Novel cyclopenta[c]pyrrol as negative allosteric modulators of NR2b

Abstract

To provide compounds that selectively modulate the activity of NR1 / NR2B receptors.SOLUTION: The present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof; a method for manufacturing the compounds of the disclosure, and its therapeutic uses. The present disclosure further provides a combination of pharmacologically active agents and a pharmaceutical composition.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present disclosure relates to compounds that selectively modulate NR1 / NR2B receptor activity. [Background technology]

[0002] NMDA receptors are likely an important signaling mechanism in the human brain. Store past information and analyze this information in the present to respond and plan for the future These incredible things allow humans to process complex, organized information so they can function. Such complex computations are performed at synapses, which are nodes for communication between neurons (approximately 1000 kJ in the human brain). By periodically adjusting the intensity of the electrons (estimated to exist in 60 trillion), It is mediated by

[0003] Glutamate is the major excitatory neurotransmitter in the brain and is responsible for 8 of these synapses. 0% is utilized. NMDA receptors mediate synaptic transmission using glutamate. NMDA receptors are one of three classes of receptors that regulate synaptic strength, i.e. Therefore, NMDA receptors play an important role in regulating synaptic plasticity. , are at the molecular core of brain function, especially the cognitive functions of learning and memory. NMD with novel drugs for treating neuropsychiatric disorders and cognitive dysfunction in Modulating A receptor function is the basis for a wide range of therapeutic benefits.

[0004] The molecular basis of NMDA receptor function is becoming increasingly well understood. four proteins: two NR1 subunits and two NR2 subunits The NR1 subunit, derived from a single gene, is distributed throughout the brain. It is ubiquitously expressed in the brain and is common to all NMDA receptors. However, there are four different NR2 The subunits NR2A-D are expressed in different brain regions and are expressed by neurons within specific regions. These genes are derived from separate genes that are differentially expressed by different populations of neurons. Neurons may express more than one type of NR2 subunit, and such neurons Each NMDA receptor expressed by the human body consists of two types of the same NR2 subunit ( For example, two different NR2B subunits) or two different subunits (one One type contains NR2A subunits, the other NR2B subunits. Drugs that selectively modulate the activity of the NR2 subunit of the target subunit Receptors expressing only two of the target subunits or only one of the target subunits may also be modeled. Therefore, it may be difficult to treat diseases related to NR1 / NR2B receptors. New treatments for Summary of the Invention

[0005] Various embodiments of the present disclosure are described herein.

[0006] In certain embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof is Provided in the document:

[0007] [ka]

[0008] In another aspect, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof: The present invention provides a pharmaceutical composition comprising:

[0009] The present disclosure further provides a method for producing a compound comprising two NR2B subunits or one other NR2 subunit. Another NR2B subunit combined with NR2A (i.e., NR2A / NR2B NR2B / NR2C, or NR2B / NR2D receptors) Compounds that selectively modulate NMDA receptor activity, including the 2B subunit Such compounds can decrease NR2B-containing NMDA receptor activity. The present disclosure also relates to therapeutic uses of such compounds.

[0010] In a further aspect, the disclosure relates to a method of treatment comprising administering a therapeutically effective amount of a compound. In particular, Parkinson's disease, Huntington's disease, Rett syndrome, amyotrophic lateral sclerosis, Multiple sclerosis, seizure disorders, autism, autism spectrum disorders, fragile X syndrome, tuberous sclerosis Disorders, Down syndrome, pain, migraine, tinnitus, bipolar disorder, obsessive-compulsive disorder, anxiety disorder, post-traumatic stress Posttraumatic stress disorder (PTSD), cocaine use disorder, major depressive disorder, treatment-refractory or A compound of formula (I) or its analogues for use in the treatment of resistant depression or suicidality. Pharmaceutically acceptable salts are provided. DETAILED DESCRIPTION OF THE INVENTION

[0011] Thus, the present disclosure provides compounds of formula (I):

[0012] [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 is C 3~8 Cycloalkyl, 3- to 7-membered heterocyclyl, phenyl, naphthyl, or or heteroaryl, each of which is optionally joined by one or more R 5 Place has been replaced; R 2 OH, CN, halogen, OR 6 , S.H., S.R. 6 , C 1~6 Alkyl, HaloC 1~ 6 alkyl, NH2, NHR 6 , hydroxy C 1~6 Alkyl, N(R 6 )(R 6 '), NHS(O)2R 6 , or NHCOR 6 where R 2 In the para position, OH Isn't it; or two R's 2 The groups, together with the ring carbon atoms to which they are attached, form a 5- to 7-membered ring. forming a heterocyclic or 5- or 6-membered heteroaryl ring; R 3 is H, O, or OH; R 4 is H or OH; R 5 are halogens, OH, C 1~6 Alkyl, OR 6 , CN, NH2, NHR 6 , N(R 6 )(R 6 '), SH, SR 6 , SOR 6 , SO2R 6 , SO2NHR 6 , SO2N(R 6 )(R 6 '), CONH2, CONHR 6 , or CON(R 6 )(R 6 ') and; Each R 6 and R 6 ', H, OC 1~6 Alkyl, C1~6 Alkyl and halo C1 ~6 independently selected from the group consisting of alkyl; B is N or CRx; Each Rx is independently H, C 1~3 alkyl, or halogen; Each n is independently 0, 1, 2, 3, or 4).

[0013] One embodiment is a compound of formula II:

[0014] [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 is C 3~8 Cycloalkyl, 3- to 7-membered heterocyclyl, phenyl, naphthyl, or or heteroaryl, each of which is optionally joined by one or more R 5 Place has been replaced; R 2 OH, CN, halogen, OR 6 , S.H., S.R. 6 , C 1~6 Alkyl, HaloC 1~ 6 alkyl, NH2, NHR 6 , hydroxy C 1~6 Alkyl, N(R 6 )(R 6 '), NHS(O)2R 6 , or NHCOR 6 and; R 3 is H, O, or OH; R 4 is H or OH; R 5 are halogens, OH, C 1~6 Alkyl, OR 6 , CN, NH2, NHR 6 , N(R 6 )(R6 '), SH, SR 6 , SOR 6 , SO2R 6 , SO2NHR 6 , SO2N(R 6 )(R 6 '), CONH2, CONHR 6 , or CON(R 6 )(R 6 ') and; Each R 6 and R 6 ', H, OC 1~6 Alkyl, C 1~6 Alkyl and halo C1 ~6 independently selected from the group consisting of alkyl; B is N or CRx; V is carbonyl, CH, or N; U is O, S, CRx, or CRxRx; Each Rx is independently H, C 1~3 alkyl, or halogen; each W is independently O, CH, or CH; ---- is an optional double bond; m is 0, 1, or 2; Each n is independently 0, 1, 2, 3, or 4).

[0015] Another embodiment is a compound of formula III:

[0016] [ka] or a pharmaceutically acceptable salt thereof, wherein R 2 OH, CN, halogen, OR 6 , S.H., S.R. 6 , C 1~6 Alkyl, HaloC 1~ 6 alkyl, NH2, NHR 6 , hydroxy C 1~6 Alkyl, N(R 6 )(R6 '), NHS(O)2R 6 , NHCOR 6 and; R 3 is H, O, or OH; R 4 is H or OH; R 5 are halogens, OH, C 1~6 Alkyl, OR 6 , CN, NH2, NHR 6 , N(R 6 )(R 6 '), SH, SR 6 , SOR 6 , SO2R 6 , SO2NHR 6 , SO2N(R 6 )(R 6 '), CONH2, CONHR 6 , and CON(R 6 )(R 6 ') and; Each R 6 and R 6 ', H, OC 1~6 Alkyl, C 1~6 Alkyl and halo C1 ~6 independently selected from the group consisting of alkyl; B is N or CRx; V is carbonyl, CH, or N; U is O, S, CRx, or CRxRx; Each Rx is independently H, C 1~3 alkyl, or halogen; each W is independently O, CH, or CH; ---- is an optional double bond; m is 0, 1, or 2; Each n is independently 0, 1, 2, 3, or 4).

[0017] Another embodiment is a compound of formula IV:

[0018] [ka] or a pharmaceutically acceptable salt thereof, wherein R 2 is a halogen; R 3 is H or OH; R 4 is H or OH; R 5 is a halogen; B is N or CH; V is carbonyl, CH, or N; U is O, S, CRx, or CRxRx; Each Rx is independently H, C 1~3 alkyl, or halogen; each W is independently O, CH, or CH; ---- is an optional double bond; m is 0, 1, or 2; Each n is independently 0, 1, 2, 3, or 4).

[0019] Another embodiment is a compound of formula IVa:

[0020] [ka] or a pharmaceutically acceptable salt thereof.

[0021] Another embodiment is a compound of formula IVb:

[0022] [ka] or a pharmaceutically acceptable salt thereof.

[0023] Another embodiment is a compound of formula IVc:

[0024] [ka] or a pharmaceutically acceptable salt thereof.

[0025] Another embodiment is a compound of formula IVd:

[0026] [ka] or a pharmaceutically acceptable salt thereof.

[0027] Another embodiment is a compound of formula IVe:

[0028] [ka] or a pharmaceutically acceptable salt thereof.

[0029] Another embodiment is a compound of formula IVf:

[0030] [ka] or a pharmaceutically acceptable salt thereof.

[0031] Another embodiment is a compound of formula V:

[0032] [ka] or a pharmaceutically acceptable salt thereof.

[0033] Another embodiment is a compound of formula Va:

[0034] [ka] or a pharmaceutically acceptable salt thereof.

[0035] Another embodiment is a compound of formula Vb:

[0036] [ka] or a pharmaceutically acceptable salt thereof.

[0037] Another embodiment is a compound of formula Vc:

[0038] [ka] or a pharmaceutically acceptable salt thereof.

[0039] Another embodiment is a compound of formula Vd:

[0040] [ka] or a pharmaceutically acceptable salt thereof.

[0041] Another embodiment is a compound of formula Ve:

[0042] [ka] or a pharmaceutically acceptable salt thereof.

[0043] Another embodiment is a compound of formula Vf:

[0044] [ka] or a pharmaceutically acceptable salt thereof.

[0045] In another embodiment, U is CRxRx and W is CH2.

[0046] In another embodiment, U is CRxRx, W is CH2, and m is 1.

[0047] In another embodiment, U is CRxRx, W is CH2, and m is 2.

[0048] In another embodiment, U is CRx, W is CH, and m is 1.

[0049] In another embodiment, U is CRxRx, W is O, and m is 1.

[0050] In another embodiment, U is CRxRx, one W is O and the other W is CH2 and m is 2.

[0051] In another embodiment, U is CRxRx and m is 0.

[0052] In another embodiment, U is O and W is CH2.

[0053] In another embodiment, U is O, W is CH 2 , and m is 1.

[0054] In another embodiment, U is O, W is CH 2 , and m is 2.

[0055] In another embodiment, U is O and m is 0.

[0056] In another embodiment, U is S, W is CH 2 , and m is 1.

[0057] In another embodiment, U is S and m is 0.

[0058] Another embodiment is a compound of formula VI:

[0059] [ka] or a pharmaceutically acceptable salt thereof, wherein R 3 is H or OH; R 4 is H or OH; R 5 is a halogen; V is CH or N; B is N or CH; Each n is independently 0, 1, 2, 3, or 4).

[0060] Another embodiment is a compound of formula VIa:

[0061] [ka] or a pharmaceutically acceptable salt thereof.

[0062] Another embodiment is a compound of formula VIb:

[0063] [ka] or a pharmaceutically acceptable salt thereof.

[0064] Another embodiment is a compound of formula VIc:

[0065] [ka] or a pharmaceutically acceptable salt thereof.

[0066] Another embodiment is a compound of formula VId:

[0067] [ka] or a pharmaceutically acceptable salt thereof.

[0068] Another embodiment is a compound of formula IIIe:

[0069] [ka] or a pharmaceutically acceptable salt thereof.

[0070] Another embodiment is a compound of formula VIf:

[0071] [ka] or a pharmaceutically acceptable salt thereof.

[0072] In another embodiment, R 2 or R 5 is F.

[0073] In another embodiment, R 3 is H.

[0074] In another embodiment, R 3 is OH.

[0075] In another embodiment, R 4 is H.

[0076] In another embodiment, R 4 is OH.

[0077] In another embodiment, R 2 CN, halogen, OR 6 , S.H., S.R. 6 , C 1~6 a Lukill, HaroC 1~6 Alkyl or hydroxy C 1~6 It is alkyl.

[0078] In another embodiment, R 2 is a halogen, C 1~6 Alkyl, HaloC 1~6 Alkyl , or hydroxy C 1~6 It is alkyl.

[0079] In another embodiment, R 2 is a halogen, C 1~6 Alkyl or haloC 1~6 a It's Rukiru.

[0080] In another embodiment, R 5 are halogens, OH, C 1~6 Alkyl, OR 6 , C.N., SH or SR 6 is.

[0081] In another embodiment, R 5 are halogens, OH, C 1~6 Alkyl, or OR 6 in be.

[0082] In another embodiment, R 5 is a halogen, OH, or C 1~6 It is alkyl.

[0083] Specific compounds include: 6-((R)-1-hydroxy-2-((3aS,5S,6aR)-3a-hydroxy- 5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl -3,4-dihydroquinolin-2(1H)-one; 6-((S)-1-hydroxy-2-((3aS,5S,6aR)-3a-hydroxy- 5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl -3,4-dihydroquinolin-2(1H)-one; 5-((R)-1-hydroxy-2-((3aS,5S,6aR)-3a-hydroxy- 5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl Indolin-2-one; 5-((S)-1-hydroxy-2-((3aS,5S,6aR)-3a-hydroxy- 5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl Indolin-2-one; 5-((R)-2-((3aS,4S,5S,6aR)-3a,4-dihydroxy-5- Phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)-yl)-1-hydro (oxyethyl)indolin-2-one; 5-((S)-2-((3aS,4S,5S,6aR)-3a,4-dihydroxy-5- Phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)-yl)-1-hydro (oxyethyl)indolin-2-one; 5-((R)-2-((3aR,4R,5R,6aS)-3a,4-dihydroxy-5- Phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)-yl)-1-hydro (oxyethyl)indolin-2-one; 5-((S)-2-((3aR,4R,5R,6aS)-3a,4-dihydroxy-5- Phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)-yl)-1-hydro (oxyethyl)indolin-2-one; 6-((R)-2-((3aS,4S,5S,6aR)-3a,4-dihydroxy-5- Phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)-yl)-1-hydro (oxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((S)-2-((3aS,4S,5S,6aR)-3a,4-dihydroxy-5- Phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)-yl)-1-hydro (oxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((R)-2-((3aR,4R,5R,6aS)-3a,4-dihydroxy-5- Phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)-yl)-1-hydro (oxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((S)-2-((3aR,4R,5R,6aS)-3a,4-dihydroxy-5- Phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)-yl)-1-hydro (oxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((R)-2-((3aS,5S,6aR)-5-(2-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy (hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((S)-2-((3aS,5S,6aR)-5-(2-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy (hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((R)-2-((3aR,5R,6aS)-5-(2-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy (hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((S)-2-((3aR,5R,6aS)-5-(2-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy (hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 8-Fluoro-6-((R)-2-((3aS,5S,6aR)-5-(2-fluorofluoro (phenoxy)-3a-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)- yl)-1-hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 8-Fluoro-6-((S)-2-((3aS,5S,6aR)-5-(2-fluorofluoro (phenoxy)-3a-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)- yl)-1-hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 8-Fluoro-6-((R)-2-((3aR,5R,6aS)-5-(2-fluorofluoro (phenoxy)-3a-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)- yl)-1-hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 8-Fluoro-6-((S)-2-((3aR,5R,6aS)-5-(2-fluorofluoro (phenoxy)-3a-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)- yl)-1-hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 7-((R)-1-hydroxy-2-((3aS,5S,6aR)-3a-hydroxy- 5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl -1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one; 7-((S)-1-hydroxy-2-((3aS,5S,6aR)-3a-hydroxy- 5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl -1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one; 6-((R)-1-hydroxy-2-((3aS,5S,6aR)-3a-hydroxy- 5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl quinolin-2(1H)-one; 6-((S)-1-hydroxy-2-((3aS,5S,6aR)-3a-hydroxy- 5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl quinolin-2(1H)-one; 5-Fluoro-6-((R)-1-hydroxy-2-((3aS,5S,6aR)-3a -Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)- yl)ethyl)-3,4-dihydroquinolin-2(1H)-one; 5-Fluoro-6-((S)-1-hydroxy-2-((3aS,5S,6aR)-3a -Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)- yl)ethyl)-3,4-dihydroquinolin-2(1H)-one; 7-Fluoro-6-((R)-1-hydroxy-2-((3aS,5S,6aR)-3a -Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)- yl)ethyl)-3,4-dihydroquinolin-2(1H)-one; 7-Fluoro-6-((S)-1-hydroxy-2-((3aS,5S,6aR)-3a -Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)- yl)ethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((R)-1-hydroxy-2-((3aS,5S,6aR)-3a-hydroxy- 5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl -3,3-dimethyl-3,4-dihydroquinolin-2(1H)-one; 6-((S)-1-hydroxy-2-((3aS,5S,6aR)-3a-hydroxy- 5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl -3,3-dimethyl-3,4-dihydroquinolin-2(1H)-one; 7-((R)-2-((3aS,5S,6aR)-5-(2-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy hydroxyethyl)-4,5-dihydrobenzo[d][1,3]oxazepine-2(1H) -on; 7-((S)-2-((3aS,5S,6aR)-5-(2-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy hydroxyethyl)-4,5-dihydrobenzo[d][1,3]oxazepine-2(1H) -on; 5-Fluoro-7-((R)-1-hydroxy-2-((3aS,5S,6aR)-3a -Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)- (yl)ethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one; 5-Fluoro-7-((S)-1-hydroxy-2-((3aS,5S,6aR)-3a -Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)- (yl)ethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one; 6-((R)-1-hydroxy-2-((3aS,5S,6aR)-3a-hydroxy- 5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl -1,4-Dihydro-2H-benzo[d][1,3]thiazin-2-one; 6-((S)-1-hydroxy-2-((3aS,5S,6aR)-3a-hydroxy- 5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl -1,4-Dihydro-2H-benzo[d][1,3]thiazin-2-one; 6-((R)-2-((3aS,5S,6aR)-5-(2-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy (hydroxyethyl)-1,4-dihydro-2H-benzo[d][1,3]thiazin-2-ol hmm; 6-((S)-2-((3aS,5S,6aR)-5-(2-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy (hydroxyethyl)-1,4-dihydro-2H-benzo[d][1,3]thiazin-2-ol hmm; 8-Fluoro-6-((R)-1-hydroxy-2-((3aS,5S,6aR)-3a -Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)- (yl)ethyl)-1,4-dihydro-2H-benzo[d][1,3]thiazin-2-one ; 8-Fluoro-6-((S)-1-hydroxy-2-((3aS,5S,6aR)-3a -Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)- (yl)ethyl)-1,4-dihydro-2H-benzo[d][1,3]thiazin-2-one ; 6-((R)-1-hydroxy-2-((3aS,5S,6aR)-3a-hydroxy- 5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl benzo[d]thiazol-2(3H)-one; 6-((S)-1-hydroxy-2-((3aS,5S,6aR)-3a-hydroxy- 5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl benzo[d]thiazol-2(3H)-one; 6-((R)-2-((3aS,5S,6aR)-5-(2-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy (hydroxyethyl)benzo[d]thiazol-2(3H)-one; 6-((S)-2-((3aS,5S,6aR)-5-(2-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy (hydroxyethyl)benzo[d]thiazol-2(3H)-one; (S)-3,8-difluoro-6-((R)-1-hydroxy-2-((3aS,5S, 6aR)-3a-Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole -2(1H)-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one; (S)-3,8-difluoro-6-((S)-1-hydroxy-2-((3aS,5S, 6aR)-3a-Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole -2(1H)-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one; (R)-3,8-difluoro-6-((R)-1-hydroxy-2-((3aS,5S, 6aR)-3a-Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole -2(1H)-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one; (R)-3,8-difluoro-6-((S)-1-hydroxy-2-((3aS,5S, 6aR)-3a-Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole -2(1H)-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one; 3,8-Difluoro-6-((R)-1-hydroxy-2-((3aS,5S,6aR) -3a-Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1 H)-yl)ethyl)quinolin-2(1H)-one; 3,8-Difluoro-6-((S)-1-hydroxy-2-((3aS,5S,6aR) -3a-Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1 H)-yl)ethyl)quinolin-2(1H)-one; (3aS,5S,6aR)-5-(2,4-difluorophenoxy)-2-((R)-2 -Hydroxy-2-(1H-indazol-5-yl)ethyl)hexahydrocyclopenta ta[c]pyrrol-3a(1H)-ol; (3aS,5S,6aR)-5-(2,4-difluorophenoxy)-2-((S)-2 -Hydroxy-2-(1H-indazol-5-yl)ethyl)hexahydrocyclopenta ta[c]pyrrol-3a(1H)-ol; (3aR,5R,6aS)-5-(2,4-difluorophenoxy)-2-((R)-2 -Hydroxy-2-(1H-indazol-5-yl)ethyl)hexahydrocyclopenta ta[c]pyrrol-3a(1H)-ol; (3aR,5R,6aS)-5-(2,4-difluorophenoxy)-2-((R)-2 -Hydroxy-2-(1H-indazol-5-yl)ethyl)hexahydrocyclopenta ta[c]pyrrol-3a(1H)-ol; 6-((R)-2-((3aS,5S,6aR)-5-(4-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy (hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((S)-2-((3aS,5S,6aR)-5-(4-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy (hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((R)-2-((3aR,5R,6aS)-5-(4-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy (hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((S)-2-((3aR,5R,6aS)-5-(4-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy (hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((R)-2-((3aS,5S,6aR)-5-(3-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy (hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((S)-2-((3aS,5S,6aR)-5-(3-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy (hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((R)-2-((3aR,5R,6aS)-5-(3-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy (hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((S)-2-((3aR,5R,6aS)-5-(3-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy (hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((R)-2-((3aS,5S,6aR)-5-(2,3-difluorophenoxy )-3a-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)- 1-hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((S)-2-((3aS,5S,6aR)-5-(2,3-difluorophenoxy )-3a-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)- 1-hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((R)-2-((3aR,5R,6aS)-5-(2,3-difluorophenoxy )-3a-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)- 1-hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((S)-2-((3aR,5R,6aS)-5-(2,3-difluorophenoxy )-3a-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)- 1-hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((R)-2-((3aS,5S,6aR)-5-(2,4-difluorophenoxy )-3a-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)- 1-hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((S)-2-((3aS,5S,6aR)-5-(2,4-difluorophenoxy )-3a-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)- 1-hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((R)-2-((3aR,5R,6aS)-5-(2,4-difluorophenoxy )-3a-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)- 1-hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((S)-2-((3aR,5R,6aS)-5-(2,4-difluorophenoxy )-3a-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)- 1-hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((R)-2-((3aS,5S,6aR)-5-(2,5-difluorophenoxy )-3a-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)- 1-hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((S)-2-((3aS,5S,6aR)-5-(2,5-difluorophenoxy )-3a-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)- 1-hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((R)-2-((3aR,5R,6aS)-5-(2,5-difluorophenoxy )-3a-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)- 1-hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((S)-2-((3aR,5R,6aS)-5-(2,5-difluorophenoxy )-3a-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)- 1-hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((R)-2-((3aS,5S,6aR)-5-(2,6-difluorophenoxy )-3a-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)- 1-hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((S)-2-((3aS,5S,6aR)-5-(2,6-difluorophenoxy )-3a-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)- 1-hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((R)-2-((3aR,5R,6aS)-5-(2,6-difluorophenoxy )-3a-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)- 1-hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((S)-2-((3aR,5R,6aS)-5-(2,6-difluorophenoxy )-3a-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)- 1-hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((R)-1-hydroxy-2-((3aS,5S,6aR)-3a-hydroxy- 5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl -1,4-Dihydro-2H-benzo[d][1,3]oxazin-2-one; 6-((S)-1-hydroxy-2-((3aS,5S,6aR)-3a-hydroxy- 5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl -1,4-Dihydro-2H-benzo[d][1,3]oxazin-2-one; 8-Fluoro-6-((R)-2-((3aS,4S,5S,6aR)-5-(2-fluoro (3a,4-dihydroxyhexahydrocyclopenta[c]pyrrole)- 2(1H)-yl)-1-hydroxyethyl)-3,4-dihydroquinoline-2(1H) -on; 8-Fluoro-6-((S)-2-((3aS,4S,5S,6aR)-5-(2-fluoro (3a,4-dihydroxyhexahydrocyclopenta[c]pyrrole)- 2(1H)-yl)-1-hydroxyethyl)-3,4-dihydroquinoline-2(1H) -on; 9-Fluoro-7-((R)-1-hydroxy-2-((3aS,5S,6aR)-3a -Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)- (yl)ethyl)-1,3,4,5-tetrahydro-2H-benzo[b]azepine-2-ol hmm; 9-Fluoro-7-((S)-1-hydroxy-2-((3aS,5S,6aR)-3a -Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)- (yl)ethyl)-1,3,4,5-tetrahydro-2H-benzo[b]azepine-2-ol hmm; 8-Fluoro-6-((R)-1-hydroxy-2-((3aS,5S,6aR)-3a -Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)- yl)ethyl)-3,4-dihydroquinolin-2(1H)-one; 8-Fluoro-6-((S)-1-hydroxy-2-((3aS,5S,6aR)-3a -Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)- yl)ethyl)-3,4-dihydroquinolin-2(1H)-one; 9-Fluoro-7-((R)-1-hydroxy-2-((3aS,5S,6aR)-3a -Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)- (yl)ethyl)-1,5-dihydrobenzo[e][1,4]oxazepine-2(3H)- on; 9-Fluoro-7-((S)-1-hydroxy-2-((3aS,5S,6aR)-3a -Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)- (yl)ethyl)-1,5-dihydrobenzo[e][1,4]oxazepine-2(3H)- on; 8-Fluoro-6-((R)-1-hydroxy-2-((3aS,5S,6aR)-3a -Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)- (yl)ethyl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-ol hmm; 8-Fluoro-6-((S)-1-hydroxy-2-((3aS,5S,6aR)-3a -Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)- (yl)ethyl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-ol hmm; 5-Fluoro-6-((R)-1-hydroxy-2-((3aS,5S,6aR)-3a -Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)- (yl)ethyl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-ol hmm; 5-Fluoro-6-((S)-1-hydroxy-2-((3aS,5S,6aR)-3a -Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)- (yl)ethyl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-ol hmm; 8-Fluoro-6-((R)-2-((3aS,5S,6aR)-5-(2-fluorofluoro (phenoxy)-3a-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)- (yl)-1-hydroxyethyl)-1,4-dihydro-2H-benzo[d][1,3]o Xazin-2-one; 8-Fluoro-6-((S)-2-((3aS,5S,6aR)-5-(2-fluorofluoro (phenoxy)-3a-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)- (yl)-1-hydroxyethyl)-1,4-dihydro-2H-benzo[d][1,3]o Xazin-2-one; 7-Fluoro-6-((R)-1-hydroxy-2-((3aS,5S,6aR)-3a -Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)- (yl)ethyl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-ol hmm; 7-Fluoro-6-((S)-1-hydroxy-2-((3aS,5S,6aR)-3a -Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)- (yl)ethyl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-ol hmm; 5,8-Difluoro-6-((R)-1-hydroxy-2-((3aS,5S,6aR) -3a-Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1 H)-yl)ethyl)-1,4-dihydro-2H-benzo[d][1,3]oxazine- 2-on; 5,8-Difluoro-6-((S)-1-hydroxy-2-((3aS,5S,6aR) -3a-Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1 H)-yl)ethyl)-1,4-dihydro-2H-benzo[d][1,3]oxazine- 2-on; 7,8-Difluoro-6-((R)-1-hydroxy-2-((3aS,5S,6aR) -3a-Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1 H)-yl)ethyl)-1,4-dihydro-2H-benzo[d][1,3]oxazine- 2-on; 7,8-Difluoro-6-((S)-1-hydroxy-2-((3aS,5S,6aR) -3a-Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1 H)-yl)ethyl)-1,4-dihydro-2H-benzo[d][1,3]oxazine- 2-on; 6-((R)-1-hydroxy-2-((3aS,5S,6aR)-3a-hydroxy- 5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl benzo[d]oxazol-2(3H)-one; 6-((S)-1-hydroxy-2-((3aS,5S,6aR)-3a-hydroxy- 5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl benzo[d]oxazol-2(3H)-one; 6-((R)-2-((3aS,5S,6aR)-5-(2-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy (hydroxyethyl)benzo[d]oxazol-2(3H)-one; 6-((S)-2-((3aS,5S,6aR)-5-(2-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy (hydroxyethyl)benzo[d]oxazol-2(3H)-one; 6-((R)-2-((3aS,5S,6aR)-5-(2-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy hydroxyethyl)-1,4-dihydro-2H-benzo[d][1,3]oxazine-2- on; 6-((S)-2-((3aS,5S,6aR)-5-(2-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy hydroxyethyl)-1,4-dihydro-2H-benzo[d][1,3]oxazine-2- on; 4-Fluoro-6-((R)-1-hydroxy-2-((3aS,5S,6aR)-3a -Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)- yl)ethyl)benzo[d]thiazol-2(3H)-one; 4-Fluoro-6-((S)-1-hydroxy-2-((3aS,5S,6aR)-3a -Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)- yl)ethyl)benzo[d]thiazol-2(3H)-one; 7-((R)-2-((3aS,5S,6aR)-5-(2-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy Hydroxyethyl)-1,3,4,5-tetrahydro-2H-benzo[b]azepine-2- on; 7-((S)-2-((3aS,5S,6aR)-5-(2-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy Hydroxyethyl)-1,3,4,5-tetrahydro-2H-benzo[b]azepine-2- on; (3aS,4S,5S,6aR)-5-(2-fluorophenoxy)-2-((R)-2 -hydroxy-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)ethyl)hexa Hydrocyclopenta[c]pyrrole-3a,4(1H)-diol; and (3aS,4S,5S,6aR)-5-(2-fluorophenoxy)-2-((S)-2 -hydroxy-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)ethyl)hexa a mixture of hydrocyclopenta[c]pyrrole-3a,4(1H)-diols, or and pharmaceutically acceptable salts thereof.

[0084] One embodiment is a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. It is a thing.

[0085] Another embodiment is a method for treating Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, Disorders, seizure disorders, autism, autism spectrum disorders, fragile X syndrome, tuberous sclerosis complex, Down syndrome syndrome, bipolar disorder, obsessive-compulsive disorder, anxiety disorder, major depressive disorder, refractory or treatment-resistant A method for treating depression or suicidality comprising administering a therapeutically effective amount of a compound of formula (I) or or a pharmaceutically acceptable salt thereof to a patient in need of such treatment. is.

[0086] Another embodiment is a method for treating post-traumatic stress disorder (PTSD).

[0087] Another embodiment is a method for treating cocaine use disorder.

[0088] Another embodiment is a method for treating pain and migraines.

[0089] Another embodiment is a method for treating Rett Syndrome.

[0090] Another embodiment is a method for treating tinnitus.

[0091] Unless otherwise specified, the term "compounds of the disclosure" or "compound of the disclosure" is used herein. The term refers to compounds of formula (I), subformulas thereof, and exemplified compounds, and salts thereof, including and all stereoisomers (including diastereoisomers and enantiomers), rotational isomers isomers, tautomers, and isotopically labeled compounds (including deuterium substitutions), as well as specific This refers to the part formed in the

[0092] definition As used herein, "halogen," "halide," or "halo" The term refers to bromo, chloro, fluoro, or iodo.

[0093] As used herein, "C 1~6 The term "alkyl" refers to a group of carbon and hydrogen atoms. It consists of only atoms, contains no unsaturation, has 1 to 6 carbon atoms, and is connected by single bonds refers to a linear or branched hydrocarbon chain radical attached to the rest of the "C 1~4 a The term "rukil" should be construed accordingly. 1~6 As an example of alkyl Examples include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl t-butyl, n-pentyl, and 1,1-dimethylethyl (t -butyl).

[0094] As used herein, "C 3~8 The term "cycloalkyl" refers to a group of carbon and and hydrogen, have 3 to 8 ring atoms, and may be saturated or partially unsaturated; Refers to a monocyclic or polycyclic radical. C 3~8 Examples of cycloalkyl include, but are not limited to: Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentyl Examples include thienyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0095] As used herein, "hydroxy C 1~6 The term "alkyl" is used in the above C as defined in 1~6 Alkyl radicals, C 1~6 Hydrogen in alkyl radicals C with one of the atoms replaced by OH 1~6 Refers to alkyl radicals. Roxy C 1~6 Examples of alkyl include, but are not limited to, hydroxy. -methyl, 2-hydroxy-ethyl, 2-hydroxy-propyl, 3-hydroxy-propyl Examples include pyryl and 5-hydroxy-pentyl.

[0096] As used herein, "halo C" refers to 1~6 The term "alkyl" is defined above. C like that 1~6 an alkyl radical, comprising one or more of the groups defined above; C substituted by halo radicals 1~6 Refers to alkyl radicals. HaloC 1~6 Archi Examples of alkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, Methyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,3 -dibromopropan-2-yl, 3-bromo-2-fluoropropyl, and 1,4,4 -trifluorobutan-2-yl.

[0097] As used herein, the term "aryl" refers to an aromatic hydrocarbon ring system. Aryl groups are monocyclic or bicyclic ring systems. Monocyclic aryl rings include phenyl. The bicyclic aryl ring refers to naphthyl. The aryl group is defined in formula (I). It may be optionally substituted with one or more substituents such as:

[0098] As used herein, the term "heterocyclic" or "heterocyclyl" , 3- to 8-membered saturated or partially unsaturated monocyclic or bicyclic rings containing 1 to 5 heteroatoms Heterocyclic ring systems are not aromatic. Heterocyclic groups containing more than one heteroatom may contain different heteroatoms. A heterocyclic ring is one in which a carbon atom is oxidized to form a ring. Heterocyclic ring systems include those in which the sulfur atom is an acid. Some ring systems are substituted to form SO or SO2. Heterocyclic groups are represented by the following formula (I): It may be optionally substituted with one or more substituents as defined. The group of formula (I) is a monocyclic, spiro, or fused or bridged bicyclic ring system. Formula compounds have from 3 to 7 ring atoms unless otherwise defined. Examples of groups include tetrahydrofuranyl, dihydrofuranyl, 1,4-dioxanyl, mono- and di-substituted aryl groups. 1,4-dithianyl, piperazinyl, piperidinyl, 1,3-dioxolanily Imidazolidinyl, imidazolinyl, pyrrolinyl, pyrrolidinyl, tetrahydropyridine Nyl, dihydropyranyl, oxathiolanyl, dithiolanyl, 1,3-dioxanyl, 1 ,3-dithianyl, oxathianyl, thiomorpholinyl, etc. Fused heterocyclic ring systems are , having 8 to 11 ring atoms, wherein the heterocyclic ring is a phenyl or monocyclic heteroaryl ring. Examples of fused heterocyclic rings include 3,4-dihydroquinoline-2(1H )-onyl, indolin-2-onyl, quinolin-2(1H)-onyl, 1,3, 4,5-tetrahydro-2H-benzo[b]azepin-2-onyl, 4,5-dihydro Benz[d][1,3]oxazepin-2(1H)-onyl, 1,4-dihydro-2H -Benzo[d][1,3]thiazin-2-onyl, benzo[d]thiazole-2(3H )-onyl, benzo[d]oxazol-2(3H)-onyl, 1H-indazolyl , 1H-indolyl, etc.

[0099] As used herein, the term "heteroaryl" refers to an alkyl group having 1 to 5 heteroaryls. Heteroaryl groups containing more than one heteroatom refer to aromatic ring systems containing one or more heteroatoms. The heteroaryl group may contain a heteroatom as defined in formula (I). The heteroaryl group may be optionally substituted with one or more substituents such as is a monocyclic ring system or a fused bicyclic ring system. The monocyclic heteroaryl ring has 5 to 10 carbon atoms. It has 6 ring atoms. Bicyclic heteroaryl rings have 8 to 10 member atoms. Aryl includes, but is not limited to, pyrrolyl, pyrazolyl, imidazolyl, and the like. Zolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl aryl, thiadiazolyl, furanyl, furanzanyl, thienyl, triazolyl pyridinyl, pyrimidinyl, pyridazinyl, trazinyl, tetrazinyl (tetrazinyl), tetrazolyl, indonyl, isoindolyl, indolizin Indolizinyl, indazolyl, purinyl, quinolinyl, isoquinolinyl, quinox Salinyl, quinazolinyl, benzimidazolyl, benzopyranyl, benzopyranyl, benz benzoxazolyl, benzisoxazolyl, benzofuranyl, benzothiazolyl, benzothiazolyl enyl, and naphthyridinyl.

[0100] Depending on the choice of starting material and procedure, the compound may be in the form of one of the possible stereoisomers. or as mixtures thereof, e.g. as pure optical isomers or stereoisomers As mixtures, e.g. racemic and diastereomeric mixtures, depending on the number of asymmetric carbon atoms The present disclosure provides racemic mixtures, diastereomeric mixtures, and photochemical mixtures. It is intended to include all such possible stereoisomers, including stereochemically pure forms. Optically active (R)- and (S)-stereoisomers can be synthesized using chiral synthons or chiral reagents. If the compound contains a double bond, it may be prepared by cleavage or resolved using conventional techniques. The group may be in the E or Z configuration. When the compound contains a disubstituted cycloalkyl, the cycloalkyl The alkyl substituent may have a cis- or trans-configuration. The body is also intended to be included.

[0101] As used herein, the term "salt" or "salts" refers to any of the compounds of the present disclosure. "Salt" specifically refers to an acid addition salt or a base addition salt of a compound. The term "pharmaceutically acceptable salts" refers to salts that are intended to protect the biological effectiveness and specificity of the compounds of the present disclosure. It refers to salts that retain their properties and are typically not biologically or otherwise undesirable. In this case, the compounds of the present disclosure may contain amino and / or carboxyl groups or similar thereto. By virtue of the presence of such groups it is possible to form acid and / or base salts.

[0102] Pharmaceutically acceptable acid addition salts may be formed with inorganic and organic acids.

[0103] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, Phosphate, etc.

[0104] Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycol Acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosa Licylic acid, etc.

[0105] Pharmaceutically acceptable base addition salts may be formed with inorganic and organic bases.

[0106] Inorganic bases from which salts can be derived include, for example, those from columns I to XII of the periodic table. In certain embodiments, the salts include ammonium salts and metal salts of sodium, Derived from potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper Particularly preferred salts include ammonium, potassium, sodium, calcium, and There are salts of magnesium and magnesium.

[0107] Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary bases. These include amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins. Certain organic amines include isopropylamine, benzathine, cholinate (c holinate), diethanolamine, diethylamine, lysine, meglumine, pipette These include thiazolidine and tromethamine.

[0108] In another aspect, the present disclosure provides a method for the preparation of a compound of formula (I) comprising administering to a subject a compound of formula (I) ... Phosphate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate Salt / Sulfate, Camphorsulfonate, Caprate, Chloride / Hydrochloride, Chloroteof Chlortheophyllonate, citrate, ethanedisulfonate, fumarate , gluceptate, gluconate, glucuronate, glutamate, glutarate, glutamate Cholic acid salts, hippurate, hydroiodide / iodide salts, isethionate, lactate, lactate Tobionate, lauryl sulfate, malate, maleate, malonate, mandelate , mesylate, methylsulfate, mucate, naphthoate, napsate, nicotinate, Nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate Salt / hydrogen phosphate / dihydrogen phosphate, polygalacturonate, propionate, sebacin Salt, stearate, succinate, sulfosalicylate, sulfate, tartrate, tosylate of the present disclosure in the form of a salt, triphenylacetate salt, trifluoroacetate salt, or xinafoate salt. A compound is provided.

[0109] Any formula given herein also includes unlabeled forms of the compounds as well as isotopically labeled forms. Isotopically labeled compounds are compounds in which one or more atoms are selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 The atomic mass or mass number of the element is replaced by an atom having the specified atomic mass or mass number. Incorporated into the compounds of the present disclosure may have a structure as illustrated by the formula given in Good isotopes include, for example, isotopes of hydrogen.

[0110] For example, formula (IV) can be prepared by the compound of formula (IVg):

[0111] [ka] or a pharmaceutically acceptable salt thereof (wherein R 5 , R 2 and n are defined as in formula (I). Righteous, RD 1 From RD 17 are independently H or D, and R3 , R 4 independently , H, D, or OH; V is carbonyl, CH, CD, or N; U is O, S, CRx, CRxRx; each Rx is independently H, D, C 1~3 Alkyl, or halogen; each W is independently O, CH, CD, CH2, or CD2; ; B is N, CH, or CD).

[0112] Additionally, certain isotopes, particularly deuterium (i.e. 2 Incorporation of H or D These compounds offer certain therapeutic advantages due to their superior metabolic stability, e.g., in vivo Increased half-life, or reduced dosage requirements, or improved therapeutic index or tolerability Deuterium in this context may provide improvements in the positioning of compounds of the present disclosure. It should be understood that the concentration of deuterium is considered to be an isotopic enrichment factor. The term "isotopic enrichment factor" as used herein may be defined as follows: In the case of a specific isotope, the term "abundance" refers to the ratio between the isotopic abundance and the natural abundance of the specified isotope. When a substituent in a compound is designated as deuterium, such a compound may be designated as each For a designated deuterium atom, at least 3500 (each designated deuterium 52.5% deuterium incorporation in sulphur atoms), at least 4000 (60% deuterium deuterium incorporation), at least 4500 (67.5% deuterium incorporation), At least 5000 (75% deuterium incorporation), at least 5500 (82. 5% deuterium incorporation), at least 6000 (90% deuterium incorporation) at least 6333.3 (95% deuterium incorporation), at least 646 6.7 (97% deuterium incorporation), at least 6600 (99% deuterium deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) The term "isotopic enrichment factor" refers to deuterium. It should be understood that the same applies to any isotope in the same manner as described above. is.

[0113] Other examples of isotopes that may be incorporated into compounds of the present disclosure include hydrogen, carbon, nitrogen, oxygen, and the like. , isotopes of phosphorus, fluorine, and chlorine, e.g., 3 H, 11 C. 13 C. 14 C , 15 N, 18 F 31 P, 32 P, 35 S, 36 Cl, 123 I, 124 I, 125 I Thus, the present disclosure provides, for example, radioisotopes, e.g. 3 H and 14 Before including C Compounds incorporating one or more of any of the above isotopes, or non- Radioactive isotopes, e.g. 2 H and 13 It should be understood that this includes cases where C is present. Such isotope-labeled compounds are useful for metabolic studies ( 14 C), reaction rate studies ( for example, 2 H or 3 H), detection or imaging techniques, e.g., drugs or Positron emission tomography (PET) or single-photon emission computed tomography (SEM) including tissue distribution assays of the substrate It is useful in computerized tomography (SPECT) or in radiation treatment of patients. In particular, 18 F or labeled compounds may be particularly desirable for PET or SPECT studies Isotopically labeled compounds of the present disclosure can generally be labeled by conventional techniques known to those of skill in the art. or by using appropriate isotopically labeled reagents in place of the unlabeled reagents used above. It may be prepared by procedures similar to those described in the Examples and Preparations.

[0114] As used herein, the term "pharmaceutical composition" refers to a pharmaceutical composition containing at least one drug. a compound of the present disclosure or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier; and a compound of the present disclosure or a pharmaceutically acceptable salt thereof in a form suitable for oral or parenteral administration. It refers to salt that is used in cooking.

[0115] As used herein, the term "pharmaceutically acceptable carrier" refers to a pharmaceutical composition refers to a substance useful in the preparation or use of a product, for example, a substance that would be known to those skilled in the art. Suitable diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonicity agents, buffers, etc. agents, emulsifiers, absorption retardants, salts, drug stabilizers, binders, excipients, disintegrants, lubricants, wetting agents , sweeteners, flavoring agents, dyes, and combinations thereof (e.g., Remington The Science and Practice of Pharmacy, 22 nd Ed. Pharmaceutical Press, 2013, pp. 1049-1070 This includes:

[0116] The term "therapeutically effective amount" of a compound of the present disclosure refers to a therapeutically effective amount of a compound that induces a biological or pharmaceutical response in a subject, e.g. For example, reduction or inhibition of enzyme, receptor, ion channel, or protein activity; may induce relief of symptoms, alleviate a condition, slow or delay progression of a disease, or prevent a disease. In one embodiment, a "therapeutically effective amount" refers to the amount of a compound of the present disclosure that will produce a therapeutically effective effect. The term refers to a compound that, when administered to a subject, (1) (i) is mediated by the NR2B receptor, or (ii) associated with NR2B receptor activity, or (iii) NR2B receptor activity (normal characterized by or at least a condition or disorder or disease (2) to partially alleviate, prevent, and / or reverse NR2B receptor agonists; (3) to decrease or inhibit receptor activity; or (4) to decrease the expression of NR2B receptors. In another embodiment, the amount of a compound of the present disclosure effective to inhibit or inhibit the The term "therapeutically effective amount" refers to a therapeutically effective amount of a cell or tissue or non-cellular biological material, or culture medium. at least partially reduce or inhibit NR2B receptor activity when administered to or at least partially reducing or inhibiting the expression of NR2B receptors. As shown in the above embodiments with respect to the NR2B receptor, The meaning of the term "therapeutically effective amount" as used herein is the same as that of any other suitable protein / peptide / The same applies to enzymes / receptors / ion channels, such as NMDA receptors.

[0117] As used herein, the term "subject" refers to a primate (e.g., human, male) (male or female), dogs, rabbits, guinea pigs, pigs, rats, and mice. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human. is.

[0118] As used herein, the terms "inhibit," "inhibition," or "inhibiting" The term "treatment" refers to the reduction or inhibition of a given condition, symptom, or disorder or disease, or refers to a significant decrease in the baseline activity of a biological activity or process.

[0119] As used herein, any disease or disorder can be "treated" or "treated" in any manner. and" or the terms "treatment" and "treatment" mean the alleviation or amelioration of a disease or disorder. (i.e., delaying or preventing the onset of a disease or at least one of its clinical symptoms) or diseases or conditions, including those that the patient may not be able to identify. reduces or at least one physical parameter or biomarker associated with the disorder It means to improve.

[0120] As used herein, any disease or disorder can be "prevented" or "prevented." and" or the term "prevention" therein means the prophylactic treatment of a disease or disorder; or Or it refers to delaying the onset or progression of a disorder.

[0121] As used herein, it refers to a condition in which a subject is biologically, medicinally, or otherwise affected by such treatment. or quality of life, such subjects may be treated. It "requires" placement.

[0122] As used herein, the terms "a," "an," "the," and "the" refer to Similar terms used in the context of the disclosure (especially in the context of the claims) are Unless otherwise indicated in the specification or clearly contradicted by context, the singular and plural should be interpreted as covering both

[0123] All methods described herein are described in detail unless otherwise indicated herein or They may be performed in any suitable order unless clearly contradicted by the context. Any and all examples or exemplary language provided (e.g., "such as" The use of "") is intended merely to clarify the present disclosure and is not intended to be a substitute for the separately claimed invention. It is not intended to limit the scope of the disclosure.

[0124] Any asymmetric atoms (e.g., carbon, etc.) of the compounds of the present disclosure may be present in racemic or enantiomeric forms. It may be enriched, for example, in the (R)-, (S)-, or (R,S)-configuration. In certain embodiments, each asymmetric atom may be in the (R)- or (S)-configuration. at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% Enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess Substituents on atoms with unsaturated double bonds should be substituted, if possible, with silyl groups. It may exist in the se-(Z)- or trans-(E)-form.

[0125] Thus, as used herein, compounds of the present disclosure include all possible stereoisomers, In the form of one of the rotamers, atropisomers, tautomers, or mixtures thereof substantially pure geometric (cis or trans) stereoisomers, diastereomers as antipodes, optical isomers (antipodes), racemates, or mixtures thereof. That's fine.

[0126] Any resulting mixture of stereoisomers may be classified based on the physicochemical differences of the constituent components, e.g. For example, pure or substantially pure hydroxybenzoates may be prepared by chromatography and / or fractional crystallization. They may be separated into geometric or optical isomers, diastereomers, and racemates.

[0127] Any resulting racemates of the compounds or intermediates of the present disclosure may be purified by known methods, e.g. For example, the diastereomeric salts obtained with optically active acids or bases can be separated and then subjected to isotopic separation. It can be resolved into optical antipodes by the addition of optically active acidic or basic compounds. Thus, in particular, the basic moiety may be, for example, an optically active acid, such as tartaric acid, dibenzoyl diacetyltartaric acid, di-O,O'-p-toluoyltartaric acid, mandelic acid, phosphorus Fractional crystallization of salts formed with camphor-10-sulfonic acid or camphor-10-sulfonic acid may be used to resolve the compounds of the present disclosure into their optical antipodes. The compounds or racemic intermediates of the present disclosure may also be purified by chiral chromatography, e.g., chiral absorption chromatography. The separation can be achieved by high pressure liquid chromatography (HPLC) using a solvent.

[0128] The present disclosure does not include any method using available intermediates as starting materials at any stage of the process. The remaining steps are carried out using the starting material or the starting material is formed in situ under the reaction conditions. or the reaction components are used in the form of their salts or optically pure materials, The compounds and intermediates of the present disclosure may also be readily apparent to those skilled in the art. They may be converted into one another according to commonly known methods.

[0129] Pharmaceutical Composition In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof. and a physiologically acceptable carrier. is a mixture of at least two pharmaceutically acceptable carriers, e.g., Pharmaceutical compositions may be administered by a particular route, such as oral administration, parenteral administration (e.g., by injection, infusion, transdermal, or topical administration), and may be formulated for rectal administration. Topical administration may also involve inhalation or intranasal application. The pharmaceutical compositions of the present disclosure comprise: Solid forms (including but not limited to capsules, tablets, pills, granules, powders, or suppositories) or in liquid form (including but not limited to solutions, suspensions, or emulsions) Tablets may be prepared by filling according to methods known in the art. Typically, the pharmaceutical composition may be coated with either a soluble or enteric coating. is a tablet or gelatin capsule containing the active ingredient together with one or more of the following: is: a) diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, thol, cellulose, and / or glycine; b) lubricants, such as silica, talcum, stearic acid, its magnesium or calcium sodium salts, and / or polyethylene glycol; in the case of tablets, additionally c) binders, such as magnesium aluminum silicate, starch paste, gelatin, Tragacanth, methylcellulose, sodium carboxymethylcellulose, and / or or polyvinylpyrrolidone; as needed d) disintegrating agents, such as starch, agar, alginic acid or its sodium salt, or granules; foaming mixture; and e) Adsorbents, colouring agents, flavouring agents and sweeteners.

[0130] How to use The compounds of the present disclosure, either in free form or in pharmaceutically acceptable salt form, possess beneficial pharmacological properties. NR2B receptor modulating properties, e.g., as described in the next section. and as shown in in vitro and in vivo tests, e.g. It exhibits properties as a negative allosteric modulator of the NR2B receptor and is therefore a potential therapeutic Adapted for use in therapy or as a research chemical, e.g., as a tool compound do.

[0131] The compounds of the present disclosure are useful in treating Parkinson's disease, Huntington's disease, Rett syndrome, amyotrophic lateral sclerosis, and other conditions. dementia, multiple sclerosis, seizure disorders, autism, autism spectrum disorders, fragile X syndrome, tuberculosis Symptoms include: muscular sclerosis, Down syndrome, pain, migraine, tinnitus, bipolar disorder, obsessive-compulsive disorder, anxiety disorder, and Post-traumatic stress disorder (PTSD), cocaine use disorder, major depressive disorder, refractory or It may be useful in the treatment of indications selected from treatment-resistant depression, or suicidality. The compounds of the present disclosure are useful for treating major depressive disorder, refractory or treatment-resistant depression, and suicidality. They may be useful in the treatment of selected indications.

[0132] Thus, in a further aspect, the present disclosure provides a compound of the present disclosure or its derivatives in therapeutic methods. In a further embodiment, the treatment comprises administering to a subject a therapeutically acceptable salt of NR 2B receptor negative allosteric modulation. In another embodiment, the disease is selected from the foregoing list.

[0133] Thus, in a further aspect, the present disclosure provides a method for producing a medicament using a compound of the present disclosure. or a pharmaceutically acceptable salt thereof. Diseases that can be treated by negative allosteric modulation of NR2B receptors In another embodiment, the disease is selected from the foregoing list. do.

[0134] In one embodiment of the present disclosure, Parkinson's disease, Huntington's disease, Rett syndrome, Amyotrophic lateral sclerosis, multiple sclerosis, seizure disorders, autism, autism spectrum disorders, frailty X syndrome, tuberous sclerosis, Down syndrome, pain, migraine, tinnitus, bipolar disorder, obsessive-compulsive disorder , anxiety disorders, post-traumatic stress disorder (PTSD), cocaine use disorders, major depressive disorder , refractory or treatment-resistant depression, or suicidality, In particular, compounds of the formula (I) are useful for treating major depressive disorder, refractory or treatment-resistant depression, or suicide. There is provided a compound of formula (I) for use in the treatment of psoriasis.

[0135] The pharmaceutical composition or combination of the present disclosure may be administered in a dose of about 50 to 70 kg of active ingredient. A unit dosage of 1 to 1000 mg, or about 1 to 500 mg of the active ingredient, or about 1 to 250 mg, or approximately 1 to 150 mg, or approximately 0.5 to 100 mg, or The compound, pharmaceutical composition, or the like may be in a unit dosage of about 1 to 50 mg. The therapeutically effective dosage of the combination will depend on the species, weight, age, and individual condition of the subject, the type of compound being treated, and the dosage of the compound. The decision of a physician of ordinary skill will depend on the underlying disorder or disease and its severity. If you are a clinician or veterinarian, you may be interested in: The effective amount of each of the active ingredients required can be readily determined.

[0136] The above-listed dosage characteristics are advantageously administered to mammals, e.g., mice, rats, dogs, monkeys, or in vitro and using isolated organs, tissues, and preparations thereof The compounds of the present disclosure may be administered in the form of a solution, e.g., an aqueous solution. in vitro and orally, parenterally, advantageously intravenously, e.g., in suspensions It may be applied in vivo as is or in aqueous solution. is about 10 -3 Molar concentration to 10 -9 The molar concentration may range between. The therapeutically effective amount in the present invention is between about 0.1 and 500 mg / kg or between about 1 and 500 mg / kg, depending on the route of administration. The dose may range between 100 mg / kg and 100 mg / kg.

[0137] combination A "combination" may be a fixed combination in a single dosage unit form or a combination of a compound of the present disclosure with A combination partner (e.g., another drug, a "therapeutic agent," or an "adjunct agent," as described below) (also called "nt") independently, simultaneously, or within a time interval, especially in combination with separately, with a time interval that allows the toners to exert a joint effect, e.g., a synergistic effect. The single components may be packaged in a kit or individually. One or both of the components (e.g., powder or liquid) may be mixed to provide the desired dosage. The term "simultaneous administration" or "combined administration" is used interchangeably with "administration in combination." The term, as used herein, refers to a selected combination partner that requires It is meant to encompass administration to a single subject (e.g., patient), and the drug is not necessarily administered to the same person. It is intended to include treatment regimens that are not administered by or simultaneously with other routes of administration. The term "pharmaceutical combination" as used herein means more than one means a product resulting from mixing or combining therapeutic agents that are a fixed combination of therapeutic agents. The term "fixed combination" includes both fixed and non-fixed combinations of therapeutic agents, e.g., The indicated compound and combination partner are both administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" refers to a combination of therapeutic agents, e.g., compounds of the present disclosure, administered in a non-fixed combination. The compound and combination partner are administered to the patient simultaneously, together, or individually as separate entities. This means that the drug is administered continuously without any time limit, and such administration is The latter provides therapeutically effective levels of two compounds in a cocktail therapy, e.g., 3 It also applies to the administration of more than one therapeutic agent.

[0138] The compounds of the present disclosure may be administered simultaneously with, before, or after one or more other therapeutic agents. The compounds of the present disclosure may be administered individually, by the same or different routes of administration, or The therapeutic agent may be administered together with other agents in the same pharmaceutical composition. have or enhance therapeutic activity when administered to a patient in combination with It may be a chemical compound, a peptide, an antibody, an antibody fragment, or a nucleic acid.

[0139] In one embodiment, the present disclosure provides a method for administering a compound of formula (I) or (II) simultaneously, separately, or sequentially in a therapeutic regimen. A compound of the present disclosure and at least one other therapeutic agent may be used as a combined preparation for use. In one embodiment, the treatment comprises activating a negative allotropic receptor for the NR2B receptor. The present invention relates to the treatment of diseases or conditions mediated by steroid modulation. The provided products include compounds of the present disclosure and other therapeutic agents together in the same pharmaceutical composition. The compounds of the present disclosure may be used in a composition or in separate forms, such as in the form of a kit, containing the compounds of the present disclosure and other therapeutic agents. There are compositions that

[0140] In one embodiment, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure and another therapeutic agent. Optionally, the pharmaceutical composition may comprise a pharmaceutically acceptable carrier as described above. It's okay to be.

[0141] In one embodiment, the present disclosure is a kit comprising two or more separate pharmaceutical compositions. and a kit is provided, at least one of which comprises a compound of the present disclosure. In embodiments, the kit includes means for separately holding the compositions, e.g., containers, Examples of such kits include divided bottles or divided foil packets. Typically, this is a blister pack such as those used to package tablets, capsules, etc. do.

[0142] The kits of the present disclosure may be used to administer different compounds in different dosage forms, e.g., orally and parenterally. to administer the individual compositions at different dosage intervals or to titrate the individual compositions together To aid in compliance, the kits of the present disclosure typically include includes instructions for administration.

[0143] In the combination therapy of the present disclosure, the compound of the present disclosure and the other therapeutic agent may be the same or different. Additionally, the compounds and compositions of the present disclosure may be manufactured and / or formulated by a manufacturer. and other therapeutic agents (i) prior to releasing the combination product to physicians (e.g., (ii) by the physician (or a physician) immediately before administration; (iii) under the supervision of a doctor; (iv) under the supervision of a patient, for example, in combination with a compound of the present disclosure and another therapeutic agent; Subsequent administration may be combined with combination therapy.

[0144] Thus, the present disclosure provides a method for the treatment of NR2B receptor-mediated allosteric modulation of NR2B receptors. Use of a compound of the present disclosure to treat a disease or condition, wherein the medicament is administered in combination with another therapeutic agent. The present disclosure also provides a method for treating a patient suffering from a rheumatoid arthritis, comprising administering to a patient a therapeutically effective amount of a compound selected from the group consisting of hydroxybenzoates, ... and the use of another therapeutic agent to treat a disease or condition mediated by steroid modulation. The present invention provides a method for administering a pharmaceutical agent in combination with a compound of the present disclosure.

[0145] The present disclosure also relates to a method for treating diseases or conditions mediated by negative allosteric modulation of the NR2B receptor. The compounds of the present disclosure for use in a method of treating a condition, wherein the compound is administered in combination with another therapeutic agent. The present disclosure also provides compounds of the present disclosure prepared for the negative action of NR2B receptors. for use in a method of treating a disease or condition mediated by allosteric modulation of another therapeutic agent for administration with the compound of the present disclosure, The present disclosure also provides another therapeutic agent for inhibiting the negative allosteric modulation of the NR2B receptor. and a compound of the present disclosure for use in a method of treating a disease or condition mediated by a steroid. The present disclosure also provides a compound of the present disclosure administered in combination with another therapeutic agent. Treating diseases or conditions mediated by negative allosteric modulation of NR2B receptors another therapeutic agent for use in the method, wherein the other therapeutic agent is administered in combination with a compound of the present disclosure Provide another therapeutic agent to be administered.

[0146] The present disclosure also provides a compound of the present disclosure for treating a disease or condition mediated by the NR2B receptor. Use of a combination of these drugs if the patient has already been treated (e.g., within 24 hours) with another therapeutic agent. The present disclosure also provides a method for treating a disease or condition mediated by the NR2B receptor. the use of another therapeutic agent to treat a patient who has already (e.g., within 24 hours) received a The present invention provides a method for treating a subject with a compound.

[0147] In one embodiment, the other therapeutic agent is selected from: (a) Lithium; (b) Stimulants, e.g., amphetamine and dextroamphetamine (Addera ll(trademark)) or methylphenidate Litalin(trademark); (c) acetylcholinesterase inhibitors, such as donepezil (Aricept™) )), rivastigmine (Exelon™), and galantamine (Razadyn e(trademark)); (d) antidepressant medications for depressed mood and irritability, such as citalopram (Cele xa™), fluoxetine (Prozac™), paroxetine (Paxil™), (trademark), sertraline (Zoloft®), trazodone (Desyrel®), (trademark)), and tricyclic antidepressants, such as amitriptyline (Elavil®); (e) Anxiolytics for anxiety, restlessness, verbal disruptive behavior, and defiant behavior, e.g., For example, lorazepam (Ativan®) and oxazepam (Serax®); (f) Antipsychotic medications for hallucinations, delusions, aggression, agitation, hostility, and uncooperativeness, e.g. , aripiprazole (Abilify™), clozapine (Clozaril™), ), haloperidol (Haldol™), olanzapine (Zyprexa™), )), quetiapine (Seroquel™), risperidone (Risperdal (Trademark)), and ziprasidone (Geodon™); (g) mood stabilizers, such as carbamazepine (Tegretol™) and dival Proex (Depakote™); (h) Pregabalin; (i) gabapentin (Neurontin™); (j) Dopamine agonists, e.g., L-dopa, pramipexole (Mirapex ( trademark), and ropinirole (Requip™); (k) analgesics, including opiates and non-opiates; (k) carbidopa; (l) Triptans, such as sumatriptan (Imitrex™) and Zolmit Liptan (Zomig(TM)); (m) nicotinic alpha-7 agonists; (n) mGluR5 antagonist; (o) H3 agonists; (p) amyloid therapeutic vaccines; and (q) Chemotherapeutic agents.

[0148] In one embodiment of the present disclosure, the compounds may be used simultaneously, separately or sequentially in a therapeutic regimen. and a combination of an NR2B modulator and a combination partner as described above as a combined preparation for use in Products including:

[0149] In another embodiment of the present disclosure, simultaneous, separate or sequential use in therapy and the combination partner as described above as a combined preparation for the treatment of Products including:

[0150] In one embodiment of the present disclosure, the NR2B modulator, the aforementioned combination partner and a pharmaceutically acceptable carrier.

[0151] In a further embodiment of the present disclosure, the NR2B modulator, the aforementioned combination partner and a pharmaceutically acceptable carrier.

[0152] Preparation of compounds The compounds of the present disclosure may be prepared as described in the examples below.

[0153] The intermediates described herein may be prepared as shown in Scheme 1 below.

[0154] [ka]

[0155] In Scheme 1, propargylamine 1 is treated with benzyl chloroformate to give the protected amine. 2 can be obtained, which can then be allylated with allyl bromide to give 4. This can be followed by a Pauson-Kand cycloaddition to give the bicyclic enone 5. This key intermediate can be oxidized at the bridgehead position to give the cis-fused alcohol 6. This can be reduced to diol 7 with control of the relative stereochemistry. 8, where R5 and n are as defined in the claims. The Mitsunobu reaction using the ether proceeds with inversion of stereochemistry, resulting in the desired complete conversion of the ether. is configuration, e.g., 9, is generated and deprotected by hydrogenation to give the free amine, e.g., 10 where R4 is H. Alternatively, 5 can be converted to aryl under Luche conditions. The phenol can be first reduced to the phenol alcohol 11. This type of reaction gives olefins such as 12, which can be di- Hydroxylation can be carried out to give diols such as 13. As previously mentioned, the protection The group can be hydrogenated to give a free amine, such as 10, where R4 is OH. This can be carried out as a racemic mixture, or intermediates 7 or 13 can be converted to their enantiomers. Chiral separation into thiomers may be carried out and these carried through the remainder of the sequence individually.

[0156] The compounds provided herein may be prepared as shown in Scheme 2 below. .

[0157] [ka]

[0158] In Scheme 2, bicyclic compounds such as 14 (wherein R2, B, U, V, W, m, and and n are as defined in the claims) are commercially available , may be prepared via standard chemical transformations as described in the individual procedures. This is often achieved using chloroacetyl chloride and a Lewis acid, such as aluminum chloride. 15 can be directly converted to α-haloketones, e.g., 16, via Friedel-Crafts acylation. Alternatively, 14 can be treated with a brominating reagent, such as N-bromosuccinimide. bromides such as 16 can be obtained by tributyl(1-ethoxyvinyl) sulfonylation. Tannane and palladium-catalyzed Stille coupling affords ketones, e.g., 1 7 can be directly converted to carboxymethyl vinyltrifluoroborate in the presence of a palladium catalyst and a base. Suzuki-Miyaura coupling with sodium affords olefins such as 18, followed by cyclohexanediol. This can also be converted via a two-step process consisting of a Kucker-type oxidation to give 17. This is preferably substituted with a halogenating agent such as benzyltrimethylammonium dichloroiodate. or phenyltrimethylammonium tribromide to give α-haloketones, e.g., 1 5 can be formed by adding a base such as potassium carbonate or N,N-diisopropyl In the presence of propylethylamine, an amine such as 10 (where R4, R5, and n are as defined in the claims) to effect nucleophilic substitution with the keto 19 can be obtained by using chiral catalysts such as RuCl(p-cymene). )[(S,S)-Ts-DPEN] was reduced with formic acid and triethylamine. This allows for the production of examples with high levels of diastereoselectivity, such as 20. Alternatively, a reducing agent such as sodium borohydride may be used to produce a mixture of diastereomers. This gives, for example, 20, which can be purified by chiral chromatography. The compound may be separated into a single diastereomer.

[0159] Alternatively, the compounds can be prepared as shown in Scheme 3 below.

[0160] [ka]

[0161] In Scheme 3, the Cbz protecting group of 7 is removed by hydrogenation to give the free amine 21. This can be converted into an α-haloketone, such as 15 (wherein R2, B, U, V, W, m and n is as defined in the claims) to form a keto This may give phenols such as 8 (where R5 and n are The Mitsunobu reaction is carried out using a keto 23 may be formed using a reducing agent such as sodium borohydride. and reduction to give a mixture of diastereomers, e.g., 24, which may be separated into single diastereomers by chiral chromatography.

[0162] Alternatively, the compounds can be prepared as shown in Scheme 4 below.

[0163] [ka]

[0164] In Scheme 4, an olefin, such as 18 (wherein R, B, U, V, W, m, and n is as defined in the claims) is N-bromosuccinimide Treatment with 25 and water gives the bromohydrin, e.g., 25. , for example, in the presence of N,N-diisopropylethylamine, an amine such as 10 (wherein R 4, R5 and n are as defined in the claims. Nuclear displacement can be carried out to give a mixture of diastereomers, e.g., 20, This may be separated into single diastereomers by chiral chromatography.

[0165] Alternatively, the compounds can be prepared as shown in Scheme 5 below.

[0166] [ka]

[0167] In Scheme 5, an alcohol, such as 25 (wherein R, B, U, V, W, m, and n is as defined in the claims) with a base, e.g., imidazoline. The silyl ethers were obtained by protection using tert-butyldimethylsilyl chloride in the presence of methylsilane. To this, a base such as N,N-diisopropylethyl ether can be added to give a methyl group such as 26. In the presence of a methylamine, an amine such as 10 (wherein R4, R5 and n are as defined in the claims) can be reacted with a methyl group. ) to give an intermediate, such as 2 7 can be obtained by the addition of an acid, such as hydrochloric acid, in an alcoholic solvent, such as methanol. or decomposed with a fluoride source, e.g., tetra-n-butylammonium fluoride. Upon protection, a mixture of diastereomers such as 20 can be obtained, which can be converted to The single diastereomers may be separated by chiral chromatography.

[0168] Alternatively, the compounds can be prepared as shown in Scheme 6 below.

[0169] [ka]

[0170] In Scheme 6, heterocycles such as 28 (where R2, B, V, and n are as defined in the patent) are prepared. as defined in the claims) may be a base, e.g. sodium hydride and and tosyl chloride to give the tosyl-protected heterocycle 29. This was then reacted with potassium vinyltrifluoroborate in the presence of a palladium catalyst and a base. A Suzuki-Miyaura coupling may then be carried out to give an olefin, such as 30, which may then be , N-bromosuccinimide, water, and an acid, such as acetic acid, followed by a base, such as charcoal The epoxide of 31 can be converted to an epoxide such as 31 by treatment with sodium hydroxide. is an amine, such as 10, where R4, R5 and n are as defined in the claims. ring-opening via nucleophilic attack by 3 2 can then be obtained. The tosyl group can then be removed using a base, e.g., sodium hydroxide. Removal can give a mixture of diastereomers, such as 33, which can be obtained by The single diastereomers may be separated by chiral chromatography.

[0171] Intermediates and Examples The following examples are intended to illustrate the present disclosure and should not be construed as limiting thereof. It's not that.

[0172] In many cases, they are prepared as mixtures of two or four stereoisomers and then purified as single The isomers were separated and these were analyzed using the NR2B rat steroids described in the Biological Data section below. All enantiomers were tested individually in a cortical neuron calcium influx assay. The stereochemistry of Example 1A was determined by single-crystal X-ray crystallography. The chemistry has led to the development of 6-((R)-1-hydroxy-2-((3aS,5 S,6aR)-3a-hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrro (2(1H)-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one It was determined that

[0173] [ka]

[0174] The crystal structure, structure-activity relationship analysis, chemical correlations, and WO2016 / 049165 From the findings of A1, in all cases, the hexahydrocyclopenta[c]pyrrole core [or or R4 is OH, (3aS,4S,5S,6aR) configuration] 6aR) configuration is the (3aR,5R,6aS) configuration [or if R4 is OH, (3a R, 4R, 5R, 6aS) configuration]. 6aR) [or (3aS,4S,5S,6aR)] configuration is a more active configuration. There is strong evidence to suggest that (3aR, 5R, 6aS) [or (3a R,4R,5R,6aS)] configuration may be highly active in some cases. The possibility still exists.

[0175] Within a series of examples where the stereochemistry of each example has not been fully determined, possible names and The chemical structures are listed according to their geometrical arrangement. Compounds containing the (3aS,4S,5S,6aR) [or (3aS,4S,5S,6aR)] core are R,5R,6aS) [or (3aR,4R,5R,6aS)] core-containing compounds The benzylic alcohols are listed in the R configuration (as shown, "up"). The compound with the S-configuration (as shown) is the benzylic alcohol. The order is given by the sequence of Within the examples, it does not necessarily correspond to an A / B or A / B / C / D order (A / The order B or A / B / C / D generally refers to the order in which compounds were obtained from chiral separation ).

[0176] For illustrative purposes, within the set of examples 5A / 5B / 5C / 5D, four possible names are and the chemical structures are listed as follows: 6-((R)-2-((3aS,5S,6aR)-5-(2-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy Hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one 6-((S)-2-((3aS,5S,6aR)-5-(2-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy Hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one 6-((R)-2-((3aR,5R,6aS)-5-(2-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy Hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one 6-((S)-2-((3aR,5R,6aS)-5-(2-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy Hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one

[0177] [ka]

[0178] In this case, Examples 5C and 5D show the NR2B rat cortical neuron calcium influx assay. It is more potent than Examples 5A and 5B in the α-amino acid group, and therefore (3aS, 5S, 6aR ) core, likely corresponding to the top two structures listed, with four possible Certain names and structures follow the ordering system used throughout the examples. are still listed in this order.

[0179] Abbreviation Abbreviations used are conventional in the art or are as follows: Ac Acetyl ACN Acetonitrile AcOH acetic acid ADDP 1,1'-(azodicarbonyl)dipiperidine aq aqueous solution atm atmospheric pressure BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl Bn Benzyl Boc tert-butyloxycarbonyl Bu butyl B2(pin)2 Bis(pinacolato)diboron C Celsius Cbz Carboxybenzyl CDI Carbonyldiimidazole Concentrated DCM dichloromethane DEA Diethylamine DIAD Diisopropyl azodicarboxylate DIPEA N,N-Diisopropylethylamine DMF N,N-dimethylformamide DMSO dimethyl sulfoxide DMT Dimercaptotriazine DPEN 1,2-Diphenylethylenediamine dppf 1,1'-bis(diphenylphosphino)ferrocene Et Ethyl EtOAc ethyl acetate EtOH ethanol Et2O diethyl ether FCC flash column chromatography g grams h time HBSS Hanks' Balanced Salt Solution HPLC High Performance Liquid Chromatography IACUC Institutional Animal Care and Use Committee and Use Committee) I C 50 50% maximum inhibitory concentration IPA Isopropyl Alcohol L liters LAH Lithium aluminum hydride LCMS Liquid Chromatography and Mass Spectrometry LiHMDS Lithium hexamethyldisilazide m-CPBA meta-chloroperbenzoic acid Me methyl MeOH Methanol mg milligram MHz Megahertz min mL milliliter mm millimeters mM millimolar concentration mmol millimole MS mass spectrometry MTBE Methyl tert-butyl ether m / z mass-to-charge ratio NADPH Nicotinamide adenine dinucleotide phosphate NBS N-Bromosuccinimide nm nanometer nM nanomolar NMO N-methylmorpholine N-oxide NMP N-methyl-2-pyrrolidone NMR nuclear magnetic resonance Pd / C Palladium on carbon PE Petroleum Ether PG protecting group Ph Phenyl PMB para-methoxybenzyl ppm (parts per million) rac racemic Rf retention factor Rt retention time RT room temperature SFC Supercritical Fluid Chromatography TBAF Tetra-n-butylammonium fluoride TBS tert-butyldimethylsilyl t-Bu tert-butyl t-BuOH tert-butanol TEA Triethylamine TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography TMTU N,N,N,N-Tetramethylthiourea Ts Tosil μL microliter μm micrometer; micron μM micromolar UPLC Ultra High Performance Liquid Chromatography UV ultraviolet light

[0180] General Procedure Where no preparative route is described, materials are commercially available. Commercially available reagents are not specifically described. Unless otherwise specified, the product was used without further purification. Room temperature (RT) is approximately 20-25°C. 1 HNMR was performed using a 300MHz Varian, a 400MHz Varian, or a 400 The chemical shifts were recorded on a 300 MHz Bruker NMR instrument. Coupling constants (J) are reported in Hertz. The abbreviations for multiplicities are: s = singlet, d = doublet, t = triplet, q = triplet. = quartet, dd = doublet of doublets, dt = doublet of triplets, br =Broad.

[0181] LCMS method A: Instrument: Waters Acquity UPLC, photodiode array detector; Serial: AcQuity UPLC BEH C 18 1.7 μm, 2.1 × 30 mm; Run time 2 min, 2% solvent B 0 to 0.1 min, 2 → 98% solvent B 0.1 to 1.8 min, 2 % solvent B for 0.2 min. Solvents: solvent A = 0.1% formic acid in water (v / v), solvent B = acetonitrile 0.1% formic acid in nitrile (v / v); injection volume 2–5 μL; UV detection array 210–4 00 nm; mass detection 120-1250 (electrospray ionization); column 50°C; Flow rate 1.0mL / min.

[0182] LCMS method B: Instrument: Waters Acquity UPLC, photodiode array detector; AcQuity UPLC BEH C 18 1.7μm 21×30mm; when running 5.2 min, 2 → 98% solvent B 0 to 5.15 min, 98% solvent B 5.15 to 5.2 0 min. Solvents: Solvent A = 0.1% formic acid in water (v / v), Solvent B = 0. 1% formic acid (v / v); injection volume 2–5 μL; UV detection array 210–400 nm; mass detection Output 120-1600; column 50°C, flow rate 1.0 mL / min.

[0183] LCMS method C: Instrument: Waters Acquity UPLC, photodiode array detector; Serial: AcQuity UPLC BEH C 18 1.7 μm, 21 × 30 mm; run Time 1.2 min, 2% solvent B 0 to 0.1 min, 2 → 80% solvent B 0.1 to 0.5 min, 80 → 95% solvent B 0.5 to 0.6 min, 95% solvent B 0.6 to 0.8 min, 95 → 2% solvent B 0.8 to 0.9 min, 2% solvent B 0.9 to 1.20 min. Solvent: Solvent A = Solvent A = 0.05% formic acid in water (v / v), solvent B = 0.04% formic acid in methanol (v / v). UV detection array 200-300 nm; mass detection 100-1600 (electrospray ionization); column 55°C; flow rate 1.0 mL / min.

[0184] LCMS method D: Instrument: API 2000, photodiode array detector; Column: Synergi 2.5 micron MAX-RP 100A Mercury; Run time 3.0 minutes, 30% melt Solvent B 0 to 0.5 min, 30 → 95% solvent B 0.5 to 1.5 min, 95% solvent B 1. 5 to 2.4 min, 95 to 30% solvent B 2.4 to 2.5 min, 30% solvent B 2.5 to 3.0 min. Solvents: Solvent A = 0.1% formic acid in water (v / v), Solvent B = acetonitrile. U V detection array 190-400; mass detection 100-1000 (electrospray ionization) ); Column 30°C; flow rate 2.0 mL / min.

[0185] LCMS method E: Instrument: API 2000, photodiode array detector; Column: Synergi 2.5 micron MAX-RP 100A Mercury; Run time 4.0 minutes, 20 to 5 0% solvent B 0.0 to 0.2 min, 50 to 95% solvent B 0.2 to 1.0 min, 95% solvent B Solvent B 1.0 to 2.5 min, 95 to 50% Solvent B 2.5 to 2.9 min, 50 to 20% Solvent B 2.9 to 3.2 min, 20% solvent B 3.2 to 4.0 min. Solvents: Solvent A = in water 0.1% formic acid (v / v), solvent B = acetonitrile. UV detection array 190-400; quality Quantity detection 100-1000 (electrospray ionization); column 30°C; flow rate 1.4 m L / min.

[0186] LCMS method F: Equipment: Shimadzu Nexera LCMS-2020, photodiode array Detector; Column: Synergi 2.5 micron MAX-RP 100A Merc ury (20 × 4 mm); run time 3.0 min, 5% solvent B 0 to 0.5 min, 5 to 95% Solvent B 0.5 to 1.0 min, 95% Solvent B 1.0 to 1.5 min, 95 → 5% Solvent B 1.5 to 2.0 min, 5% solvent B 2.0 to 3.0 min. Solvents: Solvent A = 0.1% in water Formic acid (v / v), solvent B = 0.1% formic acid (v / v) in acetonitrile. UV detection array 200-400; Mass detection 100-1000 (electrospray ionization); Column 4 0°C; flow rate 2.0mL / min.

[0187] LCMS method G: Instrument: API 3000, photodiode array detector; Column: Synergi 2.5 micron MAX-RP 100A Mercury; Run time 3.0 minutes, 10 to 2 0% solvent B 0.0 to 0.5 min, 20 to 95% solvent B 0.5 to 1.5 min, 95% solvent B Solvent B 1.5 to 2.0 min, 95 to 10% solvent B 2.0 to 2.5 min, 10% solvent B 2.5 to 3.0 min, 20% solvent B 3.2 to 4.0 min. Solvents: Solvent A = 0.1 in water % formic acid (v / v), solvent B = acetonitrile. UV detection array 190-400; mass detection 100-1000 (electrospray ionization); column 30°C; flow rate 1.4 mL / min .

[0188] LCMS method H: Instrument: Waters Acquity UPLC, photodiode array detector; Ram: SunFire C18 3.5μm 3.0×30mm; Run time 2.2min, 5 → 95% solvent B 0.0 to 1.7 min, 95% solvent B 1.7 to 2.0 min, 95 → 5% Solvent B 2.0 to 2.1 min, 5% Solvent B 2.1 to 2.2 min. Solvents: Solvent A = in water 0.05% TFA (v / v), solvent B = acetonitrile. UV detection array 200-400 nm; mass detection 150-1600 (electrospray ionization); column 40°C; flow rate 2.0mL / min.

[0189] LCMS Method I: Column: Kinetex EVO C18 2.1 x 30 mm, 5 μm; Run time 1. 5 min, 5 → 95% solvent B 0.0 to 0.8 min, 95% solvent B 0.8 to 1.2 min, 9 5 → 5% solvent B 1.2 to 1.21 min, 5% B 1.21 to 1.5 min. Solvent: Solvent A = 0.05% NH3·H2O in water (v / v), Solvent B = acetonitrile. Mass Detection 10 0-1000 (electrospray ionization); column 40°C; flow rate 1.5 mL / min.

[0190] LCMS method J: Column: Chromolith Flash RP-18e 25 x 2 mm; Run Time 1.5 min, 5% solvent B 0.0 to 0.01 min, 5 → 95% solvent B 0.01 to 0.8 min 0 min, 95% solvent B 0.80 to 1.2 min, 95→5% solvent B 1.2 to 1.21 min , 5% B 1.21 to 1.5 min. Solvents: Solvent A = 0.0375% TFA in water (v / v ), Solvent B = 0.01875% TFA in acetonitrile (v / v). Mass detection 100~ 1000 (electrospray ionization); column 50°C; flow rate 1.5 mL / min.

[0191] LCMS method K: Instrument: Waters Acquity UPLC, photodiode array detector; Serial: AcQuity UPLC BEH C 18 1.7 μm, 2.1 × 30 mm; Run time 2 min, 2% solvent B 0 to 0.1 min, 2 → 98% solvent B 0.1 to 1.8 min, 2 % Solvent B for 0.2 min. Solvents: Solvent A = 5 mM ammonium hydroxide in water, Solvent B = acetone 5 mM ammonium hydroxide in azonitrile. Injection volume 2-5 μL; UV detection array 210 ~400 nm; mass detection 120-1250 (electrospray ionization); column 50 °C; flow rate 1.0 mL / min.

[0192] LCMS method L: Column: Chromolith Flash RP-18e 25 x 2 mm; Run Time 1.5 min, 0% solvent B 0.0 to 0.01 min, 0 to 60% solvent B 0.01 to 0.8 0 min, 60% solvent B 0.80 to 1.2 min, 60→0% solvent B 1.2 to 1.21 min , 0% B 1.21 to 1.5 min. Solvents: Solvent A = 0.0375% TFA in water (v / v ), Solvent B = 0.01875% TFA in acetonitrile (v / v). Mass detection 100~ 1000 (electrospray ionization); column 50°C; flow rate 1.5 mL / min.

[0193] Synthesis of Intermediates and Examples Intermediate 1 (3aS,5S,6aR)-5-phenoxyhexahydrocyclopenta[c]pyrrole- 3a(1H)-All (3aR,5R,6aS)-5-phenoxyhexahydrocyclopenta[c]pyrrole- 3a(1H)-All A racemic mixture of

[0194] [ka]

[0195] Step 1: Benzyl prop-2-yn-1-yl carbamate

[0196] [ka] Benzyl chloroformate (273 g, 1.60 mol) was dissolved in ethanol / water (2.4 L, 1 Propargylamine (80 g, 1.45 mol) and NaHCO3 in HCl (1:1, v / v) (243.6 g, 2.9 mol) was added dropwise at 0°C for 2 hours at 0°C and then at 25°C. After stirring for 12 hours, the mixture was diluted with water (1.0 L) and extracted with MTBE (1.0 L). The phases were separated and the aqueous layer was extracted with MTBE (500 mL x 2). The combined organic layers were washed with anhydrous N Drying over a2SO4, filtering and evaporating afforded the title intermediate (280 g, crude) as a yellow solid. Obtained as a solid which was used without purification. 1 H NMR (400 MHz, CDCl3) δ7.38-7.32 (m, 5H), 5.24-5.08 (m, 3H), 4.05-3.93 (m, 2H ), 2.26 (s, 1H).

[0197] Step 2: Benzyl allyl(prop-2-yn-1-yl)carbamate

[0198] [ka] NaH (60% in mineral oil, 39 g, 0.98 mol) was dissolved in benzoyl benzoate in THF (2.0 L). prop-2-yn-1-yl carbamate (155 g, 0.817 mol) and bromide A solution of allyl (149 g, 1.23 mol) was added at 0°C and the reaction was stirred at 25°C for 2 hours. The mixture was quenched with saturated aqueous NH4Cl (500 mL) and the aqueous layer was washed with EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The crude material was purified by FCC (10% EtOAc:PE) to give the title intermediate (135 g) was obtained as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ7.44-7.31 (m, 5H), 5.87-5.74 (m, 1H), 5.29-5.15 (m, 4H ), 4.17-3.96 (m, 4H), 2.23 (s, 1H).

[0199] Step 3: (±)-Benzyl 5-oxo-3,3a,4,5-tetrahydrocyclopene ta[c]pyrrole-2(1H)-carboxylate

[0200] [ka] Benzylallyl(prop-2-yn-1-yl)carbamate in toluene (1.0 L) (20 g, 89.6 mmol) and N,N,N,N-tetramethylthiourea (5.8 9 g, 44.5 mmol) to a solution of Co2(CO)8 (7.6 g, 22.4 mmol) was added under 1 atm CO pressure at 25° C. The solution was heated to 80° C. and stirred for 3 h. The reaction mixture was cooled to room temperature, filtered through a pad of celite and concentrated. The crude material was purified by FC C (15-50% EtOAc:PE) to give the title intermediate (12 g) as a colorless oil. was obtained as. 1 H NMR (400 MHz, CDCl3) δ7.38-7.33 (m, 5H), 6.11-6.07 (m, 1H), 5.21-5.14 (m, 2H ), 4.36-4.28 (m, 2H), 4.18-4.11 (m, 1H), 3.28-3.26 (m, 1H), 2.97-2.92 (m, 1H), 2 .68-2.64 (m, 1H), 2.23-2.19 (m, 1H).

[0201] Step 4: Benzyl (3aS,6aR)-3a-hydroxy-5-oxohexahydrocyclopenta[4-(2-hydroxy-1,2-dioxo-2,2-dioxo ... [c]pyrrole-2(1H)-carboxylate Benzyl (3aR,6aS)-3a-hydroxy-5-oxohexahydrocyclopenta[4-(2-hydroxy-1,2-dioxo-2,2-dioxo ... [c]pyrrole-2(1H)-carboxylate A racemic mixture of

[0202] [ka] 2-Methyltetrahydrofuran (125 mL) was purged with nitrogen for 10 minutes, then Cu Cl (485 mg, 4.9 mmol) and rac-BINAP (3.03 g, 4.9 m After 5 min, NaOt-Bu (470 mg, 4.9 mmol) and Bis(pinacolato)diboron (30 g, 117 mmol) was added and the reaction was further purged with nitrogen. Purged for 15 minutes. (±)-Benzyl in 2-methyltetrahydrofuran (125 mL). 5-oxo-3,3a,4,5-tetrahydrocyclopenta[c]pyrrole-2(1H) A solution of 25g of 2-carboxylate (25g, 97mmol) was added and the reaction was heated under nitrogen at room temperature. The reaction was stirred at rt for 2 h. The reaction was cooled to 10 °C and MeOH (6.25 g, 7.89 mL, 1 94 mmol) was added. This was stirred for 10 minutes, then warmed to room temperature for 30 minutes, and then The mixture was cooled again by 10°C. NaOH (4.66g, 117mmol) was added, followed by 3 A 0% aqueous solution of H2O2 (33 g, 99 mL, 292 mmol) was added dropwise, and the mixture was stirred for 50 minutes. It was diluted with water (150 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with saturated aqueous sodium thiosulfate (100 mL) and NaSO The crude material was purified by FCC (0-100% EtOAc:PE) and then dried over 4°C, filtered, and concentrated. to afford the title intermediate (20 g, 90% purity) as a pale yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ7.43-7.24 (m, 5H), 5.55 (s, 1H), 5.12-4.99 (m, 2H), 3.79-3.65 (m, 1H), 3.53-3.38 (m, 2H), 3.22-3.11 (m, 1H), 2.70-2.62 (m, 1H), 2.58 -2.52 (m, 1H), 2.34-2.29 (m, 1H), 2.17-2.06 (m, 1H). 1H under the solvent peak.

[0203] Step 5: Benzyl(3aS,5R,6aR)-3a,5-dihydroxyhexahydrocyclopenta [c]pyrrole-2(1H)-carboxylate Benzyl (3aR,5S,6aS)-3a,5-dihydroxyhexahydrocyclopenta [c]pyrrole-2(1H)-carboxylate A racemic mixture of

[0204] [ka] Benzyl (3aS,6aR)-3a-hydroxy-5-oxoacetate in THF (200 mL) Hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate and benzoate Di(3aR,6aS)-3a-hydroxy-5-oxohexahydrocyclopenta[c ]pyrrole-2(1H)-carboxylate (20 g, 62.48 mmol, 90% purity) ) to a solution of the racemic mixture of LiAlH(Ot-Bu)3 (124.9 mL, 124.9 A solution of 1.0 mmol, 1.0 M in THF was added dropwise at 0° C. The reaction was warmed to 25° C. and stirred for 2 h. The reaction mixture was added dropwise to a saturated solution of NH4Cl (100 mL) at 0°C. The residue was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with saturated brine (100 ml). The organic layer was dried over Na2SO4 and concentrated. The crude material was purified by FCC (0- 15% MeOH:DCM) to give the title intermediate (16 g) as a colorless oil . LCMS: Rt 0.56 min; MS m / z 278.1 [M+H] + ; Method J. 1 H NMR (400 MHz, DMSO-d6) δ7.39-7.29 (m, 5H), 5.06-5.01 (m, 3H), 4.67-4.65 (m, 1H), 4.28-4.19 (m, 1H), 3.65-3.52 (m, 2H), 3.38-3.34 (m, 1H), 3.27-3.17 (m, 1H), 2.32-2.13 (m, 2H), 2.05-1.92 (m, 1H), 1.73-1.64 (m, 1H), 1.29-1.16 (m, 1H).

[0205] Step 6: Benzyl (3aS,5S,6aR)-3a-hydroxy-5-phenoxyhexahydrochloride Clopenta[c]pyrrole-2(1H)-carboxylate Benzyl (3aR,5R,6aS)-3a-hydroxy-5-phenoxyhexahydrochloride Clopenta[c]pyrrole-2(1H)-carboxylate A racemic mixture of

[0206] [ka] In a dry reaction flask, add triphenylphosphine (12.58 g, 48.0 mmol). , anhydrous THF (100 mL), and phenol (4.84 g, 51.4 mmol) were dissolved in nitrogen. Benzyl (3a) in anhydrous THF (10.5 mL) was added under vacuum at ambient temperature with stirring. S,5R,6aR)-3a,5-dihydroxyhexahydrocyclopenta[c]pyrrole -2(1H)-carboxylate and benzyl (3aR,5S,6aS)-3a,5- Dihydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (9.5 g, 34.3 mmol) of the racemic mixture was added and the solution was cooled in an ice bath. A solution of DIAD (9.32 mL, 48.0 mmol) in water (50 mL) was added to 15 mL of THF. The mixture was added dropwise over 20 minutes with vigorous stirring, and the pale yellow color persisted when the addition was complete. During the reaction, the maximum internal temperature reached approximately 14°C and the reaction was aged in the bath for 45 minutes. The reaction was quenched with water (50 mL) and the mixture was stirred for about 30 minutes. The organic layer was diluted with water (100 mL) and washed twice with water (50 mL). Back-extract with EtOAc (100 mL) and the combined organic extracts were washed with saturated brine (2 × 100 m L), then dried over Na2SO4, filtered, and concentrated to a yellow oil. Trituration with Et2O (100 mL) gave an off-white precipitate, and the mixture was stirred in an ice / water bath. The mixture was stirred, and heptane (50 mL) was added dropwise with vigorous stirring. The precipitate was collected and The pale yellow solid product was first separated by rotary evaporation at 35°C and washed with 2:2 heptane / Et2O. By rotating on an evaporator, then reconstitute with EtO with stirring overnight at room temperature. The slurry was filtered and all the filtrates were combined. The filtrate / washing liquid was concentrated. The yellow oil was treated with Et2O / heptane (2:1) and FCC (10-6 Purification with 0% EtOAc:hexanes gave the title intermediate (11.46 g). LCMS: Rt 2.29 min; MS m / z 354.4 [M+H] + ; Method B. 1 H NMR (400 MHz, CDCl3) δ7.38 - 7.28 (m, 7H), 7.01 - 6.96 (m, 1H), 6.88 - 6.85 (m, 2H), 5.14 (s, 2H), 4.95 - 4.92 (m, 1H), 3.81 - 3.78 (m, 2H), 3.50 - 3.46 (m, 1H), 3.30 - 3.25 (m, 1H), 2.76 - 2.72 (m, 2H), 2.47 - 2.41 (m, 1H), 2.32 - 2.27 (m, 1H), 2.18 - 2.10 (m, 1H), 1.75 (m, 1H).

[0207] Step 7: (3aS,5S,6aR)-5-phenoxyhexahydrocyclopenta[c]pyrrole- 3a(1H)-All (3aR,5R,6aS)-5-phenoxyhexahydrocyclopenta[c]pyrrole- 3a(1H)-All A racemic mixture of

[0208] [ka] Benzyl (3aS,5S,6aR)-3a-hydroxy-5-phenoxyhexahydro Cyclopenta[c]pyrrole-2(1H)-carboxylate and benzyl (3aR, 5R,6aS)-3a-Hydroxy-5-phenoxyhexahydrocyclopenta[c]pi Fragrance containing 1H-2(1H)-carboxylate (11.46 g, 32.4 mmol) The flask was equipped with a magnetic stir bar and purged with nitrogen. Anhydrous MeOH (200 mL) was added to the flask. Add the mixture at ambient temperature with stirring. Cycle the vacuum on the flask manifold to N2. Purge oxygen by repeating the above steps twice, then purge with Pd / C (10% Pd loaded, Degu SSA wet type (0.724 g, 6.80 mmol) was added to the flask while stirring. The flask was capped with a rubber septum and the vacuum was purged with two nitrogen to vacuum cycles. The balloon was attached to a long syringe needle that extended below the liquid level, and a plastic luer stopper was used to insert the syringe. The vacuum was released by opening a H2 balloon onto the empty flask. The reaction was allowed to stand at room temperature. The mixture was stirred vigorously for 2 hours at room temperature. A nitrogen inlet was placed in the flask and the flask was purged for 15 minutes. The reaction mixture was filtered through a pad of Celite and washed with DCM. The filtrate was concentrated to give the title compound. intermediate was obtained as a white solid (6.3 g) which was used in the next step without purification. . LCMS: Rt 0.85 min; MS m / z 220.3 [M+H] + ; Method B. 1H NMR (400 MHz, methanol-d4) δ 7.31–7.19 (m, 2H), 6.97–6.82 (m, 3H), 3.2 4 (dd, J = 11.6, 7.7 Hz, 1H), 2.94 - 2.81 (m, 2H), 2.66 - 2.48 (m, 2H), 2.31 - 2 .15 (m, 2H), 2.09 (ddd, J = 13.9, 4.7, 1.8 Hz, 1H), 1.81 - 1.69 (m, 1H). 1H below the work.

[0209] Intermediate 2 (3aS,5S,6aR)-5-phenoxyhexahydrocyclopenta[c]pyrrole- 3a(1H)-All

[0210] [ka] Step 1: Benzyl (3aS,5R,6aR)-3a,5-dihydroxyhexahydro Cyclopenta[c]pyrrole-2(1H)-carboxylate

[0211] [ka] Benzyl(3aS,5R,6aR)-3a,5-dihydroxyhexahydrocyclopentane ta[c]pyrrole-2(1H)-carboxylate and benzyl (3aR, 5S, 6a S)-3a,5-dihydroxyhexahydrocyclopenta[c]pyrrole-2(1H)- A racemic mixture of carboxylate (from step 5 of intermediate 1) (450 mg) , which were separated by chiral SFC using the following conditions to give benzyl (3aS,5R,6a R)-3a,5-dihydroxyhexahydrocyclopenta[c]pyrrole-2(1H)- Carboxylate (190 mg, peak 1) as a colorless oil and benzyl (3aR ,5S,6aS)-3a,5-dihydroxyhexahydrocyclopenta[c]pyrrole- The 2(1H)-carboxylate (220 mg, peak 2) was obtained as a colorless oil. Column: Chiralpak AD (250mm x 30mm, 10μm), flow rate: 70 g / min Mobile phase: CO2 (A), MeOH with 0.1% NH4OH (B), isocratic 60:40(A:B)

[0212] Peak 1: Chiral SFC: Rt 1.58 min (Column: Chiralpak AD-3 50x4. 6mm ID, 3μm, flow rate: 3mL / min, mobile phase: CO2(A), 0.05%DE MeOH containing A (B), gradient elution: 5–40% B). 1 H NMR (400 MHz, CDCl3) δ7.38 - 7.29 (m, 5H), 5.16 (s, 2H), 4.56 - 4.52 (m, 1H) , 3.82 - 3.76 (m, 2H), 3.56 - 3.53 (m, 1H), 3.44 - 3.41 (m, 1H), 2.48 - 2.39 (m, 2H), 2.24 - 2.18 (m, 1H), 1.99 - 1.94 (m, 1H), 1.81 (br s, 1H), 1.65 (br s, 1H) , 1.54 - 1.41 (m, 1H).

[0213] Peak 2: Chiral SFC: Rt 2.04 min (Column: Chiralpak AD-3 50x4. 6mm ID, 3μm, flow rate: 3mL / min, mobile phase: CO2(A), 0.05%DE MeOH containing A (B), gradient elution: 5–40% B). 1 H NMR (400 MHz, CDCl3) δ7.38 - 7.31 (m, 5H), 5.14 (s, 2H), 4.56 - 4.51 (m, 1H) , 3.82 - 3.76 (m, 2H), 3.56 - 3.52 (m, 1H), 3.44 - 3.41 (m, 1H), 2.47 - 2.39 (m, 2H), 2.24 - 2.18 (m, 1H), 1.99 - 1.94 (m, 1H), 1.82 (br s, 1H), 1.65 (br s, 1H) , 1.51 - 1.41 (m, 1H).

[0214] Step 2: Benzyl (3aS,5S,6aR)-3a-hydroxy-5-phenoxy Hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

[0215] [ka] Benzyl(3aS,5R,6aR)-3a,5-dihydroxyhexahydrocyclopentane The peaks from α[c]pyrrole-2(1H)-carboxylate (peak 1 in the previous step) Evaporation and following the procedure used in Step 6 of Intermediate 1 gave the title intermediate. LCMS: Rt 0.84 min; MS m / z 354.2 [M+H] + ; Method J. 1 H NMR (400 MHz, CDCl3) δ7.38 - 7.28 (m, 7H), 7.01 - 6.96 (m, 1H), 6.88 - 6.85 (m, 2H), 5.14 (s, 2H), 4.95 - 4.92 (m, 1H), 3.81 - 3.78 (m, 2H), 3.50 - 3.46 (m, 1H), 3.30 - 3.25 (m, 1H), 2.76 - 2.72 (m, 2H), 2.47 - 2.41 (m, 1H), 2.32 - 2.27 (m, 1H), 2.18 - 2.10 (m, 1H), 1.75 (m, 1H).

[0216] Step 3: (3aS,5S,6aR)-5-phenoxyhexahydrocyclopenta[c ]pyrrol-3a(1H)-ol

[0217] [ka] Benzyl (3aS,5S,6aR)-3a-hydroxy-5-phenoxyhexahydro Starting from cyclopenta[c]pyrrole-2(1H)-carboxylate, intermediate 1 Following the procedure used in step 7, the title intermediate was obtained. LCMS: Rt 0.86 min; MS m / z 220.0 [M+H] + ; Method I. 1 H NMR (400 MHz, DMSO-d6) δ 7.33 - 7.21 (m, 2H), 6.94 - 6.84 (m, 3H), 4.88 - 4. 66 (m, 2H), 3.06 - 3.01 (m, 1H), 2.72 - 2.65 (m, 2H), 2.53 - 2.51 (m, 1H), 2.46 - 2.42 (m, 1H), 2.30 - 2.14 (m, 2H), 2.04 - 1.94 (m, 1H), 1.92 - 1.86 (m, 1H), 1 .80 - 1.71 (m, 1H).

[0218] Intermediate 3 (3aS,5S,6aR)-5-(2-fluorophenoxy)hexahydrocyclopenta [c]pyrrol-3a(1H)-ol (3aR,5R,6aS)-5-(2-fluorophenoxy)hexahydrocyclopenta [c]pyrrol-3a(1H)-ol A racemic mixture of

[0219] [ka] This can be done in a similar manner to intermediate 1 using 2-fluorophenol in step 6. It was synthesized with. LCMS: Rt 0.66 min; MS m / z 238.3 [M+H] + ; Method B. 1 H NMR (400 MHz, DMSO-d6) δ7.26 - 7.14 (m, 2H), 7.14 - 7.02 (m, 1H), 6.96 - 6.8 7 (m, 1H), 4.88 - 4.79 (m, 1H), 4.73 (br s, 1H), 3.07 - 3.01 (m, 1H), 2.73 - 2.6 6 (m, 2H), 2.47 - 2.43 (m, 1H), 2.36 - 2.26 (m, 1H), 2.23 - 2.17 (m, 1H), 2.08 - 1.99 (m, 1H), 1.96 - 1.91 (m, 1H), 1.80 - 1.73 (m, 1H). 1H under the solvent peak.

[0220] Intermediate 4 (3aS,5S,6aR)-5-(2-fluorophenoxy)hexahydrocyclopenta [c]pyrrol-3a(1H)-ol

[0221] [ka] This can be done in a similar manner to intermediate 2 using 2-fluorophenol in step 2. It was synthesized with. LCMS: Rt 0.87 min; MS m / z 238.3 [M+H] + ; Method I. 1 H NMR (400 MHz, CDCl3) δ7.21 - 7.15 (m, 2H), 7.12 - 7.08 (m, 1H), 6.95 - 6.89 (m, 1H), 4.85 - 4.79 (m, 1H), 4.74 (br s, 1H), 3.07 - 3.01 (m, 1H), 2.73 - 2.66 (m, 2H), 2.47 - 2.43 (m, 1H), 2.36 - 2.25 (m, 1H), 2.23 - 2.17 (m, 1H), 2.08 - 1 0.99 (m, 1H), 1.97 - 1.91 (m, 1H), 1.79 - 1.73 (m, 1H). 1H under the solvent peak.

[0222] Intermediates 5 and 6 (3aS,4S,5S,6aR)-5-phenoxyhexahydrocyclopenta[c]pyrro 3a,4(1H)-diol (3aR,4R,5R,6aS)-5-phenoxyhexahydrocyclopenta[c]pyrro 3a,4(1H)-diol

[0223] [ka] Step 1: Benzyl (3aS,5R)-5-hydroxy-3,3a,4,5-tetrahydrocyclopentadiene pent[c]pyrrole-2(1H)-carboxylate Benzyl (3aR,5S)-5-hydroxy-3,3a,4,5-tetrahydrocyclopentadiene pent[c]pyrrole-2(1H)-carboxylate A racemic mixture of

[0224] [ka] (±)-Benzyl 5-oxo-3,3a,4,5-tetrahydrofuran in methanol (500 mL) Hydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Stearate of Intermediate 1) A stirred solution of CeCl3.H2O (5 .7g, 23.3mmol), followed by NaBH4 (0.35g, 9.36mmol) - The mixture was added at 70° C. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated and the material was The organic layer was dried over Na2SO4, concentrated, and purified by FCC Purification with (60% EtOAc:hexanes) gave the title intermediate (1.6 g). LCMS: Rt 0.50 min; MS m / z 260.2 [M+H] + ; Method D. 1 H NMR (400 MHz, CDCl3) δ7.37-7.29 (m, 5H), 5.59 (d, J = 16 Hz, 1H), 5.14 (m, 3 H), 4.04 (dd, J = 16.0, 6.0 Hz, 1H), 3.97-3.88 (m, 2H), 3.08-2.96 (m, 1H), 2.88 (t, J = 9.6 Hz, 1H), 2.72-2.61 (m, 1H), 1.83 (t, J = 10.0 Hz, 1H), 1.40-1.28 (m, 1H).

[0225] Step 2: Benzyl(3aS,5S)-5-phenoxy-3,3a,4,5-tetrahydrocyclopentadiene pent[c]pyrrole-2(1H)-carboxylate Benzyl(3aR,5R)-5-phenoxy-3,3a,4,5-tetrahydrocyclopentadiene pent[c]pyrrole-2(1H)-carboxylate A racemic mixture of

[0226] [ka] Benzyl (3aS,5R)-5-hydroxy-3,3a in toluene (500 mL) 4,5-Tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate and and benzyl(3aR,5S)-5-hydroxy-3,3a,4,5-tetrahydrocyclohexane Racemic penta[c]pyrrole-2(1H)-carboxylate (6.0 g, 23.1 mmol), phenol (2.6 g, 27.7 mmol), and 1,1'-(azodi A solution of (carbonyl)dipiperidine (11.6 g, 46.2 mmol) was added to the solution of tributylphosphite. Finn (14 g, 69.3 mmol) was added at room temperature, and the reaction mixture was heated at 100° C. for 16 h. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated. The crude material was purified by FCC( Purification with 0% EtOAc:hexanes gave the title intermediate (3.5 g). 1 H NMR (400 MHz, CDCl3) δ7.39-7.26 (m, 7H), 6.96-6.92 (m, 1H), 6.89 (d, J = 8 H z, 2H), 5.87 (d, J = 14.8 Hz, 1H), 5.46 (dd, J = 3.6, 2.4 Hz, 1H), 5.19-5.12 (m, 2H), 4.08-3.95 (m, 3H), 3.60-3.50 (m, 1H), 2.80 (dt, 10.4, 1.2 Hz, 1H), 2.39-2. 30 (m, 1H), 1.90-1.83 (m, 1H).

[0227] Step 3: Benzyl (3aS,4S,5S,6aR)-3a,4-dihydroxy-5-phenoxy Hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate Benzyl(3aR,4R,5R,6aS)-3a,4-dihydroxy-5-phenoxy Hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate A racemic mixture of

[0228] [ka] Benzyl (3aS,5S)-5 in acetone (200 mL) and water (200 mL) -phenoxy-3,3a,4,5-tetrahydrocyclopenta[c]pyrrole-2(1H )-carboxylate and benzyl (3aR,5R)-5-phenoxy-3,3a,4 ,5-Tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate N-methylmorpholine N-oxide monohydrate ( A solution of OsO4 (96%) in t-BuOH (20 mL) was added to the solution of 17 g of OsO4 (96%) in t-BuOH (20 mL). A solution of 1 mg, 0.37 mmol) was added at room temperature and the reaction mixture was stirred for 16 hours. The mixture was extracted with ethyl acetate, dried over Na2SO4, concentrated and purified by FCC (50% EtO Ac:hexane) to give the title intermediate (2.5 g).

[0229] LCMS:Rt 1.40 min; MS m / z 370.3[M+H] + ;Method D.

[0230] Step 4: Benzyl (3aS,4S,5S,6aR)-3a,4-dihydroxy-5-phenoxy Hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate Benzyl(3aR,4R,5R,6aS)-3a,4-dihydroxy-5-phenoxy Hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate Chiral separation of

[0231] [ka] Benzyl(3aS,4S,5S,6aR)-3a,4-dihydroxy-5-phenoxy Hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate and Benzyl (3aR,4R,5R,6aS)-3a,4-dihydroxy-5-phenoxyhexyl A racemic mixture of 2-chlorocyclopenta[c]pyrrole-2(1H)-carboxylate (2. 5g) was separated by chiral SFC using the following method to give benzil (3aS,4S ,5S,6aR)-3a,4-dihydroxy-5-phenoxyhexahydrocyclopenta [c]pyrrole-2(1H)-carboxylate (chiral SFC Rt 7.23 min, 1 .2g) and benzyl (3aR,4R,5R,6aS)-3a,4-dihydroxy-5 -Phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Chiral SFC Rt 5.86 min, 1.2 g) was obtained. Column: Chiralpak IG (10 mm x 250 mm, 5 microns), flow rate: 1 3mL / min Mobile phase: CO2 (A), EtOH:IPA, 1:1 (B), isocratic 70:3 0(A:B)

[0232] Step 5: (3aS,4S,5S,6aR)-5-phenoxyhexahydrocyclopene ta[c]pyrrole-3a,4(1H)-diol (Intermediate 5)

[0233] [ka] Benzyl (3aS,4S,5S,6aR)-3a,4-dibenzofuran in EtOH (100 mL) Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate Carboxylate (chiral SFC Rt 7.23 min, from step 4) (1.2 g A solution of 10% Pd on carbon (120 mg) was heated in H2 (balloon The reaction mixture was filtered through Celite and concentrated to give the title intermediate (7 50 mg) was obtained, which was used without further purification. LCMS: Rt 0.55 min; MS m / z 236.0 [M+H] + ; Method E. 1 H NMR (400 MHz, methanol-d4) δ 7.27-7.23 (m, 2H), 7.01-6.99 (m, 2H), 6.92 (t , J = 7.2 Hz, 1H), 4.78-4.73 (m, 1H), 3.94 (d, J = 3.6 Hz, 1H), 3.23-3.19 (m, 1H) ), 2.97 (d, J = 12.0 Hz, 1H), 2.86 (d, J = 12.0 Hz, 1H), 2.70-2.65 (m, 1H), 2.54 -2.49 (m, 1H), 2.30-2.23 (m, 1H), 1.60-1.55 (m, 1H).

[0234] Step 6: (3aR,4R,5R,6aS)-5-phenoxyhexahydrocyclopene ta[c]pyrrole-3a,4(1H)-diol (Intermediate 6)

[0235] [ka] Using the same method as in step 5, benzyl (3aR,4R,5R,6aS)-3a, 4-Dihydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H )-carboxylate (chiral SFC Rt 5.86 min, from step 4) (1 Starting from 1.0001 methylpropional (0.2g, 3.24mmol), the title intermediate was obtained (750mg). LCMS: Rt 0.55 min; MS m / z 236.0 [M+H] + ; Method E. 1 H NMR (400 MHz, methanol-d4) δ 7.27-7.23 (m, 2H), 7.01-6.99 (m, 2H), 6.92 (t , J = 7.2 Hz, 1H), 4.78-4.73 (m, 1H), 3.93 (d, J = 4.0 Hz, 1H), 3.20-3.15 (m, 1H) ), 2.94 (d, J = 12.4 Hz, 1H), 2.82 (d, J = 12.0 Hz, 1H), 2.66-2.63 (m, 1H), 2.52 -2.46 (m, 1H), 2.30-2.23 (m, 1H), 1.60-1.52 (m, 1H).

[0236] Intermediate 7 (3aS,4S,5S,6aR)-5-(2-fluorophenoxy)hexahydrocyclo Penta[c]pyrrole-3a,4(1H)-diol (3aR,4R,5R,6aS)-5-(2-fluorophenoxy)hexahydrocyclo Penta[c]pyrrole-3a,4(1H)-diol A racemic mixture of

[0237] [ka] Steps 1-3 Benzyl(3aS,4S,5S,6aR)-5-(2-fluorophenoxy)-3a,4 -Dihydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate to Benzyl(3aR,4R,5R,6aS)-5-(2-fluorophenoxy)-3a,4 -Dihydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate to A racemic mixture of

[0238] [ka] The title intermediate was prepared by substituting 2-fluorophenol in step 2 for phenol. Intermediate 5 and 6 were synthesized using the same method as steps 1-3.

[0239] LCMS:Rt 1.44 min; MS m / z 388.0[M+H] + ;Method D.

[0240] Step 4 (3aS,4S,5S,6aR)-5-(2-fluorophenoxy)hexahydrocyclo Penta[c]pyrrole-3a,4(1H)-diol (3aR,4R,5R,6aS)-5-(2-fluorophenoxy)hexahydrocyclo Penta[c]pyrrole-3a,4(1H)-diol A racemic mixture of

[0241] [ka] Using the same method as in step 5 of intermediate 5, benzyl (3aS,4S,5S,6aR )-5-(2-fluorophenoxy)-3a,4-dihydroxyhexahydrocyclopentane ta[c]pyrrole-2(1H)-carboxylate and benzyl (3aR,4R,5R ,6aS)-5-(2-fluorophenoxy)-3a,4-dihydroxyhexahydrochloride Racemic mixture of clopenta[c]pyrrole-2(1H)-carboxylate (200 mg) Starting from this product, the title intermediate was obtained (130 mg).

[0242] LCMS:Rt 0.11 min;MS m / z 253.9[M+H] + ;Method D.

[0243] Intermediate 8 (3aS,4S,5S,6aR)-5-(2-fluorophenoxy)hexahydrocyclo Penta[c]pyrrole-3a,4(1H)-diol

[0244] [ka] Step 1 Benzyl(3aS,4S,5S,6aR)-5-(2-fluorophenoxy)-3a,4 -Dihydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate to Benzyl(3aR,4R,5R,6aS)-5-(2-fluorophenoxy)-3a,4 -Dihydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate to Chiral separation of

[0245] [ka] Benzyl(3aS,4S,5S,6aR)-5-(2-fluorophenoxy)-3a, 4-Dihydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate benzyl(3aR,4R,5R,6aS)-5-(2-fluorophenoxy) -3a,4-dihydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carbohydrate A racemic mixture of carboxylate (Step 3, Intermediate 7, 1.0 g) was prepared using the following method: The benzyl (3aS,4S,5S,6aR)-5-( 2-Fluorophenoxy)-3a,4-dihydroxyhexahydrocyclopenta[c]pi rol-2(1H)-carboxylate (chiral SFC Rt 13.24 min, 0.5 g ) and benzyl(3aR,4R,5R,6aS)-5-(2-fluorophenoxy)- 3a,4-Dihydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carbo The xylate (chiral SFC Rt 19.13 min, 0.5 g) was obtained. Column: Chiralpak IG (10 mm x 250 mm, 5 microns), flow rate: 1 5mL / min Mobile phase: CO2 (A), EtOH:IPA, 1:1 (B), isocratic 70:3 0(A:B)

[0246] Step 2: (3aS,4S,5S,6aR)-5-(2-fluorophenoxy)hexa Hydrocyclopenta[c]pyrrole-3a,4(1H)-diol

[0247] [ka] Using the same method as in step 5 of intermediate 5, benzyl (3aS,4S,5S,6aR )-5-(2-fluorophenoxy)-3a,4-dihydroxyhexahydrocyclopentane ta[c]pyrrole-2(1H)-carboxylate (chiral SFC Rt 13.24 min) Starting from (500 mg) (from step 1), the title intermediate (260 mg) was obtained. Ta. LCMS: Rt 0.11 min; MS m / z 254.3 [M+H] + ; Method D. 1 H NMR (400 MHz, methanol-d4) δ 7.19 (dt, J = 8.4, 1.6 Hz, 1H), 7.11-7.06 (m, 2H), 6.97-6.91 (m, 1H), 4.78-4.73 (m, 1H), 3.92 (d, J = 3.2 Hz, 1H), 3.16 (dd, J = 12.0, 7.6 Hz, 1H), 2.93 (d, J = 12.4 Hz, 1H), 2.78 (d, J = 12.0 Hz, 1H), 2.6 2 (dd, J = 11.2, 2.8 Hz, 1H), 2.55-2.49 (m, 1H), 2.32-2.24 (m, 1H), 1.55-1.49 (m , 1H).

[0248] Intermediate 9 (3aR,4R,5R,6aS)-5-(2-fluorophenoxy)hexahydrocyclo Penta[c]pyrrole-3a,4(1H)-diol

[0249] [ka] Using the same method as in step 5 of intermediate 5, benzyl (3aR,4R,5R,6aS )-5-(2-fluorophenoxy)-3a,4-dihydroxyhexahydrocyclopentane ta[c]pyrrole-2(1H)-carboxylate (chiral SFC Rt 19.13 min) Starting from Step 1 of Intermediate 8 (500 mg), the title intermediate (270 mg) was obtained. LCMS: Rt 0.10 min; MS m / z 254.0 [M+H] + ; Method D. 1 H NMR (400 MHz, methanol-d4) δ 7.20 (dt, J = 8.0, 1.6 Hz, 1H), 7.12-7.06 (m, 2H), 6.98-6.94 (m, 1H), 4.83-4.79 (m, 1H), 4.03 (d, J = 4.0 Hz, 1H), 3.47-3.42 (m, 1H), 3.16-3.06 (m, 2H), 2.92-2.87 (m, 1H), 2.72-2.68 (m, 1H), 2.37-2.30 (m, 1H), 1.69-1.62 (m, 1H).

[0250] The following intermediates were made using analogous procedures with the appropriate starting materials:

[0251] [Table 1]

[0252] Intermediate 11 6-(2-chloroacetyl)-3,4-dihydroquinolin-2(1H)-one

[0253] [ka] In a round-bottom flask, AlCl (16.49 g, 124 mmol) was added to CS ( 88 mL) was added and it was cooled to 0° C. Chloroacetyl chloride (3.40 mL, 42 0.4 mmol) was added. After 10 minutes, 3,4-dihydroquinolin-2(1H)-one ( CAS No. 553-03-7) (5.20 g, 35.3 mmol) was added in two portions. The reaction was stirred at 45° C. for 20 minutes. The reaction was cooled to room temperature and the colorless solvent was decanted off. A brown oily precipitate remained, which was placed in an ice bath and slowly diluted with ice and cold water. The tan precipitate was filtered, washed three times with water, and then dried to give the title intermediate (7.46 g ) as an off-white solid which was used without further purification. LCMS: Rt 0.67 min; MS m / z 224.2 [M+H] + ; Method A. 1 H NMR (400 MHz, methanol-d4) δ 7.92–7.80 (m, 2H), 6.96 (d, J = 8.3 Hz, 1H) , 4.86 (s, 2H), 3.10 - 2.98 (m, 2H), 2.69 - 2.55 (m, 2H).

[0254] Intermediate 12 6-(2-chloroacetyl)quinolin-2(1H)-one

[0255] [ka] 6-(2-chloroacetyl)-3,4- in chloroform (17.35 mL) under nitrogen Dihydroquinolin-2(1H)-one (Intermediate 11) (0.194 g, 0.867 mmol) l) was added to a suspension of NBS (0.201 g, 1.13 mmol) and benzoyl peroxide. (10.5 mg, 0.043 mmol) was added and the reaction was stirred at 60° C. for 2 hours. The reaction mixture was cooled, filtered, rinsed twice with chloroform, and the solid was dried under vacuum to give the title compound. The intermediate (114 mg) was obtained as a pale brown solid, which was used without further purification. Ta. LCMS: Rt 0.66 min; MS m / z 222.1 [M+H] + ; Method A. 1 H NMR (400 MHz, methanol-d4) δ 8.39 (d, J = 2.0 Hz, 1H), 8.16 (dd, J = 8.7, 2.0 Hz, 1H), 8.06 (d, J = 9.5 Hz, 1H), 7.44 (d, J = 8.7 Hz, 1H), 6.68 (d, J = 9. 6 Hz, 1H), 4.97 (s, 2H).

[0256] Intermediate 13 6-(2-chloroacetyl)-5-fluoro-3,4-dihydroquinoline-2(1H)- on

[0257] [ka] Step 1: (2-Fluoro-6-nitrophenyl)methanol

[0258] [ka] 2-Fluoro-6-nitrobenzoic acid (CAS no. 38) in THF (50 mL) under N A solution of 5-02-4) (5 g, 27 mmol) in 10 M dimethyl sulfide (B2H6) 0 mL, 108 mmol) was added dropwise and the reaction was stirred at room temperature for 30 min, then at 60 °C for 15.5 min. The reaction was quenched very slowly with MeOH (60 mL) and the solution was allowed to stand at room temperature. The mixture was stirred at rt for 2 h and then concentrated to give the title intermediate (4.2 g) as a yellow solid. This was used without further purification. LCMS: Rt 0.33 min; MS m / z 154.2 [M+H-H2O] + ; Method J. 1 H NMR (400 MHz, DMSO-d6) δ7.78 - 7.71 (m, 1H), 7.63 - 7.55 (m, 2H), 5.43 (br s , 1H), 4.70 (d, J = 1.6 Hz, 2H).

[0259] Step 2: 2-(Bromomethyl)-1-fluoro-3-nitrobenzene

[0260] [ka] (2-Fluoro-6-nitrophenyl)methanol (3. A solution of CBr4 (14.5 g, 43.8 mmol) and P Ph3 (11.5 g, 43.8 mmol) was added and the reaction was stirred at room temperature for 3 hours. The reaction was quenched with saturated aqueous NH4Cl (30 mL) and extracted with DCM (2 x 20 mL). The crude material was purified by FCC (0-10% EtOAc). c:PE) to give the title intermediate (2.1 g) as a pale yellow oil. 1 H NMR (400 MHz, CDCl3) δ7.91 - 7.83 (m, 1H), 7.57 - 7.38 (m, 2H), 4.96 (d, J = 1.6 Hz, 1H), 4.84 (d, J = 1.6 Hz, 1H).

[0261] Step 3: Diethyl 2-(2-fluoro-6-nitrobenzyl)malonate

[0262] [ka] A solution of diethyl malonate (1.72 g, 10.7 mmol) in DMF (12 mL) NaH (60%, in mineral oil, 538 mg, 13.5 mmol) was added portionwise at 0°C. The reaction was stirred at room temperature for 30 min, then 2-(bromomethyl)- A solution of 1-fluoro-3-nitrobenzene (2.1 g, 8.97 mmol) was added dropwise to the reaction mixture. The reaction was stirred at room temperature for an additional 15.5 hours. The reaction was diluted with saturated aqueous NH4Cl (20 mL). Poured into, extracted with EtOAc (3×10 mL), dried over Na 2 SO 4 , filtered, The crude material was purified by FCC (0-50% EtOAc:PE) to give the title intermediate (2.3 g) was obtained as a pale yellow oil. LCMS: Rt 1.02 min; MS m / z 314.2 [M+H] + ; Method I. 1 H NMR (400 MHz, CDCl3) δ7.80 - 7.74 (m, 1H), 7.44 - 7.31 (m, 2H), 4.21 - 4.15 (m, 4H), 3.79 - 3.73 (m, 1H), 3.57 - 3.53 (m, 2H), 1.25 - 1.21 (m, 6H).

[0263] Step 4: Ethyl 5-fluoro-2-oxo-1,2,3,4-tetrahydroquinoline -3-carboxylate

[0264] [ka] Diethyl 2-(2-fluoro-6-nitrobenzyl)malonate in MeOH (23 mL) To a solution of 2.3 g (7.34 mmol) of methyl phosphate, 10% Pd / C (400 mg) was added. The reaction was stirred under H2 (15 psi) at room temperature for 16 h. The suspension was filtered through Celite and The combined filtrate was concentrated to give the title intermediate (1.6 g) was obtained as a white solid which was used without further purification. LCMS: Rt 0.81 min; MS m / z 238.1 [M+H] + ; Method J. 1 H NMR (400 MHz, CDCl3) δ8.20 (br s, 1H), 7.20 - 7.12 (m, 1H), 6.82 - 6.73 (m, 1H), 6.60 (d, J = 8.0 Hz, 1H), 4.28 - 4.18 (m, 2H), 3.70 - 3.56 (m, 1H), 3.49 - 3.35 (m, 1H), 3.25 - 3.15 (m, 1H), 1.28 - 1.24 (m, 3H).

[0265] Step 5: 5-Fluoro-3,4-dihydroquinolin-2(1H)-one

[0266] [ka] Ethyl 5-fluoro-2-oxo- in DMSO (160 mL) and water (16 mL) 1,2,3,4-tetrahydroquinoline-3-carboxylate (1.6 g, 6.74 m To a solution of 1.18 g (20.2 mmol) of NaCl was added and the reaction was heated to 160°C. The reaction was stirred at 0°C for 8 h. The reaction was cooled, diluted with water (100 mL) and diluted with EtOAc (3 x 3 The combined organic phase was washed with saturated aqueous NaCl (3×40 mL) and Dry over Na2SO4, filter, and concentrate to give the title intermediate (1 g) as a white solid This was used without further purification. LCMS: Rt 0.52 min; MS m / z 166.0 [M+H] + ; Method J. 1 H NMR (400 MHz, CDCl3) δ8.51 (br s, 1H), 7.18 - 7.11 (m, 1H), 6.81 - 6.69 (m, 1H), 6.60 (d, J = 8.0 Hz, 1H), 3.03 - 2.99 (m, 2H), 2.71 - 2.59 (m, 2H).

[0267] Step 6: 6-(2-chloroacetyl)-5-fluoro-3,4-dihydroquinoline- 2(1H)-On

[0268] [ka] Using the same method as intermediate 11, 5-fluoro-3,4-dihydroquinoline-2(1 Starting with H)-one (500 mg, 3.03 mmol), the crude material was obtained, which was purified by FCC (30-80% EtOAc:PE) to give the title intermediate (300 mg) as a white solid. Obtained as a material object. 1 H NMR (400 MHz, CDCl3) δ 8.60 (br s, 1H), 7.89 - 7.85 (m, 1H), 6.72 (d, J = 8. 4 Hz, 1H), 4.70 (d, J = 3.2 Hz, 2H), 3.10 - 3.06 (m, 2H), 2.74 - 2.69 (m, 2H).

[0269] Intermediate 14 7-(2-chloroacetyl)-4,5-dihydrobenzo[d][1,3]oxazepine- 2(1H)-On

[0270] [ka] Step 1: 4,5-Dihydrobenzo[d][1,3]oxazepin-2(1H)-one

[0271] [ka] 2-(2-aminophenyl)ethan-1-ol (CAS No. A solution of 5339-85-5 (4.8 g, 35.0 mmol) was added to a solution of K2CO3 (9.67 g, 70.0 mmol) and 4-nitrophenyl carbonochloridate (10.6 g, 52.5 mmol) was added, which was stirred at room temperature for 16 hours and then diluted with water (40 mL). The mixture was diluted and extracted with DCM (3 x 30 mL), dried over Na2SO4, filtered and concentrated. The crude material was purified by FCC (0-90% EtOAc:PE) to give the title intermediate (2.2 g ) was obtained as a brown solid. LCMS: Rt 0.57 min; MS m / z 164.0 [M+H] + ; Method J. 1 H NMR (400 MHz, CDCl3) δ9.08 - 8.74 (m, 1H), 7.23 - 7.15 (m, 1H), 7.11 - 7.09 (m, 1H), 7.07 - 6.96 (m, 2H), 4.62 - 4.47 (m, 2H), 3.29 - 3.14 (m, 2H).

[0272] Step 2: 7-(2-chloroacetyl)-4,5-dihydrobenzo[d][1,3]o Xazepin-2(1H)-one

[0273] [ka] Using the same method as intermediate 11, 4,5-dihydrobenzo[d][1,3]oxazepam was obtained. Starting from pin-2(1H)-one (500 mg, 3.06 mmol), the title intermediate ( 700 mg) as an off-white solid which was used without further purification . LCMS: Rt 0.64 min; MS m / z 240.0 [M+H] + ; Method J. 1 H NMR (400 MHz, DMSO-d6) δ9.97 (s, 1H), 7.87 - 7.65 (m, 2H), 7.19 (d, J = 8.4 Hz, 1H), 5.09 (s, 2H), 4.51 - 4.31 (m, 2H), 3.26 - 3.12 (m, 2H).

[0274] Intermediate 15 6-(2-chloroacetyl)-1,4-dihydro-2H-benzo[d][1,3]thiazol- On-2-On

[0275] [ka] Step 1: 1,4-Dihydro-2H-benzo[d][1,3]thiazine-2-thione

[0276] [ka] A solution of KOH (3.42 g, 60.9 mmol) in EtOH (30 mL) was treated with CS2( (7.36 mL, 122 mmol) was added dropwise at 0°C. (2-aminophenyl)methanol (CAS No. 5344-90-1) (5 g, 41 mmol) was added and the reaction was heated to 80°C. The reaction was heated for 20 hours. The reaction was cooled and concentrated. KOH (10% aqueous solution, 80 mL) was added. The filtrate was acidified with 1N HCl, and the solid was collected by filtration. This gave the title intermediate (7 g) as a white solid, which was used without further purification. Ta. LCMS: Rt 0.60 min; MS m / z 181.9 [M+H] + ; Method J. 1 H NMR (400 MHz, CDCl3) δ9.95 (br s, 1H), 7.35 - 7.28 (m, 1H), 7.23 - 7.16 (m, 2H), 6.98 (d, J = 8.0 Hz, 1H), 4.03 (s, 2H).

[0277] Step 2: 1,4-Dihydro-2H-benzo[d][1,3]thiazin-2-one

[0278] [ka] 1,4-Dihydro-2H-benzo[d][1, 3] A solution of thiazine-2-thione (2 g, 11 mmol) was added to H2O2 (3% aqueous solution, 12 0 mL) was added. This was stirred at room temperature for 1 hour, and the resulting precipitate was collected by filtration and diluted with IPA. (5 mL) to give the title intermediate (1.48 g) as a white solid, which was further was used without further purification. LCMS: Rt 0.64 min; MS m / z 166.0 [M+H] + ; Method J. 1 H NMR (400 MHz, CDCl3) δ8.55 (br s, 1H), 7.27 (s, 1H), 7.20 (d, J = 7.2 Hz, 1H ), 7.13 - 7.05 (m, 1H), 6.89 (d, J = 8.0 Hz, 1H), 4.10 (s, 2H).

[0279] Step 3: 6-(2-chloroacetyl)-1,4-dihydro-2H-benzo[d][1 ,3]thiazin-2-one

[0280] [ka] 1,4-Dihydro-2H-benzo[d][1,3]thiazide was prepared according to the method of Intermediate 11. The reaction mixture was diluted with ice and mixed. The mixture was extracted with EtOAc (3 x 20 mL), dried over Na2SO4, filtered, and concentrated. This gave the title intermediate (600 mg) as a white solid, which was carried on without further purification. Used. LCMS: Rt 0.60 min; MS m / z 241.9 [M+H] + ; Method J. 1 H NMR (400 MHz, DMSO-d6) δ11.13 (s, 1H), 7.99 - 7.81 (m, 2H), 7.11 (d, J = 8.4 Hz, 1H), 5.11 (s, 2H), 4.30 (s, 2H).

[0281] Intermediate 16 6-(2-chloroacetyl)-8-fluoro-1,4-dihydro-2H-benzo[d][ 1,3]thiazin-2-one

[0282] [ka] Step 1: (2-amino-3-fluorophenyl)methanol

[0283] [ka] Stirring LAH (13.7 g, 361 mmol) in THF (100 mL) under N2 at 0 °C To the stirred suspension was added 2-amino-3-fluorobenzoic acid (CAS No. A solution of 825-22-9) (28 g, 180 mmol) was added dropwise and the reaction was stirred at room temperature for 2 h. Water (13.7 mL) was added dropwise, followed by 15% aqueous NaOH (13.7 mL). The reaction was diluted with THF (100 mL) and water (41.1 mL) and then It was dried over Na2SO4, filtered and washed with EtOAc (2 x 100 mL). The organic phase was dried again over Na2SO4, filtered, and concentrated. The crude material was purified by FCC (0-80 % EtOAc:PE) to afford the title intermediate (20 g) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ7.01 - 6.95 (m, 1H), 6.87 (d, J=7.6 Hz, 1H), 6.68 - 6. 62 (m, 1H), 4.71 (s, 2H), 4.25 (br s, 2H), 1.68 (br s, 1H).

[0284] Step 2: 8-Fluoro-1,4-dihydro-2H-benzo[d][1,3]thiazine -2-thione

[0285] [ka] Using the same method as in Step 1 of Intermediate 15, (2-amino-3-fluorophenyl ) Starting with methanol (5 g, 35 mmol), the title intermediate (9 g) was obtained as a white solid. which was used without further purification. LCMS: Rt 0.62 min; MS m / z 199.9 [M+H] + ; Method J. 1 H NMR (400 MHz, CDCl3) δ9.47 (br s, 1H), 7.19 - 6.94 (m, 3H), 4.06 (s, 2H).

[0286] Step 3: 8-Fluoro-1,4-dihydro-2H-benzo[d][1,3]thiazine -2-on

[0287] [ka] 8-Fluoro-1,4-dihydro-2H-benzo[a]pyrrolidone in 1M aqueous KOH (20 mL) A solution of [d][1,3]thiazine-2-thione (2.0 g, 10.0 mmol) in HO 2 (30% aqueous solution, 4.0 mL, 40.2 mmol) was slowly added. The mixture was stirred for 1 hour, the pH was adjusted to about 7 with 1N HCl, and the mixture was diluted with saturated aqueous Na2S2O3. , then extracted with EtOAc (3×50 mL), dried over Na 2 SO 4 , filtered, and concentrated The crude material was purified by FCC (0-60% EtOAc:PE) to give the title intermediate (1 0.0 g) as a white solid. LCMS: Rt 0.49 min; MS m / z 183.9 [M+H] + ; Method J. 1 H NMR (400 MHz, CDCl3) δ7.82 (br s, 1H), 7.13 - 6.98 (m, 3H), 4.14 (s, 2H).

[0288] Step 4: 6-(2-chloroacetyl)-8-fluoro-1,4-dihydro-2H-benzyl Benzo[d][1,3]thiazin-2-one

[0289] [ka] 8-Fluoro-1,4-dihydro-2H-benzo[d][ The reaction mixture was diluted with ice and then washed with EtOAc. Extract three times, dry over Na2SO4, filter, and concentrate to give the title intermediate as a yellow solid. which was used without further purification. LCMS: Rt 0.70 min; MS m / z 259.9 [M+H] + ; Method J. 1 H NMR (400 MHz, DMSO-d6) δ11.18 (s, 1H), 7.83 - 7.77 (m, 2H), 5.14 (s, 2H), 4. 36 (s, 2H).

[0290] The following intermediates were made using similar procedures from the starting materials indicated.

[0291] [Table 2]

[0292] Intermediate 19 6-(2-chloroacetyl)-3,3-dimethyl-3,4-dihydroquinoline-2(1H )-on

[0293] [ka] Step 1: 3-(2-bromophenyl)-2,2-dimethylpropanenitrile

[0294] [ka] Isobutyronitrile (3.59 g, 52 mmol) in dry THF (30 mL) at 0°C To this solution was added LiHMDS (1.0 M in THF, 80 mL, 80 mmol) dropwise. The reaction was stirred for 30 min and then diluted with 1-bromo-2-(bromo)-2-(2-bromo-2-methylpropional) in dry THF (70 mL). A solution of methyl)benzene (CAS number 3433-80-5) (10 g, 40 mmol) The reaction was stirred at room temperature for 11.5 hours. The reaction was diluted with saturated aqueous NH4Cl (60 mL ), extracted with EtOAc (3 x 100 mL), dried over Na2SO4, filtered The crude material was purified by FCC (0-20% EtOAc:PE) to give the title intermediate. The compound (9.2 g) was obtained as a colorless oil. LCMS: Rt 0.88 min; MS m / z 238.0 and 240.1 [M+H] + ; Method J. 1 H NMR (400 MHz, CDCl3) δ7.61 - 7.58 (m, 1H), 7.53 - 7.50 (m, 1H), 7.35 - 7.30 (m, 1H), 7.18 - 7.13 (m, 1H), 3.09 (s, 2H), 1.44 (s, 6H).

[0295] Step 2: 3,3-Dimethyl-3,4-dihydroquinolin-2(1H)-one

[0296] [ka] 3-(2-bromophenyl)-2,2-dimethylpropane in t-BuOH (210 mL) A solution of pannitrile (5 g, 21 mmol) with CuI (600 mg, 3.15 mmol) , KI (105 mg, 0.63 mmol), NaOH (3.36 g, 84.0 mmol) and N-acetylglycine (738 mg, 0.42 mmol) were added and the reaction was brought to 1 The mixture was stirred at 00° C. for 72 h. The reaction was diluted with DCM, filtered, and the filtrate was concentrated. The material was purified by FCC (0-50% EtOAc:PE) to give the title intermediate (2.2 g) in white Obtained as a colored solid. LCMS: Rt 0.65 min; MS m / z 176.1 [M+H] + ; Method J. 1 H NMR (400 MHz, CDCl3) δ8.04 (br s, 1H), 7.22 - 7.11 (m, 2H), 7.03 - 6.95 (m, 1H), 6.77 -6.74 (m, 1H), 2.81 (s, 2H), 1.22 (s, 6H).

[0297] Step 3: 6-Bromo-3,3-dimethyl-3,4-dihydroquinoline-2(1H)- on

[0298] [ka] 3,3-Dimethyl-3,4-dihydroquinoline-2(1) in DMF (11 mL) at 0 °C A solution of NBS (1. A solution of 23 g (6.91 mmol) of HCl was added dropwise and the reaction was stirred at room temperature for 16 hours. Diluted with water (30 mL), collected the precipitated solid by filtration, washed with water (10 mL), and The title intermediate (1.26 g) was obtained as a yellow solid, which was used without further purification. Ta. LCMS: Rt 0.75 min; MS m / z 254.0 and 256.0 [M+H] + ; Method J. 1 H NMR (400 MHz, CDCl3) δ7.77 (br s, 1H), 7.32 - 7.27 (m, 2H), 6.68 - 6.58 (m, 1H), 2.78 (s, 2H), 1.21 (s, 6H).

[0299] Step 4: 3,3-dimethyl-6-vinyl-3,4-dihydroquinoline-2(1H)- on

[0300] [ka] 6-Bromo-3,3-dimethyl-3,4-dihydrochloride in isopropanol (13 mL) Quinolin-2(1H)-one (1.26 g, 4.96 mmol) and vinyltrifluoromethyl A solution of potassium borate (1.33 g, 9.92 mmol) was added to a solution of triethylamine (2.0 7 mL, 14.9 mmol) and Pd(dppf)Cl2 (363 mg, 0.50 mm ol) was added and the reaction was stirred under N2 at 90 °C for 16 h. The reaction was cooled and concentrated. , then diluted with water (20 mL), extracted with EtOAc (3×40 mL), and The crude material was purified by FCC (30-70% EtOAc:PE). Purification gave the title intermediate (800 mg) as a yellow solid. LCMS: Rt 0.83 min; MS m / z 202.1 [M+H] + ; Method J. 1 H NMR (400 MHz, CDCl3) δ7.69 (br s, 1H), 7.26 - 7.19 (m, 2H), 6.76 - 6.58 (m, 2H), 5.69 - 5.64 (m, 1H), 5.20 - 5.17 (m, 1H), 2.81 (s, 2H), 1.22 (s, 6H).

[0301] Step 5: 6-Acetyl-3,3-dimethyl-3,4-dihydroquinoline-2(1H) -on

[0302] [ka] 3,3-Dimethyl-6 in acetonitrile (16.8 mL) and water (2.4 mL) -vinyl-3,4-dihydroquinolin-2(1H)-one (700 mg, 3.48 mmol) l) solution was treated with Pd(OAc)2 (78 mg, 0.35 mmol) and Dess-Martin Peel. Ruiodinane (1.77 g, 4.17 mmol) was added, and the mixture was heated at 60 °C under N2 for 2 The mixture was stirred for 1 hour, then filtered through a small pad of silica gel and diluted with EtOAc (2 x 10 mL). The crude material was purified by FCC (50-80% EtOAc:PE). This gave the title intermediate (570 mg) as a yellow solid. LCMS: Rt 0.80 min; MS m / z 218.2 [M+H] + ; Method J. 1H NMR (400 MHz, CDCl3) δ8.08 (br s, 1H), 7.84 - 7.80 (m, 2H), 6.82 - 6.80 (m, 1H), 2.87 (s, 2H), 2.58 (s, 3H), 1.23 (s, 6H).

[0303] Step 6: 6-(2-chloroacetyl)-3,3-dimethyl-3,4-dihydroquinone On-2(1H)-On

[0304] [ka] 6-Acetyl-3,3-dimethyl-3,4-dihydrazine in acetonitrile (4.6 mL) A solution of 2(1H)-dichloroiodide (300 mg, 1.38 mmol) was added to Benzyltrimethylammonium chloride (961 mg, 2.76 mmol) was added and the reaction The mixture was stirred under N2 at 45°C for 2 hours. The reaction was concentrated and then diluted with water (10 mL). The combined organic layers were extracted with saturated aqueous sodium thiosulfate (20 mL). The crude material was purified by FCC (60- Purification with 100% EtOAc:PE gave the title intermediate (200 mg) as a yellow solid. I got it. LCMS: Rt 0.78 min; MS m / z 252.1 [M+H] + ; Method J. 1 H NMR (400 MHz, CDCl3) δ8.17 (br s, 1H), 7.84 - 7.81 (m, 2H), 6.86 - 6.83 (m, 1H), 4.66 (s, 2H), 2.88 (s, 2H), 1.24 (s, 6H).

[0305] Intermediate 20 6-(2-chloroacetyl)-3,3-dimethyl-3,4-dihydroquinoline-2(1H )-on

[0306] [ka] Steps 1 and 2: 8-Fluoro-6-vinyl-3,4-dihydroquinoline-2(1H) )-on

[0307] [ka] 8-Fluoro-3,4-dihydroxybenzoate was prepared using the same method as in steps 3 and 4 of intermediate 19. Doroquinolin-2(1H)-one (CAS number 143268-79-5) (700 mg, 4.24 mmol) to give the title intermediate (468 mg) as a yellow solid. LCMS: Rt 0.76 min; MS m / z 192.1 [M+H] + ; Method J. 1 H NMR (400 MHz, CDCl3) δ7.85 (br s, 1H), 7.08 - 6.97 (m, 2H), 6.65 - 6.51 (m, 1H), 5.68 - 5.64 (m, 1H), 5.25 - 5.22 (m, 1H), 3.02 - 2.98 (m, 2H), 2.70 - 2.63 (m, 2H).

[0308] Steps 3 and 4: 6-(2-chloroacetyl)-3,3-dimethyl-3,4-dihydrazine Loquinolin-2(1H)-one

[0309] [ka] Using the same method as in steps 5 and 6 of intermediate 19, 8-fluoro-6-vinyl- Derived from 3,4-dihydroquinolin-2(1H)-one (790 mg, 4.13 mmol) Evaporation gave the title intermediate (500 mg) as a yellow solid. LCMS: Rt 0.73 min; MS m / z 242.1 [M+H] + ; Method J. 1 H NMR (400 MHz, DMSO-d6) δ10.52 (s, 1H), 7.74 - 7.66 (m, 2H), 5.11 (s, 2H), 3. 03 - 2.99 (m, 2H), 2.56 - 2.50 (m, 2H).

[0310] Intermediate 21 7-(2-chloroacetyl)-5-fluoro-2H-benzo[b][1,4]oxazine -3(4H)-On

[0311] [ka] Step 1: 4-Fluorobenzo[d]oxazol-2(3H)-one

[0312] [ka] 2-Amino-3-fluorophenol (CAS no. 53981) in THF (60 mL) A solution of CDI (10.2 g, 62.9 m mol) was added portionwise and the reaction was heated at 60° C. for 2 h. The reaction was diluted with EtOAc (10 Dilute with 200 mL of HCl (2 × 50 mL), wash with 2 N HCl (2 × 50 mL), and rinse with saturated brine (50 mL). The crude material was purified by FCC (0-50% E tOAc:PE) to give the title intermediate (3.7 g) as a pale yellow solid. LCMS: Rt 0.73 min; MS m / z 154.1 [M+H]+ ; Method L. 1 H NMR (400 MHz, DMSO-d6) δ12.25 (br s, 1H), 7.19 - 7.14 (m, 1H), 7.12 - 7.05 ( m, 2H).

[0313] Step 2: 6-Bromo-4-fluorobenzo[d]oxazol-2(3H)-one

[0314] [ka] 4-Fluorobenzo[d]oxazole-2(3H) in acetonitrile (50 mL) A solution of NBS (5.16 g, 29.0 mmol) was added to a solution of 3.7 g of N-isopropyl ether (24.2 mmol). The reaction was stirred at room temperature for 16 hours and then poured into water (50 mL) and The mixture was concentrated to remove acetonitrile, and the aqueous layer was extracted with EtOAc (3 x 30 mL). The crude material was purified by FCC (0-50% EtO Ac:PE) to afford the title intermediate (5.3 g) as a pale yellow solid. LCMS: Rt 0.78 min; MS m / z 231.9 and 233.9 [M+H] + ; Method L. 1 H NMR (400 MHz, DMSO-d6) δ12.45 (br s, 1H), 7.50 (s, 1H), 7.44 - 7.41 (m, 1H).

[0315] Step 3: 2-Amino-5-bromo-3-fluorophenol

[0316] [ka] 6-Bromo-4-fluorobenzo[d]oxazol-2(3H)-one (5.3 g, To a solution of 22.8 mmol of 3M NaOH (50 mL) was added a 100 mL solution of 1M NaOH. The reaction was stirred at RT for 3 h. The reaction was cooled and acidified with 1N aqueous HCl to pH=6. Extract with tOAc (3 x 50 mL), dry over Na2SO4, filter, and concentrate to give the title compound. intermediate (4.46 g) as a brown solid which was used without further purification . LCMS: Rt 0.56 min; MS m / z 205.9 and 207.9 [M+H] + ; Method L. 1 H NMR (400 MHz, DMSO-d6) δ9.96 (br s, 1H), 6.80 - 6.76 (m, 1H), 6.66 (s, 1H), 4.58 (br s, 2H).

[0317] Step 4: 7-Bromo-5-fluoro-2H-benzo[b][1,4]oxazine-3 (4H)-On

[0318] [ka] 2-Amino-5-bromo-3-fluorophenol (2 g, 9 mL) in DMF (20 mL) To a solution of chloroacetyl chloride (1.12 g, 9.71 mmol) and K 2CO3 (2.68 g, 19.4 mmol) was added and this was stirred at 80°C for 2 hours. The reaction was cooled, poured into water (20 mL), extracted with DCM (5 x 20 mL), and The crude material was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. Purification by CC (0-100% EtOAc:PE) gave the title intermediate (1.7 g) in the form of Obtained as a white solid. LCMS: Rt 0.64 min; MS m / z 246.0 and 247.9 [M+H] + ; Method J. 1 H NMR (400 MHz, DMSO-d6) δ11.02 (s, 1H), 7.24 - 7.21(m, 1H), 7.08 - 7.07 (m, 1 H), 4.64 (s, 2H).

[0319] Steps 5-7: 7-(2-chloroacetyl)-5-fluoro-2H-benzo[b][1 ,4]oxazin-3(4H)-one

[0320] [ka] 7-Bromo-5-fluoro-2H-benzo[b]pyridine using the same method as in steps 4-6 of intermediate 19 Starting from benzo[b][1,4]oxazin-3(4H)-one, the title intermediate was synthesized as follows: Obtained as a colored solid. LCMS: Rt 0.69 min; MS m / z 243.9 [M+H] + ; Method L. 1 H NMR (400 MHz, DMSO-d6) δ11.32 (s, 1H), 7.55 - 7.52 (m, 1H), 7.44 (s, 1H), 5. 14 (s, 2H), 4.72 (s, 2H).

[0321] Intermediate 22 (±)-6-(2-chloroacetyl)-3,8-difluoro-3,4-dihydroquinoline -2(1H)-On

[0322] [ka] Step 1: (3-Fluoro-2-nitrophenyl)methanol

[0323] [ka] 3-Fluoro-2-nitrobenzoic acid (CAS no. 1000339-51) was dissolved in water at room temperature under N2. -4) (5.0 g, 27 mmol) in 1 M THF (100 mL, 100 mmol) B2H6 was added dropwise. The reaction was stirred at room temperature for 2 hours and then at 70 °C for 6 hours. was cooled to room temperature, MeOH (200 mL) was added dropwise, and this was stirred at room temperature for 2 hours, then The crude material was purified by FCC (0-50% EtOAc:PE) to give the title intermediate (4.3 g) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ7.71 - 7.64 (m, 1H), 7.52 - 7.45 (m, 2H), 5.64 (br s , 1H), 4.63 (s, 2H).

[0324] Step 2: 1-(Bromomethyl)-3-fluoro-2-nitrobenzene

[0325] [ka] Using the same method as in Step 2 of Intermediate 13, (3-fluoro-2-nitrophenyl ) Starting from methanol (2.0 g, 11.7 mmol), the title intermediate (2.0 g) Obtained as a pale yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ7.75 - 7.71 (m, 1H), 7.65 - 7.58 (m, 2H), 4.80 (s, 2 H).

[0326] Step 3: Diethyl 2-fluoro-2-(3-fluoro-2-nitrobenzyl)malonate Route

[0327] [ka] Diethyl 2-fluoromalonate (CAS no. 685- A solution of 88-1) (1.75 g, 9.83 mmol) in NaH (60%, in mineral oil, 455 mg, 11.4 mmol) was added in small portions and stirred at room temperature for 30 minutes. (bromomethyl)-3-fluoro-2-nitrobenzene (2.0 g, 8.6 mmol) was added. The reaction mixture was poured into saturated aqueous NH4Cl (40 mL) and stirred at room temperature for 2 hours. The mixture was extracted with EtOAc (3×30 mL), dried over Na2SO4, filtered, and concentrated. The crude material was purified by FCC (0-50% EtOAc:PE) to give the title intermediate (2.3 g) was obtained as a pale yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ7.73 - 7.66 (m, 1H), 7.62 - 7.56 (m, 1H), 7.33 - 7.3 0 (m, 1H), 4.29 - 4.17 (m, 4H), 3.76 (s, 1H), 3.70 (s, 1H), 1.17 (t, J=7.2 Hz, 6 H).

[0328] Step 4: (±)-Ethyl 3,8-difluoro-2-oxo-1,2,3,4-tetrafluoroethane Hydroquinoline-3-carboxylate

[0329] [ka] Diethyl 2-fluoro-2-(3-fluoro-2-methyl ... Starting with (fluoro-2-nitrobenzyl) malonate (2.3 g, 6.94 mmol), The title intermediate (1.5 g) was obtained as a pale yellow solid which was used without further purification. did. 1 H NMR (400 MHz, DMSO-d6) δ11.08 (s, 1H), 7.22 - 7.14 (m, 1H), 7.13 - 7.08 (m, 1H), 7.07 - 7.00 (m, 1H), 4.29 - 4.17 (m, 2H), 3.66 (d, J=4.0 Hz, 1H), 3.60 (s, 1H), 1.14 (t, J=7.2 Hz, 3H).

[0330] Step 5: (±)-3,8-Difluoro-2-oxo-1,2,3,4-tetrahydro Quinoline-3-carboxylic acid

[0331] [ka] (±)-Ethyl 3,8-difluoro-2-oxo-1,2,3 in THF (20 mL) ,4-Tetrahydroquinoline-3-carboxylate (2.1 g, 8.23 ​​mmol) To the solution was added LiOH.HO (518 mg, 12.3 mmol) in water (20 mL). The reaction mixture was stirred at room temperature for 2 hours, and the pH was adjusted to 6 with saturated aqueous citric acid. Extract with EtOAc (3 x 20 mL), dry with Na2SO4, filter, and concentrate. The title intermediate (2.0 g) was obtained as a white solid, which was used without further purification. did.

[0332] LCMS:Rt 0.43min;MS m / z 228.0[M+H] + ;Method L.

[0333] Step 6: (±)-3,8-Difluoro-3,4-dihydroquinoline-2(1H)-o hmm

[0334] [ka] (±)-3,8-Difluoro-2-oxo-1,2,3 in o-xylene (40 mL) A solution of 4-tetrahydroquinoline-3-carboxylic acid (2.0 g) was heated at 140°C for 16 hours. The mixture was stirred, then cooled, concentrated, and purified by FCC (0-50% EtOAc:PE) to give the product shown in Table 1. The title intermediate (1.5 g) was obtained as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ10.54 (br s, 1H), 7.18 - 7.06 (m, 2H), 7.03 - 6.96 ( m, 1H), 5.37 - 5.17 (m, 1H), 3.44 - 3.34 (m, 1H), 3.29 - 3.23 (m, 1H).

[0335] Step 7: (±)-6-Bromo-3,8-difluoro-3,4-dihydroquinoline-2 (1H)-On

[0336] [ka] Using the same method as in Step 3 of Intermediate 19, (±)-3,8-difluoro-3,4 Starting from -dihydroquinolin-2(1H)-one (1.4 g, 7.64 mmol), The title intermediate (1.7 g) was obtained as a yellow solid which was used without further purification. . LCMS: Rt 0.64 min; MS m / z 262.0 and 264.0 [M+H] + ; Method J. 1 H NMR (400 MHz, DMSO-d6) δ10.67 (s, 1H), 7.48 - 7.45 (m, 1H), 7.36 (s, 1H), 5. 36 - 5.17 (m, 1H), 3.45 - 3.35 (m, 1H), 3.30 (br s, 1H).

[0337] Step 8: (±)-6-Acetyl-3,8-difluoro-3,4-dihydroquinoline- 2(1H)-On

[0338] [ka] (±)-6-Bromo-3,8-difluoro-3,4-dihydro- A solution of quinolin-2(1H)-one (500 mg, 1.91 mmol) was added to the solution of tributyl (1 -ethoxyvinyl)stannane (CAS No. 97674-02-7) (1.29 mL, 1 0.38 g, 3.82 mmol) and Pd(PPh3)2Cl2 (134 mg, 0.19 (mmol) was added and this was stirred at 100° C. for 16 hours. The reaction was cooled and saturated KF water was added. Dilute with HCl (10 mL), extract with EtOAc (3 x 20 mL), and dry with Na2SO4 The crude material was purified by FCC (0-60% EtOAc:PE). This gave the title intermediate (260 mg) as a yellow solid. LCMS: Rt 0.32 min; MS m / z 226.1 [M+H] + ; Method J. 1 H NMR (400 MHz, DMSO-d6) δ10.63 (s, 1H), 7.41 - 7.28 (m, 2H), 5.41 - 5.14 (m, 1H), 4.77 - 4.76 (m, 1H), 4.28 - 4.27 (m, 1H), 3.32 (s, 3H).

[0339] Step 9: (±)-6-(2-chloroacetyl)-3,8-difluoro-3,4-dihydroxybenzoate Doroquinolin-2(1H)-one

[0340] [ka] Using the same method as in Step 6 of Intermediate 19, (±)-6-acetyl-3,8-difluoromethylpropional was prepared. Fluoro-3,4-dihydroquinolin-2(1H)-one (160 mg, 0.710 mmol) Starting from l), the title intermediate (80 mg) was obtained as a yellow solid. LCMS: Rt 0.55 min; MS m / z 260.0 [M+H] + ; Method J. 1 H NMR (400 MHz, CDCl3) δ7.77 (br s, 1H), 7.72 - 7.68 (m, 2H), 5.30 - 5.13 (m, 1H), 4.61 (s, 2H), 3.51 - 3.43 (m, 2H).

[0341] Intermediate 23 6-(2-chloroacetyl)-3,3,8-trifluoro-3,4-dihydroquinoline- 2(1H)-On

[0342] [ka] Step 1: Ethyl 2,2-difluoro-3-(3-fluoro-2-nitrophenyl)propionate Lopanoate

[0343] [ka] Ethyl 2,2-difluoro-2-iodoacetate (CAS 0711123) in DMSO (40 mL) No. 7648-30-8) (6.4 g, 25.6 mmol) in a solution of Cu (3.58 g, 56.4 mmol) and 1-(bromomethyl)-3-fluoro-2-nitrobenzene ( (4.0 g, 17.1 mmol) from Step 2 of Intermediate 22 was added and this was The reaction was stirred at room temperature for 16 hours. The reaction was diluted with water (100 mL), filtered, and diluted with EtOAc (2× The combined filtrate was extracted with EtOAc (3 x 20 mL) and The crude material was washed with water (50 mL), dried over Na2SO4, filtered and concentrated. C (0-15% EtOAc:PE) to give the title intermediate (3.0 g) as a pale yellow oil. Obtained as a material object. 1 H NMR (400 MHz, DMSO-d6) δ7.77 - 7.71 (m, 1H), 7.67 - 7.61 (m, 1H), 7.45 - 7.4 2 (m, 1H), 4.31- 4.25 (m, 2H), 3.81 - 3.71 (m, 2H), 1.25 - 1.20 (m, 3H).

[0344] Step 2: 3,3,8-trifluoro-3,4-dihydroquinolin-2(1H)-one

[0345] [ka] Using the same method as in Step 4 of Intermediate 13, ethyl 2,2-difluoro-3-(3 -fluoro-2-nitrophenyl)propanoate (1.5 g, 5.41 mmol) Starting from this, the title intermediate (920 mg) was obtained as a pale yellow solid, which could be further purified. I used it without any problems. 1 H NMR (400 MHz, DMSO-d6) δ11.18 (br s, 1H), 7.27 - 7.03 (m, 3H), 3.73 (t, J=17 .2 Hz, 2H).

[0346] Steps 3-5: 6-(2-chloroacetyl)-3,3,8-trifluoro-3,4-dichloroacetyl Hydroquinolin-2(1H)-one

[0347] [ka] Using the same method as in steps 7-9 of intermediate 22, 3,3,8-trifluoro-3, Starting from 4-dihydroquinolin-2(1H)-one, the title intermediate was obtained as a yellow solid. Got it. LCMS: Rt 0.69 min; MS m / z 277.9 [M+H] + ; Method J. 1 H NMR (400 MHz, CDCl3) δ8.29 (br s, 1H), 7.80 - 7.62 (m, 2H), 4.61 (s, 2H), 3. 66 - 3.58 (m, 2H).

[0348] Intermediate 24 2-Bromo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (5-yl)ethan-1-one

[0349] [ka] Step 1: 1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5 -carbonitrile

[0350] [ka] 1H-Indazole-5-carbonitrile (CAS no. 746) in THF (50 mL) 26-47-4) (2.0 g, 14.0 mmol) and benzenesulfonic acid (221 m g, 1.40 mmol) was added to a solution of 3,4-dihydro-2H-pyran (CAS no. 110- 87-2) (4.70 g, 55.9 mmol) was added, and this was stirred at room temperature for 3 hours, then 5 The reaction was stirred overnight at 0° C. The reaction was concentrated and purified with FCC (0-25% EtOAc:heptane). Preparation gave the title intermediate (3.2 g) as a pale pink oil. 1 H NMR (400 MHz, DCM-d2) δ8.17 (t, J = 1.1 Hz, 1H), 8.13 (d, J = 1.0 Hz, 1H), 7 .76 (dt, J = 8.7, 1.0 Hz, 1H), 7.63 (dd, J = 8.8, 1.5 Hz, 1H), 5.78 (dd, J = 9.3 , 2.7 Hz, 1H), 4.07 - 3.98 (m, 1H), 3.84 - 3.73 (m, 1H), 2.58 - 2.46 (m, 1H), 2. 23 - 2.06 (m, 2H), 1.89 - 1.64 (m, 3H).

[0351] Step 2: 1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazole) (5-yl)ethan-1-one

[0352] [ka] 1-(tetrahydro-2H-pyran-2-yl)propan-2-yl 1-(2-methyl-2-pyran-2-yl)propan-2-yl ... )-1H-indazole-5-carbonitrile (3.38 g, 14.9 mmol) solution Methylmagnesium bromide (3.0 M in diethyl ether, 24.8 mL, 74.4 m The resulting suspension was heated at 60°C for 3 hours, at 73°C for 2 hours, and then It was diluted with water (100 mL) and 1N HCl to pH = 7. It was extracted with EtOAc. Extraction, washing with saturated brine, drying over Na2SO4, filtering and concentrating to give the title intermediate (3.78 g) was obtained as an orange oil which was used without further purification.

[0353] LCMS:Rt 1.11 min; MS m / z 245.2[M+H] + ;Method K.

[0354] Step 3: 2-Bromo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H -indazol-5-yl)ethan-1-one

[0355] [ka] 1-(1-(tetrahydro-2H-pyran-2-yl)methyl)-2-(2-methyl-2H-pyran-2-yl ... -1H-indazol-5-yl)ethan-1-one (1.86 g, 7.6 mmol) To the solution was added phenyltrimethylammonium tribromide (3.0 g, A solution of 8.0 mmol) was added. After 10 min, the reaction was filtered and the filtrate was concentrated and (0-20% EtOAc:heptane) to give the title intermediate (880 mg) as a pale yellow color. Obtained as an oil.

[0356] LCMS: Rt 1.26 min; MS m / z 323.2 and 325.2 [M+H] + ;Method K.

[0357] Intermediate 25 6-(2-bromo-1-hydroxyethyl)-1,4-dihydro-2H-benzo[d][ 1,3]oxazin-2-one

[0358] [ka] Step 1: 6-Bromo-1,4-dihydro-2H-benzo[d][1,3]oxazine -2-on

[0359] [ka] (2-amino-5-bromophenyl)methanol ( CAS No. 20712-12-3) (1.2 g, 5.94 mmol) in THF ( A solution of triphosgene (2.11 g, 7.13 mmol) in 150 ml of HCl (5 mL) was added slowly. After 10 minutes, triethylamine (2.92 mL, 20.79 mmol) was added dropwise and the reaction The reaction was warmed to room temperature and stirred for 1 hour. The reaction was poured onto crushed ice and ethyl acetate (3×30 The crude material was extracted with 0.5 mL of FCC (0.5 mL), dried over Na2SO4, filtered, and concentrated. 50% EtOAc:PE) to give the title intermediate (850 mg) as a white solid Got it. LCMS: Rt 0.60 min; MS m / z 228.0 and 230.0 [M+H] + ; Method J. 1 H NMR (400 MHz, CDCl3) δ8.40 (br s, 1H), 7.41 - 7.38 (m, 1H), 7.27 - 7.26 (m, 1H), 6.76 - 6.73 (m, 1H), 5.30 (s, 2H).

[0360] Step 2: 6-Vinyl-1,4-dihydro-2H-benzo[d][1,3]oxazine -2-on

[0361] [ka] Using the same method as in Step 4 of Intermediate 19, 6-bromo-1,4-dihydro-2H Starting from benzo[d][1,3]oxazin-2-one, the title intermediate (400 mg ) was obtained as a white solid. 1 H NMR (400 MHz, CDCl3) δ8.33 - 8.26 (m, 1H), 7.33 - 7.30 (m, 1H), 7.18 (s, 1H) , 6.82 - 6.79 (m, 1H), 6.69 - 6.62 (m, 1H), 5.70 - 5.65 (m, 1H), 5.34 (s, 2H), 5 .24 - 5.20 (m, 1H).

[0362] Step 3: 6-(2-bromo-1-hydroxyethyl)-1,4-dihydro-2H-benzyl Benzo[d][1,3]oxazin-2-one

[0363] [ka] 6-Vinyl-1,4- in HO (1.5 mL) and t-BuOH (0.75 mL) Dihydro-2H-benzo[d][1,3]oxazin-2-one (190 mg, 0.57 NBS (91 mg, 0.51 mmol) was added to a solution of 1 mmol of NBS and the mixture was heated at 40 °C for 1 The mixture was stirred for 1 hour.

[0364] The reaction was diluted with HO (10 mL), extracted with EtOAc (2 x 5 mL), and The crude material was purified by preparative TLC (2:1 EtOAc:PE, R f =0.5) to afford the title intermediate (210 mg) as a yellow solid.

[0365] LCMS: Rt 0.62 min; MS m / z 272.0 and 274.0 [M+H] + ;Method J.

[0366] Intermediate 26 6-(2-Bromo-1-hydroxyethyl)-8-fluoro-3,4-dihydroquinoline -2(1H)-On

[0367] [ka] Using the same method as in Step 3 of Intermediate 25, 8-fluoro-6-vinyl-3,4- Dihydroquinolin-2(1H)-one (from step 2 of intermediate 20, 400 mg) , 2.09 mmol) to give the title intermediate (564 mg) as a white solid. . LCMS: Rt 0.66 min; MS m / z 288.0 and 290.0 [M+H] + ; Method J. 1 H NMR (400 MHz, methanol-d4) δ 7.21 - 6.97 (m, 2H), 4.83 - 4.79 (m, 1H), 3.6 6 - 3.57 (m, 1H), 3.56 - 3.48 (m, 1H), 3.02 - 2.99 (m, 2H), 2.62 - 2.57 (m, 2H).

[0368] Intermediate 27 7-(2-Bromo-1-hydroxyethyl)-9-fluoro-1,3,4,5-tetrahydrofuran dro-2H-benzo[b]azepin-2-one

[0369] [ka] Step 1: 7-Bromo-9-fluoro-1,3,4,5-tetrahydro-2H-benzo [b]Azepin-2-one

[0370] [ka] 9-Fluoro-1,3,4,5-tetrahydro-2H in AcOH (10 mL) at room temperature -Benz[b]azepin-2-one (CAS number 1151397-80-6) (1g, 5 To a solution of 0.6 mmol of H2SO4 (0.05 mL) was added followed by AcOH (8.6 A solution of Br2 (1.96 g, 0.63 mL, 12.3 mmol) in HCl (1.96 g, 0.63 mL, 12.3 mmol) was added dropwise. The reaction vessel was sealed and stirred at room temperature for 12 hours, then poured onto ice and cooled with ammonium hydroxide. It was neutralized to pH = 7. It was extracted with EtOAc (3 x 10 mL) and saturated NaHCO3 Washed with aqueous solution (20 mL), then saturated brine (20 mL), dried over Na2SO4 The crude material was purified by FCC (0-50% EtOAc:PE) to give the product shown in Table 1. The title intermediate (850 mg) was obtained as an off-white solid. LCMS: Rt 0.68 min; MS m / z 258.0 and 260.0 [M+H] + ; Method J. 1 H NMR (400 MHz, DMSO-d6) δ9.50 (s, 1H), 7.51 - 7.44 (m, 1H), 7.37 (br s, 1H), 2.72 (t, J = 7.2 Hz, 2H), 2.19 - 2.07 (m, 4H).

[0371] Steps 2 and 3: 7-(2-bromo-1-hydroxyethyl)-9-fluoro-1, 3,4,5-Tetrahydro-2H-benzo[b]azepin-2-one

[0372] [ka] Using the same method as in steps 2 and 3 of intermediate 25, 7-bromo-9-fluoro- Starting from 1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one, The title intermediate was obtained as a white solid. LCMS: Rt 0.58 min; MS m / z 302.0 and 304.0 [M+H] + ; Method J. 1 H NMR (400 MHz, DMSO-d6) δ9.44 (s, 1H), 7.19 - 7.13 (m, 2H), 5.91 - 5.90 (m, 1 H), 4.80 - 4.75 (m, 1H), 3.70 - 3.67 (m, 1H), 3.59 - 3.55 (m, 1H), 2.73 - 2.69 ( m, 2H), 2.16 - 2.09 (m, 4H).

[0373] Intermediate 28 6-(2-Bromo-1-((tert-butyldimethylsilyl)oxy)ethyl)-4- Fluorobenzo[d]thiazol-2(3H)-one

[0374] [ka] Step 1: 6-Bromo-4-fluorobenzo[d]thiazole-2-thiol

[0375] [ka] 4-Bromo-2,6-difluoroaniline (CAS no. 67) in DMF (300 mL) 567-26-4) (15.0 g, 72.1 mmol) was added to a solution of O-ethylcarbonyl Potassium thiosulfate (CAS number 140-89-6) (25.43 g, 158.6 mmol) was added and this was stirred at 120° C. for 16 hours. The reaction was cooled and then water (200 mL ) and acidified with 2N HCl to pH=4. The resulting precipitate was collected by filtration. Washing with water (2×40 mL) and drying afforded the title intermediate (20 g, crude) as a yellow solid. which was used without further purification.

[0376] LCMS: Rt 0.86 min; MS m / z 264.0 and 266.0 [M+H] + ;Method J.

[0377] Step 2: 6-Bromo-4-fluoro-2-(methylthio)benzo[d]thiazole

[0378] [ka] 6-Bromo-4-fluorobenzo[d]thiazole in acetonitrile (400 mL) A suspension of α-2-thiol (20 g, crude) was treated with MeSO (28.65 g, 21.5 m L, 227.2 mmol) was added and this was stirred at 80° C. for 2.5 hours. The resulting precipitate was collected by filtration and dried to give the title intermediate (20 g, crude). Obtained as a pale yellow solid which was used without further purification. LCMS: Rt 0.98 min; MS m / z 277.9 and 279.9 [M+H] + ; Method J. 1 H NMR (400 MHz, DMSO-d6) δ8.18 (s, 1H), 7.66 (m, 1H), 2.85 (s, 3H).

[0379] Step 3: 6-Bromo-4-fluoro-2-(methylsulfonyl)benzo[d]thiazo Rule

[0380] [ka] 6-Bromo-4-fluoro-2-(methylthio)benzo[d] in DCM (80 mL) A solution of thiazole (8 g, crude) was added to m-CPBA (12.8 g, 85% purity, 63.3 The reaction was stirred at room temperature for 2 hours. Dilute with HCl (3 x 50 mL), extract with DCM (2 x 40 mL), dry with Na2SO4, Filtration and concentration gave the title intermediate (12 g, crude) as a white solid, which was further was used without further purification.

[0381] LCMS: Rt 0.86 min; MS m / z 309.9 and 311.9 [M+H] + ;Method J.

[0382] Step 4: 6-Bromo-4-fluorobenzo[d]thiazol-2(3H)-one

[0383] [ka] 6-Bromo-4-fluoro-2-(methylsulfonyl)sulfonyl ether in 5N aqueous NaOH (100 mL) A solution of (diaminobenzo[d]thiazole) (12 g, crude) was stirred at 100°C for 2 h. The reaction was cooled, diluted with water (10 mL), and acidified to pH=4 with 2N HCl. The resulting precipitate was collected by filtration, dissolved in EtOAc (100 mL), and saturated NaHCO The crude product was washed with aqueous 3 (3×100 mL), dried over Na2SO4, filtered, and concentrated. The resulting material was triturated with 5:1 PE:EtOAc (50 mL) and filtered to give the title intermediate (2. 5g) as a white solid which was used without further purification.

[0384] LCMS: Rt 0.76 min; MS m / z 247.8 and 249.8 [M+H] + ;Method J.

[0385] Steps 5 and 6: 6-(2-bromo-1-hydroxyethyl)-4-fluorobenzo [d]thiazol-2(3H)-one

[0386] [ka] 6-Bromo-4-fluorobenzylamine was prepared using the same method as in steps 2 and 3 of intermediate 25. Starting from benzo[d]thiazol-2(3H)-one, the title intermediate was obtained as a yellow solid. Got it. LCMS: Rt 0.65 min; MS m / z 291.8 and 293.8 [M+H] + ; Method J. 1 H NMR (400 MHz, DMSO-d6) δ12.40 (s, 1H), 7.46 (s, 1H), 7.25 - 7.22 (m, 1H), 5. 97 (br s, 1H), 4.83 - 4.81 (m, 1H), 3.71 - 3.67 (m, 1H), 3.43 - 3.40 (m, 1H).

[0387] Step 7: 6-(2-bromo-1-((tert-butyldimethylsilyl)oxy)ethoxy)ethoxy (C1H)-4-fluorobenzo[d]thiazol-2(3H)-one

[0388] [ka] 6-(2-bromo-1-hydroxyethyl)-4-fluorobenzyl alcohol in DMF (13 mL) To a solution of benzo[d]thiazol-2(3H)-one (1.3 g, 4.45 mmol), BS-Cl (2.0 g, 13.3 mmol) and imidazole (1.2 g, 17.8 mmol) mol) was added and the reaction was stirred at 60° C. for 6 hours. The reaction was cooled and water (20 mL) Dilute with ethyl acetate, extract with EtOAc (3 x 20 mL), wash with saturated brine (50 mL), and The crude material was purified by FCC (0-60% EtOAc: PE) to give the title intermediate (1.8 g) as a yellow oil. LCMS: Rt 1.02 min; MS m / z 405.8 and 407.8 [M+H] + ; Method J. 1 H NMR (400 MHz, CDCl3) δ9.09 (br s, 1H), 7.20 (s, 1H), 7.09 - 7.06 (m, 1H), 4. 85 - 4.82 (m, 1H), 3.47 - 3.38 (m, 2H), 0.91 (s, 9H), 0.13 - 0.11 (m, 6H).

[0389] Intermediate 29 7-(2-Bromo-1-((tert-butyldimethylsilyl)oxy)ethyl)-9- Fluoro-1,5-dihydrobenzo[e][1,4]oxazepin-2(3H)-one

[0390] [ka] Step 1: 2-chloro-N-(2-fluoro-6-(hydroxymethyl)phenyl)a Cetoamide

[0391] [ka] (2-amino-3-fluorophenyl)methanol (CAS no. 1001-0001) in DCM (50 mL) No. 906811-49-2) (2.5 g, 17.7 mmol) in a solution of triethylamine (3.58 g, 25.4 mmol) was added to the solution. The mixture was cooled to 0° C. and chloroacetyl chloride was added. C. (2.4 g, 21.2 mmol) was added, and the reaction was stirred at room temperature for 16 hours. The reaction mixture was washed with saturated aqueous NH4Cl (40 mL) and the aqueous layer was diluted with DCM (2 x 20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude material was Purification by CC (0-60% EtOAc:PE) gave the title intermediate (1.5 g) as a pale yellow solid. Obtained as a physical object. 1 H NMR (400 MHz, DMSO-d6) δ9.75 (s, 1H), 7.43 - 7.27 (m, 2H), 7.23 - 7.10 (m, 1 H), 5.28 (t, J=5.8 Hz, 1H), 4.46 - 4.42 (m, 2H), 4.32 (s, 2H).

[0392] Step 2: 9-Fluoro-1,5-dihydrobenzo[e][1,4]oxazepine-2 (3H)-On

[0393] [ka] 2-Chloro-N-(2-fluoro-6-(hydroxymethyl)methyl)-2-(2-chloro-N-(2-fluoro-6-(hydroxymethyl) ... A solution of NaH (60%, in mineral oil, 827 mg, 20.7 The reaction was stirred at room temperature for 2 hours. The solution was diluted with 20 mL of ethyl acetate, extracted with 3×15 mL of EtOAc, and then washed with saturated brine (15 m The crude material was washed with 1 L of HCl, dried over Na2SO4, filtered, and concentrated. Purification with 0.00% EtOAc:PE gave the title intermediate (1.0 g) as a yellow solid. Ta. 1 H NMR (400 MHz, DMSO-d6) δ9.77 (br s, 1H), 7.27 - 7.18 (m, 1H), 7.11 - 7.05 (m , 2H), 4.72 (s, 2H), 4.36 (s, 2H).

[0394] Step 3: 7-Bromo-9-fluoro-1,5-dihydrobenzo[e][1,4]oxo Sazepin-2(3H)-one

[0395] [ka] 9-Fluoro-1,5-dihydrobenzophenone was prepared using the same method as in Step 3 of Intermediate 19. Starting from zo[e][1,4]oxazepin-2(3H)-one (1 g, 5.5 mmol) This gave the title intermediate (1.4 g) as a white solid, which was used without further purification. Used. LCMS: Rt 0.68 min; MS m / z 259.8 and 261.9 [M+H] + ; Method J. 1 H NMR (400 MHz, DMSO-d6) δ9.86 (s, 1H), 7.57 - 7.54 (m, 1H), 7.37 (s, 1H), 4.7 2 (s, 2H), 4.39 (s, 2H).

[0396] Steps 4 and 5: 7-(2-bromo-1-hydroxyethyl)-9-fluoro-1, 5-Dihydrobenzo[e][1,4]oxazepin-2(3H)-one

[0397] [ka] Using the same method as in steps 2 and 3 of intermediate 25, 7-bromo-9-fluoro- Starting from 1,5-dihydrobenzo[e][1,4]oxazepin-2(3H)-one, The title intermediate was obtained as a colorless oil.

[0398] LCMS: Rt 0.41 min; MS m / z 304.0 and 306.0 [M+H] + ;Method J.

[0399] Step 6: 7-(2-bromo-1-((tert-butyldimethylsilyl)oxy)ethoxy) (ethyl)-9-fluoro-1,5-dihydrobenzo[e][1,4]oxazepine-2(3 H)-on

[0400] [ka] Using the same method as in Step 7 of Intermediate 28, 7-(2-bromo-1-hydroxyethyl) (ethyl)-9-fluoro-1,5-dihydrobenzo[e][1,4]oxazepine-2(3 Starting from H)-one, the title intermediate was obtained as a white solid. LCMS: Rt 1.11 min; MS m / z 418.1 and 420.0 [M+H] + ; Method J. 1 H NMR (400 MHz, CDCl3) δ7.82 (br s, 1H), 7.12 - 7.10 (m, 1H), 6.88 (s, 1H), 4. 77 (s, 3H), 4.63 (s, 2H), 3.58 -3.31 (m, 2H), 0.91 - 0.89 (m, 9H), 0.12 (d, J = 4.0 Hz, 3H), -0.03 - -0.06 (m, 3H).

[0401] Intermediate 30 6-(2-Bromo-1-((tert-butyldimethylsilyl)oxy)ethyl)-5- Fluoro-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one

[0402] [ka] Step 1: (2-amino-6-fluorophenyl)methanol

[0403] [ka] Using the same method as in Step 1 of Intermediate 16, 2-amino-6-fluorobenzoic acid ( Starting from CAS No. 434-76-4 (5 g, 32 mmol), the title intermediate (4 g ) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ6.98 - 6.92 (m, 1H), 6.45 (d, J = 8.4 Hz, 1H), 6.35 - 6.18 (m, 1H), 5.28 (br s, 2H), 4.94 - 4.92 (m, 1H), 4.44 - 4.43 (m, 2H).

[0404] Step 2: 5-Fluoro-1,4-dihydro-2H-benzo[d][1,3]oxazolidinyl On-2-On

[0405] [ka] Using the same method as in Step 1 of Intermediate 25, (2-amino-6-fluorophenyl ) Starting from methanol (4 g, 28 mmol), the title intermediate (3 g) was obtained as a white solid. And got it. LCMS: Rt 0.30 min; MS m / z 168.0 [M+H] + ; Method J. 1 H NMR (400 MHz, DMSO-d6) δ10.38 (br s, 1H), 7.31 - 7.27 (m, 1H), 6.93 - 6.78 ( m, 1H), 6.71 (d, J = 8.0 Hz, 1H), 5.37 (s, 2H).

[0406] Step 3: 6-Bromo-5-fluoro-1,4-dihydro-2H-benzo[d][1, 3] Oxazin-2-one

[0407] [ka] Using the same method as in Step 3 of Intermediate 19, 5-fluoro-1,4-dihydro-2 H-benzo[d][1,3]oxazin-2-one (1.5 g, 9.0 mmol) Evaporation gave the title intermediate (1.6 g) as a white solid, which was carried on without further purification. Used. LCMS: Rt 0.61 min; MS m / z 245.9 and 247.9 [M+H] + ; Method J. 1 H NMR (400 MHz, DMSO-d6) δ10.51 (s, 1H), 7.56 (t, J = 8.0 Hz, 1H), 6.68 - 6.66 (m, 1H), 5.40 (s, 2H).

[0408] Steps 4-6: 6-(2-bromo-1-((tert-butyldimethylsilyl)oxy) )Ethyl)-5-fluoro-1,4-dihydro-2H-benzo[d][1,3]oxazolidinyl On-2-On

[0409] [ka] Using the same method as in steps 4-6 of intermediate 29, 6-bromo-5-fluoro-1, Starting from 4-dihydro-2H-benzo[d][1,3]oxazin-2-one, The intermediate was obtained as a white solid. LCMS: Rt 1.10 min; MS m / z 403.9 and 405.9 [M+H] + ; Method J. 1 H NMR (400 MHz, CDCl3) δ7.94 (br s, 1H), 7.42 (t, J = 8.0 Hz, 1H), 6.64 (d, J = 8.4 Hz, 1H), 5.43 (s, 2H), 5.15 - 5.13 (m, 1H), 3.53 - 3.40 (m, 2H), 0.94 - 0. 87 (m, 9H), 0.14 (s, 3H), -0.04 (s, 3H).

[0410] The following intermediates were made using similar procedures from the starting materials indicated.

[0411] [Table 3-1]

[0412] [Table 3-2]

[0413] [Table 3-3]

[0414] Intermediate 39 5-(oxiran-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine

[0415] [ka] Step 1: 5-Bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine

[0416] [ka] 5-Bromo-1H-pyrrolo[2,3-b]pyridine (C A solution of NaH(6 0%, in mineral oil, 761 mg, 19.0 mmol) was added, and this was stirred at room temperature for 20 minutes. , then cooled again to 0°C and 4-methylbenzenesulfonyl chloride (2.9 g, 15.2 The reaction was stirred at room temperature for 2 hours and then poured into ice water. The solid was filtered to give the title intermediate (3.0 g), which was used without further purification. Used.

[0417] LCMS: Rt 1.87 min; MS m / z 351.1 and 353.1 [M+H] + ;Method D.

[0418] Step 2: 1-Tosyl-5-vinyl-1H-pyrrolo[2,3-b]pyridine

[0419] [ka] 5-Bromo-1-tosyl-1H-pyrrolidine in THF (90 mL) and water (20 mL) 2,3-b]pyridine (3.0 g, 8.5 mmol) and vinyltrifluoroboron A solution of potassium carbonate (2.28 g, 17.1 mmol) was added to Cs2CO3 (8.35 g, 2 5.6 mmol) was added and the reaction was degassed with argon for 10 minutes. was added and the reaction was stirred at 90° C. for 16 hours. The reaction was extracted with EtOAc and The crude material was purified by FCC (10% EtOAc:Hexanes) and dried over O4, filtered, and concentrated. to give the title intermediate (2.0 g).

[0420] LCMS:Rt 1.80 min; MS m / z 299.2[M+H] + ;Method D.

[0421] Step 3: 5-(oxiran-2-yl)-1-tosyl-1H-pyrrolo[2,3-b] Pyridine

[0422] [ka] 1-Tosyl-5-vinyl-1H- in dioxane (30 mL) and water (150 mL) A solution of pyrrolo[2,3-b]pyridine (2.0 g, 6.7 mmol) was added to AcOH (40 NBS (870 mg, 7.4 mmol) was added and the reaction The mixture was stirred at room temperature for 1 hour. Na2CO3 (2.13 g, 20.1 mmol) was added, and The reaction was stirred for 16 h, then extracted with EtOAc, dried over Na2SO4, filtered, and The crude material was purified by FCC (20% EtOAc:hexanes) to give the title intermediate. The compound (1.5 g) was obtained.

[0423] LCMS:Rt 1.58 min; MS m / z 315.2[M+H] + ;Method D.

[0424] Intermediate 40 6-(2-((3aS,5R,6aR)-3a,5-dihydroxyhexahydrocyclopenta[4 ... pentane[c]pyrrol-2(1H)-yl)acetyl)-3,4-dihydroquinoline-2( 1H)-On 6-(2-((3aR,5S,6aS)-3a,5-dihydroxyhexahydrocyclopenta[4 ... pentane[c]pyrrol-2(1H)-yl)acetyl)-3,4-dihydroquinoline-2( 1H)-On A racemic mixture of

[0425] [ka] Step 1: (3aS,5R,6aR)-Hexahydrocyclopenta[c]pyrrole-3a,5(1H )-diol (3aR,5S,6aS)-Hexahydrocyclopenta[c]pyrrole-3a,5(1H )-diol A racemic mixture of

[0426] [ka] Using the same method as in Step 4 of Intermediate 13, benzyl (3aS,5R,6aR)- 3a,5-Dihydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carbo Xylates and benzyl (3aR,5S,6aS)-3a,5-dihydroxyhexyl cyclopenta[c]pyrrole-2(1H)-carboxylate (Step 1 of Intermediate) Starting from a racemic mixture of 5 (2.4 g, 8.65 mmol), The compound (1.2 g) was obtained as a colorless gum which was used without further purification. 1 H NMR (400 MHz, DMSO-d6) δ4.69 (br s, 1H), 4.05 - 3.98 (m, 1H), 2.95 - 2.87 (m , 1H), 2.82 - 2.75 (m, 1H), 2.58 - 2.52 (m, 2H), 2.14- 1.99 (m, 2H), 1.94 - 1.89 (m, 1H), 1.63 - 1.57 (m, 1H), 1.23 - 1.16 (m, 1H). 2H below the solvent peak.

[0427] Step 2 6-(2-((3aS,5R,6aR)-3a,5-dihydroxyhexahydrocyclopenta[4 ... pentane[c]pyrrol-2(1H)-yl)acetyl)-3,4-dihydroquinoline-2( 1H)-On 6-(2-((3aR,5S,6aS)-3a,5-dihydroxyhexahydrocyclopenta[4 ... pentane[c]pyrrol-2(1H)-yl)acetyl)-3,4-dihydroquinoline-2( 1H)-On A racemic mixture of

[0428] [ka] (3aS,5R,6aR)-Hexahydrocyclopenta[c] in DMF (10 mL) Pyrrole-3a,5(1H)-diol and (3aR,5S,6aS)-hexahydro Cyclopenta[c]pyrrole-3a,5(1H)-diol (900 mg, 6.29 mm To a solution of the racemic mixture of 6-(2-chloroacetyl)-3,4-dihydroquinone ion-2(1H)-one (Intermediate 11, 1.41 g, 6.29 mmol) and K2CO3 (1.74 g, 12.6 mmol) was added and this was stirred at room temperature for 4 hours. (10 mL), extracted with EtOAc (3 × 10 mL), and saturated brine (15 mL). The crude material was purified by preparative HPLC (Wa ters Xbridge C18, 150 x 50 mm, 10 microns, mobile phase A: 10 HCl (H2O; B: acetonitrile, gradient 5-30% B) The title intermediate (1.2 g) was obtained as a white solid. LCMS: Rt 0.75 min; MS m / z 331.3 [M+H] + ; Method I. 1 H NMR (400 MHz, CDCl3) δ8.04 - 7.88 (m, 1H), 7.82 - 7.71 (m, 2H), 6.81 - 6.78 (m, 1H), 6.17 - 5.95 (br s, 1H), 4.21 (t, J = 4.0 Hz, 1H), 3.93 (s, 2H), 3.37 (d , J = 9.2 Hz, 1H), 3.08 - 2.93 (m, 3H), 2.77 - 2.65 (m, 3H), 2.52 - 2.33 (m, 3H) , 2.25 - 2.19 (m, 1H), 2.14 - 2.05 (m, 1H), 1.82 - 1.68 (m, 2H).

[0429] Example 1A 6-((R)-1-hydroxy-2-((3aS,5S,6aR)-3a-hydroxy- 5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl -3,4-dihydroquinolin-2(1H)-one

[0430] [ka] Step 1: 6-(2-((3aS,5S,6aR)-3a-hydroxy-5-phenoxy) Dihexahydrocyclopenta[c]pyrrole-2(1H)-yl)acetyl)-3,4- Dihydroquinolin-2(1H)-one

[0431] [ka] Intermediate 11 (8.10 g, 3 mL) in CHCN (100 mL) and DMF (10 mL) To a solution of Intermediate 2 (6.5 g, 29.6 mmol) and Intermediate 3 (6.5 g, 29.6 mmol), (10.35 mL, 59.3 mmol) was added and this was stirred at room temperature overnight. It was concentrated, diluted with EtOAc, and washed three times with water. The aqueous layers were combined and extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered, and concentrated. The crude material was purified by FCC( 100% EtOAc) to give the title intermediate (6.0 g) as a pale yellow foam .

[0432] LCMS:Rt 0.67min;MS m / z 407.4[M+H] + ;Method A.

[0433] Step 2: 6-((R)-1-hydroxy-2-((3aS,5S,6aR)-3a- Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)-isocyanate (ethyl)-3,4-dihydroquinolin-2(1H)-one

[0434] [ka] Triethylamine (4.11 mL, 29.5 mmol) in THF (20 mL) at 0 °C To the solution was added formic acid (3.40 mL, 89 mmol), and the mixture was diluted with THF (50 mL) under nitrogen. L) in 6-(2-((3aS,5S,6aR)-3a-hydroxy-5-phenoxy) (1H)-hexahydrocyclopenta[c]pyrrol-2(1H)-yl)acetyl)-3,4-dihydroxy To a solution of 2-chloroquinolin-2(1H)-one (6.0 g, 14.8 mmol) was added. RuCl(p-cymene)[(S,S)-Ts-DPEN] (CAS no.) in MF (5 mL) A solution of 192139-90-5) (0.240 g, 0.369 mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 2 days. Triethylamine (4.1%) in THF (10 mL) at 0° C. 1 mL) and formic acid (3.40 mL), followed by another solution of RuCl in DMF (3 mL). Another solution of (p-cymene) [(S,S)-Ts-DPEN] (100 mg) was added, and this This was stirred at room temperature for 9 days. The reaction was partially concentrated to remove THF and washed with EtOAc. The organic layers were combined and extracted with EtOAc. The crude material was dried over Na2SO4, filtered and concentrated. This was then purified with 0-10% MeOH:DCM to give a brown oil, which was then purified with DCM (4 SiliaMetS DMT resin (S ilicycle, 2 g, 0.64 mmol / g loaded) was added and the slurry was allowed to stand at room temperature. The reaction was stirred at rt for 5 h. The reaction was filtered, rinsed with DCM, and the filtrate was added additional SiliaMetS The reaction was treated with DMT resin (2 g) and stirred overnight. The reaction was filtered, concentrated, and diluted with EtOAc. This was concentrated to remove residual MeOH and DCM, then redissolved in EtOAc. This was again concentrated until a precipitate was observed, at which point the flask was cooled to 0°C. Cool for 20 minutes. The solid was collected by filtration, washed three times with EtOAc, and dried. It was partially concentrated and sonicated until precipitation occurred. The solid was collected and processed as before. The process was repeated to obtain a third batch of solids. All three batches were combined and freeze-dried. This gave the title compound (1.59 g) as an off-white solid. LCMS: Rt 0.60 min; MS m / z 409.5 [M+H] + ; Method A. 1 H NMR (400 MHz, methanol-d4) δ 7.27–7.15 (m, 4H), 6.92–6.79 (m, 4H), 4.7 7 (p, J = 5.8 Hz, 1H), 4.69 (dd, J = 8.3, 5.0 Hz, 1H), 2.91 (td, J = 7.5, 2.0 Hz , 2H), 2.86 - 2.77 (m, 2H), 2.73 (dd, J = 12.4, 8.3 Hz, 1H), 2.62 (d, J = 9.3 Hz , 1H), 2.56 (dd, J = 12.4, 5.0 Hz, 1H), 2.52 - 2.39 (m, 4H), 2.27 (dd, J = 13.2, 5.4 Hz, 1H), 2.18 - 2.08 (m, 1H), 2.01 (dd, J = 12.9, 6.6 Hz, 1H), 1.83 (dt, J = 13.0, 5.0 Hz, 1H).

[0435] X-ray structure of Example 1A complexed with DCM:

[0436] [ka]

[0437] Example 1B 6-((S)-1-hydroxy-2-((3aS,5S,6aR)-3a-hydroxy- 5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl -3,4-dihydroquinolin-2(1H)-one

[0438] [ka] Step 1 6-((S)-1-hydroxy-2-((3aS,5S,6aR)-3a-hydroxy- 5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl -3,4-dihydroquinolin-2(1H)-one 6-((R)-1-hydroxy-2-((3aS,5S,6aR)-3a-hydroxy- 5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl -3,4-dihydroquinolin-2(1H)-one A mixture of

[0439] [ka] 6-(2-((3aS,5S,6aR)-3a-hydroxybenzoate) in MeOH (15 mL) -5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)acetyl (I)-3,4-dihydroquinolin-2(1H)-one (from Step 1 of Example 1A) (300 mg, 0.73 mmol) was added to a suspension of NaBH4 (55 mg, 1.46 mmol) ) was added and stirred at room temperature for 1 hour. The reaction was diluted with water and extracted with EtOAc. The crude material was dried over Na2SO4, filtered, and concentrated. ), which was then purified by preparative HPLC using the following method to give the title intermediate (75 mg). Got it. Column: Kinetex (21.2 mm x 150 mm), flow rate: 20.0 mL / min Mobile phase: 0.02% NH4OH in water (A), acetonitrile (B)

[0440] LCMS:Rt 0.11 min;MS m / z 409.2[M+H] + ;Method D.

[0441] Step 2: 6-((S)-1-hydroxy-2-((3aS,5S,6aR)-3a- Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)-isocyanate (ethyl)-3,4-dihydroquinolin-2(1H)-one

[0442] [ka] The mixture (75 mg) obtained from the previous step was separated using the following chiral HPLC method: did: Column: C-4, Flow rate: 19 mL / min Mobile phase: Hexane (A), EtOH:MeOH 80:20 containing 0.1% DEA (B) , Isocratic: 80:20 (A:B)

[0443] Example 1B (chiral HPLC Rt 7.08 min): 32 mg. LCMS: Rt 0.43 min; MS m / z 409.2 [M+H] + ; Method C. 1 H NMR (400 MHz, methanol-d4) δ 7.26–7.16 (m, 4H), 6.90–6.78 (m, 4H), 4.7 7 (p, J = 5.8 Hz, 1H), 4.70 (dd, J = 8.2, 5.1 Hz, 1H), 2.95 - 2.83 (m, 3H), 2.81 (d, J = 9.3 Hz, 1H), 2.71 (dd, J = 12.4, 8.2 Hz, 1H), 2.62 - 2.52 (m, 2H), 2.52 - 2.40 (m, 4H), 2.29 - 2.21 (m, 1H), 2.20 - 2.11 (m, 1H), 2.03 - 1.94 (m, 1H), 1.89 - 1.77 (m, 1H).

[0444] Examples 2A and 2B 5-((R)-1-hydroxy-2-((3aS,5S,6aR)-3a-hydroxy- 5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl Indolin-2-one 5-((S)-1-hydroxy-2-((3aS,5S,6aR)-3a-hydroxy- 5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl Indolin-2-one

[0445] [ka] Step 1: 5-(2-((3aS,5S,6aR)-3a-hydroxy-5-phenoxy) Dihexahydrocyclopenta[c]pyrrol-2(1H)-yl)acetyl)indoline -2-on

[0446] [ka] 5-(2-chloroacetyl)indolin-2-one (CAS 506222) in DMF (1.0 mL) No. 65435-04-3) (150 mg, 0.71 mmol) and potassium carbonate (1 96 mg, 1.42 mmol) and potassium iodide (5.0 mg, 0.03 mmol). To the stirred suspension was added Intermediate 2 (156 mg, 0.71 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction was poured into ice water and the precipitate was filtered and dried to give the title intermediate (25 0 mg) which was used without further purification.

[0447] LCMS:Rt 0.12min;MS m / z 393.2[M+H] + ;Method D.

[0448] Step 2 5-((R)-1-hydroxy-2-((3aS,5S,6aR)-3a-hydroxy- 5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl Indolin-2-one 5-((S)-1-hydroxy-2-((3aS,5S,6aR)-3a-hydroxy- 5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl Indolin-2-one A mixture of

[0449] [ka] Using the same method as in Step 1 of Example 1B, 5-(2-((3aS,5S,6aR)- 3a-Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H Starting from )-yl)acetyl)indolin-2-one (250 mg, 0.64 mmol) As a result, a mixture of Examples 2A and 2B (30 mg) was obtained.

[0450] LCMS:Rt 0.39min;MS m / z 395.1[M+H] + ;Method E.

[0451] Step 3: Chiral separation The two diastereomers were separated using the following chiral HPLC method: Column: Chiralpak IA (10mm x 250mm, 5μm), flow rate: 15m L / min Mobile phase: hexane (A), 0.1% DEA in IPA:MeOH 1:1 (B), isopropyl alcohol Classic: 45:55 (A:B)

[0452] Example 2A (chiral HPLC Rt 14.85 min): 10 mg. LCMS: Rt 0.45 min; MS m / z 395.1 [M+H] + ; Method E. 1 H NMR (400 MHz, methanol-d4) δ 7.28 (s, 1H), 7.26-7.18 (m, 3H), 6.90-6.81 (m , 4H), 4.82-4.75 (m, 1H), 4.74-4.67 (m, 1H), 2.85-2.69 (m, 3H), 2.61 (d, J = 9.6 Hz, 1H), 2.54 (dd, J = 12.4, 5.2 Hz, 1H), 2.50-2.40 (m, 2H), 2.27 (dd, J = 13.2 , 5.6 Hz, 1H), 2.18-2.08 (m, 1H), 2.01 (dd, J = 13.2, 6.4 Hz, 1H), 1.86-1.77 (m, 1H). 2H under the solvent peak.

[0453] Example 2B (chiral HPLC Rt 22.07 min): 10 mg. LCMS: Rt 0.49 min; MS m / z 395.2 [M+H] + ; Method E. 1 H NMR (400 MHz, methanol-d4) δ 7.28 (d, J = 2.0 Hz, 1H), 7.25-7.18 (m, 3H), 6.90-6.80 (m, 4H), 4.80-4.75 (m, 1H), 4.74-4.68 (m, 1H), 2.91-2.84 (m, 1H), 2.79 (d, J = 9.2 Hz, 1H), 2.74-2.67 (m, 1H), 2.59-2.52 (m, 2H), 2.50-2.41 (m, 2H), 2 .24 (dd, J = 13.2, 5.2 Hz, 1H), 2.20-2.10 (m, 1H), 1.98 (dd, J = 13.2, 6.4 Hz, 1 H), 1.88-1.80 (m, 1H). 2H below the solvent peak.

[0454] Examples 3A, 3B, 3C, and 3D 5-((R)-2-((3aS,4S,5S,6aR)-3a,4-dihydroxy-5- Phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)-yl)-1-hydro (oxyethyl)indolin-2-one 5-((S)-2-((3aS,4S,5S,6aR)-3a,4-dihydroxy-5- Phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)-yl)-1-hydro (oxyethyl)indolin-2-one 5-((R)-2-((3aR,4R,5R,6aS)-3a,4-dihydroxy-5- Phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)-yl)-1-hydro (oxyethyl)indolin-2-one 5-((S)-2-((3aR,4R,5R,6aS)-3a,4-dihydroxy-5- Phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)-yl)-1-hydro (oxyethyl)indolin-2-one

[0455] [ka] Using the same method as in Examples 2A / 2B, intermediate 6 and 5-(2-chloroacetyl)isopropyl Starting from dolin-2-one, the mixture of Examples 3A and 3B was obtained. The SFC method was used to separate: Column: Chiralpak IG (10 mm x 250 mm, 5 μm), flow rate: 13 mL / min Mobile phase: CO2 (A), 0.02% NH3 in IPA (B), Isocratic: 55 :45(A:B)

[0456] Example 3A (chiral SFC Rt 7.91 min): 25 mg. LCMS: Rt 0.13 min; MS m / z 411.1 [M+H] + ; Method D. 1 H NMR (400 MHz, methanol-d4) δ 7.30-7.22 (m, 4H), 6.94-6.85 (m, 4H), 4.75-4. 67 (m, 2H), 3.92 (d, J = 3.6 Hz, 1H), 2.94 (d, J = 9.2 Hz, 1H), 2.79-2.61 (m, 4H ), 2.42-2.36 (m, 2H), 2.31-2.23 (m, 1H), 1.67-1.62 (m, 1H). 2H under the solvent peak.

[0457] Example 3B (chiral SFC Rt 15.41 min): 25 mg. LCMS: Rt 1.24 min; MS m / z 411.2 [M+H] + ; Method F. 1 H NMR (400 MHz, methanol-d4) δ 7.30-7.22 (m, 4H), 6.94-6.85 (m, 4H), 4.75-4. 68 (m, 2H), 3.96 (d, J = 3.6 Hz, 1H), 3.00 (d, J = 10.0 Hz, 1H), 2.80-2.63 (m, 4 H), 2.47 (d, J = 9.2 Hz, 1H), 2.52-2.46 (m, 1H), 2.28-2.20 (m, 1H), 1.63-1.59 (m , 1H). 2H is below the solvent peak.

[0458] The same procedure was used to prepare intermediate 5 and 5-(2-chloroacetyl)indoline-2-ol. Starting from this, the mixtures of Examples 3C and 3D were obtained. The mixtures were analyzed using the following chiral SFC method: and separated: Column: Chiralpak IG (10mm x 250mm, 5μm), flow rate: 13m L / min Mobile phase: CO2 (A), 0.02% NH3 in IPA (B), Isocratic: 80 :20(A:B)

[0459] Example 3C (chiral SFC Rt 12.08 min): 12 mg. LCMS: Rt 0.13 min; MS m / z 411.2 [M+H] + ; Method D. 1H NMR (400 MHz, methanol-d4) δ 7.30-7.22 (m, 4H), 6.94-6.85 (m, 4H), 4.74-4. 64 (m, 2H), 3.96 (d, J = 3.6 Hz, 1H), 2.99 (d, J = 9.2 Hz, 1H), 2.78-2.61 (m, 4H ), 2.44-2.36 (m, 2H), 2.27-2.17 (m, 1H), 1.64-1.58 (m, 1H). 2H under the solvent peak.

[0460] Example 3D (chiral SFC Rt 18.76 min): 12 mg. LCMS: Rt 0.13 min; MS m / z 411.2 [M+H] + ; Method D. 1 H NMR (400 MHz, methanol-d4) δ 7.30-7.22 (m, 4H), 6.94-6.85 (m, 4H), 4.75-4. 69 (m, 2H), 3.92 (d, J = 2.8 Hz, 1H), 2.94 (d, J = 9.6 Hz, 1H), 2.78-2.61 (m, 4H ), 2.40-2.23 (m, 2H), 2.27-2.17 (m, 1H), 1.66-1.62 (m, 1H). 2H under the solvent peak.

[0461] Examples 4A, 4B, 4C, and 4D 6-((R)-2-((3aS,4S,5S,6aR)-3a,4-dihydroxy-5- Phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)-yl)-1-hydro (xyethyl)-3,4-dihydroquinolin-2(1H)-one 6-((S)-2-((3aS,4S,5S,6aR)-3a,4-dihydroxy-5- Phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)-yl)-1-hydro (xyethyl)-3,4-dihydroquinolin-2(1H)-one 6-((R)-2-((3aR,4R,5R,6aS)-3a,4-dihydroxy-5- Phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)-yl)-1-hydro (xyethyl)-3,4-dihydroquinolin-2(1H)-one 6-((S)-2-((3aR,4R,5R,6aS)-3a,4-dihydroxy-5- Phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)-yl)-1-hydro (xyethyl)-3,4-dihydroquinolin-2(1H)-one

[0462] [ka] Using the same method as in Examples 2A / 2B, starting from Intermediate 5 and Intermediate 11, A mixture of 4A and 4B was obtained. The mixture was separated using the following chiral HPLC method: Column: Chiralpak IA (10 mm x 250 mm), flow rate: 9 mL / min Mobile phase: Hexane (A), EtOH:MeOH 1:1 (B), Isocratic: 60 :40(A:B)

[0463] Example 4A (chiral HPLC Rt 14.18 min): 15 mg. LCMS: Rt 1.24 min; MS m / z 425.4 [M+H] + ; Method F. 1 H NMR (400 MHz, methanol-d4) δ 7.24-7.18 (m, 4H), 6.91-6.82 (m, 4H), 4.70-4. 63 (m, 2H), 3.93 (d, J = 3.6 Hz, 1H), 2.96 (d, J = 9.6 Hz, 1H), 2.89-2.84 (m, 2H ), 2.74-2.60 (m, 4H), 2.50-2.34 (m, 4H), 2.25-2.18 (m, 1H), 1.62-1.56 (m, 1H).

[0464] Example 4B (chiral HPLC Rt 28.51 min): 15 mg. LCMS: Rt 1.25 min; MS m / z 425.4 [M+H] + ; Method F. 1 H NMR (400 MHz, methanol-d4) δ 7.24-7.18 (m, 4H), 6.92-6.81 (m, 4H), 4.71-4. 64 (m, 2H), 3.90 (d, J = 3.2 Hz, 1H), 2.93-2.85 (m, 3H), 2.75-2.59 (m, 4H), 2.44 (t, J = 8.4 Hz, 2H), 2.39-2.32 (m, 2H), 2.29-2.21 (m, 1H), 1.64-1.59 (m, 1H). Using the same method, starting from intermediate 6 and intermediate 11, a mixture of examples 4C and 4D was prepared. The mixture was separated using the following chiral HPLC method: Column: C-4, flow rate: 20 mL / min Mobile phase: Hexane (A), 0.1% DEA in EtOH (B), Isocratic: 6 5:35(A:B)

[0465] Example 4C (chiral HPLC Rt 5.63 min): 30 mg. LCMS: Rt 0.43 min; MS m / z 425.2 [M+H] + ; Method D. 1 H NMR (400 MHz, methanol-d4) δ 7.26-7.20 (m, 4H), 6.94-6.84 (m, 4H), 4.74-4. 66 (m, 2H), 3.93 (d, J = 3.6 Hz, 1H), 2.96-2.87 (m, 3H), 2.78-2.62 (m, 4H), 2.49 -2.37 (m, 4H), 2.31-2.26 (m, 1H), 1.66-1.61 (m, 1H).

[0466] Example 4D (chiral HPLC Rt 6.27 min): 40 mg. LCMS: Rt 1.24 min; MS m / z 425.4 [M+H] + ; Method F. 1 H NMR (400 MHz, methanol-d4) δ 7.27-7.20 (m, 4H), 6.94-6.84 (m, 4H), 4.74-4. 66 (m, 2H), 3.93 (d, J = 3.6 Hz, 1H), 2.96-2.87 (m, 3H), 2.78-2.62 (m, 4H), 2.49 -2.37 (m, 4H), 2.31-2.24 (m, 1H), 1.67-1.61 (m, 1H).

[0467] Examples 5A, 5B, 5C, and 5D 6-((R)-2-((3aS,5S,6aR)-5-(2-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy Hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one 6-((S)-2-((3aS,5S,6aR)-5-(2-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy Hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one 6-((R)-2-((3aR,5R,6aS)-5-(2-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy Hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one 6-((S)-2-((3aR,5R,6aS)-5-(2-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy Hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one

[0468] [ka] Step 1: 6-(2-((3aS,5S,6aR)-5-(2-fluorophenoxy)-3a-hydroxy hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)acetyl)-3, 4-Dihydroquinolin-2(1H)-one 6-(2-((3aR,5R,6aS)-5-(2-fluorophenoxy)-3a-hydroxy hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)acetyl)-3, 4-Dihydroquinolin-2(1H)-one A racemic mixture of

[0469] [ka] Using the same method as in Step 1 of Example 1A, intermediate 3 (75 mg, 0.32 mmol) and intermediate 11 (106 mg, 0.38 mmol) to give the title intermediate (120 mg) was obtained.

[0470] LCMS:Rt 0.92min;MS m / z 425.3[M+H] + ;Method I.

[0471] Step 2: Mixtures of Examples 5A, 5B, 5C, and 5D

[0472] [ka] Using the same method as in Step 1 of Example 1B, the intermediate mixture from the previous step (1 Starting with 20 mg of the hydroxybenzoate, a mixture of Examples 5A, 5B, 5C, and 5D (40 mg) was obtained.

[0473] LCMS:Rt 1.24 min; MS m / z 426.1[M+H] + ;Method E.

[0474] Step 3: Chiral separation of Examples 5A, 5B, 5C, and 5D The mixture was first separated using the following chiral SFC method: Column: Daicel Chiralpak AD (250mm x 30mm, 10μm) , flow rate: 70g / min Mobile phase: CO2 (A), EtOH containing 0.1% NH3·H2O (B), isocratic 50:50 (A:B)

[0475] This gives two peaks, each containing two of the isomers. Both peaks were further separated using the following chiral SFC method: Column: Daicel Chiralpak IG (250mm x 50mm, 10μm) , flow rate: 70g / min Mobile phase: CO2 (A), MeOH:ACN (1:1) containing 0.1% NH3·H2O (B) ), isocratic 40:60 (A:B)

[0476] Example 5A: 6 mg. Analytical chiral SFC: Rt 1.14 min (column: Chiralpak IG-350 × 4.6 mm, 3 μm, flow rate 3 mL / min, mobile phase: 0.05% DEA in CO2 0% MeOH:ACN (1:1). LCMS: Rt 0.89 min; MS m / z 427.4 [M+H] +; Method I. 1 H NMR (400 MHz, CDCl3) δ7.66 (s, 1H), 7.23 - 7.15 (m, 2H), 7.14 - 6.93 (m, 4H) , 6.72 (d, J = 7.6 Hz, 1H), 5.01 (s, 1H), 4.82 - 4.70 (m, 1H), 3.31 - 3.28 (m, 1 H), 3.03 - 2.93 (m, 3H), 2.86 - 2.69 (m, 2H), 2.68 - 2.58 (m, 4H), 2.54 - 2.45 ( m, 2H), 2.39 (d, J = 15.4 Hz, 1H), 2.22 - 2.13 (m, 1H), 1.71 - 1.60 (m, 1H).

[0477] Example 5B: 7 mg. Analysis of キラルSFC:Rt 1.56 points (カラム:Chiralpak IG-350 ×4.6mm, 3μm, flow rate 3mL / min, mobile phase: 0.05% DEA in CO2, containing 5 0% MeOH:ACN (1:1)). LCMS: Rt 0.89 min; MS m / z 427.4 [M+H] + ; Method I. 1 H NMR (400 MHz, CDCl3) δ7.68 (s, 1H), 7.21 (s, 1H), 7.19 - 7.15 (m, 1H), 7.13 - 7.06 (m, 2H), 7.05 - 6.93 (m, 2H), 6.72 (d, J = 8.4 Hz, 1H), 5.02 (s, 1H), 4.7 5 (d, J = 8.4 Hz, 1H), 3.14 - 3.04 (m, 1H), 3.01 - 2.93 (m, 3H), 2.88 - 2.70 (m, 3H), 2.70 - 2.57 (m, 4H), 2.55 - 2.46 (m, 1H), 2.38 (d, J = 14.4 Hz, 1H), 2.25 - 2.18 (m, 1H), 1.54 - 1.43 (m, 1H).

[0478] Example 5C: 7 mg. Analytical chiral SFC: Rt 2.46 min (column: Chiralpak IG-350 ×4.6 mm, 3 μm, flow rate 3 mL / min, mobile phase: 5 0% MeOH: ACN (1:1)) containing 0.05% DEA in CO2. LCMS: Rt 0.90 min; MS m / z 427.4 [M+H] + ; Method I. 1 1H NMR (400 MHz, CDCl3) δ7.78 (s, 1H), 7.23 - 7.15 (m, 2H), 7.14 - 6.93 (m, 4H) , 6.73 - 6.71 (m, 1H), 5.01 (s, 1H), 4.73 (d, J = 9.5 Hz, 1H), 3.12 - 3.03 (m, 1 H), 3.01 - 2.91 (m, 3H), 2.83 (t, J = 11.6 Hz, 1H), 2.78 - 2.46 (m, 7H), 2.38 (d , J = 14.4 Hz, 1H), 2.20 (d, J = 13.2 Hz, 1H), 1.69 - 1.52 (m, 1H).

[0479] Example 5D: 8 mg. Analytical chiral SFC: Rt 5.04 min (column: Chiralpak IG-350 ×4.6 mm, 3 μm, flow rate 3 mL / min, mobile phase: 5 0% MeOH: ACN (1:1)) containing 0.05% DEA in CO2. LCMS: Rt 0.89 min; MS m / z 427.4 [M+H] + ; Method I. 1 H NMR (400 MHz, CDCl3) δ7.76 (s, 1H), 7.25 - 7.15 (m, 2H), 7.15 - 7.06 (m, 2H) , 7.05 - 6.93 (m, 2H), 6.73 - 6.71 (d, J = 8.0 Hz, 1H), 5.01 (s, 1H), 4.83 - 4.6 9 (m, 1H), 3.39 - 3.23 (m, 1H), 3.03 - 2.93 (m, 3H), 2.84 - 2.72 (m, 2H), 2.68 - 2.58 (m, 4H), 2.54 - 2.44 (m, 2H), 2.39 (d, J = 14.4 Hz, 1H), 2.22 - 2.14 (m, 1 H), 1.73 - 1.61 (m, 1H).

[0480] Examples 6A, 6B, 6C, and 6D 8-Fluoro-6-((R)-2-((3aS,5S,6aR)-5-(2-fluorofluoro (phenoxy)-3a-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)- (yl)-1-hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one 8-Fluoro-6-((S)-2-((3aS,5S,6aR)-5-(2-fluorofluoro (phenoxy)-3a-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)- (yl)-1-hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one 8-Fluoro-6-((R)-2-((3aR,5R,6aS)-5-(2-fluorofluoro (phenoxy)-3a-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)- (yl)-1-hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one 8-Fluoro-6-((S)-2-((3aR,5R,6aS)-5-(2-fluorofluoro (phenoxy)-3a-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)- (yl)-1-hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one

[0481] [ka] Using the same method as in Examples 5A / 5B / 5C / 5D, starting from intermediate 3 and intermediate 20 This gave a mixture of Examples 6A / 6B / 6C / 6D. The mixture was analyzed using the following chiral SFC method: and separated: Column: Daicel Chiralpak AD (250mm x 30mm, 10μm) , flow rate: 70g / min Mobile phase: CO2 (A), EtOH containing 0.1% NH3·H2O (B), isocratic 50:50 (A:B)

[0482] Example 6A: 16 mg. Analytical chiral SFC: Rt 0.88 min (column: Chiralpak AD-3 5 0×4.6 mm, 3 μm, flow rate 3 mL / min, mobile phase: 0.05% DEA in CO2 40% EtOH). LCMS: Rt 0.89 min; MS m / z 445.3 [M+H] + ; Method I. 1 H NMR (400 MHz, CDCl3) δ7.55 (s, 1H), 7.13 - 6.95 (m, 6H), 5.01 (br s, 1H), 4. 66 - 4.62 (m, 1H), 3.20 - 3.19 (m, 1H), 3.05 - 2.85 (m, 4H), 2.68 - 2.58 (m, 4H) , 2.57 - 2.46 (m, 3H), 2.42 - 2.36 (m, 2H), 2.08 - 2.04 (m, 1H), 1.58 - 1.54 (m, 1H).

[0483] Example 6B: 16 mg. Analytical chiral SFC: Rt 1.02 min (column: Chiralpak AD-3 5 0×4.6 mm, 3 μm, flow rate 3 mL / min, mobile phase: 0.05% DEA in CO2 containing 40% EtOH). LCMS: Rt 0.89 min; MS m / z 445.3 [M+H] + ; Method I. 1 H NMR (400 MHz, CDCl3) δ7.59 (s, 1H), 7.14 - 6.93 (m, 6H), 5.01 (br s, 1H), 4. 63 - 4.59 (m, 1H), 3.04 - 2.78 (m, 5H), 2.75 - 2.58 (m, 6H), 2.54 - 2.47 (m, 2H) , 2.40 - 2.36 (m, 1H), 2.12 - 2.07 (m, 1H), 1.55 - 1.49 (m, 1H).

[0484] Example 6C: 16 mg. Analytical chiral SFC: Rt 1.54 min (column: Chiralpak AD-3 5 0×4.6 mm, 3 μm, flow rate 3 mL / min, mobile phase: 0.05% DEA in CO2 containing 40% EtOH). LCMS: Rt 0.90 min; MS m / z 445.3 [M+H] + ; Method I. 1 H NMR (400 MHz, CDCl3) δ7.58 (s, 1H), 7.14 - 7.06 (m, 2H), 7.05 - 7.00 (m, 2H) , 7.00 - 6.93 (m, 2H), 5.01 (br s, 1H), 4.65 - 4.58 (m, 1H), 3.80 (br s, 1H), 3. 04 - 2.90 (m, 4H), 2.88 - 2.81 (m, 1H), 2.75 - 2.59 (m, 6H), 2.55 - 2.46 (m, 2H) , 2.42 - 2.35 (m, 1H), 2.14 - 2.06 (m, 1H), 1.56 - 1.49 (m, 1H).

[0485] Example 6D: 15 mg. Analytical chiral SFC: Rt 1.81 min (column: Chiralpak AD-3 5 0×4.6 mm, 3 μm, flow rate 3 mL / min, mobile phase: 0.05% DEA in CO2 40% EtOH). LCMS: Rt 0.89 min; MS m / z 445.3 [M+H] + ; Method I. 1 H NMR (400 MHz, CDCl3) δ7.66 (s, 1H), 7.14 - 7.00 (m, 4H), 6.99 - 6.92 (m, 2H) , 5.01 (br s, 1H), 4.67 - 4.60 (m, 1H), 3.79 (br s, 1H), 3.20 (d, J = 8.8 Hz, 1H ), 3.07 - 2.83 (m, 4H), 2.68 - 2.46 (m, 7H), 2.42 - 2.34 (m, 2H), 2.10 - 2.02 (m , 1H), 1.61 - 1.51 (m, 1H).

[0486] These examples are the diastereomeric pairs prepared using the same method as in Examples 5A / 5B / 5C / 5D. The compounds were prepared as shown and isolated using the conditions indicated, starting from the intermediates indicated.

[0487] [Table 4-1]

[0488]

Table 4-2

[0489]

Table 4-3

[0490]

Table 4-4

[0491]

Table 4-5

[0492]

Table 4-6

[0493]

Table 4-7

[0494]

Table 4-8

[0495]

Table 4-9

[0496]

Table 4-10

[0497]

Table 4-11

[0498]

Table 4-12

[0499] Example 19 (S)-3,8-difluoro-6-((R)-1-hydroxy-2-((3aS,5S, 6aR)-3a-Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole -2(1H)-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one (S)-3,8-difluoro-6-((S)-1-hydroxy-2-((3aS,5S, 6aR)-3a-Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole -2(1H)-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one (R)-3,8-difluoro-6-((R)-1-hydroxy-2-((3aS,5S, 6aR)-3a-Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole -2(1H)-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one (R)-3,8-difluoro-6-((S)-1-hydroxy-2-((3aS,5S, 6aR)-3a-Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole -2(1H)-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one A mixture of

[0500] [ka] Using the same method as in Examples 5A / 5B / 5C / 5D, starting from intermediate 2 and intermediate 22 As a result, Example 19 was obtained as a mixture of four diastereomers. LCMS: Rt 0.90 min; MS m / z 445.4 [M+H] + ; Method I. 1H NMR (400 MHz, CDCl3) δ7.58 (br s, 1H), 7.35 - 7.31 (m, 2H), 7.14 - 6.99 (m, 3H), 6.93 (d, J = 8.0 Hz, 2H), 5.28 - 5.08 (m, 1H), 4.99 (br s, 1H), 4.70 - 4.63 (m, 1H), 3.40 - 3.34 (m, 2H), 3.22 - 2.84 (m, 2H), 2.77 - 2.51 (m, 6H), 2.49 - 2.31 (m, 2H), 2.18 - 2.08 (m, 1H).

[0501] Examples 20A and 20B 3,8-Difluoro-6-((R)-1-hydroxy-2-((3aS,5S,6aR) -3a-Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1 H)-yl)ethyl)quinolin-2(1H)-one 3,8-Difluoro-6-((S)-1-hydroxy-2-((3aS,5S,6aR) -3a-Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1 H)-yl)ethyl)quinolin-2(1H)-one

[0502] [ka] Step 1: 3,8-Difluoro-6-(2-((3aS,5S,6aR)-3a-hydrogen 5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl Acetyl)quinolin-2(1H)-one

[0503] [ka] Using the same method as in Step 1 of Example 1A, intermediate 2 (260 mg, 1.19 mmol) was obtained. ) and intermediate 23 (300 mg, 1.08 mmol) to give the title intermediate (50 0 mg) which was used without further purification.

[0504] LCMS:Rt 0.74min;MS m / z 441.2[M+H] + ;Method J.

[0505] Step 2: 3,8-Difluoro-6-((R)-1-hydroxy-2-((3aS,5S,6aR) -3a-Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1 H)-yl)ethyl)quinolin-2(1H)-one 3,8-Difluoro-6-((S)-1-hydroxy-2-((3aS,5S,6aR) -3a-Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1 H)-yl)ethyl)quinolin-2(1H)-one A mixture of

[0506] [ka] Using the same method as in Step 1 of Example 1B, 3,8-difluoro-6-(2-((3a S,5S,6aR)-3a-hydroxy-5-phenoxyhexahydrocyclopenta[c ]pyrrol-2(1H)-yl)acetyl)quinolin-2(1H)-one (500mg) Starting from the above, a mixture of Examples 20A and 20B (100 mg) was obtained.

[0507] LCMS:Rt 0.85min;MS m / z 443.4[M+H] + ;Method I.

[0508] Step 3: Chiral separation The two diastereomers were separated using the following chiral SFC method: カラム:Daicel Chiralpak IG (250mm×30mm, 10μm) Flow rate: 70g / min Mobile phase: 0.1% NH3·H2O in supercritical CO2 containing 50% IPA: ACN (1:1 )

[0509] Example 20A: 21 mg. Analysis of キラルSFC:Rt 1.05 points(カラム:Chiralpak IG-3(5 0×4.6mm, 3μm), flow rate: 3mL / min, mobile phase: 0.05%DEA in CO2 Contains 50% IPA:ACN(1:1)). LCMS: Rt 0.84 min; MS m / z 443.3 [M+H] + ; Method I. 1 H NMR (400 MHz, CDCl3) δ9.46 (br s, 1H), 7.51 - 7.45 (m, 1H), 7.38 - 7.30 (m, 4H), 7.03 - 6.99 (m, 1H), 6.96 - 6.90 (m, 2H), 5.00 (br s, 1H), 4.79 - 4.71 (m, 1H), 3.93 (br s, 1H), 2.96 - 2.93 (m, 1H), 2.87 - 2.84 (m, 1H), 2.78 - 2.52 (m, 7H), 2.40 - 2.36 (m, 1H), 2.18 - 2.11 (m, 1H), 1.58 - 1.55 (m, 1H).

[0510] Example 20B: 20 ​​mg. Analysis of キラルSFC:Rt 1.51 points(カラム:Chiralpak IG-3(5 0×4.6mm, 3μm), flow rate: 3mL / min, mobile phase: 0.05%DEA in CO2 Contains 50% IPA:ACN(1:1)). LCMS: Rt 0.84 min; MS m / z 443.4 [M+H]+ ; Method I. 1 H NMR (400 MHz, CDCl3) δ9.33 (br s, 1H), 7.48 - 7.45 (m, 1H), 7.37 - 7.28 (m, 4H), 7.01 - 6.97 (m, 1H), 6.96 - 6.86 (m, 2H), 4.98 (br s, 1H), 4.77 - 4.74 (m, 1H), 3.90 (br s, 1H), 3.20 - 3.17 (m, 1H), 2.98 - 2.87 (m, 1H), 2.72 - 2.47 (m, 6H), 2.44 - 2.34 (m, 2H), 2.11 - 2.06 (m, 1H), 1.61 - 1.60 (m, 1H).

[0511] Example 21 (3aS,5S,6aR)-5-(2,4-difluorophenoxy)-2-((R)-2 -Hydroxy-2-(1H-indazol-5-yl)ethyl)hexahydrocyclopenta ta[c]pyrrol-3a(1H)-ol (3aS,5S,6aR)-5-(2,4-difluorophenoxy)-2-((S)-2 -Hydroxy-2-(1H-indazol-5-yl)ethyl)hexahydrocyclopenta ta[c]pyrrol-3a(1H)-ol (3aR,5R,6aS)-5-(2,4-difluorophenoxy)-2-((R)-2 -Hydroxy-2-(1H-indazol-5-yl)ethyl)hexahydrocyclopenta ta[c]pyrrol-3a(1H)-ol (3aR,5R,6aS)-5-(2,4-difluorophenoxy)-2-((R)-2 -Hydroxy-2-(1H-indazol-5-yl)ethyl)hexahydrocyclopenta ta[c]pyrrol-3a(1H)-ol A mixture of

[0512] [ka] Step 1: 2-((3aS,5S,6aR)-5-(2,4-difluorophenoxy)-3a-hydroxybenzoate hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(1-(tetrahydropyrrol-2(1H)-yl)- tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)ethane-1- on 2-((3aR,5R,6aS)-5-(2,4-difluorophenoxy)-3a-hydroxy hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-(1-(tetrahydropyrrol-2(1H)-yl)- tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)ethane-1- on A mixture of

[0513] [ka] To a solution of intermediate 10 (74 mg, 0.29 mmol) in ACN (2 mL) was added KCO 3 (120 mg, 0.87 mmol) and intermediate 24 (76 mg, 0.23 mmol) This was stirred at room temperature for 3 hours, then filtered and the filtrate was concentrated to give the title intermediate (112 mg) was obtained which was used without further purification.

[0514] LCMS:Rt 1.03 min; MS m / z 498.4[M+H] + ;Method H.

[0515] Step 2: (3aS,5S,6aR)-5-(2,4-difluorophenoxy)-2-((2R)- 2-Hydroxy-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-indole (5-isopropyl)hexahydrocyclopenta[c]pyrrole-3a(1H)- Oar (3aS,5S,6aR)-5-(2,4-difluorophenoxy)-2-((2S)- 2-Hydroxy-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-indole (5-isopropyl)hexahydrocyclopenta[c]pyrrole-3a(1H)- Oar (3aR,5R,6aS)-5-(2,4-difluorophenoxy)-2-((2R)- 2-Hydroxy-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-indole (5-isopropyl)hexahydrocyclopenta[c]pyrrole-3a(1H)- Oar (3aR,5R,6aS)-5-(2,4-difluorophenoxy)-2-((2S)- 2-Hydroxy-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-indole (5-isopropyl)hexahydrocyclopenta[c]pyrrole-3a(1H)- Oar A mixture of

[0516] [ka] Using the same method as in Step 1 of Example 1B, the intermediate mixture from the previous step (7 Starting from 100 mg, 0.14 mmol), the title intermediate was obtained as a mixture (70 mg). .

[0517] LCMS:Rt 1.00 min; MS m / z 500.4[M+H] + ;Method H.

[0518] Step 3: (3aS,5S,6aR)-5-(2,4-difluorophenoxy)-2-((R)-2 -Hydroxy-2-(1H-indazol-5-yl)ethyl)hexahydrocyclopenta ta[c]pyrrol-3a(1H)-ol (3aS,5S,6aR)-5-(2,4-difluorophenoxy)-2-((S)-2 -Hydroxy-2-(1H-indazol-5-yl)ethyl)hexahydrocyclopenta ta[c]pyrrol-3a(1H)-ol (3aR,5R,6aS)-5-(2,4-difluorophenoxy)-2-((R)-2 -Hydroxy-2-(1H-indazol-5-yl)ethyl)hexahydrocyclopenta ta[c]pyrrol-3a(1H)-ol (3aR,5R,6aS)-5-(2,4-difluorophenoxy)-2-((R)-2 -Hydroxy-2-(1H-indazol-5-yl)ethyl)hexahydrocyclopenta ta[c]pyrrol-3a(1H)-ol A mixture of

[0519] [ka] A mixture of intermediates from the previous step (70 mg, 0.14 mmHg) in DCM (1 mL) To a solution of 1 ml of TFA was added. This was stirred at room temperature for 2 hours and then concentrated. , preparative HPLC (Waters Xbridge 5μm, 30×50mm, flow rate 75m L / min, mobile phase A: water containing 10 mM NH4OH, B: water containing 10 mM NH4OH Purification with acetonitrile (gradient 25-50% B) afforded Example 21 as a mixture of four diastereomers. Obtained as a mixture (34 mg). LCMS: Rt 1.08 min; MS m / z 416.0 [M+H] + ; Method B. 1H NMR (400 MHz, methanol-d4) δ 8.00 (t, J = 0.8 Hz, 1H), 7.80–7.74 (m, 1H) , 7.55 - 7.41 (m, 2H), 6.98 - 6.88 (m, 2H), 6.82 - 6.73 (m, 1H), 4.90 - 4.85 (m, 1H), 4.75 - 4.67 (m, 1H), 2.91 - 2.75 (m, 3H), 2.69 - 2.41 (m, 4H), 2.27 - 2.11 (m, 2H), 2.08 - 1.98 (m, 1H), 1.85 - 1.72 (m, 1H).

[0520] Examples 22A, 22B, 22C, and 22D 6-((R)-2-((3aS,5S,6aR)-5-(4-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy Hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one 6-((S)-2-((3aS,5S,6aR)-5-(4-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy Hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one 6-((R)-2-((3aR,5R,6aS)-5-(4-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy Hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one 6-((S)-2-((3aR,5R,6aS)-5-(4-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy Hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one

[0521] [ka] Step 1: 6-(2-((3aS,5S,6aR)-5-(4-fluorophenoxy)-3a-hydroxybenzoate hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)acetyl)-3, 4-Dihydroquinolin-2(1H)-one 6-(2-((3aR,5R,6aS)-5-(4-fluorophenoxy)-3a-hydroxybenzoate hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)acetyl)-3, 4-Dihydroquinolin-2(1H)-one A racemic mixture of

[0522] [ka] PPh3 (179 mg, 0.68 mmol) in THF (0.5 mL) under nitrogen at 0 °C To a solution of DIAD (138 mg, 0.68 mmol), followed by THF (1.0 mL) Intermediate 40 (150 mg, 0.45 mmol) and 4-fluorophenol (76 mg A solution of 1,2-dimethyl-3,4-dichloro-2 ... Dilute with 1 mL of ethyl acetate, extract with EtOAc (3 x 5 mL), wash with saturated brine (5 mL), and The crude material was purified by FCC (0-15% MeOH:D Purification by CM) gave the title intermediate (140 mg).

[0523] LCMS:Rt 0.57min;MS m / z 425.0[M+H] + ;Method J.

[0524] Step 2: Mixtures of Examples 22A, 22B, 22C, and 22D

[0525] [ka] Using the same method as in Step 1 of Example 1B, the intermediate mixture from the previous step (1 Starting from 20 mg, 0.14 mmol), Examples 22A, 22B, 22C, and 22D A mixture (85 mg) was obtained.

[0526] LCMS:Rt 0.87min;MS m / z 427.3[M+H] + ;Method I.

[0527] Step 3: Chiral separation of Examples 22A, 22B, 22C, and 22D The mixture was separated and the single isomers were analyzed using the following chiral SFC method: Separation: Column: Daicel Chiralpak AD (250 mm x 30 mm, 10 μm), flow rate: 80 g / min, mobile phase: 60% M containing 0.1% NH3·H2O in CO2 eOH Analytical: Column: Chiralpak AD-3 (50 x 4.6 mm, 3 μm), flow rate: 3 mL / min, mobile phase: 50% MeOH:ACN (1: 1)

[0528] Example 22A (Analytical Chiral SFC Rt 0.74 min): 22 mg. LCMS: Rt 0.87 min; MS m / z 427.3 [M+H] + ; Method I. 1 H NMR (400 MHz, CDCl3) δ7.88 (s, 1H), 7.23 - 7.14 (m, 2H), 7.03 - 6.95 (m, 2H) , 6.89 - 6.82 (m, 2H), 6.73 (d, J = 8.0 Hz, 1H), 4.88 (br s, 1H), 4.69 - 4.62 (m , 1H), 3.18 (d, J = 9.2 Hz, 1H), 3.01 - 2.89 (m, 3H), 2.73 - 2.30 (m, 10H), 2.12 - 2.07 (m, 1H), 1.64 - 1.53 (m, 1H).

[0529] Example 22B (Analyzed KRAL SFC Rt 1.01 points): 20 mg. LCMS: Rt 0.87 min; MS m / z 427.3 [M+H] + ; Method I. 1 H NMR (400 MHz, CDCl3) δ7.99 (br s, 1H), 7.23 - 7.13 (m, 2H), 7.04 - 6.95 (m, 2H), 6.89 - 6.81 (m, 2H), 6.73 (d, J = 8.0 Hz, 1H), 4.88 (br s, 1H), 4.73 - 4.58 (m, 1H), 3.01 - 2.90 (m, 3H), 2.85 - 2.73 (m, 2H), 2.70 - 2.42 (m, 8H), 2.35 - 2.31 (m, 1H), 2.16 - 2.11 (m, 1H), 1.60 - 1.53 (m, 1H).

[0530] Example 22C (Analyzed KRAL SFC Rt 2.07 points): 20 mg. LCMS: Rt 0.87 min; MS m / z 427.3 [M+H] + ; Method I. 1 H NMR (400 MHz, CDCl3) δ8.02 (s, 1H), 7.23 - 7.14 (m, 2H), 7.03 - 6.95 (m, 2H) , 6.89 - 6.82 (m, 2H), 6.74 (d, J = 8.0 Hz, 1H), 4.88 (br s, 1H), 4.70 - 4.61 (m , 1H), 3.18 (d, J = 9.2 Hz, 1H), 3.02 - 2.89 (m, 3H), 2.74 - 2.30 (m, 10H), 2.13 - 2.07 (m, 1H), 1.63 - 1.57 (m, 1H).

[0531] Example 22D (Analytical chiral SFC Rt 2.73 min).

[0532] This compound was further purified by the following preparative HPLC method to give 16 mg. Column: Phenomenex Gemini NX-C18 (75 mm x 30 mm) , 3.0 μm Mobile phase: 10 mM NH4HCO3 in water (A), acetonitrile (B), eluted over 8 min. Gradient of 18-48%B LCMS: Rt 0.89 min; MS m / z 427.4 [M+H] + ; Method I. 1 H NMR (400 MHz, CDCl3) δ8.10 (br s, 1H), 7.23 - 7.10 (m, 2H), 7.06 - 6.92 (m, 2H), 6.91 - 6.80 (m, 2H), 6.74 (d, J = 8.0 Hz, 1H), 4.88 (br s, 1H), 4.71 - 4.57 (m, 1H), 3.02 - 2.90 (m, 3H), 2.86 - 2.55 (m, 8H), 2.52 - 2.45 (m, 2H), 2.35 - 2.31 (m, 1H), 2.16 - 2.10 (m, 1H), 1.60 - 1.52 (m, 1H).

[0533] Examples 23A, 23B, 23C, and 23D 6-((R)-2-((3aS,5S,6aR)-5-(3-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy Hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one 6-((S)-2-((3aS,5S,6aR)-5-(3-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy Hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one 6-((R)-2-((3aR,5R,6aS)-5-(3-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy Hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one 6-((S)-2-((3aR,5R,6aS)-5-(3-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy Hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one

[0534] [ka] Use the same method as in Examples 22A / 22B / 22C / 22D, but in step 1, use 4- Using 3-fluorophenol instead of fluorophenol, Examples 23A / 23B / A mixture of 23C / 23D was obtained, which was separated using the following chiral SFC method: Column: Daicel Chiralpak AD (250mm x 30mm, 10μm ), Flow rate: 70 g / min, Mobile phase: 40% EtO containing 0.1% NH3·H2O in CO2 H

[0535] This method allowed separation of Examples 23A and 23B from the other two isomers that co-eluted. The remaining two isomers were separated using the following chiral SFC method: Column: Daicel Chiralpak IG (250mm x 30mm, 10μm ), Flow rate: 70 g / min, Mobile phase: 50% MeO containing 0.1% NH3·H2O in CO2 H:ACN(1:1)

[0536] Analysis of the separated isomers was carried out using the following analytical chiral SFC method: Column: Chiralpak AD-3 (50×4.6mm, 3μm), flow rate: 3mL / min, mobile phase: 40% MeOH:ACN (1:1) with 0.05% DEA in CO

[0537] Example 23A (Analytical Chiral SFC Rt 1.26 min): 11 mg. LCMS: Rt 0.87 min; MS m / z 427.2 [M+H] + ; Method I. 1 H NMR (400 MHz, CDCl3) δ7.62 (s, 1H), 7.26 - 7.14 (m, 3H), 6.73 - 6.59 (m, 4H) , 4.93 (br s, 1H), 4.72 - 4.65 (m, 1H), 3.23 - 3.18 (m, 1H), 3.03 - 2.91 (m, 3H) , 2.78 - 2.41 (m, 9H), 2.33 - 2.15 (m, 1H), 2.19 - 2.10 (m, 1H), 1.70 - 1.64 (m, 1H).

[0538] Example 23B (Analytical Chiral SFC Rt 1.47 min): 11 mg. LCMS: Rt 0.87 min; MS m / z 427.3 [M+H] + ; Method I. 1 H NMR (400 MHz, CDCl3) δ7.47 - 7.37 (m, 1H), 7.26 - 7.15 (m, 3H), 6.74 - 6.60 (m, 4H), 4.94 (br s, 1H), 4.69 - 4.61 (m, 1H), 3.03 - 2.72 (m, 5H), 2.71 - 2.46 (m, 8H), 2.39 - 2.30 (m, 1H), 2.20 - 2.12 (m, 1H), 1.65 - 1.59 (m, 1H).

[0539] Example 23C (Analyzed KRAL SFC Rt 2.97 points): 13 mg. LCMS: Rt 0.89 min; MS m / z 427.5 [M+H] + ; Method I. 1 H NMR (400 MHz, CDCl3) δ7.55 - 7.45 (m, 1H), 7.26 - 7.13 (m, 3H), 6.74 - 6.58 (m, 4H), 4.94 (br s, 1H), 4.78 - 4.68 (m, 1H), 3.08 - 2.47 (m, 13H), 2.39 - 2.30 (m, 1H), 2.27 - 2.19 (m, 1H), 1.68 - 1.62 (m, 1H).

[0540] Example 23D (Analyzed KRAL SFC Rt 3.38 points): 13 mg. LCMS: Rt 0.89 min; MS m / z 427.5 [M+H] + ; Method I. 1 H NMR (400 MHz, CDCl3) δ7.76 - 7.52 (m, 1H), 7.26 - 7.15 (m, 3H), 6.76 - 6.60 (m, 4H), 4.93 (br s, 1H), 4.72 - 4.65 (m, 1H), 3.20 (d, J = 9.2 Hz, 1H), 3.01 - 2.92 (m, 3H), 2.77 - 2.29 (m, 10H), 2.17 - 2.10 (m, 1H), 1.69 - 1.60 (m, 1H).

[0541] Examples 24A, 24B, 24C, and 24D 6-((R)-2-((3aS,5S,6aR)-5-(2,3-difluorophenoxy )-3a-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)- 1-Hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one 6-((S)-2-((3aS,5S,6aR)-5-(2,3-difluorophenoxy )-3a-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)- 1-Hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one 6-((R)-2-((3aR,5R,6aS)-5-(2,3-difluorophenoxy )-3a-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)- 1-Hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one 6-((S)-2-((3aR,5R,6aS)-5-(2,3-difluorophenoxy )-3a-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)- 1-Hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one

[0542] [ka] Use the same method as in Examples 22A / 22B / 22C / 22D, but in step 1, use 4- Example 24A / 2 using 2,3-difluorophenol instead of fluorophenol A mixture of 4B / 24C / 24D was obtained. The mixture was separated using the following chiral SFC method: Ta: Column: Daicel Chiralpak AD (250mm x 30mm, 10μm ), Flow rate: 80 g / min, Mobile phase: 60% MeO containing 0.1% NH3·H2O in CO2 H

[0543] By this method, examples 24C and 24D were isolated from the other two isomers that co-eluted. The remaining two isomers were separated using the following chiral SFC method: Column: Daicel Chiralpak IG (250mm x 30mm, 10μm ), Flow rate: 70 g / min, Mobile phase: 60% MeO containing 0.1% NH3·H2O in CO2 H:ACN(1:1)

[0544] Analysis of the separated isomers was carried out using the following analytical chiral SFC method: Column: Chiralpak IG-3 (50×4.6mm, 3μm), flow rate: 3mL / min, mobile phase: 50% EtOH with 0.05% DEA in CO2

[0545] Example 24A (Analytical Chiral SFC Rt 1.05 min): 13 mg. LCMS: Rt 0.91 min; MS m / z 445.4 [M+H] + ; Method I. 1 H NMR (400 MHz, CDCl3) δ7.81 - 7.62 (m, 1H), 7.23 - 7.14 (m, 2H), 7.06 - 6.97 (m, 1H), 6.89 - 6.69 (m, 3H), 5.02 (br s, 1H), 4.69 - 4.62 (m, 1H), 3.23 (d, J = 8.6 Hz, 1H), 3.02 - 2.88 (m, 3H), 2.81 - 2.60 (m, 5H), 2.58 - 2.36 (m, 5H), 2.1 4 - 2.06 (m, 1H), 1.65 - 1.56 (m, 1H).

[0546] Example 24B (Analytical Chiral SFC Rt 1.18 min): 15 mg. LCMS: Rt 0.91 min; MS m / z 445.5 [M+H] + ; Method I. 1 H NMR (400 MHz, CDCl3) δ7.59 (br s, 1H), 7.22 - 7.14 (m, 2H), 7.05 - 6.95 (m, 1H), 6.88 - 6.76 (m, 2H), 6.71 (d, J = 8.0 Hz, 1H), 5.02 (br s, 1H), 4.68 - 4.63 (m, 1H), 3.03 - 2.95 (m, 3H), 2.91 - 2.36 (m, 12H), 2.20 - 2.12 (m, 1H), 1.63 - 1.53 (m, 1H).

[0547] Example 24C (Analyzed KRAL SFC Rt 3.05 points): 17 mg. LCMS: Rt 0.91 min; MS m / z 445.4 [M+H] + ; Method I. 1 H NMR (400 MHz, CDCl3) δ7.92 (s, 1H), 7.22 - 7.13 (m, 2H), 7.06 - 6.95 (m, 1H) , 6.87 - 6.76 (m, 2H), 6.74 - 6.71 (m, 1H), 5.01 (br s, 1H), 4.68 - 4.63 (m, 1H) , 3.88 - 3.59 (br s, 1H), 3.22 (d, J = 9.2 Hz, 1H), 3.03 - 2.88 (m, 3H), 2.84 - 2.59 (m, 5H), 2.57 - 2.35 (m, 5H), 2.14 - 2.06 (m, 1H), 1.63 - 1.55 (m, 1H).

[0548] Example 24D (Analyzed KRAL SFC Rt 1.73 points): 13 mg. LCMS: Rt 0.91 min; MS m / z 445.4 [M+H]+ ; Method I. 1 H NMR (400 MHz, CDCl3) δ7.88 (s, 1H), 7.23 - 7.14 (m, 2H), 7.05 - 6.96 (m, 1H) , 6.88 - 6.70 (m, 3H), 5.01 (br s, 1H), 4.69 - 4.62 (m, 1H), 3.88 - 3.59 (br s, 1H), 3.22 (d, J = 9.2 Hz, 1H), 3.02 - 2.87 (m, 3H), 2.83 - 2.58 (m, 5H), 2.57 - 2.35 (m, 5H), 2.13 - 2.06 (m, 1H), 1.63 - 1.56 (m, 1H).

[0549] Examples 25A, 25B, 25C, and 25D 6-((R)-2-((3aS,5S,6aR)-5-(2,4-difluorophenoxy )-3a-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)- 1-Hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one 6-((S)-2-((3aS,5S,6aR)-5-(2,4-difluorophenoxy )-3a-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)- 1-Hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one 6-((R)-2-((3aR,5R,6aS)-5-(2,4-difluorophenoxy )-3a-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)- 1-Hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one 6-((S)-2-((3aR,5R,6aS)-5-(2,4-difluorophenoxy )-3a-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)- 1-Hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one

[0550] [ka]

[0551] Use the same method as in Examples 22A / 22B / 22C / 22D, but in step 1, use 4- Example 25A / 2 using 2,4-difluorophenol instead of fluorophenol A mixture of 5B / 25C / 25D was obtained. The mixture was separated using the following chiral SFC method: Ta: Column: Daicel Chiralpak AD (250mm x 30mm, 10μm ), Flow rate: 70 g / min, Mobile phase: 50% EtO containing 0.1% NH3·H2O in CO2 H

[0552] This method separated the four isomers into two peaks, each of which was divided into two types. It contained isomers of

[0553] The first peak was separated using the following chiral SFC method to give Examples 25A and 25B: Column: Daicel Chiralpak IG (250 mm x 30 mm, 10 μm), flow rate: 70 g / min, mobile phase: 50% M containing 0.1% NH3·H2O in CO2 eOH:ACN(1:1)

[0554] The second peak was separated using the following chiral SFC method to give Examples 25C and 25D. Got: Column: Daicel Chiralpak IG (250mm x 30mm, 10μm) , Flow rate: 70 g / min, Mobile phase: 50% EtOH containing 0.1% NH3·H2O in CO2 :ACN(1:1)

[0555] Analysis of the separated isomers was carried out using the following analytical chiral SFC method: Column: Chiralpak AD-3 (50×4.6mm, 3μm), flow rate: 3mL / min, mobile phase: 40% EtOH with 0.05% DEA in CO2

[0556] Example 25A (Analytical Chiral SFC Rt 1.03 min): 12 mg. LCMS: Rt 0.90 min; MS m / z 445.3 [M+H] + ; Method I. 1 H NMR (400 MHz, CDCl3) δ7.95 (br s, 1H), 7.23 - 7.13 (m, 2H), 7.03 - 6.94 (m, 1H), 6.92 - 6.78 (m, 2H), 6.73 (d, J = 8.0 Hz, 1H), 4.92 (br s, 1H), 4.66 - 4.57 (m, 1H), 3.01 - 2.71 (m, 6H), 2.67 - 2.57 (m, 5H), 2.51 - 2.43 (m, 2H), 2.41 - 2.33 (m, 1H), 2.14 - 2.07 (m, 1H), 1.55 - 1.47 (m, 1H).

[0557] Example 25B (Analytical Chiral SFC Rt 0.90 min): 14 mg. LCMS: Rt 0.90 min; MS m / z 445.3 [M+H] + ; Method I. 1 H NMR (400 MHz, CDCl3) δ8.21 - 8.08 (m, 1H), 7.22 - 7.13 (m, 2H), 7.02 - 6.94 (m, 1H), 6.92 - 6.79 (m, 2H), 6.74 (d, J = 8.0 Hz, 1H), 4.91 (br s, 1H), 4.70 - 4.60 (m, 1H), 3.22 - 3.15 (m, 1H), 3.01 - 2.85 (m, 3H), 2.74 - 2.30 (m, 10H), 2. 10 - 2.02 (m, 1H), 1.59 - 1.50 (m, 1H).

[0558] Example 25C (Analyzed KRAL SFC Rt 1.45 points): 13 mg. LCMS: Rt 0.90 min; MS m / z 445.3 [M+H] + ; Method I. 1 H NMR (400 MHz, CDCl3) δ8.08 (br s, 1H), 7.22 - 7.13 (m, 2H), 7.02 - 6.94 (m, 1H), 6.92 - 6.79 (m, 2H), 6.74 (d, J = 8.0 Hz, 1H), 4.92 (br s, 1H), 4.68 - 4.59 (m, 1H), 3.00 - 2.73 (m, 6H), 2.67 - 2.58 (m, 5H), 2.52 - 2.43 (m, 2H), 2.39 - 2.34 (m, 1H), 2.13 - 2.07 (m, 1H), 1.55 - 1.48 (m, 1H).

[0559] Example 25D (Analyzed KRAL SFC Rt 1.30 points): 17 mg. LCMS: Rt 0.90 min; MS m / z 445.3 [M+H] + ; Method I. 1 H NMR (400 MHz, CDCl3) δ7.90 (s, 1H), 7.23 - 7.11 (m, 2H), 7.03 - 6.94 (m, 1H) , 6.93 - 6.78 (m, 2H), 6.73 (d, J = 8.0 Hz, 1H), 4.92 (br s, 1H), 4.72 - 4.59 (m , 1H), 3.22 - 3.16 (m, 1H), 3.00 - 2.88 (m, 3H), 2.74 - 2.29 (m, 10H), 2.10 - 2. 03 (m, 1H), 1.58 - 1.52 (m, 1H).

[0560] Examples 26A, 26B, 26C, and 26D 6-((R)-2-((3aS,5S,6aR)-5-(2,5-difluorophenoxy )-3a-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)- 1-Hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one 6-((S)-2-((3aS,5S,6aR)-5-(2,5-difluorophenoxy )-3a-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)- 1-Hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one 6-((R)-2-((3aR,5R,6aS)-5-(2,5-difluorophenoxy )-3a-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)- 1-Hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one 6-((S)-2-((3aR,5R,6aS)-5-(2,5-difluorophenoxy )-3a-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)- 1-Hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one

[0561] [ka] Use the same method as in Examples 22A / 22B / 22C / 22D, but in step 1, use 4- Example 26A / 2 using 2,5-difluorophenol instead of fluorophenol A mixture of 6B / 26C / 26D was obtained. The mixture was separated using the following chiral SFC method: Ta: Column: Daicel Chiralpak AD (250mm x 30mm, 10μm ), Flow rate: 80 g / min, Mobile phase: 50% EtO containing 0.1% NH3·H2O in CO2 H

[0562] This method separated the four isomers into two peaks, each of which was divided into two types. It contained isomers of

[0563] The first peak was separated using the following chiral SFC method to give Examples 26A and 26B: Got: Column: Daicel Chiralpak IG (250mm x 30mm, 10μm ), Flow rate: 70 g / min, Mobile phase: 50% EtO containing 0.1% NH3·H2O in CO2 H

[0564] The second peak was separated using the following chiral SFC method to give Examples 26C and 26D. Got: Column: Daicel Chiralpak IG (250mm x 30mm, 10μm ), Flow rate: 80 g / min, Mobile phase: 70% EtO containing 0.1% NH3·H2O in CO2 H

[0565] Analysis of the separated isomers was carried out using the following analytical chiral SFC method: Column: Chiralpak AD-3 (50×4.6mm, 3μm), flow rate: 3mL / min, mobile phase: 40% EtOH with 0.05% DEA in CO2

[0566] Example 26A (Analytical Chiral SFC Rt 0.94 min). This compound was further purified by the following preparative HPLC method to give 12 mg. カラム:Waters Xbridge (150mm×25mm), 5μm Mobile phase: 10mM NH4HCO3 (A) in water, Atotron (B), 10 minutes of にわ たり27~57%B's combination LCMS: Rt 0.90 min; MS m / z 445.3 [M+H] + ; Method I. 1 H NMR (400 MHz, CDCl3) δ7.71 (s, 1H), 7.23 - 7.14 (m, 2H), 7.10 - 6.99 (m, 1H) , 6.78 - 6.70 (m, 2H), 6.69 - 6.60 (m, 1H), 4.97 (br s, 1H), 4.69 - 4.62 (m, 1H) , 3.70 (br s, 1H), 3.21 (d, J = 8.8 Hz, 1H), 3.01 - 2.88 (m, 3H), 2.79 - 2.59 (m , 5H), 2.57 - 2.46 (m, 3H), 2.42 - 2.34 (m, 2H), 2.13 - 2.05 (m, 1H), 1.63 - 1.5 9 (m, 1H).

[0567] Example 26B (Analyzed Koral SFC Rt 1.05 points): 14 mg. LCMS: Rt 0.89 min; MS m / z 445.3 [M+H] + ; Method I. 1 H NMR (400 MHz, CDCl3) δ7.75 (s, 1H), 7.23 - 7.14 (m, 2H), 7.09 - 7.00 (m, 1H) , 6.79 - 6.69 (m, 2H), 6.69 - 6.61 (m, 1H), 4.97 (br s, 1H), 4.68 - 4.60 (m, 1H) , 3.02 - 2.91 (m, 3H), 2.90 - 2.71 (m, 3H), 2.67 - 2.57 (m, 5H), 2.54 - 2.47 (m, 2H), 2.40 - 2.36 (m, 1H), 2.17 - 2.08 (m, 1H), 1.60 - 1.55 (m, 1H).

[0568] Example 26C (Analyzed Koral SFC Rt 1.46 points): 13 mg. LCMS: Rt 0.90 min; MS m / z 445.3 [M+H] + ; Method I. 1 H NMR (400 MHz, CDCl3) δ7.84 (s, 1H), 7.25 - 7.15 (m, 2H), 7.12 - 7.00 (m, 1H) , 6.82 - 6.71 (m, 2H), 6.70 - 6.62 (m, 1H), 4.99 (br s, 1H), 4.73 - 4.58 (m, 1H) , 3.04 - 2.93 (m, 3H), 2.91 - 2.74 (m, 3H), 2.69 - 2.58 (m, 5H), 2.56 - 2.49 (m, 2H), 2.42 - 2.35 (m, 1H), 2.19 - 2.10 (m, 1H), 1.62 - 1.56 (m, 1H).

[0569] Example 26D (Analyzed KRAL SFC Rt 1.62 points): 13 mg. LCMS: Rt 0.90 min; MS m / z 445.3 [M+H] + ; Method I. 1 H NMR (400 MHz, CDCl3) δ 7.79 (s, 1H), 7.23 - 7.14 (m, 2H), 7.09 - 7.00 (m, 1H ), 6.79 - 6.68 (m, 2H), 6.68 - 6.61 (m, 1H), 4.97 (br s, 1H), 4.71 - 4.59 (m, 1H ), 3.21 (d, J = 9.2 Hz, 1H), 3.02 - 2.88 (m, 3H), 2.74 - 2.33 (m, 10H), 2.14 - 2 .07 (m, 1H), 1.63 - 1.58 (m, 1H).

[0570] Examples 27A, 27B, 27C, and 27D 6-((R)-2-((3aS,5S,6aR)-5-(2,6-difluorophenoxy )-3a-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)- 1-Hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one 6-((S)-2-((3aS,5S,6aR)-5-(2,6-difluorophenoxy )-3a-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)- 1-Hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one 6-((R)-2-((3aR,5R,6aS)-5-(2,6-difluorophenoxy )-3a-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)- 1-Hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one 6-((S)-2-((3aR,5R,6aS)-5-(2,6-difluorophenoxy )-3a-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)- 1-Hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one

[0571] [ka] Use the same method as in Examples 22A / 22B / 22C / 22D, but in step 1, use 4- Example 27A / 2 using 2,6-difluorophenol instead of fluorophenol A mixture of 7B / 27C / 27D was obtained. The mixture was separated using the following chiral SFC method: Ta: Column: Daicel Chiralpak AD (250mm x 30mm, 10μm ), Flow rate: 80 g / min, Mobile phase: 50% EtO containing 0.1% NH3·H2O in CO2 H

[0572] This method separated the four isomers into two peaks, each of which was divided into two types. It contained a variety of isomers.

[0573] The first peak was separated using the following chiral SFC method to give Examples 27A and 27B. Column: Daicel Chiralpak IG (250 mm x 30 mm, 10 μm), flow rate: 70 g / min, mobile phase: 60% M containing 0.1% NH3·H2O in CO2 eOH

[0574] The second peak was separated using the following chiral SFC method to give Examples 27C and 27D. Column: Daicel Chiralpak IG (250 mm x 30 mm, 10 μm), flow rate: 80 g / min, mobile phase: 60% E containing 0.1% NH3·H2O in CO2 tOH:ACN(1:1)

[0575] Analysis of the separated isomers was carried out using the following analytical chiral SFC method: Column: Chiralpak IG-3 (50×4.6mm, 3μm), flow rate: 3mL / min, mobile phase: 60% EtOH with 0.05% DEA in CO2

[0576] Example 27A (Analytical Chiral SFC Rt 0.74 min): 15 mg. LCMS: Rt 0.90 min; MS m / z 445.5 [M+H] + ; Method I. 1 H NMR (400 MHz, CDCl3) δ7.88 (s, 1H), 7.23 - 7.12 (m, 2H), 7.05 - 6.89 (m, 3H) , 6.73 (d, J = 8.0 Hz, 1H), 5.03 (br s, 1H), 4.67 - 4.64 (m, 1H), 3.23 - 3.21 (m , 1H), 3.05 - 2.82 (m, 4H), 2.74 - 2.58 (m, 5H), 2.55 - 2.35 (m, 4H), 2.10 - 2.0 5 (m, 1H), 1.55 - 1.52 (m, 1H).

[0577] Example 27B (Analyzed Koral SFC Rt 0.89 points): 10 mg. LCMS: Rt 0.90 min; MS m / z 445.4 [M+H] + ; Method I. 1 H NMR (400 MHz, CDCl3) δ7.87 - 7.74 (m, 1H), 7.23 - 7.12 (m, 2H), 7.06 - 6.91 (m, 3H), 6.73 - 6.71 (m, 1H), 5.04 (br s, 1H), 4.64 - 4.61 (m, 1H), 3.06 - 2.89 (m, 4H), 2.86 - 2.80 (m, 1H), 2.79 - 2.59 (m, 6H), 2.51 - 2.39 (m, 3H), 2.09 - 2 .06 (m, 1H), 1.51 - 1.45 (m, 1H).

[0578] Example 27C (Analyzed KRAL SFC Rt 1.09 points): 15 mg. LCMS: Rt 0.90 min; MS m / z 445.5 [M+H] + ; Method I. 1H NMR (400 MHz, CDCl3) δ8.03 (br s, 1H), 7.22 - 7.13 (m, 2H), 7.06 - 6.88 (m, 3H), 6.74 - 6.72 (m, 1H), 5.03 (br s, 1H), 4.64 - 4.61 (m, 1H), 3.08 - 2.89 (m, 4H), 2.85 - 2.77 (m, 1H), 2.79 - 2.59 (m, 6H), 2.52 - 2.38 (m, 3H), 2.09 - 2.05 (m, 1H), 1.51 - 1.44 (m, 1H).

[0579] Example 27D (Analytical Chiral SFC Rt 1.99 min): 15 mg. LCMS: Rt 0.90 min; MS m / z 445.4 [M+H] + ; Method I. 1 H NMR (400 MHz, CDCl3) δ7.75 (s, 1H), 7.16 - 7.01 (m, 2H), 6.98 - 6.79 (m, 3H) , 6.64 (d, J = 8.2 Hz, 1H), 4.95 (br s, 1H), 4.58 - 4.55 (m, 1H), 4.04 - 3.23 (m , 1H), 3.15 - 3.13 (m, 1H), 2.96 - 2.75 (m, 4H), 2.66 - 2.26 (m, 9H), 1.97 - 1.9 3 (m, 1H), 1.46 - 1.38 (m, 1H).

[0580] Examples 28A and 28B 6-((R)-1-hydroxy-2-((3aS,5S,6aR)-3a-hydroxy- 5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl -1,4-Dihydro-2H-benzo[d][1,3]oxazin-2-one 6-((S)-1-hydroxy-2-((3aS,5S,6aR)-3a-hydroxy- 5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl -1,4-Dihydro-2H-benzo[d][1,3]oxazin-2-one

[0581] [ka] Step 1: 6-((R)-1-hydroxy-2-((3aS,5S,6aR)-3a-hydroxy- 5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl -1,4-Dihydro-2H-benzo[d][1,3]oxazin-2-one 6-((S)-1-hydroxy-2-((3aS,5S,6aR)-3a-hydroxy- 5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl -1,4-Dihydro-2H-benzo[d][1,3]oxazin-2-one A mixture of

[0582] [ka] Intermediate 2 (80 mg, 0.36 mmol) and Intermediate 25 (1 mL) in ACN (2 mL) A solution of DIPEA (170 mg, 0.23 mL, 1.3 1 mmol) was added, and the mixture was stirred at 40°C for 16 hours. The reaction mixture was filtered, and the filtrate was collected. HPLC (column: Waters Xbridge (150 × 25 mm × 5 μm); transfer Phases: Water containing 0.05% NH4HCO3 v / v (A); ACN (B); over 10 min 5-50% B; flow rate: 25 mL / min) to obtain a mixture of Examples 28A and 28B and Two undesired regioisomers were obtained.

[0583] LCMS:Rt 0.88 min; MS m / z 411.4[M+H] + ;Method I.

[0584] Step 2: Chiral separation of Examples 28A and 28B The mixture was separated using the following chiral SFC method: Column: Daicel Chiralpak AD (250mm x 30mm, 10μm ), Flow rate: 70 g / min, Mobile phase: 60% EtO containing 0.1% NH3·H2O in CO2 H

[0585] This method produces, in order, the undesired regioisomer, then Example 28A, then Example 28B, and A mixture of the above and other undesired regioisomers was obtained.

[0586] The remaining mixture was separated using the following chiral SFC method: Column: Daicel Chiralpak OJ-H (250mm x 30mm, 5μm), flow rate: 65g / min, Mobile phase: 35% MeOH containing 0.1% NH3·H2O in CO2

[0587] Analysis of the separated isomers was carried out using the following analytical chiral SFC method: Column: Chiralpak AD-3 (50×4.6mm, 3μm), flow rate: 3mL / min, mobile phase: 50% EtOH with 0.05% DEA in CO2

[0588] Example 28A (Analytical Chiral SFC Rt 1.30 min): 15 mg. LCMS: Rt 0.87 min; MS m / z 411.4 [M+H] + ; Method I. 1 H NMR (400 MHz, CDCl3) δ7.86 - 7.81 (m, 1H), 7.33 - 7.28 (m, 2H), 7.24 (s, 1H) , 7.18 (s, 1H), 7.01 - 6.96 (m, 1H), 6.92 - 6.85 (m, 2H), 6.80 - 6.78 (m, 1H), 5 .32 (s, 2H), 4.96 (br s, 1H), 4.70 - 4.66 (m, 1H), 3.19 - 3.16 (m, 1H), 2.95 - 2 .90 (m, 1H), 2.67 - 2.46 (m, 6H), 2.41 - 2.33 (m, 2H), 2.12 - 2.07 (m, 1H), 1.61 - 1.59 (m, 2H).

[0589] Example 28B (Analytical Chiral SFC Rt 1.91 min): 15 mg. LCMS: Rt 0.88 min; MS m / z 411.2 [M+H] + ; Method I. 1 H NMR (400 MHz, methanol-d4) δ 7.35–7.33 (m, 1H), 7.27–7.22 (m, 3H), 6.9 2 - 6.88 (m, 4H), 5.34 - 5.26 (m, 2H), 4.86 (br s, 2H), 3.09 - 2.90 (m, 7H), 2.7 5 - 2.64 (m, 1H), 2.43 - 2.37 (m, 1H), 2.23 - 2.15 (m, 1H), 1.93 - 1.87 (m, 1H).

[0590] Examples 29A and 29B 8-Fluoro-6-((R)-2-((3aS,4S,5S,6aR)-5-(2-fluoro (3a,4-dihydroxyhexahydrocyclopenta[c]pyrrole)- 2(1H)-yl)-1-hydroxyethyl)-3,4-dihydroquinoline-2(1H) -on 8-Fluoro-6-((S)-2-((3aS,4S,5S,6aR)-5-(2-fluoro (3a,4-dihydroxyhexahydrocyclopenta[c]pyrrole)- 2(1H)-yl)-1-hydroxyethyl)-3,4-dihydroquinoline-2(1H) -on

[0591] [ka] Using the same method as in Examples 28A / 28B, starting from intermediates 8 and 26, examples 29A and 29B were prepared. A mixture of 29B and 29C as well as two undesired regioisomers was obtained. Separation was performed using the SFC method: Column: Daicel Chiralpak IG (250mm x 30mm, 10μm ), flow rate: 80g / min Mobile phase: 60% EtOH containing 0.1% NH3·H2O in CO2

[0592] This method sequentially produces the undesired regioisomer, followed by Example 29A and another undesired A mixture of regioisomers was obtained, followed by Example 29B.

[0593] The remaining mixture was separated using the following chiral SFC method: Column: Daicel Chiralcel OJ (250 mm x 30 mm, 10 μm ), flow rate: 70g / min Mobile phase: 40% MeOH containing 0.1% NH3·H2O in CO2

[0594] Analysis of the separated isomers was carried out using the following analytical chiral SFC method: Column: Chiralpak IG-3 (50×4.6mm, 3μm), flow rate: 3mL / min, mobile phase: 50% EtOH with 0.05% DEA in CO2

[0595] Example 29A (Analyzed Koral SFC Rt 2.29 points): 18 mg. LCMS: Rt 0.84 min; MS m / z 461.4 [M+H] + ; Method I. 1 H NMR (400 MHz, CDCl3) δ7.60 (s, 1H), 7.15 - 6.96 (m, 6H), 4.86 - 4.81 (m, 1H) , 4.67 - 4.59 (m, 1H), 4.03 - 4.02 (m, 1H), 3.05 - 2.96 (m, 4H), 2.86 - 2.84 (m, 1H), 2.76 - 2.70 (m, 1H), 2.68 - 2.60 (m, 4H), 2.59 - 2.56 (m, 1H), 2.54 - 2.48 (m, 1H), 2.43 - 2.33 (m, 1H), 1.54 - 1.48 (m, 1H).

[0596] Example 29B (Analyzed Koral SFC Rt3.40 points): 20 mg. LCMS: Rt 0.85 min; MS m / z 461.4 [M+H] + ; Method I. 1 H NMR (400 MHz, CDCl3) δ7.60 (s, 1H), 7.17 - 6.92 (m, 6H), 4.84 - 4.81 (m, 1H) , 4.66 - 4.62 (m, 1H), 3.99 - 3.98 (m, 1H), 3.69 - 3.45 (m, 1H), 3.26 - 3.24 (m, 1H), 3.05 - 2.86 (m, 4H), 2.70 - 2.60 (m, 4H), 2.58 - 2.50 (m, 2H), 2.43 - 2.30 (m, 2H), 1.58 - 1.49 (m, 2H).

[0597] Example 30Aおよび30B 9-Fluoro-7-((R)-1-hydroxy-2-((3aS,5S,6aR)-3a -Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)- (yl)ethyl)-1,3,4,5-tetrahydro-2H-benzo[b]azepine-2-ol hmm 9-Fluoro-7-((S)-1-hydroxy-2-((3aS,5S,6aR)-3a -Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)- (yl)ethyl)-1,3,4,5-tetrahydro-2H-benzo[b]azepine-2-ol hmm

[0598] [ka] Using the same method as in Examples 28A / 28B, starting from intermediates 2 and 27, examples 30A and 30B were prepared. A mixture of 30A and 30B was obtained. The mixture was separated using the following chiral SFC method: Column: Daicel Chiralpak AD (250mm x 30mm, 10μm ), flow rate: 70g / min Mobile phase: 40% IPA:ACN (1:1) containing 0.1% NH3·H2O in CO2

[0599] Analysis of the separated isomers was carried out using the following analytical chiral SFC method: Column: Chiralpak AD-3 (50×4.6mm, 3μm), flow rate: 3mL / min, mobile phase: 40% IPA:ACN (1:1) with 0.05% DEA in CO

[0600] Example 30A (Analytical chiral SFC Rt 0.74 min): 13 mg. LCMS: Rt 0.91 min; MS m / z 441.4 [M+H] + ; Method I. 1H NMR (400 MHz, CDCl3) δ7.34 - 7.28 (m, 2H), 7.14 (br s, 1H), 7.10 - 6.96 (m, 3H), 6.91 (d, J = 7.8 Hz, 2H), 4.97 (br s, 1H), 4.67 - 4.65 (m, 1H), 3.18 (d, J = 9.2 Hz, 1H), 2.97 - 2.89 (m, 1H), 2.84 (t, J = 7.2 Hz, 2H), 2.70 - 2.63 (m, 1H ), 2.61 - 2.47 (m, 4H), 2.43 - 2.33 (m, 4H), 2.27 - 2.25 (m, 2H), 2.10 - 2.00 (m , 1H), 1.64 - 1.56 (m, 1H).

[0601] Example 30B (Analyzed Koral SFC Rt 0.93 points): 10 mg. LCMS: Rt 0.91 min; MS m / z 441.4 [M+H] + ; Method I. 1 H NMR (400 MHz, CDCl3) δ7.33 - 7.29 (m, 2H), 7.07 - 6.97 (m, 4H), 6.94 - 6.88 (m, 2H), 4.98 (br s, 1H), 4.66 - 4.63 (m, 1H), 3.84 (br s, 1H), 2.93 - 2.85 (m, 1H), 2.83 - 2.81 (m, 3H), 2.77 - 2.49 (m, 7H), 2.43 - 2.33 (m, 3H), 2.30 - 2.21 (m, 2H), 2.14 - 2.10 (m, 1H), 1.57 (br s, 1H).

[0602] Example 31Aおよび31B 8-フルオロ-6-((R)-1-ヒドロキシ-2-((3aS,5S,6aR)-3a -Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)- (yl)ethyl)-3,4-dihydroquinolin-2(1H)-one 8-Fluoro-6-((S)-1-hydroxy-2-((3aS,5S,6aR)-3a -Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)- (yl)ethyl)-3,4-dihydroquinolin-2(1H)-one

[0603] [ka] Step 1: 6-((R)-1-((tert-butyldimethylsilyl)oxy)-2-((3aS, 5S,6aR)-3a-Hydroxy-5-phenoxyhexahydrocyclopenta[c]pi rol-2(1H)-yl)ethyl)-8-fluoro-3,4-dihydroquinoline-2( 1H)-On 6-((S)-1-((tert-butyldimethylsilyl)oxy)-2-((3aS, 5S,6aR)-3a-Hydroxy-5-phenoxyhexahydrocyclopenta[c]pi rol-2(1H)-yl)ethyl)-8-fluoro-3,4-dihydroquinoline-2( 1H)-On A mixture of

[0604] [ka] In a microwave-safe vial, prepare Intermediate 2 (100 mg, 0.456 mL) in NMP (2 mL). A solution of 200 mg (0.547 mmol) and intermediate 37 (200 mg, 0.547 mmol) was treated with DIPEA ( The vial was sealed and Bi 2 in a tage Smith Synthesizer under microwave irradiation at 150 °C. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The crude material was washed with saturated brine (5 mL), dried over Na2SO4, filtered, and concentrated. The material was purified by FCC (0-20% MeOH:DCM) to give the title intermediate (200 mg). Obtained as a yellow oil.

[0605] LCMS:Rt 0.81min;MS m / z 541.0[M+H] + ;Method J.

[0606] Step 2: Mixture of Examples 31A and 31B

[0607] [ka] The intermediate from the previous step (200 mg, 0.37 mmHg) in MeOH (7.4 mL) Concentrated HCl (7.4 mL) was slowly added to a solution of 1 ml of HCl, which was stirred at room temperature for 1 hour. The reaction mixture was concentrated and purified by preparative HPLC (column: Phenomenex Gemini NX- C18 (75 × 30 mm × 3 μm); Mobile phase: Water containing 10 mM NH4HCO3 (A) acetonitrile (B); 20-50% B over 8 min) to give the title compound (90 mg) was obtained as a white solid.

[0608] LCMS:Rt 0.90min;MS m / z 427.4[M+H] + ;Method I.

[0609] Step 3: Chiral separation of Examples 31A and 31B The mixture was separated using the following chiral SFC method: Column: Daicel Chiralpak OJ (250 mm x 50 mm, 10 μm ), flow rate: 55g / min Mobile phase: 25% MeOH (0.1% NH3·H2O) in supercritical CO2

[0610] Example 31A: 42 mg. Analytical chiral SFC: Rt 1.79 min (column: Chiralcel OJ-350 ×4.6 mm, 3 μm, flow rate 3 mL / min, mobile phase: 5 ~40% MeOH containing 0.05% DEA in CO2). LCMS: Rt 0.90 min; MS m / z 427.3 [M+H] + ; Method I. 1 H NMR (400 MHz, CDCl3) δ7.56 (s, 1H), 7.35 - 7.28 (m, 2H), 7.06 - 6.96 (m, 3H) , 6.94 - 6.88 (m, 2H), 4.97 (br s, 1H), 4.66 - 4.57 (m, 1H), 3.81 (br s, 1H), 3. 05 - 2.90 (m, 3H), 2.83 (d, J = 8.4 Hz, 1H), 2.75 - 2.58 (m, 7H), 2.56 - 2.47 (m , 2H), 2.37 - 2.34 (m, 1H), 2.17 - 2.10 (m, 1H), 1.59 - 1.54 (m, 1H).

[0611] Example 31B: 35 mg. Analytical chiral SFC: Rt 1.92 min (column: Chiralcel OJ-350 ×4.6 mm, 3 μm, flow rate 3 mL / min, mobile phase: 5 ~40% MeOH containing 0.05% DEA in CO2). LCMS: Rt 0.90 min; MS m / z 427.3 [M+H] + ; Method I. 1 H NMR (400 MHz, CDCl3) δ7.57 (s, 1H), 7.34 - 7.28 (m, 2H), 7.08 - 6.96 (m, 3H) , 6.94 - 6.88 (m, 2H), 4.97 (br s, 1H), 4.69 - 4.58 (m, 1H), 3.18 (d, J = 8.8 Hz , 1H), 3.03 - 2.89 (m, 3H), 2.72 - 2.44 (m, 8H), 2.40 - 2.33 (m, 2H), 2.12 - 2.0 6 (m, 1H), 1.63 - 1.57 (m, 1H).

[0612] Examples 32A and 32B 9-Fluoro-7-((R)-1-hydroxy-2-((3aS,5S,6aR)-3a -Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)- (yl)ethyl)-1,5-dihydrobenzo[e][1,4]oxazepine-2(3H)- on 9-Fluoro-7-((S)-1-hydroxy-2-((3aS,5S,6aR)-3a -Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)- (yl)ethyl)-1,5-dihydrobenzo[e][1,4]oxazepine-2(3H)- on

[0613] [ka] Step 1: 7-((R)-1-((tert-butyldimethylsilyl)oxy)-2-((3aS, 5S,6aR)-3a-Hydroxy-5-phenoxyhexahydrocyclopenta[c]pi 2(1H)-yl)ethyl)-9-fluoro-1,5-dihydrobenzo[e][ 1,4]oxazepin-2(3H)-one 7-((S)-1-((tert-butyldimethylsilyl)oxy)-2-((3aS, 5S,6aR)-3a-Hydroxy-5-phenoxyhexahydrocyclopenta[c]pi 2(1H)-yl)ethyl)-9-fluoro-1,5-dihydrobenzo[e][ 1,4]oxazepin-2(3H)-one A mixture of

[0614] [ka] Using the same method as in Step 1 of Examples 31A / 31B, intermediate 2 (300 mg, 1.3 Starting from intermediate 29 (700 mg, 1.67 mmol) and intermediate 30 (700 mg, 1.67 mmol), A mixture of intermediates (400 mg) was obtained as a yellow oil.

[0615] LCMS:Rt 1.17 min; MS m / z 557.6[M+H] + ;Method I.

[0616] Step 2: Mixture of Examples 32A and 32B

[0617] [ka] The intermediate from the previous step (200 mg, 0.36 mmol) in THF (4.5 mL) l) to the solution, TBAF (1 M in THF, 0.36 mL, 0.36 mmol) was added; This was stirred at room temperature for 2 hours. The reaction was diluted with water (3 mL) and added to EtOAc (3×5 mL ), dried over Na2SO4, filtered, and concentrated. The crude material was purified by reversed-phase FCC ( System: C18; Mobile phase: water with 0.05% v / v TFA (A); ACN (B); Gradient 5 ~95% B), followed by preparative TLC (15:1 DCM containing 1% NH3·H2O). The product-containing band was further purified with 15:1 DCM (MeOH, Rf=0.6). : Taken up in MeOH (15 mL) for 30 min, then filtered and concentrated to give the title intermediate (60 mg) was obtained as a white solid.

[0618] LCMS:Rt 0.88 min; MS m / z 443.3[M+H] + ;Method I.

[0619] Step 3: Chiral separation of Examples 32A and 32B The mixture was separated using the following chiral SFC method: Column: Daicel Chiralpak AD (250mm x 30mm, 10μm ), flow rate: 70g / min Mobile phase: 70% EtOH (0.1% NH3·H2O) in supercritical CO2

[0620] Example 32A: 10 mg. Analytical chiral SFC: Rt 1.69 min (column: Chiralcel AD-3 5 0×4.6 mm, 3 μm, flow rate 3 mL / min, mobile phase: 0.05% DEA in CO2 60% EtOH). LCMS: Rt 0.89 min; MS m / z 444.3 [M+H] + ; Method I. 1 H NMR (400 MHz, CDCl3) δ7.78 - 7.76 (m, 1H), 7.33 - 7.28 (m, 2H), 7.15- 7.11 ( m, 1H), 7.02 - 6.97 (m, 4H), 4.97 (br s, 1H), 4.77 (s, 2H), 4.70 - 4.64 (m, 1H), 4.62 (s, 2H), 3.21 - 3.17 (m, 1H), 2.99 - 2.93 (m, 1H), 2.68 - 2.34 (m, 9H), 2. 14 - 2.09 (m, 1H), 1.67 - 1.58 (m, 1H).

[0621] Example 32B: 18 mg. Analytical chiral SFC: Rt 2.23 min (Column: Chiralcel AD-3 5 0×4.6 mm, 3 μm, flow rate 3 mL / min, mobile phase: 0.05% DEA in CO2 60% EtOH). LCMS: Rt 0.87 min; MS m / z 444.3 [M+H] + ; Method I. 1 H NMR (400 MHz, CDCl3) δ7.78 - 7.76 (m, 1H), 7.33 - 7.28 (m, 2H), 7.15- 7.11 ( m, 1H), 7.02 - 6.97 (m, 4H), 4.97 (br s, 1H), 4.77 (s, 2H), 4.70 - 4.64 (m, 1H), 4.62 (s, 2H), 3.21 - 3.17 (m, 1H), 2.99 - 2.93 (m, 1H), 2.69 - 2.58 (m, 8H), 2. 55 - 2.33 (m, 1H), 2.14 - 2.09 (m, 1H), 1.67 - 1.58 (m, 1H).

[0622] These examples are prepared by starting from the intermediates shown and using the same methods as in Examples 31A / 31B. They were prepared as pairs of asteomers and separated using the conditions shown.

[0623] [Table 5-1]

[0624] [Table 5-2]

[0625] [Table 5-3]

[0626] [Table 5-4]

[0627] [Table 5-5]

[0628] [Table 5-6]

[0629] [Table 5-7]

[0630] [Table 5-8]

[0631] [Table 5-9]

[0632] [Table 5-10]

[0633] [Table 5-11]

[0634] Examples 44A and 44B (3aS,4S,5S,6aR)-5-(2-fluorophenoxy)-2-((R)-2 -hydroxy-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)ethyl)hexa Hydrocyclopenta[c]pyrrole-3a,4(1H)-diol (3aS,4S,5S,6aR)-5-(2-fluorophenoxy)-2-((S)-2 -hydroxy-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)ethyl)hexa Hydrocyclopenta[c]pyrrole-3a,4(1H)-diol

[0635] [ka] Step 1: (3aS,4S,5S,6aR)-5-(2-fluorophenoxy)-2-((S)-2 -hydroxy-2-(1-tosyl-1H-pyrrolo[2,3-c]pyridin-5-yl) ester (Cithyl)hexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol (3aS,4S,5S,6aR)-5-(2-fluorophenoxy)-2-((R)-2 -hydroxy-2-(1-tosyl-1H-pyrrolo[2,3-c]pyridin-5-yl) (Cithyl)hexahydrocyclopenta[c]pyrrole-3a,4(1H)-diol A mixture of

[0636] [ka] Intermediate 8 (200 mg, 0.79 mmol) and Intermediate 3 in EtOH (10 mL) A solution of 9 (248 mg, 0.79 mmol) was stirred at 90 °C for 4 h. The reaction was concentrated. Purification by FCC (5% MeOH:DCM) gave the title intermediate (200 mg).

[0637] LCMS:Rt 0.45min;MS m / z 568.3[M+H] + ;Method D.

[0638] Step 2: Mixture of Examples 44A and 44B

[0639] [ka] The intermediate (200) from the previous step in THF (5 mL) and MeOH (1 mL) mg, 0.35 mmol) was added to a solution of 1N NaOH (1.05 mL, 1.05 m mol) was added and stirred at 60° C. for 6 hours. The reaction mixture was concentrated and diluted with 1N HCl Neutralized with NaHCO3, basified with saturated aqueous NaHCO3, then extracted with DCM and The crude material was purified by the following preparative HPLC method to give the title compound. The intermediate (90 mg) was obtained. Column: Kinetex Evo (150 mm x 21.2 mm), 5.0 μm, flow rate: 18.0mL / min Mobile phase: 0.02% NH4OH in water (A), acetonitrile (B)

[0640] LCMS:Rt 0.11 min;MS m / z 414.3[M+H] + ;Method D.

[0641] Step 3: Chiral separation of Examples 44A and 44B The mixture was separated using the following chiral HPLC method: Column: Chiralpak IC (10 mm x 250 mm, 5 microns), flow rate: 8 mL / min Mobile phase: Hexane (A), EtOH:MeOH 1:1 (B), Isocratic: 65 :35(A:B)

[0642] Example 44A (chiral HPLC Rt 6.42 min): 35 mg. LCMS: Rt 0.12 min; MS m / z 414.0 [M+H] + ; Method D. 1 H NMR (400 MHz, methanol-d4) δ 8.21 (d, J = 2.0 Hz, 1H), 8.03 (d, J = 2.0 Hz , 1H), 7.36 (d, J = 3.2 Hz, 1H), 7.08-6.90 (m, 4H), 6.46 (d, J = 3.6 Hz, 1H), 4. 68-4.65 (m, 1H), 3.93 (d, J = 3.6 Hz, 1H), 3.01 (d, J = 9.6 Hz, 1H), 2.88-2.82 ( m, 1H), 2.74-2.63 (m, 3H), 2.44-2.37 (m, 2H), 2.27-2.20 (m, 1H), 1.55-1.50 (m, 1 H). 1H under the solvent peak.

[0643] Example 44B (chiral HPLC Rt 7.75 min): 35 mg. LCMS: Rt 0.12 min; MS m / z 414.2 [M+H] + ; Method D. 1 H NMR (400 MHz, methanol-d4) δ 8.21 (d, J = 2.0 Hz, 1H), 8.03 (d, J = 2.0 Hz , 1H), 7.36 (d, J = 3.2 Hz, 1H), 7.08-6.90 (m, 4H), 6.46 (d, J = 3.6 Hz, 1H), 4. 68-4.65 (m, 1H), 3.93 (d, J = 3.6 Hz, 1H), 3.01 (d, J = 9.6 Hz, 1H), 2.88-2.82 ( m, 1H), 2.74-2.63 (m, 3H), 2.44-2.37 (m, 2H), 2.27-2.20 (m, 1H), 1.55-1.50 (m, 1 H). 1H under the solvent peak.

[0644] Biological assays and data The activity of compounds according to the present disclosure was demonstrated by the following in vitro and in vivo methods. It can be evaluated based on this.

[0645] Example 1: NR2B Rat Cortical Neuron Calcium Influx Assay Protocol Pregnant Sprague Dawley rats on embryonic day 18 were admitted to the Institutional Animal Care and Use Committee. The animals were euthanized according to the IACUC protocol. After incising the skin midline, the uterus and The embryos were then exposed, removed, and placed in chilled Hibernate medium. The cerebral cortex was isolated by extracting the brain and removing the midbrain and meninges. The cortices were then dissociated with a papain dissociation system according to the manufacturer's protocol. n system)(Worthington Biochemical Corporation n) were used to dissociate neurons.

[0646] Dissociated neurons were counted and plated onto 384-well poly-D-lysine coated plates ( Corning® BioCoat™ with Neurobasal / B27 Neurons were plated at a density of 20,000 cells / well in 30 μL of complete medium. The cells were cultured at 37°C for 2 days. On the day of the assay, the medium was removed and the cells were incubated according to the manufacturer's instructions. According to the manual, 1.8 mM Ca 2+ Ca suspended in HBSS containing Ca (Ca-HBSS) Calcium 6 Assay Kit, Molecular Device ces) 20 μL / well.

[0647] Compounds of interest from 10 mM stock solutions were diluted to the desired concentration in 1.8 mM Ca-HBSS. Compounds and neurons were incubated in the dark at 37°C. and incubated for 2 hours.

[0648] Using the FDSS7000EX (Hamamatsu Photonics) fluorescence measurement equipment, 1.8mM Ca 2+ -Four mixtures containing glutamic acid and glycine prepared in HBSS 10 μL of the ligand solution was added to each well. The fluorescent signal was measured before and after adding the ligand. The data were collected for a total of 2 minutes. The data were converted into the ratio of peak fluorescence to the fluorescence at the start of the measurement. did.

[0649] Each data point was measured in duplicate. Dose-response curves were used to determine the IC 50 and maximum inhibition value Identified IC 50 represents the concentration of compound in μM that exhibits half-maximal compound effect. The maximum inhibition of a compound is expressed as the highest percent inhibition of activity relative to the compound-free control. can be.

[0650] [Table 6-1]

[0651] [Table 6-2]

[0652] [Table 6-3]

[0653] [Table 6-4]

[0654] Example 2. Microsome and hepatocyte assay protocols. Microsome incubation: Experiments were performed on an automated platform at 37°C in a shaking incubator. The experiment was carried out in a 96-well format with incubation. Test compounds were added to 100 mM L-lysine containing cofactors (2 mM NADPH, 4 mM MgCl2). Dilute 1:5000 in potassium phosphate, pH 7.4 (KPi) solution to a concentration of 2 μM Rat or human liver microsomal proteins suspended in 100 mM KPi buffer were analyzed. The reaction was initiated by adding an equal volume of 1 mg / mL of methacrylate to the protein. At (0, 5, 15, and 30 min), reaction aliquots were removed and analyzed using an internal standard (0. Terminate the reaction by adding 3 volumes of acetonitrile containing 4 μM glyburide. The samples were then centrifuged at 4000 x g for 10 minutes at 4°C, and the supernatant was analyzed by LC / MS / MS. The remaining test compound was quantified by MS analysis. The percentage of test compound that is eliminated is used to determine the in vitro elimination rate constant (k mic ) is estimated which were then used to calculate in vitro metabolic clearance rates.

[0655] Incubation of hepatocytes: Experiments were carried out in a shaking incubator at 37°C on an automated platform. The experiment was carried out in a 96-well format with incubation. Test compounds were added at a concentration of 10 mM in DMSO. The compound was diluted 1:5000 in Leibovitz's L15 medium (L-15) to give a 2 μM The concentration was 2 million cells / mL in L-15 medium solution. The reaction was initiated by adding an equal volume of 1000 mg ... At 40, 60, and 80 min, reaction aliquots were removed and analyzed using an internal standard (0.4 μL). The reaction was terminated by adding three volumes of acetonitrile containing HCl (glyburide). The samples were then centrifuged at 4000 x g for 10 minutes at 4°C, and the supernatant was analyzed by LC / MS / MS. The remaining test compound was quantified by analyzing the remaining test compound at 0 min of incubation. The percentage of test compound was used to determine the in vitro elimination rate constant (k mic ) is estimated, This was then used to calculate the in vitro metabolic clearance rate.

[0656] LC / MS / MS analysis: Samples were collected using a Shimadzu 30 series autosampler and High performance liquid chromatograph consisting of an AB Sciex API6500 and an HPLC pump connected to it. High Performance Liquid Chromatography (HPLC)-Tandem Mass Spectrometry (LC / MS / MS) System The compound-specific parameters (precursor ions, product ions, declustering potentials, and collision energies, for monitoring a single reaction) It was obtained by automatic tuning using Multiquant software V3.0. Samples were collected using a Shimadzu 30 series autosampler on an ACE 3 C18 The components were loaded onto a 2.1 mm x 30 mm, 3 μm column. (mobile phase A) and a gradient of 0.1% formic acid in acetonitrile (mobile phase B), 700 μL / min flow rate with the following gradient: 0 min 2% B; 0.25 min 2% B; 1.00 min 98% B; 1. Elution was performed using 55 min 98% B; 1.95 min 2% B; 2.00 min 2% B. Analyte concentration Multiquant software V3.0 (Sciex, Framingham, MA) was used to measure the analytes relative to an internal standard (glyburide, m / z 494→169). Calculated from the chromatographic peak area ratio.

[0657] Example 3. hERG Qpatch assay protocol. This assay is described in Skepper et al., J. Med. Chem. 2020, 63, 7773-7816. This was done using the method currently available.

[0658] hERG-expressing cell lines were induced using CHO-K1T-Rex-inducible plasmid vectors as previously described. was generated in-house at Novartis using the Cao system (Invitrogen). (Et al., Assay Drug Dev. Technol. 2010, 8, 766-780). Cell lines were analyzed using the SelecT automated Cell culture system (TAP Biosystems, Cambridge, UK) Use 10% FBS, blasticidin (10 mg / mL; InvivoGen), Hygromycin B (200 mg / mL; InvivoGen), Zeocin (200 mg / mL, Invitrogen), and neomycin (200 mg / mL, Inv They were maintained in Ham's F12 nutrient mixture containing 1000 mg of riboflavin. The expression of hERG and hCav1.2 channels was maintained by tetracycline (0.25- 1 μg / mL, Invitrogen) for at least 24 hours before the experiment. went.

[0659] hERG currents were measured using a Qpatch automated patch clamp system (Sophion Bio Science Inc., North Brunswick, NJ) to hERG-expressing CHO-K1 cells were recorded in a single-cell configuration. The cells were collected using modified serum-free SFM-2 medium (Life Technologies) and cultured in a 200-well plate. The extracellular solution was stored at room temperature in NaCl (145%), KCl (4%), , HEPES at pH 7.4 containing MgCl2(1), CaCl2(2), and NaOH The intracellular solution contained (in mM): KCl (135), MgCl2 (1 .75), CaCl2(5.4), EGTA(10), K2-ATP(4), and KO After achieving whole-cell placement, the cells were Hold the voltage at -90 mV, deliver a 0.1 second pulse to -50 mV, and measure the leakage current. This was subtracted from the online tail current. The cell was then de-energized to +20 mV for 4 seconds. hERG measurements were taken by polarizing the voltage (prepulse) to -50 mV followed by a 4-second test pulse to -50 mV. This voltage protocol was used to monitor changes in current amplitude. The test compound was first administered for six dose-response experiments. The solution was diluted in DMSO and then transferred to a Freedom EVO liquid handling robot system. extracellular using Stem (Tecan, Mannedorf, Switzerland) The final DMSO concentration in the sample was 0.3% v / v. Ptyline (Sigma) was tested as a positive control. Data were analyzed using an in-house developed Mat Analyses were performed using a Lab-based program (MathWorks, Natick, MA). did.

[0660] Example 4. Experimental measurement of efflux using the MDCK-MDR1 protocol Cell culture. MDCK-MDR1 cells were cultured in 10% FBS, penicillin-streptomycin-containing medium. The cells were incubated in DMEM containing 100 μg / mL of ATP and 2 mM Ala-Gln at 5% CO2 The cells were cultured at 37°C and 95% relative humidity in a humidified atmosphere. The cells were subcultured every 3 to 4 days. For this purpose, the cells were grown at a density of approximately 265,000 cells / cm. 2 96-well Trans well plate (Corning Life Sciences, Acton, MA) and cultured for 4 days in the same medium as above.

[0661] Assay: Apparent permeability (P app ) judgement is made by A → B (apical to basal) and B → A (basal) The assay was performed in both directions (bottom to top) and each compound was assayed in triplicate. Tatin is a poorly permeable compound and was used as a marker of monolayer integrity. To begin incubation, aspirate the medium and resuspend the cells and basal chamber in 10 mM HEP The cells were washed three times with Hank's Balanced Salt Solution (HBSS) containing ES (pH 7.4). The test solution was prepared by adding 10 mM HEPES (pH 7.4) and 0.02% bovine serum albumin ( Prepared in triplicate in HBSS containing 100 mM BSA to a final concentration of 10 μM and heated at 4000 g. The solution was centrifuged for 2 minutes and then applied to the donor compartment at time 0. A 37°C solution (HBSS + 10 mM HEPES (pH 7.4) + 0.02% BSA) was added to the receiver chamber of the Transwell plate. A time 0 sample of the donor solution was also sampled for further analysis. The assay was carried out at 37°C for 120 minutes without any disruption. At the end of the assay, samples were collected from each donor comparator. from the compartment and each acceptor compartment of the Transwell plate. The 0 and 120 min samples were each diluted with water:acetonitrile, 50:50 (v:v). An internal standard solution containing glyburide in 1000 mg / L was added. A concentration curve was plotted using the same matrix as above. Samples and concentration curve samples were prepared using abcyte Echo. It was centrifuged for 10 minutes and then analyzed by mass spectrometry.

[0662] Mass spectroscopy. Assay samples were collected using a RapidFire autosampler (Agilent (Santa Clara, CA) to load RapidFire C4 cartridges. Chromatography was performed at a flow rate of 1.25 mL / min with 0.1% formic acid in water. The column was loaded and eluted with 0.1% formic acid in methanol. Mass spectroscopy was performed using a turbo ion spray analyzer. AB Sciex API5500 (Sciex, Framingham) equipped with a 3000 W power source Analyte concentrations were determined using Multiquant software V3. 0 (Sciex, Framingham, MA) was used as an internal standard (glibenclamine). The peak area was calculated from the chromatographic peak area ratio of the analyte to the m / z 494→169. I calculated it.

[0663] Calculation. P app The values ​​were determined as follows: Papp=VAS[D0]×A120tPapp=VAS[D0]×A120t

[0664] Recovery values ​​were determined as follows: Recovery % = 100 x (A120 + D120D0) Recovery % = 100 x A120 + D120D0

[0665] In the formula, V A is the volume of the acceptor (mL), S is the surface area of ​​the membrane, and D0 is t = is the concentration of the donor solution at 0, D 120 is the concentration of the donor solution at t=120, and A 120is the concentration of the acceptor solution at t=120, where t=time (seconds).

[0666] Hepatocytes were used to determine the in vitro intrinsic clearance of compounds. Cryopreserved hepatocytes can be used to understand differences between species. Hepatocyte clearance in rats [CL(hep.)] was calculated based on the oral bioavailability of rats. This assay is one of the important markers for assessing viability. The compounds profiled are shown in Table 1.

[0667] The suitability of the compounds for oral administration and / or for use as CNS therapeutic agents is Typically, M to investigate its drug efflux potential mediated by P-glycoprotein (P-gp) MDCK-MDR1 permeability assay. The ER ratio has been used as a predictor of blood-brain barrier permeability. Selected compounds profiled in this study are shown in Table 1.

[0668] [Table 7]

[0669] [Table 8]

[0670] As shown in Table 3, compounds from the present disclosure are comparable in structure to those without a core hydroxy group. Furthermore, as can be seen in Tables 1 and 2, Preferred compounds from the present disclosure generally have overall properties suitable for oral administration as a CNS therapy. These include more favorable pharmacokinetics and Decreased clearance in hepatocytes, which may be related to the profile; The MDCK-MRD1 efflux ratio (ER), an indicator of cellular proliferation, was also favorable. The compounds shown have low activity in the hERG Qpatch assay, which may be due to cardiac safety concerns. This is thought to be related to an improvement in the profile. The present application provides, for example, the following inventions. [1] A compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, R 1 is C 3~8 Cycloalkyl, C 3~7 Heterocyclyl, phenyl, naphthyl, or is heteroaryl, each of which is optionally joined by one or more R 5 Replace with It has been; R 2 OH, CN, halogen, OR 6 , S.H., S.R. 6 , C 1~6 Alkyl, HaloC 1~ 6 alkyl, NH2, NHR 6、 Hydroxy C 1~6 Alkyl, N(R 6 )(R 6 '), NHS(O)2R 6 , or NHCOR 6 where R 2 In the para position, OH Isn't it; or two R's 2 The groups, together with the ring carbon atoms to which they are attached, form a 5- to 7-membered ring. forming a heterocyclic or 5- or 6-membered heteroaryl ring; R3 is H, O, or OH; R 4 is H or OH; R 5 are halogens, OH, C 1~6 Alkyl, OR 6 , CN, NH2, NHR 6 , N(R 6 )(R 6 '), SH, SR 6 , SOR 6 , SO2R 6 , SO2NHR 6 , SO2N(R 6 )(R 6 '), CONH2, CONHR 6 , or CON(R 6 )(R 6 ') and; Each R 6 and R 6 ', H, OC 1~6 Alkyl, C 1~6 Alkyl and halo C1 ~6 independently selected from the group consisting of alkyl; B is N or CRx; Each Rx is independently H, C 1~3 alkyl, or halogen; Each n is independently 0, 1, 2, 3, or 4). [2] Compound of Formula II: [ka] or a pharmaceutically acceptable salt thereof, R 1 is C 3~8 Cycloalkyl, C 3~7 Heterocyclyl, phenyl, naphthyl, or is heteroaryl, each of which is optionally joined by one or more R 5 Replace with It has been; R 2 OH, CN, halogen, OR 6, S.H., S.R. 6 , C 1~6 Alkyl, HaloC 1~ 6 alkyl, NH2, NHR 6 , hydroxy C 1~6 Alkyl, N(R 6 )(R 6 '), NHS(O)2R 6 , or NHCOR 6 and; R 3 is H, O, or OH; R 4 is H or OH; R 5 are halogens, OH, C 1~6 Alkyl, OR 6 , CN, NH2, NHR 6 , N(R 6 )(R 6 '), SH, SR 6 , SOR 6 , SO2R 6 , SO2NHR 6 , SO2N(R 6 )(R 6 '), CONH2, CONHR 6 , or CON(R 6 )(R 6 ') and; Each R 6 and R 6 ', H, OC 1~6 Alkyl, C 1~6 Alkyl and halo C1 ~6 independently selected from the group consisting of alkyl; B is N or CRx; V is carbonyl, CH, or N; U is O, S, CRx, or CRxRx; Each Rx is independently H, C 1~3 alkyl, or halogen; each W is independently O, CH, or CH; ---- is an optional double bond; m is 0, 1, or 2; Each n is independently 0, 1, 2, 3, or 4). [3] Compound of Formula III: [ka] or a pharmaceutically acceptable salt thereof, R 2 OH, CN, halogen, OR 6 , S.H., S.R. 6 , C 1~6 Alkyl, C 1~6 , NH2, NHR 6 , hydroxy C 1~6 Alkyl, N(R 6 )(R 6 '), NHS(O) 2nd Round 6 , or NHCOR 6 and; R 3 is H, O, or OH; R 4 is H or OH; R 5 are halogens, OH, C 1~6 Alkyl, OR 6 , CN, NH2, NHR 6 , N(R 6 )(R 6 '), SH, SR 6 , SOR 6 , SO2R 6 , SO2NHR 6 , SO2N(R 6 )(R 6 '), CONH2, CONHR 6 , or CON(R 6 )(R 6 ') and; Each R 6 and R 6 ', H, OC 1~6 Alkyl, C 1~6 Alkyl, and C 1~6 independently selected from the group consisting of: B is N or CRx; V is carbonyl, CH, or N; U is O, S, CRx, or CRxRx; Each Rx is independently H, C 1~3 alkyl, or halogen; each W is independently O, CH, or CH; ---- is an optional double bond; m is 0, 1, or 2; Each n is independently 0, 1, 2, 3, or 4). [4] Compound of Formula IV: [ka] or a pharmaceutically acceptable salt thereof, R 2 is a halogen; R 3 is H or OH; R 4 is H or OH; R 5 is a halogen; B is N or CH; V is carbonyl, CH, or N; U is O, S, CRx, or CRxRx; Each Rx is independently H, C 1~3 alkyl, or halogen; each W is independently O, CH, or CH; ---- is an optional double bond; m is 0, 1, or 2; Each n is independently 0, 1, 2, 3, or 4). [5] Formula IVa: [ka] The compound according to the above [4] or a pharmaceutically acceptable salt thereof. [6] Formula IVb: [ka] The compound according to the above [4] or a pharmaceutically acceptable salt thereof. [7] Formula IVc: [ka] The compound according to the above [4] or a pharmaceutically acceptable salt thereof. [8] Formula IVd: [ka] The compound according to the above [4] or a pharmaceutically acceptable salt thereof. [9] Formula IVe: [ka] The compound according to the above [4] or a pharmaceutically acceptable salt thereof.

[10] Formula IVf: [ka] The compound according to the above [4] or a pharmaceutically acceptable salt thereof.

[11] Formula V: [ka] The compound according to the above [4] or a pharmaceutically acceptable salt thereof.

[12] Equation Va: [ka] The compound according to the above [4] or a pharmaceutically acceptable salt thereof.

[13] Formula Vb: [ka] The compound according to the above [4] or a pharmaceutically acceptable salt thereof.

[14] Formula Vc: [ka] The compound according to the above [4] or a pharmaceutically acceptable salt thereof.

[15] Formula Vd: [ka] The compound according to the above [4] or a pharmaceutically acceptable salt thereof.

[16] Equation Ve: [ka] The compound according to the above [4] or a pharmaceutically acceptable salt thereof.

[17] Formula Vf: [ka] The compound according to the above [4] or a pharmaceutically acceptable salt thereof.

[18] Any one of

[11] to

[17] above, wherein U is CRxRx and W is CH2. Item 1. The compound according to item 1, or a pharmaceutically acceptable salt thereof.

[19] The compound according to

[18] above, wherein m is 1, or a pharmaceutically acceptable salt thereof.

[20] The compound according to

[18] above, wherein m is 2, or a pharmaceutically acceptable salt thereof.

[21] Any of

[11] to

[17] above, wherein U is CRx, W is CH, and m is 1. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

[22] U is CRxRx, W is O, and m is 1, as in

[11] to

[17] above. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

[23] U is CRxRx, one W is O, the other W is CH2, and m

[0033] The compound according to any one of the above

[11] to

[17] , wherein R is 2, or a pharmaceutically acceptable salt thereof Acceptable salt.

[24] Any one of

[11] to

[17] above, wherein U is CRxRx and m is 0. The compound described above or a pharmaceutically acceptable salt thereof.

[25] Any one of

[11] to

[17] above, wherein U is O and W is CH2. or a pharmaceutically acceptable salt thereof.

[26] The compound according to

[25] above, wherein m is 1, or a pharmaceutically acceptable salt thereof.

[27] The compound according to

[25] above, wherein m is 2, or a pharmaceutically acceptable salt thereof.

[28] The compound according to any one of

[11] to

[17] above, wherein U is O and m is 0. or a pharmaceutically acceptable salt thereof.

[29] Any of the above

[11] to

[17] , wherein U is S, W is CH2, and m is 1. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

[30] The compound according to any one of

[11] to

[17] above, wherein U is S and m is 0. or a pharmaceutically acceptable salt thereof.

[31] Equation VI: [ka] The compound according to the above [4] or a pharmaceutically acceptable salt thereof (wherein R 3 is H or OH; R 4 is H or OH; R 5 is a halogen; V is CH or N; B is N or CH; Each n is independently 0, 1, 2, 3, or 4).

[32] Formula VIa: [ka] The compound according to the above [4] or a pharmaceutically acceptable salt thereof.

[33] Formula VIb: [ka] The compound according to the above [4] or a pharmaceutically acceptable salt thereof.

[34] Formula VIc: [ka] The compound according to the above [4] or a pharmaceutically acceptable salt thereof.

[35] Formula VId: [ka] The compound according to the above [4] or a pharmaceutically acceptable salt thereof.

[36] Equation VIe: [ka] The compound according to the above [4] or a pharmaceutically acceptable salt thereof.

[37] Formula VIf: [ka] The compound according to the above [4] or a pharmaceutically acceptable salt thereof.

[38] R 2 or R 5 is F, ), (II), (III), (IV), (V), or (VI).

[39] R 3 is H, ), or a compound of formula (III), (IV), (V), or (VI).

[40] R 3 is OH, I), or a compound of formula (III), (IV), (V), or (VI).

[41] R 4 is H, ), or a compound of formula (III), (IV), (V), or (VI).

[42] R 4 is OH, I), or a compound of formula (III), (IV), (V), or (VI).

[43] R 2 CN, halogen, OR 6 , S.H., S.R. 6 , C 1~6 Alkyl, Halo C1 ~6 Alkyl or hydroxy C 1~6 Any of the above [1] to

[37] , which is alkyl. Formula (I), (II), (III), (IV), (V), or (VI) according to any one of claims 1 to 5, compound.

[44] R 2 But halogen, C 1~6 Alkyl, HaloC 1~6 Alkyl or hydroxy C 1~6 The formula (I) according to any one of the above [1] to

[37] , (I Compound I), (III), (IV), (V), or (VI).

[45] R 2 But halogen, C 1~6 Alkyl or haloC 1~6 Alkyl, on Formula (I), (II), (III), (IV) according to any one of [1] to

[37] , Compound (V) or (VI).

[46] R 5 But halogens, OH, C 1~6 Alkyl, OR 6 , CN, SH, or SR 6 Formula (I), (II), (III) according to any one of [1] to

[37] above, , (IV), (V), or (VI).

[47] R 5 But halogens, OH, C 1~6Alkyl, or OR 6 That is, the above [1]

[37] , wherein the formula (I), (II), (III), (IV), or (V) is or a compound of formula (VI).

[48] ​​R 5 But halogen, OH, or C 1~6 Alkyl, [1] to

[37] above Formula (I), (II), (III), (IV), (V), or ( VI) Compound.

[49] 6-((R)-1-hydroxy-2-((3aS,5S,6aR)-3a-hydroxy) 5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl Ethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((S)-1-hydroxy-2-((3aS,5S,6aR)-3a-hydroxy- 5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl -3,4-dihydroquinolin-2(1H)-one; 5-((R)-1-hydroxy-2-((3aS,5S,6aR)-3a-hydroxy- 5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl Indolin-2-one; 5-((S)-1-hydroxy-2-((3aS,5S,6aR)-3a-hydroxy- 5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl Indolin-2-one; 5-((R)-2-((3aS,4S,5S,6aR)-3a,4-dihydroxy-5- Phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)-yl)-1-hydro (oxyethyl)indolin-2-one; 5-((S)-2-((3aS,4S,5S,6aR)-3a,4-dihydroxy-5- Phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)-yl)-1-hydro (oxyethyl)indolin-2-one; 5-((R)-2-((3aR,4R,5R,6aS)-3a,4-dihydroxy-5- Phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)-yl)-1-hydro (oxyethyl)indolin-2-one; 5-((S)-2-((3aR,4R,5R,6aS)-3a,4-dihydroxy-5- Phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)-yl)-1-hydro (oxyethyl)indolin-2-one; 6-((R)-2-((3aS,4S,5S,6aR)-3a,4-dihydroxy-5- Phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)-yl)-1-hydro (oxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((S)-2-((3aS,4S,5S,6aR)-3a,4-dihydroxy-5- Phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)-yl)-1-hydro (oxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((R)-2-((3aR,4R,5R,6aS)-3a,4-dihydroxy-5- Phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)-yl)-1-hydro (oxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((S)-2-((3aR,4R,5R,6aS)-3a,4-dihydroxy-5- Phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)-yl)-1-hydro (oxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((R)-2-((3aS,5S,6aR)-5-(2-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy (hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((S)-2-((3aS,5S,6aR)-5-(2-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy (hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((R)-2-((3aR,5R,6aS)-5-(2-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy (hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((S)-2-((3aR,5R,6aS)-5-(2-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy (hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 8-Fluoro-6-((R)-2-((3aS,5S,6aR)-5-(2-fluorofluoro (phenoxy)-3a-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)- yl)-1-hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 8-Fluoro-6-((S)-2-((3aS,5S,6aR)-5-(2-fluorofluoro (phenoxy)-3a-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)- yl)-1-hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 8-Fluoro-6-((R)-2-((3aR,5R,6aS)-5-(2-fluorofluoro (phenoxy)-3a-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)- yl)-1-hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 8-Fluoro-6-((S)-2-((3aR,5R,6aS)-5-(2-fluorofluoro (phenoxy)-3a-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)- yl)-1-hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 7-((R)-1-hydroxy-2-((3aS,5S,6aR)-3a-hydroxy- 5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl -1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one; 7-((S)-1-hydroxy-2-((3aS,5S,6aR)-3a-hydroxy- 5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl -1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one; 6-((R)-1-hydroxy-2-((3aS,5S,6aR)-3a-hydroxy- 5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl quinolin-2(1H)-one; 6-((S)-1-hydroxy-2-((3aS,5S,6aR)-3a-hydroxy- 5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl quinolin-2(1H)-one; 5-Fluoro-6-((R)-1-hydroxy-2-((3aS,5S,6aR)-3a -Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)- yl)ethyl)-3,4-dihydroquinolin-2(1H)-one; 5-Fluoro-6-((S)-1-hydroxy-2-((3aS,5S,6aR)-3a -Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)- yl)ethyl)-3,4-dihydroquinolin-2(1H)-one; 7-Fluoro-6-((R)-1-hydroxy-2-((3aS,5S,6aR)-3a -Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)- yl)ethyl)-3,4-dihydroquinolin-2(1H)-one; 7-Fluoro-6-((S)-1-hydroxy-2-((3aS,5S,6aR)-3a -Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)- yl)ethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((R)-1-hydroxy-2-((3aS,5S,6aR)-3a-hydroxy- 5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl -3,3-dimethyl-3,4-dihydroquinolin-2(1H)-one; 6-((S)-1-hydroxy-2-((3aS,5S,6aR)-3a-hydroxy- 5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl -3,3-dimethyl-3,4-dihydroquinolin-2(1H)-one; 7-((R)-2-((3aS,5S,6aR)-5-(2-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy hydroxyethyl)-4,5-dihydrobenzo[d][1,3]oxazepine-2(1H) -on; 7-((S)-2-((3aS,5S,6aR)-5-(2-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy hydroxyethyl)-4,5-dihydrobenzo[d][1,3]oxazepine-2(1H) -on; 5-Fluoro-7-((R)-1-hydroxy-2-((3aS,5S,6aR)-3a -Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)- (yl)ethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one; 5-Fluoro-7-((S)-1-hydroxy-2-((3aS,5S,6aR)-3a -Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)- (yl)ethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one; 6-((R)-1-hydroxy-2-((3aS,5S,6aR)-3a-hydroxy- 5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl -1,4-Dihydro-2H-benzo[d][1,3]thiazin-2-one; 6-((S)-1-hydroxy-2-((3aS,5S,6aR)-3a-hydroxy- 5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl -1,4-Dihydro-2H-benzo[d][1,3]thiazin-2-one; 6-((R)-2-((3aS,5S,6aR)-5-(2-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy (hydroxyethyl)-1,4-dihydro-2H-benzo[d][1,3]thiazin-2-ol hmm; 6-((S)-2-((3aS,5S,6aR)-5-(2-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy (hydroxyethyl)-1,4-dihydro-2H-benzo[d][1,3]thiazin-2-ol hmm; 8-Fluoro-6-((R)-1-hydroxy-2-((3aS,5S,6aR)-3a -Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)- (yl)ethyl)-1,4-dihydro-2H-benzo[d][1,3]thiazin-2-one ; 8-Fluoro-6-((S)-1-hydroxy-2-((3aS,5S,6aR)-3a -Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)- (yl)ethyl)-1,4-dihydro-2H-benzo[d][1,3]thiazin-2-one ; 6-((R)-1-hydroxy-2-((3aS,5S,6aR)-3a-hydroxy- 5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl benzo[d]thiazol-2(3H)-one; 6-((S)-1-hydroxy-2-((3aS,5S,6aR)-3a-hydroxy- 5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl benzo[d]thiazol-2(3H)-one; 6-((R)-2-((3aS,5S,6aR)-5-(2-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy (hydroxyethyl)benzo[d]thiazol-2(3H)-one; 6-((S)-2-((3aS,5S,6aR)-5-(2-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy (hydroxyethyl)benzo[d]thiazol-2(3H)-one; (S)-3,8-difluoro-6-((R)-1-hydroxy-2-((3aS,5S, 6aR)-3a-Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole -2(1H)-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one; (S)-3,8-difluoro-6-((S)-1-hydroxy-2-((3aS,5S, 6aR)-3a-Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole -2(1H)-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one; (R)-3,8-difluoro-6-((R)-1-hydroxy-2-((3aS,5S, 6aR)-3a-Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole -2(1H)-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one; (R)-3,8-difluoro-6-((S)-1-hydroxy-2-((3aS,5S, 6aR)-3a-Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole -2(1H)-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one; 3,8-Difluoro-6-((R)-1-hydroxy-2-((3aS,5S,6aR) -3a-Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1 H)-yl)ethyl)quinolin-2(1H)-one; 3,8-Difluoro-6-((S)-1-hydroxy-2-((3aS,5S,6aR) -3a-Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1 H)-yl)ethyl)quinolin-2(1H)-one; (3aS,5S,6aR)-5-(2,4-difluorophenoxy)-2-((R)-2 -Hydroxy-2-(1H-indazol-5-yl)ethyl)hexahydrocyclopenta ta[c]pyrrol-3a(1H)-ol; (3aS,5S,6aR)-5-(2,4-difluorophenoxy)-2-((S)-2 -Hydroxy-2-(1H-indazol-5-yl)ethyl)hexahydrocyclopenta ta[c]pyrrol-3a(1H)-ol; (3aR,5R,6aS)-5-(2,4-difluorophenoxy)-2-((R)-2 -Hydroxy-2-(1H-indazol-5-yl)ethyl)hexahydrocyclopenta ta[c]pyrrol-3a(1H)-ol; (3aR,5R,6aS)-5-(2,4-difluorophenoxy)-2-((R)-2 -Hydroxy-2-(1H-indazol-5-yl)ethyl)hexahydrocyclopenta ta[c]pyrrol-3a(1H)-ol; 6-((R)-2-((3aS,5S,6aR)-5-(4-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy (hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((S)-2-((3aS,5S,6aR)-5-(4-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy (hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((R)-2-((3aR,5R,6aS)-5-(4-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy (hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((S)-2-((3aR,5R,6aS)-5-(4-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy (hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((R)-2-((3aS,5S,6aR)-5-(3-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy (hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((S)-2-((3aS,5S,6aR)-5-(3-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy (hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((R)-2-((3aR,5R,6aS)-5-(3-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy (hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((S)-2-((3aR,5R,6aS)-5-(3-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy (hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((R)-2-((3aS,5S,6aR)-5-(2,3-difluorophenoxy )-3a-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)- 1-hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((S)-2-((3aS,5S,6aR)-5-(2,3-difluorophenoxy )-3a-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)- 1-hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((R)-2-((3aR,5R,6aS)-5-(2,3-difluorophenoxy )-3a-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)- 1-hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((S)-2-((3aR,5R,6aS)-5-(2,3-difluorophenoxy )-3a-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)- 1-hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((R)-2-((3aS,5S,6aR)-5-(2,4-difluorophenoxy )-3a-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)- 1-hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((S)-2-((3aS,5S,6aR)-5-(2,4-difluorophenoxy )-3a-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)- 1-hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((R)-2-((3aR,5R,6aS)-5-(2,4-difluorophenoxy )-3a-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)- 1-hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((S)-2-((3aR,5R,6aS)-5-(2,4-difluorophenoxy )-3a-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)- 1-hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((R)-2-((3aS,5S,6aR)-5-(2,5-difluorophenoxy )-3a-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)- 1-hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((S)-2-((3aS,5S,6aR)-5-(2,5-difluorophenoxy )-3a-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)- 1-hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((R)-2-((3aR,5R,6aS)-5-(2,5-difluorophenoxy )-3a-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)- 1-hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((S)-2-((3aR,5R,6aS)-5-(2,5-difluorophenoxy )-3a-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)- 1-hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((R)-2-((3aS,5S,6aR)-5-(2,6-difluorophenoxy )-3a-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)- 1-hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((S)-2-((3aS,5S,6aR)-5-(2,6-difluorophenoxy )-3a-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)- 1-hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((R)-2-((3aR,5R,6aS)-5-(2,6-difluorophenoxy )-3a-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)- 1-hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((S)-2-((3aR,5R,6aS)-5-(2,6-difluorophenoxy )-3a-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)- 1-hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one; 6-((R)-1-hydroxy-2-((3aS,5S,6aR)-3a-hydroxy- 5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl -1,4-Dihydro-2H-benzo[d][1,3]oxazin-2-one; 6-((S)-1-hydroxy-2-((3aS,5S,6aR)-3a-hydroxy- 5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl -1,4-Dihydro-2H-benzo[d][1,3]oxazin-2-one; 8-Fluoro-6-((R)-2-((3aS,4S,5S,6aR)-5-(2-fluoro (3a,4-dihydroxyhexahydrocyclopenta[c]pyrrole)- 2(1H)-yl)-1-hydroxyethyl)-3,4-dihydroquinoline-2(1H) -on; 8-Fluoro-6-((S)-2-((3aS,4S,5S,6aR)-5-(2-fluoro (3a,4-dihydroxyhexahydrocyclopenta[c]pyrrole)- 2(1H)-yl)-1-hydroxyethyl)-3,4-dihydroquinoline-2(1H) -on; 9-Fluoro-7-((R)-1-hydroxy-2-((3aS,5S,6aR)-3a -Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)- (yl)ethyl)-1,3,4,5-tetrahydro-2H-benzo[b]azepine-2-ol hmm; 9-Fluoro-7-((S)-1-hydroxy-2-((3aS,5S,6aR)-3a -Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)- (yl)ethyl)-1,3,4,5-tetrahydro-2H-benzo[b]azepine-2-ol hmm; 8-Fluoro-6-((R)-1-hydroxy-2-((3aS,5S,6aR)-3a -Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)- yl)ethyl)-3,4-dihydroquinolin-2(1H)-one; 8-Fluoro-6-((S)-1-hydroxy-2-((3aS,5S,6aR)-3a -Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)- yl)ethyl)-3,4-dihydroquinolin-2(1H)-one; 9-Fluoro-7-((R)-1-hydroxy-2-((3aS,5S,6aR)-3a -Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)- (yl)ethyl)-1,5-dihydrobenzo[e][1,4]oxazepine-2(3H)- on; 9-Fluoro-7-((S)-1-hydroxy-2-((3aS,5S,6aR)-3a -Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)- (yl)ethyl)-1,5-dihydrobenzo[e][1,4]oxazepine-2(3H)- on; 8-Fluoro-6-((R)-1-hydroxy-2-((3aS,5S,6aR)-3a -Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)- (yl)ethyl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-ol hmm; 8-Fluoro-6-((S)-1-hydroxy-2-((3aS,5S,6aR)-3a -Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)- (yl)ethyl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-ol hmm; 5-Fluoro-6-((R)-1-hydroxy-2-((3aS,5S,6aR)-3a -Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)- (yl)ethyl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-ol hmm; 5-Fluoro-6-((S)-1-hydroxy-2-((3aS,5S,6aR)-3a -Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)- (yl)ethyl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-ol hmm; 8-Fluoro-6-((R)-2-((3aS,5S,6aR)-5-(2-fluorofluoro (phenoxy)-3a-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)- (yl)-1-hydroxyethyl)-1,4-dihydro-2H-benzo[d][1,3]o Xazin-2-one; 8-Fluoro-6-((S)-2-((3aS,5S,6aR)-5-(2-fluorofluoro (phenoxy)-3a-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)- (yl)-1-hydroxyethyl)-1,4-dihydro-2H-benzo[d][1,3]o Xazin-2-one; 7-Fluoro-6-((R)-1-hydroxy-2-((3aS,5S,6aR)-3a -Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)- (yl)ethyl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-ol hmm; 7-Fluoro-6-((S)-1-hydroxy-2-((3aS,5S,6aR)-3a -Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)- (yl)ethyl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-ol hmm; 5,8-Difluoro-6-((R)-1-hydroxy-2-((3aS,5S,6aR) -3a-Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1 H)-yl)ethyl)-1,4-dihydro-2H-benzo[d][1,3]oxazine- 2-on; 5,8-Difluoro-6-((S)-1-hydroxy-2-((3aS,5S,6aR) -3a-Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1 H)-yl)ethyl)-1,4-dihydro-2H-benzo[d][1,3]oxazine- 2-on; 7,8-Difluoro-6-((R)-1-hydroxy-2-((3aS,5S,6aR) -3a-Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1 H)-yl)ethyl)-1,4-dihydro-2H-benzo[d][1,3]oxazine- 2-on; 7,8-Difluoro-6-((S)-1-hydroxy-2-((3aS,5S,6aR) -3a-Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1 H)-yl)ethyl)-1,4-dihydro-2H-benzo[d][1,3]oxazine- 2-on; 6-((R)-1-hydroxy-2-((3aS,5S,6aR)-3a-hydroxy- 5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl benzo[d]oxazol-2(3H)-one; 6-((S)-1-hydroxy-2-((3aS,5S,6aR)-3a-hydroxy- 5-phenoxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethyl benzo[d]oxazol-2(3H)-one; 6-((R)-2-((3aS,5S,6aR)-5-(2-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy (hydroxyethyl)benzo[d]oxazol-2(3H)-one; 6-((S)-2-((3aS,5S,6aR)-5-(2-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy (hydroxyethyl)benzo[d]oxazol-2(3H)-one; 6-((R)-2-((3aS,5S,6aR)-5-(2-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy hydroxyethyl)-1,4-dihydro-2H-benzo[d][1,3]oxazine-2- on; 6-((S)-2-((3aS,5S,6aR)-5-(2-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy hydroxyethyl)-1,4-dihydro-2H-benzo[d][1,3]oxazine-2- on; 4-Fluoro-6-((R)-1-hydroxy-2-((3aS,5S,6aR)-3a -Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)- yl)ethyl)benzo[d]thiazol-2(3H)-one; 4-Fluoro-6-((S)-1-hydroxy-2-((3aS,5S,6aR)-3a -Hydroxy-5-phenoxyhexahydrocyclopenta[c]pyrrole-2(1H)- yl)ethyl)benzo[d]thiazol-2(3H)-one; 7-((R)-2-((3aS,5S,6aR)-5-(2-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy Hydroxyethyl)-1,3,4,5-tetrahydro-2H-benzo[b]azepine-2- on; 7-((S)-2-((3aS,5S,6aR)-5-(2-fluorophenoxy)-3 α-Hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxy Hydroxyethyl)-1,3,4,5-tetrahydro-2H-benzo[b]azepine-2- on; (3aS,4S,5S,6aR)-5-(2-fluorophenoxy)-2-((R)-2 -hydroxy-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)ethyl)hexa Hydrocyclopenta[c]pyrrole-3a,4(1H)-diol; and (3aS,4S,5S,6aR)-5-(2-fluorophenoxy)-2-((S)-2 -hydroxy-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)ethyl)hexa The compound is a mixture of hydrocyclopenta[c]pyrrole-3a,4(1H)-diols. or a pharmaceutically acceptable salt thereof.

[50] The compound according to any one of [1] to

[49] above or a pharmaceutically acceptable salt thereof A pharmaceutical composition comprising a salt thereof.

[51] Parkinson's disease, Huntington's disease, Rett syndrome, amyotrophic lateral sclerosis, multiple sclerosis Sclerosis, seizure disorders, autism, autism spectrum disorders, fragile X syndrome, tuberous sclerosis, Ung's syndrome, pain, migraine, tinnitus, bipolar disorder, obsessive-compulsive disorder, anxiety disorder, post-traumatic stress Disorder (PTSD), cocaine use disorder, major depressive disorder, treatment-refractory or treatment-resistant A method for treating depression or suicidality, comprising administering a therapeutically effective amount of any one of [1] to

[49] above. or a pharmaceutically acceptable salt thereof, or the compound according to the above

[50] The method comprises administering the composition described above to a patient in need of such treatment.

Claims

[Claim 1] The invention described in the present specification.