propan-1-one and isolated as an off-white powder.

1 H NMR (DMSO d6 ): 7.86 (1H, m), 4.45 (1H, quin, J=8.5 Hz), 4.22 (1H, dd, J=11.2, 9.5 Hz), 3.80 (1H, dd, J=11.6, 7.8 Hz), 3.45 (3H, s), 3.37 (3H, m), 3.25 (2H, t, J=6.9 Hz), 3.00 (1H, br dd, J=15.7, 7.9 Hz), 2.72 (2H, m), 2.53 (2H, t, J=7.7 Hz), 1.83 (2H, quin, J=6.7 Hz), 1.74 (2H, m).

13 C NMR (DMSO d6 ): 168.9, 155.8, 146.4, 146.4, 146.3, 146.3, 146.3, 146.3, 146.2, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 144.8, 144.8, 144.7, 144.7, 144.6, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 143.6, 126.7, 120.9, 120.6, 120.4, 120.3, 105.8, 105.7, 105.5, 49.1, 45.7, 45.3, 34.9, 31.5, 31.1, 29.2, 25.5, 23.9, 19.3.

Example 262: (S)-3-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propanamide

Compound was prepared analogous manner to Example 32 from (S)-1-(1H-imidazol-1-yl)-3-(6-(3-chloro-2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propan-1-one and isolated as an off-white solid.

1 H NMR (DMSO d6 ): 7.62 (1H, m), 7.31 (1H, br s), 7.21 (1H, m), 6.86 (1H, br s), 4.42 (1H, quin, J=8.7 Hz), 4.20 (1H, dd, J=9.3, 11.1 Hz), 3.77 (1H, dd, J=11.6, 7.9 Hz), 3.44 (3H, s), 3.32 (1H, m), 2.94 (1H, dd, J=15.7, 8.2 Hz), 2.71 (2H, t, J=7.3 Hz), 2.35 (2H, t, J=7.4 Hz).

13 C NMR (DMSO d6 ): 172.8, 160.1, 160.1, 158.5, 158.5, 156.6, 156.5, 155.8, 155, 154.9, 129.7, 129.7, 126.8, 120.8, 118.8, 118.7, 118.6, 116.1, 116.1, 116, 115.9, 113.3, 113.2, 113.1, 113.1, 49.2, 34.8, 32.5, 31.1, 29.4, 19.8.

Example 263: (R)-3-(6-(2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propanamide

Compound was prepared analogous manner to Example 32 from (R)-1-(H-imidazol-1-yl)-3-(6-(2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propan-1-one and isolated as an off-white solid.

1 H NMR (DMSO d6 ): 7.41 (1H, m), 7.31 (1H, br s), 7.14 (1H, m), 6.87 (1H, br s), 4.39 (1H, quin, J=8.8 Hz), 4.19 (1H, dd, J=10.6, 9.9 Hz), 3.75 (1H, dd, J=11.3, 8.4 Hz), 3.44 (3H, s), 3.31 (1H, br dd, J=15.5, 9.3 Hz), 2.93 (1H, dd, J=15.6, 8.7 Hz), 2.71 (2H, t, J=7.3 Hz), 2.36 (2H, t, J=7.3 Hz).

13 C NMR (DMSO d6 ): 172.9, 161.6, 161.6, 160, 159.9, 155.8, 129.8, 129.8, 129.7, 126.9, 120.8, 116.6, 116.5, 116.3, 112.3, 112.2, 112.1, 112.1, 49.2, 34.5, 32.5, 31.1, 29.6, 19.8.

Example 264: (R)-3-(6-(2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(pyrrolidin-1-yl)propan-1-one

Compound was prepared analogous manner to Example 32 from (R)-1-(H-imidazol-1-yl)-3-(6-(2,6-difluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propan-1-one and isolated as an off-white solid.

1 H NMR (DMSO d6 ): 7.41 (1H, m), 7.14 (2H, m), 4.38 (1H, quin, J=8.8 Hz), 4.19 (1H, m), 3.75 (1H, dd, J=11.2, 8.4 Hz), 3.45 (3H, s), 3.37 (2H, m), 3.32 (1H, m), 3.25 (2H, t, J=6.8 Hz), 2.95 (1H, dd, J=15.6, 8.7 Hz), 2.72 (2H, t, J=7.7 Hz), 2.54 (2H, t, J=7.5 Hz), 1.83 (2H, m), 1.74 (2H, m).

13 C NMR (DMSO d6 ): 168.9, 161.6, 161.6, 160, 159.9, 155.8, 129.8, 129.7, 129.7, 127, 120.9, 116.6, 116.5, 116.3, 112.2, 112.2, 112.1, 49.2, 45.7, 45.3, 34.4, 31.5, 31.1, 29.4, 25.5, 23.9, 19.3.

Example 265: 3-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydrofuran-3-yl)propanamide

Compound was prepared analogous manner to Example 32 from (R)-1-(H-imidazol-1-yl)-3-(6-(2,3,6-trifluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propan-1-one and isolated as a beige powder.

1 H NMR (DMSO d6 ): 8.09 (1H, d, J=6.6 Hz), 7.48 (1H, m), 7.18 (1H, br t, J=9.5 Hz), 4.40 (1H, quin, J=8.6 Hz), 4.20 (1H, dd, J=9.4, 11.5 Hz), 4.19 (1H, m), 3.78 (1H, dd, J=11.4, 7.9 Hz), 3.74-3.66 (2H, m), 3.63 (1H, m), 3.44 (3H, s), 3.38 (1H, dd, J=8.9, 3.6 Hz), 3.33 (1H, m), 2.92 (1H, dd, J=15.6, 8.1 Hz), 2.72 (2H, t, J=7.3 Hz), 2.37 (2H, t, J=7.3 Hz), 2.03 (1H, m), 1.62 (1H, m).

13 C NMR (DMSO d6 ): 170.5, 156.9, 156.9, 155.9, 155.3, 155.3, 149.1, 149, 149, 148.9, 147.5, 147.4, 147.4, 147.3, 145.9, 145.9, 145.8, 145.8, 126.8, 120.6, 119, 118.9, 118.8, 118.7, 116.5, 116.4, 116.4, 116.3, 112, 112, 111.9, 111.9, 111.8, 111.8, 111.8, 111.8, 72.4, 66.2, 49.5, 49.1, 34.7, 32.6, 32.1, 31.1, 29.5, 19.9.

Example 266: (R)-3-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-morpholinopropan-1-one

Compound was prepared analogous manner to Example 32 from (R)-1-(H-imidazol-1-yl)-3-(6-(2,3,6-trifluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propan-1-one and isolated as a cream powder.

1 H NMR (DMSO d6 ): 7.48 (1H, m), 7.18 (1H, t, J=9.4 Hz), 4.40 (1H, quin, J=8.7 Hz), 4.21 (1H, dd, J=9.4, 11.3 Hz), 3.78 (1H, dd, J=11.5, 8.1 Hz), 3.51 (4H, m), 3.45 (3H, s), 3.41 (4H, m), 3.38 (1H, m), 2.98 (1H, dd, J=15.6, 8.4 Hz), 2.72 (2H, m), 2.63 (2H, m).

13 C NMR (DMSO d6 ): 169.6, 157, 156.9, 155.8, 155.3, 155.3, 149.1, 149.1, 149, 149, 147.6, 147.5, 147.5, 147.4, 147.4, 147.4, 147.3, 145.9, 145.8, 126.8, 120.8, 118.9, 118.8, 118.7, 116.5, 116.4, 116.4, 116.3, 112, 112, 112, 111.9, 111.8, 111.8, 111.8, 111.8, 111.8, 66.1, 66, 49.1, 45.1, 41.5, 34.8, 31.1, 29.7, 29.3, 19.6.

Example 267: 1-((S)-2-(hydroxymethyl)pyrrolidin-1-yl)-3-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propan-1-one

Compound was prepared analogous manner to Example 32 from (R)-1-(H-imidazol-1-yl)-3-(6-(2,3,6-trifluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propan-1-one and isolated as a white powder.

1 H NMR (DMSO d6 ): 7.47 (1H, m), 7.18 (1H, br t, J=9.5 Hz), 4.92 (0.35H, t, J=5.7 Hz), 4.72 (0.65H, t, J=5.7 Hz), 4.40 (1H, m), 4.20 (1H, br t, J=10.3 Hz), 3.90 (1H, m), 3.77 (1H, m), 3.46 (0.65H, m), 3.45 (3H, s), 3.42-3.27 (3H, m), 3.26-3.15 (1.35H, m), 2.97 (1H, m), 2.71 (2H, m), 2.68-2.51 (2H, m), 1.94-1.68 (4H, m).

13 C NMR (DMSO d6 ): 169.6, 169.6, 156.9, 156.9, 155.8, 155.8, 155.3, 155.3, 149.1, 149, 147.5, 147.5, 145.9, 145.9, 145.8, 145.8, 126.8, 126.8, 120.9, 120.9, 118.9, 118.8, 118.8, 118.7, 116.5, 116.4, 116.4, 116.3, 112, 112, 112, 111.9, 111.9, 111.8, 111.8, 111.8, 111.7, 62.6, 61, 58.6, 58.5, 49.1, 46.5, 45.3, 34.8, 31.6, 31.3, 31.1, 29.3, 26.6, 23.3, 21.3, 19.2.

Example 268: (S)-3-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(pyridin-2-yl)propanamide

Compound was prepared analogous manner to Example 168 from (S)-3-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propanoic acid and isolated as an off-white solid.

1 H NMR (DMSO d6 ): 10.54 (1H, s), 8.27 (1H, ddd, J=0.7, 1.8, 4.8 Hz), 8.01 (1H, br d, J=8.4 Hz), 7.75 (1H, m), 7.57 (1H, m), 7.12 (1H, m), 7.08 (1H, ddd, J=7.3, 4.9, 1.0 Hz), 4.38 (1H, quin, J=8.5 Hz), 4.17 (1H, dd, J=11.4, 9.4 Hz), 3.74 (1H, dd, J=11.7, 7.6 Hz), 3.47 (3H, s), 3.33 (1H, dd, J=15.8, 9.5 Hz), 2.90 (1H, dd, J=15.6, 7.7 Hz), 2.82 (2H, m), 2.69 (2H, m).

13 C NMR (DMSO d6 ): 170.8, 160, 160, 158.4, 158.3, 156.5, 156.4, 155.9, 154.8, 154.8, 151.8, 147.6, 138.4, 129.6, 129.6, 127.1, 120.3, 119.3, 118.9, 118.8, 118.7, 116, 116, 115.9, 115.9, 113.4, 113.1, 113.1, 113, 113, 49.3, 34.7, 33.8, 31.1, 29.4, 21.6, 19.7.

Example 269: (R)-3-(6-(2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(pyridin-2-yl)propanamide

Compound was prepared analogous manner to Example 168 from (R)-3-(6-(2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propanoic acid and isolated as an off-white solid.

1 H NMR (DMSO d6 ): 10.52 (1H, s), 8.28 (1H, ddd, J=0.9, 1.9, 4.9 Hz), 8.03 (1H, br d, J=8.2 Hz), 7.75 (1H, m), 7.38 (1H, m), 7.09 (1H, ddd, J=1.0, 4.9, 7.4 Hz), 7.06 (2H, m), 4.36 (1H, quin, J=8.7 Hz), 4.17 (1H, dd, J=9.7, 11.3 Hz), 3.73 (1H, dd, J=11.4, 8.0 Hz), 3.48 (3H, s), 3.31 (1H, dd, J=15.6, 9.4 Hz), 2.90 (1H, dd, J=15.7, 8.4 Hz), 2.82 (2H, m), 2.70 (2H, m).

13 C NMR (DMSO d6 ): 170.8, 161.5, 161.4, 159.9, 159.8, 155.9, 151.9, 147.8, 138.2, 129.7, 129.7, 129.6, 127.2, 120.3, 119.3, 116.6, 113.3, 112.1, 112.1, 112, 112, 49.4, 34.3, 33.8, 31.1, 29.6, 19.7.

Example 270: (R)—N-(cyanomethyl)-3-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propanamide

Compound was prepared analogous manner to Example 34 from (R)-3-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propanoic acid and isolated as a cream powder.

1 H NMR (DMSO d6 ): 8.60 (1H, t, J=5.6 Hz), 7.47 (1H, m), 7.17 (1H, t, J=9.6 Hz), 4.41 (1H, quin, J=8.6 Hz), 4.19 (1H, dd, J=9.7, 11.3 Hz), 4.11 (2H, m), 3.77 (1H, dd, J=11.5, 8.0 Hz), 3.44 (3H, s), 3.31 (1H, dd, J=9.2, 15.5 Hz), 2.93 (1H, dd, J=15.6, 8.1 Hz), 2.76 (2H, t, J=7.3 Hz), 2.45 (2H, t, J=7.3 Hz).

13 C NMR (DMSO d6 ): 171.5, 156.9, 156.9, 156, 155.3, 155.3, 149.1, 149, 149, 148.9, 147.5, 147.5, 147.4, 147.4, 147.3, 147.3, 145.9, 145.9, 145.8, 145.8, 127, 120.2, 118.9, 118.8, 118.8, 118.7, 117.6, 116.5, 116.4, 116.4, 116.3, 112, 111.9, 111.9, 111.9, 111.8, 111.8, 111.8, 111.7, 49.2, 34.7, 32.4, 31.1, 29.3, 27, 19.6.

Example 271: 2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-cyclopentylacetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a beige solid.

1 H NMR (DMSO d6 ): 8.12 (1H, br d, J=7.0 Hz), 7.64 (1H, td, J=8.6, 5.6 Hz), 7.21 (1H, td, J=1.0, 9.0 Hz), 4.10 (1H, d, J=12.0 Hz), 4.00 (1H, sxt, J=6.8 Hz), 3.79 (1H, d, J=12.2 Hz), 3.47 (2H, m), 3.35 (3H, s), 2.78 (1H, dd, J=8.4, 4.4 Hz), 1.80 (2H, m), 1.69 (1H, dd, J=8.2, 5.6 Hz), 1.63 (2H, m), 1.50 (2H, m), 1.39 (2H, m), 1.25 (1H, t, J=4.9 Hz).

13 C NMR (DMSO d6 ): 167.1, 161.3, 161.2, 159.6, 159.6, 157.8, 157.8, 156.7, 156.2, 156.1, 130.5, 130.3, 130.2, 117.1, 116.9, 116.8, 116.7, 115.8, 115.7, 115.6, 115.6, 112.9, 112.9, 112.8, 112.8, 52.2, 50.5, 32.2, 32.2, 31.4, 31.2, 25.6, 23.4, 21.7, 21.3.

Example 272: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-cyclopentylacetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a beige solid.

1 H NMR (DMSO d6 ): 8.10 (1H, d, J=7.2 Hz), 7.58 (1H, dd, J=2.5, 6.7 Hz), 7.56 (1H, ddd, J=6.5, 4.4, 2.2 Hz), 7.24 (1H, dd, J=10.1, 8.8 Hz), 4.14 (1H, d, J=12.0 Hz), 4.00 (1H, sxt, J=6.8 Hz), 3.85 (1H, d, J=12.0 Hz), 3.47 (2H, m), 3.34 (3H, s), 2.87 (1H, dd, J=8.4, 4.1 Hz), 1.81 (2H, m), 1.70 (1H, dd, J=8.3, 5.4 Hz), 1.63 (2H, m), 1.51 (2H, m), 1.39 (2H, m), 1.13 (1H, t, J=4.8 Hz).

13 C NMR (DMSO d6 ): 167.1, 161.8, 160.1, 156.8, 133.1, 133, 132.4, 132.3, 130.9, 129.2, 129.1, 118, 117.8, 116.3, 116.2, 116.2, 52.4, 50.5, 32.2, 32.2, 31.5, 31.4, 31.2, 23.4, 22.1, 20.7.

Example 273: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-cyclopentylacetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as an off-white solid.

1 H NMR (DMSO d6 ): 8.11 (1H, d, J=7.2 Hz), 7.46 (1H, dd, J=6.5, 2.7 Hz), 7.43 (1H, ddd, J=8.7, 4.3, 2.6 Hz), 7.30 (1H, dd, J=9.9, 8.9 Hz), 4.14 (1H, d, J=12.0 Hz), 4.00 (1H, sxt, J=6.8 Hz), 3.85 (1H, d, J=12.0 Hz), 3.47 (2H, d, J=5.6 Hz), 3.35 (3H, s), 2.87 (1H, dd, J=8.3, 4.2 Hz), 1.81 (2H, m), 1.70 (1H, dd, J=8.3, 5.4 Hz), 1.63 (2H, m), 1.51 (2H, m), 1.39 (2H, dq, J=12.9, 6.4 Hz), 1.13 (1H, t, J=4.8 Hz).

13 C NMR (DMSO d6 ): 167.1, 161.3, 159.6, 156.8, 130.9, 130.2, 130.2, 129.4, 129.3, 128.8, 128.7, 128.3, 117.6, 117.4, 116.3, 52.4, 50.6, 32.2, 32.2, 31.5, 31.4, 31.2, 23.4, 22.1, 20.8.

Example 274:2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a beige solid.

1 H NMR (DMSO d6 ): 8.42 (1H, d, J=6.6 Hz), 7.64 (1H, td, J=8.6, 5.8 Hz), 7.21 (1H, dt, J=1.0, 9.1 Hz), 4.25 (1H, m), 4.10 (1H, d, J=12.0 Hz), 3.79 (2H, m), 3.74 (1H, dd, J=8.9, 5.9 Hz), 3.68 (1H, td, J=8.2, 5.6 Hz), 3.50 (2H, m), 3.48 (1H, dd, J=3.6, 8.9 Hz), 3.35 (3 H, s), 2.78 (1H, dd, J=8.4, 4.4 Hz), 2.09 (1H, dq, J=12.7, 7.6 Hz), 1.73 (1H, m), 1.69 (1H, dd, J=8.4, 5.6 Hz), 1.26 (1H, t, J=4.9 Hz).

13 C NMR (DMSO d6 ): 167.6, 161.3, 161.2, 159.6, 159.6, 157.8, 157.8, 156.8, 156.2, 156.1, 130.6, 130.3, 130.2, 117.1, 116.9, 116.8, 116.5, 115.8, 115.7, 115.6, 115.6, 112.9, 112.9, 112.8, 112.8, 72.3, 66.3, 52.2, 49.8, 32.1, 31.5, 31, 25.6, 21.7, 21.2.

Example 275: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic acid

Compound was prepared in an analogous manner to Example 229 from tert-butyl (1S,5R)-1-(5-bromo-2-fluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate and isolated as a beige solid.

1 H NMR (DMSO d6 ): 12.79 (1H, br s), 7.58 (1H, dd, J=6.7, 2.6 Hz), 7.56 (1H, m), 7.24 (1H, dd, J=10.1, 8.7 Hz), 4.16 (1H, d, J=12.0 Hz), 3.86 (1H, d, J=12.0 Hz), 3.73 (2H, m), 3.35 (3H, s), 2.97 (1H, dd, J=8.4, 4.3 Hz), 1.70 (1H, dd, J=8.4, 5.4 Hz), 1.13 (1H, t, J=4.8 Hz).

13 C NMR (DMSO d6 ): 170.9, 161.8, 160.2, 157.1, 133, 133, 132.4, 132.3, 131.2, 129.1, 129, 118, 117.8, 116.2, 116.2, 115.2, 52.5, 52.5, 31.5, 31.4, 29.7, 22.1, 20.5.

Example 276: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic Acid

Compound was prepared in an analogous manner to Example 229 from tert-butyl (1S,5R)-1-(5-chloro-2-fluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate and isolated as a beige solid.

1 H NMR (DMSO d6 ): 12.77 (1H, m), 7.47 (1H, dd, J=6.5, 2.7 Hz), 7.43 (1H, ddd, J=8.7, 4.3, 2.8 Hz), 7.30 (1H, dd, J=9.9, 8.9 Hz), 4.16 (1H, d, J=12.0 Hz), 3.87 (1H, d, J=12.0 Hz), 3.73 (2H, m), 3.36 (3H, s), 2.97 (1H, dd, J=8.4, 4.2 Hz), 1.70 (1H, dd, J=8.4, 5.4 Hz), 1.13 (1H, t, J=4.8 Hz).

13 C NMR (DMSO d6 ): 170.9, 161.3, 159.6, 157.1, 131.2, 130.2, 130.1, 129.4, 129.3, 128.7, 128.6, 128.3, 128.3, 117.6, 117.4, 115.2, 52.4, 52.4, 31.6, 31.4, 29.7, 22.1, 20.6.

Example 277: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydro-2H-pyran-3-yl)acetamide

Compound was prepared analogous manner to Example 34 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as an off-white solid.

1 H NMR (DMSO d6 ): 8.15 (1H, br d, J=7.3 Hz), 7.58 (1H, dd, J=6.7, 2.6 Hz), 7.56 (1H, ddd, J=2.5, 4.5, 8.5 Hz), 7.24 (1H, dd, J=8.8, 10.1 Hz), 4.14 (1H, d, J=12.0 Hz), 3.85 (1H, d, J=12.2 Hz), 3.73-3.67 (2H, m), 3.65 (1H, m), 3.52 (2H, m), 3.37 (1H, m), 3.14 (1H, m), 3.34 (3H, s), 2.88 (1H, dd, J=8.4, 4.3 Hz), 1.83 (1H, m), 1.70 (1H, dd, J=8.3, 5.4 Hz), 1.69 (1H, m), 1.49 (2H, m), 1.12 (1H, t, J=4.8 Hz).

13 C NMR (DMSO d6 ): 167.4, 161.8, 160.1, 156.8, 133.1, 133, 132.4, 132.3, 130.9, 129.2, 129.1, 118, 117.8, 116.2, 116.2, 70.1, 67, 52.4, 45.2, 31.5, 31.4, 31.1, 28.6, 23.9, 22.1, 20.7.

Example 278: 2-((R)-2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydro-2H-pyran-3-yl)acetamide

Compound was prepared analogous manner to Example 34 from (R)-2-(2-methyl-3-thioxo-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as an off-white powder.

1 H NMR (DMSO d6 ): 8.13 (1H, br d, J=7.3 Hz), 7.85 (1H, m), 4.48 (1H, quin, J=8.5 Hz), 4.24 (1H, dd, J=11.4, 9.2 Hz), 3.84 (1H, dd, J=11.7, 7.7 Hz), 3.72-3.59 (3H, m), 3.45 (2H, s), 3.40 (3H, s), 3.36 (1H, m), 3.30 (1H, dd, J=9.4, 16.0 Hz), 3.12 (1H, m), 2.92 (1H, dd, J=15.9, 7.8 Hz), 1.80 (1H, m), 1.66 (1H, m), 1.46 (2H, m).

13 C NMR (DMSO d6 ): 167.3, 156.2, 146.4, 146.3, 146.3, 145.4, 145.3, 145.3, 145.3, 145.2, 144.9, 144.8, 144.8, 144.7, 144.7, 144.7, 144.7, 144.6, 144.6, 144.6, 143.8, 143.7, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 128.2, 120.5, 120.4, 120.3, 116.5, 105.9, 105.7, 105.6, 70.1, 67, 49.4, 45.1, 34.9, 31.5, 31.2, 29.1, 28.5, 23.8.

Example 279: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a beige solid.

1 H NMR (DMSO d6 ): 8.40 (1H, d, J=6.6 Hz), 7.58 (1H, dd, J=6.6, 2.5 Hz), 7.56 (1H, ddd, J=8.6, 4.5, 2.6 Hz), 7.24 (1H, dd, J=10.1, 8.8 Hz), 4.26 (1H, m), 4.14 (1H, d, J=12.0 Hz), 3.85 (1H, d, J=12.0 Hz), 3.79 (1H, q, J=7.3 Hz), 3.74 (1H, dd, J=8.9, 5.9 Hz), 3.68 (1H, td, J=8.2, 5.6 Hz), 3.56-3.45 (3H, m), 3.35 (3H, s), 2.88 (1H, dd, J=8.4, 4.3 Hz), 2.10 (1H, m), 1.74 (1H, m), 1.70 (1H, dd, J=8.4, 5.3 Hz), 1.13 (1H, t, J=4.8 Hz).

13 C NMR (DMSO d6 ): 167.7, 161.8, 160.1, 156.8, 133.1, 133, 132.4, 132.3, 131, 129.2, 129.1, 118, 117.8, 116.2, 116.2, 116.1, 72.3, 66.3, 52.4, 49.8, 32.1, 31.5, 31.4, 31, 22.1, 20.7.

Example 280: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a beige solid.

1 H NMR (DMSO d6 ): 7.59 (1H, dd, J=6.7, 2.6 Hz), 7.56 (1H, ddd, J=8.7, 4.4, 2.6 Hz), 7.53 (1H, br s), 7.24 (1H, dd, J=10.0, 8.8 Hz), 7.14 (1H, br s), 4.14 (1H, d, J=11.9 Hz), 3.85 (1H, d, J=12.0 Hz), 3.49 (2H, m), 3.35 (3H, s), 2.93 (1H, dd, J=8.4, 4.1 Hz), 1.67 (1H, dd, J=8.3, 5.4 Hz), 1.17 (1H, t, J=4.8 Hz).

13 C NMR (DMSO d6 ): 170, 161.8, 160.1, 156.8, 133, 133, 132.3, 132.3, 131.1, 129.2, 129.1, 118, 117.8, 116.2, 116.2, 52.5, 52.4, 31.5, 31.4, 30.9, 22.1, 20.6.

Example 281: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a beige solid.

1 H NMR (DMSO d6 ): 8.41 (1H, br d, J=6.6 Hz), 7.47 (1H, dd, J=6.6, 2.6 Hz), 7.43 (1H, ddd, J=8.7, 4.3, 2.8 Hz), 7.30 (1H, dd, J=8.9, 9.8 Hz), 4.26 (1H, m), 4.14 (1H, d, J=12.0 Hz), 3.85 (1H, d, J=12.0 Hz), 3.79 (1H, q, J=7.5 Hz), 3.74 (1H, dd, J=8.9, 6.0 Hz), 3.68 (1H, m), 3.56-3.46 (3H, m), 3.35 (3H, s), 2.88 (1H, dd, J=8.3, 4.2 Hz), 2.10 (1H, dq, J=12.7, 7.6 Hz), 1.74 (1H, m), 1.70 (1H, dd, J=8.3, 5.4 Hz), 1.13 (1H, t, J=4.8 Hz).

13 C NMR (DMSO d6 ): 167.7, 161.3, 159.6, 156.8, 131, 130.2, 130.2, 129.4, 129.3, 128.8, 128.6, 128.3, 128.3, 117.6, 117.4, 116.1, 72.3, 66.3, 52.4, 49.8, 32.1, 31.6, 31.5, 31, 22.1, 20.7.

Example 282: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as an off-white solid.

1 H NMR (DMSO d6 ): 7.53 (1H, br s), 7.48 (1H, dd, J=6.5, 2.6 Hz), 7.43 (1H, ddd, J=8.7, 4.3, 2.6 Hz), 7.30 (1H, dd, J=9.8, 9.0 Hz), 7.14 (1H, br s), 4.14 (1H, d, J=12.0 Hz), 3.85 (1H, d, J=12.0 Hz), 3.49 (2H, m), 3.35 (3H, s), 2.93 (1H, dd, J=8.4, 4.1 Hz), 1.68 (1H, dd, J=8.4, 5.3 Hz), 1.17 (1H, m).

13 C NMR (DMSO d6 ): 170, 161.3, 159.6, 156.8, 131.1, 130.2, 130.2, 129.4, 129.3, 128.8, 128.7, 128.3, 128.3, 117.6, 117.4, 116.2, 52.4, 31.5, 31.4, 30.9, 22.1, 20.6.

Example 283: 1-((S)-2-(methoxymethyl)pyrrolidin-1-yl)-2-((R)-2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from (R)-1-(H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as an off-white powder.

1 H NMR (DMSO d6 ): 7.86 (1H, m), 4.48 (1H, quin, J=8.4 Hz), 4.29-4.18 (1.35H, m), 4.04 (0.65H, m), 3.88-3.82 (1H, m), 3.79 (0.65H, m), 3.66 (1.35H, s), 3.54-3.41 (1.65H, m), 3.40 (1H, m), 3.37, 3.36 (3H, 2 s), 3.32-3.23 (3.4H, m), 3.22 (1.95H, s), 2.91 (1H, m), 2.0-1.73 (4H, m).

13 C NMR (DMSO d6 ): 166.9, 166.6, 156.3, 156.1, 146.4, 146.3, 146.3, 146.3, 146.2, 146.2, 145.3, 145.3, 145.2, 145.2, 145.2, 144.8, 144.8, 144.7, 144.6, 144.6, 143.7, 143.7, 143.6, 143.6, 128.1, 128, 120.5, 120.4, 120.3, 116.8, 116.3, 105.9, 105.7, 105.6, 73.8, 71.6, 58.5, 58.3, 56.3, 56.2, 49.4, 46.8, 45.4, 34.9, 31.5, 30.6, 29.8, 29, 29, 28.2, 27.1, 23.5, 21.5.

Example 284: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-isopropylacetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as an off-white solid.

1 H NMR (DMSO d6 ): 8.01 (1H, br d, J=7.6 Hz), 7.58 (1H, dd, J=6.7, 2.6 Hz), 7.57 (1H, ddd, J=2.6, 4.5, 8.5 Hz), 7.24 (1H, dd, J=10.1, 8.9 Hz), 4.14 (1H, d, J=12.0 Hz), 3.90-3.80 (2H, m), 3.46 (2H, m), 3.35 (3H, s), 2.88 (1H, dd, J=8.3, 4.2 Hz), 1.70 (1H, dd, J=8.3, 5.4 Hz), 1.13 (1H, t, J=4.8 Hz), 1.07 (6H, d, J=6.6 Hz).

13 C NMR (DMSO d6 ): 166.7, 161.8, 160.1, 156.8, 133.1, 133, 132.3, 132.3, 130.9, 129.2, 129.1, 118, 117.8, 116.3, 116.2, 116.2, 52.4, 52.4, 40.7, 31.5, 31.4, 31.2, 22.3, 22.3, 22, 20.7.

Example 285: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(1,3,4-thiadiazol-2-yl)acetamide

Compound was prepared analogous manner to Example 258 from (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as an off-white solid.

1 H NMR (DMSO d6 ): 9.17 (1H, s), 7.61 (1H, m), 7.21 (1H, m), 4.45 (1H, quin, J=8.5 Hz), 4.24 (1H, dd, J=11.4, 9.5 Hz), 3.90 (2H, m), 3.82 (1H, dd, J=11.6, 7.8 Hz), 3.42 (3H, s), 3.31 (1H, m), 2.92 (1H, dd, J=16.0, 8.1 Hz).

13 C NMR (DMSO d6 ): 167.6, 160.2, 160.1, 158.7, 158.5, 158.5, 156.6, 156.5, 154.9, 154.9, 148.9, 129.7, 129.7, 129.3, 118.8, 118.6, 118.5, 116.1, 116.1, 116, 115.9, 114.7, 113.3, 113.2, 113.1, 113.1, 49.6, 34.7, 31.6, 30.9, 29.1.

Example 286: (R)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(oxazol-2-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(H-imidazol-1-yl)-2-(6-(2,3,6-trifluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a light cream powder.

1 H NMR (DMSO d6 ): 1.45 (1H, br s), 7.87 (1H, s), 7.47 (1H, m), 7.18 (1H, m), 7.10 (1H, s), 4.44 (1H, quin, J=8.6 Hz), 4.25 (1H, dd, J=9.6, 11.2 Hz), 3.83 (1H, dd, J=11.5, 8.0 Hz), 3.79 (2H, br s), 3.41 (3H, s), 3.33 (1H, m), 2.94 (1H, dd, J=15.8, 8.2 Hz).

13 C NMR (DMSO d6 ): 166.7, 157, 156.9, 156.5, 155.3, 155.3, 155.3, 153, 149.1, 149, 149, 149, 148.9, 147.5, 147.5, 147.5, 147.4, 147.4, 147.4, 147.4, 147.3, 145.9, 145.9, 145.9, 145.8, 136.2, 129.1, 126.7, 118.8, 118.8, 118.7, 118.7, 118.6, 116.5, 116.5, 116.4, 116.3, 115.1, 112, 112, 112, 111.8, 111.8, 111.8, 49.5, 34.7, 31.6, 31.4, 29.1.

Example 287: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(pyridin-4-yl)acetamide Hydrochloride

Compound was prepared analogous manner to Example 168 from (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as an off-white solid.

1 H NMR (DMSO d6 ): 12.16 (1H, s), 8.71 (2H, d, J=7.2 Hz), 8.13 (2H, d, J=7.2 Hz), 7.62 (1H, m), 7.22 (1H, m), 4.46 (1H, quin, J=8.5 Hz), 4.25 (1H, dd, J=9.6, 11.3 Hz), 3.97 (2H, m), 3.83 (1H, dd, J=11.6, 7.8 Hz), 3.45 (3H, s), 3.37 (1H, dd, J=9.3, 16.0 Hz), 2.95 (1H, dd, J=16.0, 7.9 Hz).

13 C NMR (DMSO d6 ): 169.6, 160.1, 160.1, 158.5, 158.4, 156.6, 156.6, 156.5, 154.9, 154.9, 152.6, 142.6, 129.7, 129.7, 129.4, 118.8, 118.7, 118.5, 116.1, 116, 115.9, 115.9, 114.7, 114.4, 113.3, 113.2, 113.1, 113.1, 49.6, 34.7, 32.5, 31.7, 29.3.

Example 288: 3-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydro-2H-pyran-3-yl)propanamide

Compound was prepared analogous manner to Example 34 from (R)-3-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)propanoic acid and isolated as an off-white solid.

1 H NMR (DMSO d6 ): 7.82 (1H, d, J=7.5 Hz), 7.48 (1H, m), 7.18 (1H, br t, J=9.4 Hz), 4.40 (1H, quin, J=8.6 Hz), 4.20 (1H, dd, J=11.2, 9.3 Hz), 3.78 (1H, dd, J=11.6, 7.9 Hz), 3.66-3.58 (3H, m), 3.44 (3H, m), 3.34 (1H, m), 3.32 (1H, m), 3.04 (1H, m), 2.92 (1H, dd, J=15.7, 8.2 Hz), 2.72 (2H, t, J=7.3 Hz), 2.38 (2H, m), 1.74 (1H, m), 1.61 (1H, m), 1.40 (2H, m).

13 C NMR (DMSO d6 ): 170.3, 156.9, 156.9, 156.9, 155.9, 155.5, 155.3, 155.3, 149.1, 149, 149, 148.9, 147.5, 147.5, 147.5, 147.4, 147.4, 147.3, 147.3, 145.9, 145.9, 145.8, 145.8, 126.8, 120.6, 118.9, 118.9, 118.8, 118.7, 116.5, 116.5, 116.4, 116.3, 112, 112, 112, 111.9, 111.8, 111.8, 111.8, 111.8, 70.2, 67, 49.1, 44.8, 34.8, 32.6, 31.1, 29.5, 28.6, 23.8, 19.9.

Example 289: 2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((S)-tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(2,3,6-trifluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a white powder.

1 H NMR (DMSO d6 ): 8.37 (1H, d, J=6.6 Hz), 7.47 (1H, m), 7.18 (1H, br t, J=9.6 Hz), 4.43 (1H, quin, J=8.7 Hz), 4.23 (2H, m), 3.81 (1H, dd, J=10.9, 7.4 Hz), 3.77 (1H, m), 3.72 (1H, dd, J=8.9, 6.0 Hz), 3.66 (1H, td, J=8.2, 5.6 Hz), 3.46 (1H, dd, J=8.9, 3.7 Hz), 3.43 (2H, m), 3.40 (3H, s), 3.29 (1H, dd, J=15.7, 9.4 Hz), 2.90 (1H, dd, J=15.8, 8.3 Hz), 2.08 (1H, m), 1.71 (1H, m).

13 C NMR (DMSO d6 ): 167.6, 157, 156.9, 156.9, 156.9, 156.2, 155.3, 155.3, 149.1, 149, 147.6, 147.5, 147.5, 147.4, 147.4, 147.4, 145.9, 145.9, 145.9, 145.8, 128.4, 118.9, 118.8, 118.7, 118.6, 116.5, 116.4, 116.4, 116.3, 112, 112, 112, 111.9, 111.8, 111.8, 111.8, 111.8, 72.4, 66.3, 49.8, 49.4, 34.7, 32, 31.5, 31.1, 29.1.

Example 290: (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(pyridin-3-ylmethyl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as an off-white solid.

1 H NMR (DMSO d6 ): 8.67 (1H, br t, J=5.9 Hz), 8.50 (1H, d, J=1.8 Hz), 8.44 (1H, dd, J=4.7, 1.3 Hz), 7.70 (1H, m), 7.62 (1H, m), 7.37 (1H, dd, J=7.8, 4.8 Hz), 7.22 (1H, m), 4.41 (1H, quin, J=8.6 Hz), 4.31 (2H, m), 4.22 (1H, dd, J=9.5, 11.0 Hz), 3.80 (1H, dd, J=11.5, 8.0 Hz), 3.52 (2H, m), 3.38 (3H, m), 3.22 (1H, dd, J=15.8, 9.3 Hz), 2.82 (1H, dd, J=15.8, 8.3 Hz).

13 C NMR (DMSO d6 ): 168, 160.1, 160.1, 158.5, 158.5, 156.6, 156.5, 156.3, 154.9, 154.9, 148.4, 147.7, 135.7, 135, 129.7, 129.7, 128.5, 123.6, 118.6, 118.5, 118.4, 116.1, 116.1, 116, 115.9, 115.9, 113.3, 113.2, 113.1, 113.1, 49.4, 39.8, 34.7, 31.4, 31.2, 29.1.

Example 291: (S)—N-(benzo[d][1,3]dioxol-5-ylmethyl)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 32 from (S)-2-(6-(3-chloro-2,6-difluorophenyl)-2-methyl-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as an off-white solid.

1 H NMR (DMSO d6 ): 8.52 (1H, t, J=5.9 Hz), 7.62 (1H, m), 7.22 (1H, m), 6.81 (2H, m), 6.72 (1H, m), 5.95 (2H, m), 4.41 (1H, quin, J=8.7 Hz), 4.21 (1H, dd, J=9.4, 11.4 Hz), 4.17 (2H, m), 3.79 (1H, dd, J=11.6, 8.1 Hz), 3.49 (2H, m), 3.39 (3H, s), 3.22 (1H, dd, J=15.8, 9.3 Hz), 2.83 (1H, dd, J=15.8, 8.2 Hz).

13 C NMR (DMSO d6 ): 167.6, 160.1, 160.1, 158.5, 158.5, 156.6, 156.5, 156.3, 154.9, 154.9, 147.2, 146.1, 133, 129.7, 129.7, 128.4, 120.6, 118.6, 118.5, 118.4, 116.3, 116.1, 116, 115.9, 115.9, 113.2, 113.2, 113.1, 113.1, 108.1, 108, 100.8, 49.4, 42.2, 34.7, 31.4, 31.3, 29.1.

Example 292: 1-((R)-3-fluoropyrrolidin-1-yl)-2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 34 from (R)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as a white solid.

1 H NMR (DMSO d6 ): 7.47 (1H, m), 7.18 (1H, m), 5.36 (1H, m t, J=52 Hz), 4.44 (1H, m), 4.24 (1H, m), 3.87-3.52 (6H, m), 3.51-3.40 (0.5H, m), 3.37 (3H, s), 3.31-3.24 (1.5H, m), 2.88 (1H, m), 2.29-1.92 (2H, m).

13 C NMR (DMSO d6 ): 166.6, 166.5, 156.9, 156.9, 156.3, 155.3, 155.3, 155.3, 155.3, 149.1, 149, 149, 148.9, 147.5, 147.4, 147.4, 147.4, 147.3, 145.9, 145.9, 145.9, 145.8, 128.3, 128.2, 118.9, 118.8, 118.8, 118.7, 116.5, 116.4, 116.4, 116.3, 116.1, 116, 112, 111.8, 94.2, 93, 92.6, 91.4, 62.8, 54.9, 52.8, 52.6, 52.4, 52.3, 49.4, 43.8, 43.5, 34.7, 32.1, 32, 31.5, 30.5, 30.4, 30.2, 29.1, 29.1.

Example 293: (R)—N-(2-hydroxyethyl)-N-methyl-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(H-imidazol-1-yl)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one and isolated as a cream powder.

1 H NMR (DMSO d6 ): 7.47 (1H, m), 7.18 (1H, br t, J=9.7 Hz), 4.93 (0.6H, t, J=5.3 Hz), 4.67 (0.4H, t, J=5.4 Hz), 4.43 (1H, m), 4.24 (1H, brt, J=10.3 Hz), 3.81 (1H, dd, J=11.6, 8.1 Hz), 3.79 (1.2H, s), 3.71 (0.8H, s), 3.56 (1.2H, q, J=5.3 Hz), 3.47 (0.8H, q, J=5.8 Hz), 3.42 (1.2H, m), 3.35 (0.8H, m), 3.35 (3H, s), 3.32-3.21 (1H, m), 3.06 (1.2H, s), 2.88 (1H, m), 2.84 (1.8H, s).

13 C NMR (DMSO d6 ): 168.3, 167.9, 157, 156.9, 156.2, 156.1, 155.3, 155.3, 155.3, 155.3, 149.1, 149, 149, 149, 148.9, 147.5, 147.5, 147.5, 147.4, 147.4, 147.4, 147.4, 147.3, 145.9, 145.9, 145.9, 145.8, 128.2, 128.1, 118.9, 118.9, 118.8, 118.8, 118.8, 118.7, 118.7, 118.6, 116.9, 116.6, 116.5, 116.4, 116.4, 116.3, 112, 112, 111.9, 111.9, 111.8, 111.8, 111.8, 111.8, 58.5, 58.3, 51.4, 50, 49.4, 36.3, 34.7, 33.2, 31.5, 29.4, 29.1, 29, 29.

Example 294: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-cyclohexylacetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a beige solid.

1 H NMR (DMSO d6 ): 8.01 (1H, d, J=7.8 Hz), 7.58 (1H, dd, J=2.5, 8.9 Hz), 7.55 (1H, m), 7.24 (1H, dd, J=10.1, 8.7 Hz), 4.14 (1H, d, J=12.0 Hz), 3.85 (1H, d, J=12.0 Hz), 3.55 (1H, m), 3.47 (2H, m), 3.34 (3H, s), 2.87 (1H, dd, J=8.3, 4.2 Hz), 1.75 (2H, m), 1.70 (1H, dd, J=5.5, 8.4 Hz), 1.67 (2H, m), 1.55 (1H, m), 1.25 (2H, m), 1.21-1.08 (4H, m).

13 C NMR (DMSO d6 ): 166.6, 161.8, 160.1, 156.8, 133.1, 133, 132.4, 132.3, 130.9, 129.2, 129.1, 118, 117.8, 116.3, 116.2, 116.2, 52.4, 52.4, 47.8, 32.4, 32.3, 31.5, 31.4, 31.2, 25.2, 24.5, 22, 20.7.

Example 295: 2-((R)-2-methyl-3-thioxo-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N—((S)-tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as an off-white powder.

1 H NMR (DMSO d6 ): 8.37 (1H, br d, J=6.6 Hz), 7.85 (1H, m), 4.48 (1H, quin, J=8.5 Hz), 4.23 (2H, m), 3.84 (1H, dd, J=11.6, 7.6 Hz), 3.78 (1H, q, J=7.3 Hz), 3.72 (1H, dd, J=8.9, 6.0 Hz), 3.66 (1H, td, J=8.2, 5.6 Hz), 3.46 (1H, dd, J=9.0, 3.6 Hz), 3.43 (2H, m), 3.40 (3H, m), 3.31 (1H, dd, J=9.2, 15.8 Hz), 2.93 (1H, dd, J=16.0, 7.9 Hz), 2.08 (1H, m), 1.71 (1H, m).

13 C NMR (DMSO d6 ): 167.6, 156.2, 146.4, 146.4, 146.3, 146.3, 146.3, 146.2, 145.3, 145.3, 145.3, 145.2, 145.2, 144.8, 144.7, 144.6, 143.7, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 128.2, 120.4, 116.4, 105.9, 105.7, 105.6, 72.4, 66.3, 49.8, 49.4, 34.9, 32, 31.5, 31.1, 29.1.

Example 296: 1-((S)-2-(fluoromethyl)pyrrolidin-1-yl)-2-((R)-2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 34 from (R)-2-(2-methyl-3-thioxo-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as a white solid.

1 H NMR (DMSO d6 ): 7.47 (1H, m), 7.18 (1H, br t, J=9.6 Hz), 4.53-4.30 (3.25H, m), 4.24 (1H, m), 4.13 (0.75H, m), 3.82 (1.25H, m), 3.70 (1.5H, s), 3.70 (0.25H, m), 3.56-3.42 (1.75H, m), 3.37, 3.36 (3H, 2 s), 3.32-3.24 (1.25H, m), 2.89 (1H, m), 2.05-1.77 (4H, m).

13 C NMR (DMSO d6 ): 167.1, 167, 156.9, 156.9, 156.3, 156.2, 155.3, 155.3, 155.3, 149.1, 149, 149, 148.9, 147.5, 147.5, 147.4, 147.3, 147.3, 145.9, 145.9, 145.9, 145.8, 128.3, 128.3, 118.9, 118.8, 118.8, 118.7, 116.5, 116.5, 116.4, 116.4, 116.3, 116.1, 112, 112, 111.9, 111.9, 111.8, 111.8, 111.8, 111.8, 84.6, 83.5, 83.1, 82, 56.4, 56.3, 56.2, 56.1, 49.5, 46.9, 45.7, 34.8, 34.7, 31.5, 30.5, 29.7, 29.7, 29.1, 27.3, 27.3, 26.5, 26.5, 23.8, 21.5.

Example 297: (R)-2-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as an off-white powder.

1 H NMR (DMSO d6 ): 8.12 (1H, d, J=7.6 Hz), 7.86 (1H, m), 4.48 (1H, quin, J=8.5 Hz), 4.24 (1H, dd, J=11.6, 9.2 Hz), 3.84 (1H, dd, J=7.6, 11.7 Hz), 3.81 (2H, m), 3.75 (1H, m), 3.42 (2H, s), 3.40 (3H, s), 3.36-3.28 (3H, m), 2.93 (1H, dd, J=15.8, 7.9 Hz), 1.69 (2H, m), 1.38 (2H, m).

13 C NMR (DMSO d6 ): 166.8, 156.2, 146.4, 146.3, 146.3, 146.3, 146.2, 146.2, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 144.8, 144.8, 144.7, 144.7, 144.7, 144.6, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 128.2, 120.5, 120.4, 120.3, 116.5, 105.9, 105.7, 105.6, 65.8, 49.4, 45.2, 34.9, 32.4, 32.4, 31.5, 31.3, 29.1.

Example 298: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a beige solid.

1 H NMR (DMSO d6 ): 8.80 (1H, t, J=6.3 Hz), 7.58 (1H, dd, J=2.5, 6.7 Hz), 7.56 (1H, ddd, J=6.5, 4.4, 2.2 Hz), 7.24 (1H, dd, J=10.0, 8.8 Hz), 4.15 (1H, d, J=12.0 Hz), 3.95 (2H, m), 3.86 (1H, d, J=12.0 Hz), 3.64 (2H, m), 3.34 (3H, s), 2.91 (1H, dd, J=8.4, 4.3 Hz), 1.69 (1H, dd, J=8.3, 5.4 Hz), 1.15 (1H, t, J=4.8 Hz).

13 C NMR (DMSO d6 ): 168.9, 161.8, 160.1, 157.1, 133, 133, 132.4, 132.3, 131.4, 129.1, 129, 127.5, 125.6, 123.8, 121.9, 118, 117.8, 116.2, 116.2, 115.3, 52.5, 52.4, 31.5, 31.3, 30.8, 22.8, 22, 20.6.

Example 299: (R)-2-(2-methyl-6-(2,3,6-trifluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(H-imidazol-1-yl)-2-(6-(2,3,6-trifluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazol-1-yl)ethanone and isolated as a white powder.

1 H NMR (DMSO d6 ): 8.12 (1H, d, J=7.6 Hz), 7.47 (1H, m), 7.18 (1H, br t, J=9.6 Hz), 4.43 (1H, quin, J=8.6 Hz), 4.23 (1H, dd, J=9.7, 11.3 Hz), 3.79 (3H, m), 3.75 (1H, m), 3.42 (2H, m), 3.40 (3H, s), 3.33 (2H, m), 3.29 (1H, dd, J=9.3, 15.7 Hz), 2.90 (1H, dd, J=15.7, 8.2 Hz), 1.69 (2H, m d), 1.38 (2H, m q).

13 C NMR (DMSO d6 ): 166.8, 156.9, 156.9, 156.2, 155.3, 155.3, 155.3, 155.3, 149.1, 149, 149, 148.9, 147.5, 147.5, 147.4, 147.4, 147.4, 147.3, 145.9, 145.9, 145.9, 145.8, 145.8, 128.3, 118.9, 118.8, 118.8, 118.7, 116.5, 116.4, 116.4, 116.3, 112, 112, 111.9, 111.9, 111.8, 111.8, 111.8, 111.8, 65.8, 49.4, 45.2, 34.7, 32.4, 31.5, 31.3, 29.2.

Example 300: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a beige solid.

1 H NMR (DMSO d6 ): 8.80 (1H, t, J=6.3 Hz), 7.46 (1H, dd, J=6.5, 2.7 Hz), 7.43 (1H, ddd, J=8.8, 4.4, 2.7 Hz), 7.30 (1H, dd, J=9.9, 8.7 Hz), 4.15 (1H, d, J=12.0 Hz), 3.95 (2H, m), 3.86 (1H, d, J=12.0 Hz), 3.64 (2H, m), 3.34 (3H, s), 2.91 (1H, dd, J=8.4, 4.3 Hz), 1.69 (1H, dd, J=8.4, 5.3 Hz), 1.16 (1H, t, J=4.8 Hz).

13 C NMR (DMSO d6 ): 168.9, 161.3, 159.6, 157.1, 131.4, 130.2, 130.2, 129.4, 129.3, 128.7, 128.6, 128.3, 128.3, 127.5, 125.6, 123.8, 121.9, 117.6, 117.4, 115.3, 52.4, 52.4, 39.9, 31.5, 31.3, 30.8, 22, 20.6.

Example 301: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydro-2H-pyran-3-yl)acetamide

Compound was prepared analogous manner to Example 34 from 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)acetic acid and isolated as a beige solid.

1 H NMR (DMSO d6 ): 8.15 (1H, d, J=7.3 Hz), 7.47 (1H, dd, J=6.5, 2.6 Hz), 7.43 (1H, ddd, J=8.7, 4.3, 2.8 Hz), 7.30 (1H, dd, J=10.0, 8.8 Hz), 4.14 (1H, d, J=12.0 Hz), 3.85 (1H, d, J=12.0 Hz), 3.70 (2H, m), 3.65 (1H, m), 3.52 (2H, m), 3.38 (1H, m), 3.34 (3H, s), 3.14 (1H, m), 2.88 (1H, dd, J=8.4, 4.1 Hz), 1.83 (1H, m), 1.70 (1H, dd, J=5.5, 8.4 Hz), 1.68 (1H, m), 1.49 (2H, m), 1.13 (1H, t, J=4.8 Hz).

13 C NMR (DMSO d6 ): 167.4, 161.3, 159.6, 156.8, 130.9, 130.2, 130.2, 129.4, 129.3, 128.7, 128.6, 128.3, 128.3, 117.6, 117.4, 116.2, 70.1, 67, 52.4, 52.4, 45.2, 31.5, 31.4, 31.1, 28.6, 23.9, 22.1, 20.7.

Example 302: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-cyclohexylacetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a beige solid.

1 H NMR (DMSO d6 ): 8.01 (1H, d, J=7.8 Hz), 7.46 (1H, dd, J=6.5, 2.6 Hz), 7.43 (1H, ddd, J=8.7, 4.3, 2.7 Hz), 7.30 (1H, dd, J=9.9, 8.9 Hz), 4.14 (1H, d, J=12.0 Hz), 3.85 (1H, d, J=12.0 Hz), 3.55 (1H, m), 3.48 (2H, m), 3.35 (3H, s), 2.88 (1H, dd, J=8.3, 4.2 Hz), 1.75 (2H, br d, J=11.2 Hz), 1.70 (1H, dd, J=5.4, 8.3 Hz), 1.69 (2H, m), 1.55 (1H, m), 1.25 (2H, m), 1.15 (4H, m). 166.6, 161.3, 159.6, 156.8, 130.9, 130.2, 130.2, 129.4, 129.3, 128.8, 128.6, 128.3, 128.3, 117.6, 117.4, 116.3, 52.4, 52.4, 47.8, 32.4, 32.3, 31.5, 31.4, 31.2, 25.2, 24.5, 22, 20.8.

Example 303: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-isopropylacetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a grey solid.

1 H NMR (DMSO d6 ): 8.02 (1H, d, J=7.6 Hz), 7.47 (1H, dd, J=6.5, 2.7 Hz), 7.43 (1H, ddd, J=8.7, 4.4, 2.7 Hz), 7.30 (1H, dd, J=10.0, 8.8 Hz), 4.14 (1H, d, J=12.0 Hz), 3.85 (2H, m), 3.46 (2H, d, J=7.3 Hz), 3.35 (3H, s), 2.88 (1H, dd, J=8.4, 4.2 Hz), 1.70 (1H, dd, J=8.4, 5.4 Hz), 1.14 (1H, t, J=4.8 Hz), 1.07 (6H, d, J=6.6 Hz).

13 C NMR (DMSO d6 ): 166.7, 161.3, 159.6, 156.8, 130.9, 130.2, 130.2, 129.4, 129.3, 128.8, 128.7, 128.3, 128.3, 117.6, 117.4, 116.3, 52.4, 52.4, 40.7, 31.5, 31.4, 31.2, 22.3, 22.3, 22.1, 20.7.

Example 304: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(cyanomethyl)acetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a beige solid.

1 H NMR (DMSO d6 ): 8.77 (1H, t, J=5.6 Hz), 7.47 (1H, dd, J=6.5, 2.6 Hz), 7.43 (1H, ddd, J=8.7, 4.3, 2.8 Hz), 7.30 (1H, dd, J=9.8, 8.9 Hz), 4.18 (2H, d, J=5.6 Hz), 4.16 (1H, d, J=12.0 Hz), 3.87 (1H, d, J=12.0 Hz), 3.63 (2H, m), 3.34 (3H, s), 2.92 (1H, dd, J=8.4, 4.3 Hz), 1.68 (1H, dd, J=8.3, 5.4 Hz), 1.18 (1H, t, J=4.8 Hz).

13 C NMR (DMSO d6 ): 168.7, 161.2, 159.6, 157.1, 131.4, 130.2, 130.1, 129.4, 129.3, 128.7, 128.6, 128.3, 128.3, 117.6, 117.5, 117.4, 115.1, 52.4, 31.6, 31.3, 30.7, 27.3, 22.1, 20.6.

Example 305: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(cyanomethyl)acetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a white solid.

1 H NMR (DMSO d6 ): 8.77 (1H, t, J=5.6 Hz), 7.59 (1H, dd, J=6.7, 2.6 Hz), 7.56 (1H, ddd, J=8.6, 4.5, 2.6 Hz), 7.24 (1H, dd, J=8.7, 10.2 Hz), 4.18 (2H, d, J=5.6 Hz), 4.15 (1H, d, J=12.0 Hz), 3.86 (1H, d, J=12.0 Hz), 3.63 (2H, m), 3.34 (3H, s), 2.92 (1H, dd, J=8.4, 4.2 Hz), 1.68 (1H, dd, J=8.4, 5.4 Hz), 1.18 (1H, t, J=4.8 Hz).

13 C NMR (DMSO d6 ): 168.7, 161.8, 160.1, 157.1, 133, 133, 132.4, 132.3, 131.4, 129.1, 129, 118, 117.8, 117.5, 116.2, 116.2, 115.1, 52.5, 31.5, 31.3, 30.7, 27.3, 22.1, 20.6.

Example 306: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N—((S)-tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a light beige solid.

1 H NMR (DMSO d6 ): 8.39 (1H, br d, J=6.6 Hz), 7.47 (1H, dd, J=6.5, 2.7 Hz), 7.43 (1H, ddd, J=8.7, 4.3, 2.7 Hz), 7.30 (1H, dd, J=9.1, 9.9 Hz), 4.26 (1H, m), 4.15 (1H, d, J=12.0 Hz), 3.86 (1H, d, J=12.0 Hz), 3.80 (1H, q, J=7.3 Hz), 3.74 (1H, dd, J=9.0, 5.9 Hz), 3.67 (1H, td, J=8.2, 5.6 Hz), 3.51 (2H, m), 3.49 (1H, dd, J=3.6, 9.0 Hz), 3.34 (3H, s), 2.89 (1H, dd, J=8.3, 4.2 Hz), 2.10 (1H, dq, J=12.7, 7.6 Hz), 1.75 (1H, m), 1.70 (1H, dd, J=8.3, 5.4 Hz), 1.13 (1H, t, J=4.8 Hz).

13 C NMR (DMSO d6 ): 167.7, 161.3, 159.6, 156.8, 131, 130.2, 130.2, 129.4, 129.3, 128.8, 128.6, 128.3, 128.3, 117.6, 117.4, 116.1, 72.4, 66.3, 52.4, 52.4, 49.8, 32, 31.5, 31.4, 31, 22.1, 20.7.

Example 307: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N—((R)-tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a brown solid.

1 H NMR (DMSO d6 ): 11.66 (1H, s), 8.23 (1H, br d, J=6.6 Hz), 7.56 (3H, m), 7.24 (2H, dd, J=10.1, 8.5 Hz), 4.24 (1H, m), 4.07 (1H, d, J=12.0 Hz), 3.78 (2H, m), 3.74 (1H, dd, J=8.9, 5.9 Hz), 3.67 (1H, td, J=8.2, 5.6 Hz), 3.49 (1H, dd, J=8.9, 3.7 Hz), 3.30 (2H, m), 2.81 (1H, dd, J=8.4, 4.1 Hz), 2.08 (1H, m), 1.75 (1H, m), 1.66 (1H, dd, J=8.3, 5.4 Hz), 1.12 (1H, t, J=4.8 Hz).

13 C NMR (DMSO d6 ): 167.6, 161.8, 160.1, 155.9, 133, 132.3, 132.3, 131.7, 129.3, 129.2, 118, 117.8, 116.2, 113.9, 72.4, 66.3, 51.5, 49.8, 32.2, 32, 31.2, 22.1, 20.7.

Example 308: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N—((S)-tetrahydrofuran-3-yl)acetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a beige solid.

1 H NMR (DMSO d6 ): 8.39 (1H, d, J=6.6 Hz), 7.58 (1H, dd, J=6.6, 2.5 Hz), 7.56 (1H, ddd, J=8.7, 4.5, 2.6 Hz), 7.24 (1H, dd, J=10.1, 8.8 Hz), 4.26 (1H, m), 4.14 (1H, d, J=12.0 Hz), 3.85 (1H, d, J=12.2 Hz), 3.80 (1H, q, J=7.3 Hz), 3.74 (1H, dd, J=8.9, 6.0 Hz), 3.67 (1H, td, J=8.2, 5.6 Hz), 3.51 (2H, m), 3.49 (1H, dd, J=3.7, 9.0 Hz), 3.35 (3H, s), 2.89 (1H, dd, J=8.3, 4.2 Hz), 2.09 (1H, m), 1.75 (1H, m), 1.70 (1H, dd, J=8.3, 5.4 Hz), 1.13 (1H, t, J=4.8 Hz).

13 C NMR (DMSO d6 ): 167.7, 161.8, 160.1, 156.8, 133, 133, 132.3, 132.3, 131, 129.2, 129.1, 118, 117.8, 116.2, 116.2, 116.1, 72.4, 66.3, 52.4, 49.8, 32, 31.5, 31.4, 31, 22.1, 20.7.

Example 309: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(pyrrolidin-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a beige solid.

1 H NMR (DMSO d6 ): 7.46 (1H, dd, J=6.5, 2.6 Hz), 7.43 (1H, ddd, J=8.7, 4.3, 2.8 Hz), 7.30 (1H, dd, J=8.9, 9.8 Hz), 4.15 (1H, d, J=12.0 Hz), 3.86 (1H, d, J=12.0 Hz), 3.72 (2H, m), 3.52 (2H, t, J=6.8 Hz), 3.34 (3H, s), 3.32 (2H, t, J=7.1 Hz), 2.87 (1H, dd, J=8.2, 4.3 Hz), 1.91 (2H, quin, J=6.7 Hz), 1.79 (2H, quin, J=6.8 Hz), 1.69 (1H, dd, J=8.3, 5.4 Hz), 1.12 (1H, t, J=4.8 Hz).

13 C NMR (DMSO d6 ): 166.2, 161.3, 159.6, 156.8, 130.7, 130.2, 130.2, 129.4, 129.3, 128.7, 128.6, 128.3, 128.3, 117.6, 117.4, 116, 52.4, 52.4, 46.1, 45.6, 31.6, 31.5, 30.4, 25.6, 24, 22.1, 20.7.

Example 310:2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(pyrrolidin-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a beige solid.

1 H NMR (DMSO d6 ): 7.43 (2H, m), 7.00 (1H, dd, J=9.8, 8.6 Hz), 4.23 (1H, d, J=12.2 Hz), 3.99 (1H, d, J=12.0 Hz), 3.53 (2H, s), 3.46 (3H, s), 3.43 (4H, m), 2.59 (1H, dd, J=8.3, 4.2 Hz), 1.98 (2H, m), 1.87 (2H, m), 1.61 (1H, dd, J=8.2, 5.6 Hz), 1.15 (1H, m).

13 C NMR (DMSO d6 ): 166.4, 162.7, 161.1, 158.7, 133.8, 133.8, 133, 132.9, 131.4, 129.4, 129.3, 118.2, 118.1, 117.1, 117.1, 116, 53.4, 53.4, 47.4, 46.7, 32.4, 32.3, 32.1, 26.8, 24.9, 22.6, 21.7.

Example 311: 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(piperidin-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as an off-white solid.

1 H NMR (DMSO d6 ): 7.46 (1H, dd, J=6.5, 2.7 Hz), 7.43 (1H, ddd, J=8.7, 4.3, 2.8 Hz), 7.30 (1H, dd, J=10.1, 8.7 Hz), 4.15 (1H, d, J=12.0 Hz), 3.86 (1H, d, J=12.0 Hz), 3.79 (2H, m), 3.51-3.40 (4H, m), 3.32 (3H, s), 2.87 (1H, dd, J=8.4, 4.1 Hz), 1.71 (1H, dd, J=8.3, 5.4 Hz), 1.59 (2H, m), 1.53 (2H, m), 1.45 (2H, m), 1.12 (1H, t, J=4.8 Hz).

13 C NMR (DMSO d6 ): 166.2, 161.3, 159.6, 156.9, 130.6, 130.2, 130.2, 129.4, 129.3, 128.7, 128.6, 128.3, 128.3, 117.6, 117.4, 116.3, 52.4, 52.4, 46.2, 42.3, 31.6, 31.5, 29.1, 26, 25.2, 23.9, 22.1, 20.7.

Example 312: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(piperidin-1-yl)ethan-1-one

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as an off-white solid.

1 H NMR (DMSO d6 ): 7.56 (2H, m), 7.24 (1H, dd, J=10.0, 8.7 Hz), 4.15 (1H, d, J=12.0 Hz), 3.85 (1H, d, J=12.0 Hz), 3.79 (2H, m), 3.46 (4H, m), 3.32 (3H, s), 2.87 (1H, dd, J=8.3, 4.2 Hz), 1.71 (1H, dd, J=8.2, 5.4 Hz), 1.59 (2H, m), 1.53 (2H, m), 1.45 (2H, m), 1.11 (1H, t, J=4.8 Hz).

13 C NMR (DMSO d6 ): 166.2, 161.8, 160.1, 156.9, 133, 133, 132.3, 132.3, 130.6, 129.1, 129, 118, 117.8, 116.3, 116.2, 116.2, 52.4, 52.4, 46.2, 42.3, 31.5, 31.4, 29.1, 26, 25.2, 23.9, 22.1, 20.7.

Example 313:2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)acetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a light beige solid.

1 H NMR (DMSO d6 ): 8.14 (1H, d, J=7.6 Hz), 7.46 (1H, dd, J=6.6, 2.6 Hz), 7.43 (1H, ddd, J=8.7, 4.4, 2.8 Hz), 7.30 (1H, t, J=9.3 Hz), 4.14 (1H, d, J=12.0 Hz), 3.86 (1H, d, J=12.0 Hz), 3.82 (2H, dt, J=11.2, 3.1 Hz), 3.78 (1H, m), 3.50 (2H, m), 3.35 (2H, m), 3.35 (3H, s), 2.88 (1H, dd, J=8.4, 4.3 Hz), 1.71 (3H, m), 1.41 (2H, m), 1.13 (1H, t, J=4.8 Hz).

13 C NMR (DMSO d6 ): 166.9, 161.3, 159.6, 156.8, 130.9, 130.2, 130.2, 129.4, 129.3, 128.7, 128.6, 128.3, 128.3, 117.6, 117.4, 116.2, 65.8, 52.4, 52.4, 45.2, 32.4, 32.4, 31.5, 31.4, 31.2, 22, 21.6, 20.8.

Example 314: 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)acetamide

Compound was prepared analogous manner to Example 32 from 2-((5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-2-methyl-3-thioxo-2,3,5,5a,6,6a-hexahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazol-1-yl)-1-(1H-imidazol-1-yl)ethan-1-one and isolated as a beige solid.

1 H NMR (DMSO d6 ): 8.14 (1H, d, J=7.6 Hz), 7.58 (1H, m), 7.56 (1H, ddd, J=6.5, 4.4, 2.2 Hz), 7.24 (1H, dd, J=10.1, 8.7 Hz), 4.14 (1H, d, J=12.0 Hz), 3.85 (1H, d, J=12.2 Hz), 3.82 (2H, m), 3.77 (1H, m), 3.50 (2H, m), 3.35 (3H, s), 3.34 (2H, m), 2.88 (1H, dd, J=8.4, 4.1 Hz), 1.72 (2H, m), 1.71 (1H, dd, J=5.4, 8.5 Hz), 1.41 (2H, m), 1.13 (1H, t, J=4.8 Hz).

13 C NMR (DMSO d6 ): 166.9, 161.8, 160.1, 156.8, 133.1, 133, 132.3, 132.3, 130.9, 129.2, 129.1, 118, 117.8, 116.2, 116.2, 65.8, 52.4, 52.4, 45.2, 32.4, 32.3, 31.5, 31.4, 31.2, 22, 20.7.

Example 315: (R)-2-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(1H-imidazol-1-yl)-2-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one and isolated as a light cream powder.

1 H NMR (DMSO d6 ): 8.77 (1H, br t, J=6.2 Hz), 7.85 (1H, m), 4.48 (1H, quin, J=8.5 Hz), 4.25 (1H, dd, J=11.4, 9.3 Hz), 3.93 (2H, m), 3.85 (1H, dd, J=11.6, 7.6 Hz), 3.57 (2H, m), 3.39 (3H, s), 3.32 (1H, dd, J=9.2, 16.0 Hz), 2.93 (1H, dd, J=15.9, 8.0 Hz).

13 C NMR (DMSO d6 ): 168.7, 156.5, 146.4, 146.4, 146.3, 146.3, 146.3, 146.3, 146.2, 145.3, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2, 145.2, 144.8, 144.8, 144.7, 144.7, 144.6, 144.6, 143.7, 143.7, 143.7, 143.7, 143.6, 143.6, 143.6, 143.6, 128.6, 127.5, 125.6, 123.8, 121.9, 120.4, 120.3, 120.2, 115.7, 105.9, 105.7, 105.6, 49.4, 39.5, 34.9, 31.4, 30.9, 29.

Example 316: (R)-2-(2-methyl-3-thioxo-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)-N-(oxazol-2-yl)acetamide

Compound was prepared analogous manner to Example 32 from (R)-1-(H-imidazol-1-yl)-2-(2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-1-yl)ethan-1-one and isolated as a cream powder.

1 H NMR