NZ618372B2 - Amide compound and pharmaceutical application therefor - Google Patents

Amide compound and pharmaceutical application therefor Download PDF

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Publication number
NZ618372B2
NZ618372B2 NZ618372A NZ61837212A NZ618372B2 NZ 618372 B2 NZ618372 B2 NZ 618372B2 NZ 618372 A NZ618372 A NZ 618372A NZ 61837212 A NZ61837212 A NZ 61837212A NZ 618372 B2 NZ618372 B2 NZ 618372B2
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New Zealand
Prior art keywords
group
compound
disease
substituted
reaction
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NZ618372A
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NZ618372A (en
Inventor
Shintaro Hirashima
Kazuyuki Hirata
Masayuki Kotoku
Takaki Maeba
Katsuya Maeda
Shingo Obika
Takayuki Sakai
Noriyoshi Seki
Makoto Shiozaki
Hiroshi Yamanaka
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Japan Tobacco Inc
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Priority claimed from PCT/JP2012/061352 external-priority patent/WO2012147916A1/en
Publication of NZ618372A publication Critical patent/NZ618372A/en
Publication of NZ618372B2 publication Critical patent/NZ618372B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4192—1,2,3-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P17/00—Drugs for dermatological disorders
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
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    • A61P37/02—Immunomodulators
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Abstract

Disclosed herein is a compound of formula [I-W] and pharmaceutical compositions thereof which can inhibit retinoid-related orphan receptor gamma (ROR?), thereby the differentiation and activation of T helper L7 (Thl-7) cells can be inhibited, and the production of interleukin-17 (IL-l7) can be inhibited. This is useful for preventing or treating a disease related to Th17 cells, for example, an autoimmune disease. In one embodiment tert-butyl 4-(2-chloro-4-methylphenylcarbamoyl)-3-{4-cyclopropyl-5-[3-(Z-ethylbutyl)cyclobutyl]isoxazol-3-yl)butanoate. ited. This is useful for preventing or treating a disease related to Th17 cells, for example, an autoimmune disease. In one embodiment tert-butyl 4-(2-chloro-4-methylphenylcarbamoyl)-3-{4-cyclopropyl-5-[3-(Z-ethylbutyl)cyclobutyl]isoxazol-3-yl)butanoate.

Description

DESCRIPTION PHARMACEUTICAL APPLICATION THEREFOR AMIDE COMPOUND AND Technical Field amide compounds and The present invention relates to medicinal use thereof. presenL relates In particular, t.he invention orphan inhibit retinoid-related 1_0 compounds which can (RORy), differentiation and receptor garnma thereby the (Thl-7) can be inhibited, activation of T helper L7 cells (IL-l-7) can be production of interleukin-17 and the inhibited. j-on relates to icalIy, the present. invent Specif a disease relat.ed compounds for preventing or treating such as autoimmune disease Thl-7 ce1ls, for example, bowel disease rheumatoid psoriasis, inflammatory arthrit,is, multiple colitis, such as Crohn's disease and ulceraLive (SLE), ankylosing lupus erythematosus sclerosis, systemic type I polymyalgia rheumatica, and spondylitis, uveitis, dry eYe; disease such as asLhma; d.iabetes; allergic and primary biliary fibrosis as pulmonary fibrosis such such as diabetes cirrhosis; and. metabolic disease medicinal use thereof.
Background Art RORγ is a nuclear receptor which is important for the differentiation and activation of Th17 cells. RORγt is also referred to as a splice variant of RORγ. RORγ and RORγt differ only in their N-terminal domains, and share the same ligand-binding domain and DNA-binding domain. It is reported that RORγ is expressed in other tissues besides Th17 cells. By inhibiting RORγ, the differentiation and activation of Th17 cells can be inhibited. IL-17 produced in Th17 cells is involved in the induction of a variety of chemokines, cytokines, metalloproteases and other inflammatory mediators, and the migration of neutrophil, hence, the inhibition of IL-17 may lead to the inhibition of such induction and migration. RORγ in adipose tissues is related to the regulation of adipogenesis, and by inhibiting RORγ, insulin resistance can be improved.
It has been disclosed that Th17 cells are involved in autoimmune disease such as rheumatoid arthritis, psoriasis, inflammatory bowel disease such as Crohn's disease and ulcerative colitis, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, uveitis, polymyalgia rheumatica, and type I diabetes; allergic disease; dry eye; and fibrosis such as pulmonary fibrosis and primary biliary CITTNOSIS. it is for example, rheumatoid. arthritis, As for antibody of anti-AL1 reported that the administration with joint associated and destruction improve swelling reported that it is arthritis. Moreover, collaqen-induced with collagen- joint associated swelling and destruction mice- in IL-ldeficient can be improved induced arthritis in a clinical- psoriasis, it is reported that As for f ri :'l l- he anti antibody of -lL-L7 errv administration psoriasis. 1-0 ef f ect,ive in treating Crohn's such as bowel disease As for inflammatory induced in a colitis model colitis, disease and ulcerative T-ce1ls, the adaptive of naive by the adaptive transfer mice does from RORy-KO naive T-cells derived transfer of the onset in the mucosa, thereby not increase IL-L/ colitis can be suppressed. of mouse disease state As for muttiple sclerosis, the is an model which encephalomyelitis experimental autoimmune can be suppressed of multiple sclerosis animal model RORyI-KO mice. reported iL is lupus eryLhematosus, As for systemic is an animal nephritis model which that the onset of GBM RORyt-KO inhibited in glomerulonephritis can be model of be suppressed.
SLE may also mice. Nephritis associated with t.hat the is reported As for ankylosing spondylitis, is effective administration of anti-IL-17 antibody treating ankylosing spondylitis. the administration As for uveitis, it is reported that uveitis in treating of anti-IL-17 antibodv is effective and Harada Sarcoidosis associated with Behcet's disease, ,l.i urDgaDE. ^^-^^ of anti-IL- polymyalgia an efficacy As for rheumaLica, polymyalgia rheumatica Li antibody in treatment of currently tested in a clinical trial. of NOD mice I d.iabetes, the disease state l0 As for type by the be suppressed which is a type I diabetes model can antibodv. administrat.ion of anti -IL-L7 in OVA- as asthma, As for allerqic disease such pulmonary eosinophilic sensitized mode1, the attenuated CD4+ lymphocytes, and t_5 inflammation, the reduced numbers of leve1 are the decrease of T162 cytokines/chemokines reaction RORy-KO mice, that is, the allergenic exhibited in can be inhibited in RORv-KO mice. the Th17 cells it is reported that As for dry €Y€, eye, and. an efficacy zv increases in an animal model of d.ry tested patient is currently anti antibody in dry eye -IL-L7 in trial. a clinical pulmonary As for fibrosis, in a bleomycin-induced pulmonary which is an animal model fibrosis model antibody fibrosis, the administration of anti-TL-L7 inhibit inflammation and fibrosis in lung and can increase survival of the animal.
As for primary biliary cirrhosis, it is reported that Th17 cells in the lesion area of a patient with a primary biliary cirrhosis increase, and an efficacy of an antibody to IL-23 which activates Th17 cells is currently tested in a clinical trial.
As for metabolic disease, the insulin resistance which is induced by feeding a high-fat diet can be suppressed in RORγ KO mice.
On the basis of these findings, RORγ antagonists are thought to be useful for preventing or treating autoimmune disease such as rheumatoid arthritis, psoriasis, inflammatory bowel disease such as Crohn's disease and ulcerative colitis, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, uveitis, polymyalgia rheumatica, and type I diabetes; allergic disease such as asthma; dry eye; fibrosis such as pulmonary fibrosis and primary biliary cirrhosis; and metabolic disease such as diabetes. [0002a] The discussion of documents, acts, materials, devices, articles and the like is included in this specification solely for the purpose of providing a context for the present invention. It is not suggested or represented that any or all of these matters formed part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed before the priority date of each claim of this application.
Where the terms "comprise", "comprises", "comprised" or "comprising" are used in this specification (including the claims) they are to be interpreted as specifying the presence of the stated features, integers, steps or components, but not precluding the presence of one or more other features, integers, steps or components, or group thereof.
Summary of Invention An aspect of the present invention is to provide novel RORγ antagonists. Another aspect of the present invention is to provide medicaments of preventing or treating autoimmune disease such as rheumatoid arthritis, psoriasis, inflammatory bowel disease such as Crohn's disease and ulcerative colitis, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, uveitis, polymyalgia rheumatica, and type I diabetes; allergic disease such as asthma; dry eye; fibrosis such as pulmonary fibrosis and primary biliary cirrhosis; and metabolic disease such as diabetes.
The present invention provides the following aspects.
[01] A compound of formula [I-W]: tt-wl wherein -rrd ttua a **N 'Gb'--.
R' is /1\ a1 substituted with the \12 clr^yf ='lLrr'l which may be \r,/ ^?nrlh Yr\J\ry selected from Group same or different l- to 5 substituents wherein Ya single bond, or tf I I group/ C1-5 alkylene cyclic moiety U is (i) substituted with group which may be C:-z cycloalkyl from selected the same or different 1 to 5 substituents Group A, (ii) group which may be cycloalkyl Cs-rr spirocyclic 1- to 5 substituents substituted with the same or different selected from Group A, or (iii) group may be substituted with Ce-ro aryl which from Group 1 5 substituents selected same or different to (1) (3): group from the following Rb is a selected (1) with the same group which may be substituted Cr-a a1kyl Group A' selected from or different 1- to 5 subst.ituents (2) with the group which may be substituted Cz-z alkenyl Group A, selected from l_5 same or different l- to 5 substituents (3) with the group which may be substituted C:_z cycloalkyl from Group same or different 1 to 5 substituents selected R' is hydrogen atom, or group; C1-6 a1kyl (1) (7): the following to Y' is a group sel-ected from single bond (2) with Cr_e alkylene group which may be substituted from Group A, selected same or different 1 to 5 substituents C1 C1 (3) -NR - wherein R is hydrogen atom or C alkyl group, (4) -O-, (5) C cycloalkylene group which may be substituted with 3-10 the same or different 1 to 5 substituents selected from Group A, (6) C arylene group which may be substituted with the 6-10 same or different 1 to 5 substituents selected from Group A, (7) thiazolyene group which may be substituted with the same or different 1 to 5 substituents selected from Group A; Y is (1) single bond, or (2) C alkylene group which may be substituted with the same or different 1 to 5 substituents selected from Group A; or alternatively c d1 both Y and Y may be methine and be linked each other directly or via C alkylene group to form C cycloalkyl 1-4 3-7 ring; Y is (1) single bond, or (2) C alkylene group; d1 d2 d3 d4 d5 R , R , R , R , and R are the same or different (1) (7) group to : select.ed from the following hydrogen atom halogen atom, group substituted with the same Cr-e alkyl which may be or different 1 5 substituents selected from Group group (4) or Cr-e alkyt wherein Rd10 is hydrogen atom -oRdl-o 1 to 5 which with the same or different may be substituted substituents select.ed from Group A, (5) aIkyl is hydrogen atom or Cr-e -cooRd11 wherein Rdlr- t_0 group, (5) group substi-tuted with the Cr-z cycloalkyl which may be Group A, same or different 1 to 5 substitr:ents selected from (7) group, cyano or alternatively Rd2 Rd3 can be taken together Rd1 and Rd', or and rarm /'r' benzene ring to which !vr[r 4 = \-5_]-0 ce.ryl ring fused to the may be wherein the Co-ro aryl ring they are all attached 4 substituents substituted with the same or different 1 to selected from Group A; R' is hydrogen atom, or group, Cr-: a1ky1 or al-ternat.ively together to form R" and Rd1, or Re and Rds can be taken :'l lrrrl ana. -f-++vlrv/ ts^ A 1 uv n'l is an integer selected from 0 or {-n? 0 or t_ rf2 is an integer selected from nd is an integer selected from O or 1 to 3, Group A is C1-5 alkyl group, halogen atom, and wherein g"roup, -oRA1 RAl is hydrogen atom or C1-5 alky1 pharmaceutically or a acceptable salt thereof.
The compound formula according to lo2l of [I-w] R.t3 Oy-N-Y ge--co Re-c: . .=c 'Go- -pr*j "\.- (\::".q.u.o ;"rVo-*" t-wt wherein F:ru R" is Cs-rz alkyl group which may be substituted with the same from Group A, or different 1 to 5 substituents selected wherein Y" is single bond, or (ii) group, C1-5 alkylene cyclic moiety U is with (i) be substituted group which may C:-z cycloalkyl from substituents selected the same or dif f erent l- to 5 flrnr rrr A nr may be (ii) group which Cs-11 spirocyclic cycloalkyl substituents different 1 to 5 substituted with the same or from Group A; selected (1) (3): group from the following Rb is a selected (1) with the same group which may be substituted Cr-r alkyt Group A, selected from or different 1 to 5 substituents with the (2) group which may be substit.uted Cz-z alkenyl Group A, selected from l- to 5 substituents same or d.ifferent with the (3) group may be substituted C:-, cycloatkyl which Group selected from 1 to 5 substituents same or different R' is hydrogen atom, or (2) group; C1-6 alkyl (1) (7): following group selected from the Y' is a (1) single bond, (2) C alkylene group which may be substituted with the same or different 1 to 5 substituents selected from Group A, C1 C1 (3) -NR - wherein R is hydrogen atom or C alkyl group, (4) -O-, (5) C cycloalkylene group which may be substituted with 3-10 the same or different 1 to 5 substituents selected from Group A, (6) C arylene group which may be substituted with the 6-10 same or different 1 to 5 substituents selected from Group A, (7) thiazolyene group which may be substituted with the same or different 1 to 5 substituents selected from Group; Y is (1) single bond, or (2) C alkylene group which may be substituted with the same or different 1 to 5 substituents selected from Group Y is (1) single bond, or (2) C alkylene group; d1 d2 d3 d4 d5 R , R , R , R , and R are the same or different (1) (4): group to selected from the following hydrogen atom halogen atom, same (3) group may be substituted with the Cr-e alkyl which or different 1 to 5 substituents selected from Group group (4) atom or Cr-e a1kyl -ORd10 wherein Rd10 is hydrogen 1 to 5 which with the same or different may be substituted alternatively substituents selected from Group A, or Rd3 can be taken together Rd1 and Ru', or Rd2 and benzene ring to which 1-O form a Ce-ro aryl ring fused to the may be the Ce-ro aryl ring they are all attached wherein 4 substituents substituted with the same or different l- to selected from Group A; integer selected from O or 1 to n" is an 0 or 1 to 3, rf is an integer selected from from O or 1 to 3, nd is an integer selected R' is hydrogen atom, Group A is C1-5 aIkyl group/ halogen atom, and (c) group, hydrogen atom or C1-5 alky1 -oRA1 wherein RA1 is thereof. or a pharmaceutically acceptable salt according to The compound of formula III] 2s : Rol R'rz o\-il-Ysa<-}R" ,o.-H *ott-\oo \-J ,**_I,* .n^*ii-o-*, till wherein each symbol is as defined [ot], thereof. or a pharmaceutically acceptable salt according to The compound of formula IIII] [04 ] f n"'l ,}-Ro' --{,. *o'r-\oo \^\_,,O'r_" lnti wherein each symbot is as defined [Ot], or a pharmaceutically acceptable salt thereof. [000e] formula according The compound. of IIV] t05l [0+] wherein R is C alkyl group, and the other symbols are as defined in [01], or a pharmaceutically acceptable salt thereof. [0009a] The compound of formula [IV-D1] according to wherein R is C alkyl group, and the other symbols are as defined in [01], or a pharmaceutically acceptable salt thereof. [0009b] The compound of formula [IV-D2] according to wherein R is C alkyl group, and the other symbols are as defined in [01], or a pharmaceutically acceptable salt thereof. [0009c] The compound of formula [IV-D3] according to wherein R is C alkyl group, and the other symbols are as defined in [01], or a pharmaceutically acceptable salt thereof. [0009d] The compound of formula [IV-D4] according to wherein R is C alkyl group, and the other symbols are as defined in [01], or a pharmaceutically acceptable salt thereof.
The compound of formula [V] according to wherein each symbol is as defined in [01], or a pharmaceutically acceptable salt thereof.
The compound according to any one of [01] to wherein: R is C cycloalkyl group which may be substituted with the same or different 1 to 5 substituents selected from Group A, or a pharmaceutically acceptable salt thereof.
The compound according to any one of [01] to wherein: R is cyclopropyl group, or a pharmaceutically acceptable salt thereof.
The compound according to any one of [01] to wherein: the cyclic moiety U is C cycloalkyl group which may be substituted with the same or different 1 to 5 substituents selected from Group A, or a pharmaceutically acceptable salt thereof.
[0014] The compound according to any one of [01] to wherein: the cyclic moiety U is cyclobutyl group which may be substituted with the same or different 1 to 5 substituents selected from Group A, or a pharmaceutically acceptable salt thereof.
The compound according to [01] or [02] which is selected from the group consisting of the following formulas or a pharmaceutically acceptable salt thereof: o-.--'ft-",{ .'^ .o-tt -,"' H.c1 /.-,__1_ i: I ll I \z -nu \--'-.-./ -\,/ \o-oH ovNrA n P-ry 'j"/\_/\---(ll ":t- I tr .t r-.r3c %ol H ?H. ttt.\ \4nu vr 13 Ftc. 9t A ,O-N Ft3c *\t-\ .%"r, \.2-"., vr 13 o-rv v, ,3 "Y\A *.t*'n-r3-il %.*, The compound according to [01] or [02] which is selected from the group consisting of the following formulas or a pharmaceutically acceptable salt thereof: [0016a] The compound according to [01] or [02], which is or a pharmaceutically acceptable salt thereof. [0016b]
[18] The compound according to [01] or [02], which is or a pharmaceutically acceptable salt thereof. [0016c]
[19] The compound according to [01] or [02], which is or a pharmaceutically acceptable salt thereof. [0016d]
[20] The compound according to [01] or [02], which is or a pharmaceutically acceptable salt thereof. [0016e]
[21] The compound according to [01] or [02], which is or a pharmaceutically acceptable salt thereof. [0016f]
[22] The compound according to [01] or [02], which is [0016g] The compound according to [01] or [02], which is [0016h] The compound according to [01] or [02], which is [0016i] The compound according to [01] or [02], which is . [0016j] The compound according to [01] or [02], which is [0016k] The compound according to [01] or [02], which is
[28] A pharmaceutical composition comprising the compound according to any one of [01] and [17] to [21] or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
A RORγ antagonist comprising the compound according to any one of [01] and [17] to [21] or a pharmaceutically acceptable salt thereof.
[0019] A medicament for treating or preventing a disease selected from the group consisting of autoimmune disease, allergic disease, dry eye, fibrosis and metabolic disease, comprising the compound according to any one of
[01] and [17] to [21] or a pharmaceutically acceptable salt thereof. [30a] A medicament for treating or preventing a disease selected from the group consisting of autoimmune disease and allergic disease, comprising the compound according to any one of [01] and [17] to [21] or a pharmaceutically acceptable salt thereof.
The medicament according to [30] wherein the autoimmune disease is selected from the group consisting of rheumatoid arthritis, psoriasis, inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, uveitis, polymyalgia rheumatica, and type I diabetes. [0021a] The medicament according to [31] wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis. [0021b] The medicament according to [30] wherein the allergic disease is asthma. [0021c] The medicament according to [30] wherein the fibrosis is pulmonary fibrosis or primary biliary cirrhosis.
The medicament according to [30] wherein the metabolic disease is diabetes. [0022a] The medicament according to [35] wherein the diabetes is type I diabetes or type II diabetes.
[0023] A method of inhibiting RORγ in a mammal, comprising administering to said mammal a therapeutically effective amount of the compound according to any one of and [17] to [21] or a pharmaceutically acceptable salt thereof.
A method of treating or preventing a disease in a mammal selected from the group consisting of autoimmune disease, allergic disease, dry eye, fibrosis and metabolic disease, comprising administering to said mammal a therapeutically effective amount of the compound according to any one of [01] and [17] to [21] or a pharmaceutically acceptable salt thereof. [38a] A method of treating or preventing a disease in a mammal selected from the group consisting of autoimmune disease and allergic disease, comprising administering to said mammal a therapeutically effective amount of the compound according to any one of [01] and
[17] to [21] or a pharmaceutically acceptable salt thereof.
The method according to [38] wherein the autoimmune disease is selected from the group consisting of rheumatoid arthritis, psoriasis, inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, uveitis, polymyalgia rheumatica, and type I diabetes. [0026a] The method according to [39] wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis. [0026b] The method according to [38] wherein the allergic disease is asthma. [0026c] The method according to [38] wherein the fibrosis is pulmonary fibrosis or primary biliary cirrhosis.
The method according to [38] wherein the metabolic disease is diabetes. [0027a] The method according to [43] wherein the diabetes is type I diabetes or type II diabetes. [0027b]
[45] A pharmaceutical composition comprising the compound according to any one of [22] to [27], and a pharmaceutically acceptable carrier. [0027c] A RORγ antagonist comprising the compound according to any one of [22] to [27]. [0027d] A medicament for treating or preventing a disease selected from the group consisting of autoimmune disease, allergic disease, dry eye, fibrosis, and metabolic disease, comprising the compound according to any one of to [27]. [0027e] The medicament according to [47] wherein the autoimmune disease is selected from the group consisting of rheumatoid arthritis, psoriasis, inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, uveitis, polymyalgia rheumatica, and type I diabetes. [0027f]
[49] The medicament according to [48] wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis. [0027h] The medicament according to [47] wherein the allergic disease is asthma. [0027i] The medicament according to [47] wherein the fibrosis is pulmonary fibrosis or primary biliary cirrhosis. [0027j] The medicament according to [47] wherein the metabolic disease is diabetes. [0027k] The medicament according to [52] wherein the diabetes is type I diabetes or type II diabetes. [0027l] A method of inhibiting RORγ in a mammal, comprising administering to said mammal a therapeutically effective amount of the compound according to any one of
[22] to [27]. [0027m] A method of treating or preventing a disease in a mammal selected from the group consisting of autoimmune disease, allergic disease, dry eye, fibrosis, and metabolic disease, comprising administering to said mammal a therapeutically effective amount of the compound according to any one of [22] to [27]. [0027n] The method according to [55] wherein the autoimmune disease is selected from the group consisting of rheumatoid arthritis, psoriasis, inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, uveitis, polymyalgia rheumatica, and type I diabetes. [0027o] The method according to [56] wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis. [0027p]
[58] The method according to [55] wherein the allergic disease is asthma. [0027q] The method according to [55] wherein the fibrosis is pulmonary fibrosis or primary biliary cirrhosis. [0027r] The method according to [55] wherein the metabolic disease is diabetes. [0027s] The method according to [60] wherein the diabetes is type I diabetes or type II diabetes.
A pharmaceutical composition for treating or preventing a disease selected from the group consisting of autoimmune disease, allergic disease, and metabolic disease, which comprises: (a) the compound according to any one of [01] and to [21] or a pharmaceutically acceptable salt thereof, (b) at least one additional medicament for treating or preventing a disease selected from the group consisting of autoimmune disease, allergic disease, and metabolic disease.
A combination drug comprising: (a) the compound according to any one of [01] and to [21] or a pharmaceutically acceptable salt thereof, (b) at least one additional medicament for treating or preventing a disease selected from the group consisting of autoimmune disease, allergic disease and metabolic disease, wherein the compound of (a) and the additional medicament of (b) may be administered simultaneously, separately or consecutively.
Use of the compound according to any one of
[01] and [17] to [21] or a pharmaceutically acceptable salt thereof in the manufacture of a RORγ antagonist.
Use of the compound according to any one of and [17] to [21] or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a disease selected from the group consisting of autoimmune disease, allergic disease, and metabolic disease.
The use according to [65] wherein the autoimmune disease is selected from the group consisting of rheumatoid arthritis, psoriasis, inflammatory bowel disease such as Crohn's disease and ulcerative colitis, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, uveitis, polymyalgia rheumatica, and type I diabetes.
The use according to [65] wherein the metabolic disease is diabetes.
[68] The compound according to any one of [01] to and [17] to [21] or a pharmaceutically acceptable salt thereof for use in treating or preventing a disease selected from the group consisting of autoimmune disease, allergic disease, and metabolic disease.
[0035] A commercial package comprising the medicament according to [30], and instructions which explain that the medicament can be used to treat and / or prevent a disease selected from the group consisting of autoimmune disease, allergic disease, and metabolic disease.
The commercial package comprising the combination drug according to [63], and instructions which explain that the combination drug can be used to treat and / or prevent a disease selected from the group consisting of autoimmune disease, allergic disease, and metabolic disease.
A medicament for treating or preventing a disease selected from the group consisting of autoimmune disease such as rheumatoid arthritis, psoriasis, inflammatory bowel disease such as Crohn's disease and ulcerative colitis, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, uveitis, polymyalgia rheumatica, and type I diabetes; allergic disease such as asthma; dry eye; fibrosis such as pulmonary fibrosis and primary biliary cirrhosis; and metabolic disease such as diabetes, comprising the compound according to any one of to and [17] to [21] or a pharmaceutically acceptable salt thereof.
A pharmaceutical composition for treating or preventing a disease selected from the group consisting of: autoimmune disease such as rheumatoid arthritis, psoriasis, inflammatory bowel disease such as Crohn's disease and ulcerative colitis, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, uveitis, polymyalgia rheumatica, and type I diabetes; allergic disease such as asthma; dry eye; fibrosis such as pulmonary fibrosis and primary biliary cirrhosis; and metabolic disease such as diabetes, comprising: (a) the compound according to any one of [01] and to [21] or a pharmaceutically acceptable salt thereof, (b) at least one additional medicament for treating or preventing a disease selected from the group consisting of autoimmune disease such as rheumatoid arthritis, psoriasis, inflammatory bowel disease such as Crohn's disease and ulcerative colitis, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, uveitis, polymyalgia rheumatica, and type I diabetes; allergic disease such as asthma; dry eye; fibrosis such as pulmonary fibrosis and primary biliary cirrhosis; and metabolic disease such as diabetes.
[0039] A combination drug comprising: (a) the compound according to any one of [01] and to [21] or a pharmaceutically acceptable salt thereof, (b) at least one an additional medicament for treating or preventing a disease selected from the group consisting of autoimmune disease such as rheumatoid arthritis, psoriasis, inflammatory bowel disease such as Crohn's disease and ulcerative colitis, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, uveitis, polymyalgia rheumatica, and type I diabetes; allergic disease such as asthma; dry eye; fibrosis such as pulmonary fibrosis and primary biliary cirrhosis; and metabolic disease such as diabetes, wherein the compound of (a) and the additional medicament of (b) may be administered simultaneously, separately or consecutively. [0039a] Use of the compound according to any one of
[01] and [17] to [21] or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the inhibition of RORγ in a mammal. [0039b] Use of the compound according to any one of
[01] and [17] to [21] or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of a disease selected from the group consisting of autoimmune disease, allergic disease, dry eye, fibrosis, and metabolic disease. [0039c] The use according to [74] wherein the autoimmune disease is selected from the group consisting of rheumatoid arthritis, psoriasis, inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, uveitis, polymyalgia rheumatica, and type I diabetes. [0039d] The use according to [75] wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis. [0039e] The use according to [74] wherein the allergic disease is asthma. [0039f] The use according to [74] wherein the fibrosis is pulmonary fibrosis or primary biliary cirrhosis. [0039g] The use according to [74] wherein the metabolic disease is diabetes. [0039h] The use according to claim [79] wherein the diabetes is type I diabetes or type II diabetes. [0039i]
[81] Use of the compound according to any one of to [27] for the manufacture of a medicament for the inhibition RORγ in a mammal. [0039j] Use of the compound according to any one of
[22] to [27] for the manufacture of a medicament for the treatment or prevention of a disease in a mammal selected from the group consisting of autoimmune disease, allergic disease, dry eye, fibrosis, and metabolic disease. [0039k]
[83] The use according to [82] wherein the autoimmune disease is selected from the group consisting of rheumatoid arthritis, psoriasis, inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, uveitis, polymyalgia rheumatica, and type I diabetes. [0039l] The use according to [83] wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis. [0039m] The use according to [82] wherein the allergic disease is asthma. [0039n] The use according to [82] wherein the fibrosis is pulmonary fibrosis or primary biliary cirrhosis. [0039o] The use according to [82] wherein the metabolic disease is diabetes. [0039p]
[88] The use according to [87] wherein the diabetes is type I diabetes or type II diabetes.
Each symbol of the formulas described in the following to [122] has the same meaning as defined in the formula [I] in the following [101]. a c d1 d1 d2 d3 d4 d5 In particular, R ; Y and Y ; R , R , R , R , and R of the formulas described in [102] to [122] have the same described in meaning as defined in the formula [101]. f 1n1'l A compound of formula lrl: g1-co nlol 'r^ b'lJ'- ""']io-*" wherein ,Gi ,F:fi| ,r\a : N ,,\c '^b-u\ 1.,^ R' is group be substituted with the Cs-r.z alkyl which may | 1fn Group A, same or differen L I UV 5 substituents selected from l_0 or wherein Y" is single bond, or (ii) group, C1-5 alkylene cyclic moiety U is with (i) group which may be substituted Cz-t cycloalkyl selected from l- to 5 substituents the same or dif f erent Group A, or (ii) group which may be cycloalkyl Cs-rr spirocyclic 1 to 5 substituents with the same or different substituted selected from Group A; (1) (3): group from the following Rb is a selected same (1) group be substituted with the Cr-: alky1 which may Group A, selected from or different 1 to 5 substituents (2) substituted with the Cz-t alkenyl group which may be from Group A, selected same or different 1 to 5 substituents (3) with the group which may be substituted Ct-t cycloalkyt from Group selected same or different 1- to 5 substituents R' is hydrogen atom, or C1-5 aIkyl group; tn (1) (7) to z group from the following Yc is a selected single bond, with the (2) group may be substituted Cr_s alkylene which from Group substituents sel-ected same or different 1 to 5 group, (3) atom or C1-6 alkyl wherein Rc1 is hyd.rogen -NRclo-, (5) substituted with group which may be C:-ro cycloalkylene selected from the same or different 1 to 5 substituents Group A, (5) with the Ce-ro arylene group which may be substituted selected from Group same or different 1 to 5 substituents (7) may be group which monocyclic heteroaromatic 1 to 5 substituents substituted with the same or different heteroaromatic A wherein the monocyclic selected from Group Same or different ring consists of carbon atoms and the atom from nitrogen atom, oxygen to 4 hetero atoms selected and is 3 to 7-membered; and sulfur atom, Yd1 is single bond, (2) group be substituted with Cr-e alkylene which may from Group t-5 1 to 5 substituents selected same or different Yd2 is bond, or single (2) group; C1-5 alkylene group d.ifferent zv Rdt, Rdn, and Rdt are the same or Rd', Rdt, (1) , selected from the following to hydrogen atom halogen atom, same (3) group be substituted with the C1-5 a1kyl which may from Group A, 1 5 substituenLs selected or different to (4) group wherein Rdro is hydrogen atom or Cr-e alkyl -ORd10 1 to 5 which mav be substituted with the same or different A, or alternatj-veIy substituents selected from Group Rd2 and Rd3 can be taken together Rd1 and Rd', or ring to which form a Ce-ro aryl ring fused to the benzene may be the Ce-ro aryl ring they are all attached wherein subst.it,uted with the same or different 1- to substituents selected from Group A; from 0 or 1 to 3, n'l is an inLeqer selected or l- to 3, rf2 is an inteser selected from 0 from 0 or 1 to 3, nd is an inteqer selected Group A is grouP/ Cr-e alkyl halogen atom, and (c) group, atom or C1-5 alky1 -oRA1 wherein RA1 is hydrogen or pharmaceutically acceptable salt thereof. 0 041] according to The compound of formula III] *o\-** o"ft-ve{fn" 9.-N no Rot' '"Ti-o-*' IIII wherein is as defined in each symbol [1-0]-l , pharmaceutically salt thereof. or a acceptable formula according The compound of [IrI] or : [1-02] *-r-o-*" [ilr] wherein each symbol is as def ined in []-011 , salt thereof. or a pharmaceutically acceptable according to of formula The compound tIVl ft-{r,F*" 9--ru *oun** n-.-n-o'..O ltvl group, other symbols are wherein R"1 is C:--e alkyl and the defined in thereof. or a pharmaceut,ically acceptable salt formula according to The compound of tvl t10sl *oL*,F* otil-ve$n" ,N--N nq-Ni I .r,,J,n. **n** //Y---t YZ\t (\yll$1o:*" wherein each symbol is as defined [1-01] or pharmaceutically acceptable salt thereof. one of The compound according to any [101] t1o6l to wherein: group, 1_5 Rb is cyctopropyl or a pharmaceutically acceptable salt thereof. f l n ?1 any one of / The compound according to [101] LJ-\J I r a'\ l1n6l r^Tarain L+vvl group/ moiety U is cyclobutyl the cyclic or a pharmaceutically acceptable salt thereof. [004s] pharmaceutical composition comprising t10Bl to or a compound accord.ing to any one of [107] pharmaceutically salt thereof, and acceptable pharmaceutically carrier. acceptable compound comprising the A RORy antagonist to or a according to any one of [107] pharmaceutically salt thereof. l-5 acceptable preventrng a treating or A medicament for []_10l of autoimmune group consisting disease selected from the the compound disease and allergic disease, comprising or a zv of to according to any one [101] [107] pharmaceutically salt thereof. acceptable f-r'r I wherein med.icament according to The [110] group from the the autoimmune disease is selected psoriasis, inflammatory consisting of rheumatoid arthritis, lupus multiple sclerosis, and systemic bowel disease, erythematosus. f i r for treating or ^] A pharmaceutical composition LTTZ J group of preventing from t.he consisting a disease selected autoimmune and allergic disease, comprising disease (a) to any one of the compound according [101] pharmaceutically acceptable salt thereof, or a (b) medicament for treating L0 at least one additional- group preventing from the consisting or a disease selected of autoimmune disease and allerqic disease. loo47l comprising: A combination drug (a) of to according to any one [101] the compound salt thereof, and or a pharmaceutically acceptable t1o7l (b) medicament at least one an additional group from the treating or preventing a disease selected allergic disease, consisting of autoimmune disease and (a) additional of and the wherein the compound (b) simultaneously, med.icament of may be administered separately or consecutively. mammal, inhibiting RORy in a A method of therapeutically comprising administering to said mammaf a according to any one of effective amount of the compound salt or a pharmaceutically acceptable t1071 thereof. f 11c] preventing a disease A method of treating or L++Jl from the group consisting in a mammal selected comprising autoimmune disease and allergic disease, a therapeutically effective administering to said. mammal amount according to any one of of the compound [101] thereof. or a pharmaceutically acceptable salt f 1 1 ?1 wherein the The method according to LJ-IOJ [115] group of is from the consisting autoimmune d.isease selected bowel disease, rheumatoid arthritis, psoriasis, inflammatory erythemaLosus multiple sclerosis, and systemic lupus [004e] one of according to any Use of the compound salt. a pharmaceutically acceptable to [107] or RORy antagonist. thereof in the manufacture of a according to any one of Use of the compound salt pharmaceutically acceptable to or a
[107] for treating thereof in the manufacture of a medicament group consisting preventing a disease selected from the disease. autoimmune disease and allerqic f 11o1 to where The use according [118] LLLJ J group consisting of is selected from the autoimmune disease bowel disease, rheumatoid arthritis, psoriasj-s, inflammatory systemic lupus erythematosus. muttiple sclerosis, and according to any one [101] The compound salt thereof for pharmaceutically accept,able to or a selected from use in treating or preventing a disease allergic disease. group of autoimmune disease and consisting 1tr lnnqnl LvvJvJ package comprising A commercial IT2I) which and instructions med.icament according to to treat and ot medicament can be used / explain that the prevent group consisting a disease selected from the allerqic disease. autoimmune disease and package comprising the A commercial lL22l instructions which to and combination drug according [1-]-31 , drug can be used to treat explain that the combination group consisting prevent selected from t.he or a disease and allergic disease. of autoimmune disease Effects of The Invention [00s1] present invention can of the The amide compound compound is inhibit the RoRy activity, thereby Lhe preventing a for Lreating or effective as a medicament such aS rheumatoid d.isease such aS autoimmune disease such as psoriasis, inflammatory bowel disease arthritis, sclerosis, ul-cerative colitis, multiple Crohn's disease and all-ergic disease; and systemic lupus erythematosus; and fibrosis. metabolic disease; dry eye; Brief Description of Drawings [00s2] like of NMR results and the l-5 J_l Structures, lr,'r-gure Exampl-es A-4.
A-1 to results and the like 2] Structures, NMR fFigure Examples A-5 to A-8.
L-homoserine as Example A-5 was prepared by using (AUX-H) auxiliary reagent ZU material without using any chiral A-6 aS described preparati-on methods of according to the bel-ow. acid as a prepared by using r,(-)-maIic Example A-8 was (AUX-H) auxiliary reagent material without using any chiral described preparation of A-8 as according to the methods bel-ow. the like of NMR resul-ts and 3] Structures, IFigure Examples A-9 to A-12. as a prepared by using L-homoserine Example A-9 was (AUX-H) material wj-thout using any chiral auxiliary reagent preparation of A-9 as described accord.ing to the methods below. results and t.he like 4] SLructures, NMR fFigure Examples A-13 to A-15. and the like of 5] Structures, NMR resulLs fFigure Examples A-17 to A-20. the like of 6] SLructures, NMR results and fFigure Examples A-21 to A-24. like of NMR results and the [Figure 7] Structures, Examples A-25 to A-28. like of NMR results and the 8] Structures, [Figure Examples A-29 to A-32. like of result,s and the 9] Structures, NMR [Figure Examples A-33 to A-36. like of and the zv 10] Structures, NMR results [Figure Examples A-37 to A-40. like of results and the 11] Structures, NMR frigure Examples A-41 to A-44. and the like of L2) Structures, NMR results fFigure Examples A-45 to A-48. the like of 13] Structures, NMR results and [Figure Examples A-49 to A-52.
NMR results and the like 1,4] Structures, [Figure Examples A-53 to A-56 and the like of 15] Structures, NMR results lFigure Examples A-57 A-50. and the like of 16] Structures, NMR results [Figure Examples A-51 to A-64. and the like of I7] Structures, NMR resul-ts [Figure Examples A-65 to A-58. the like of NMR results and 18] Structures, [Figure Examnles A-69 to A like of NMR results and the 19] Structures, lFigure Examples A-73 to A-76. the like of NMR resul-ts and 20] StrucLures, [Figure Examples A-77 to A-80. results and the like 2I] Structures, NMR lFigure A-83 and B-1.
Examples A-81 to and the like of 22] StrucLures, NMR resufts frigure A-85.
Examples B-2 and A-84 and and the like of 23] Structures, NMR results lFigure Examples A-86 to A-89. the like of NMR results and 24] Structures, [Figure Examples B-3, B-4 C-l and C-2. the like of NMR results and 25] Structures, [Figure Examples D-1, D-2, A-90, and A-91. like of 26] Structures, NMR results and the fFigure Examples A-92 to A-94 and D-3. like of NMR results and the 27] Structures, fFigure Examples D-4, C-3, C-4, and A-95. and the like of 2B] Structures, NMR results fFigure Examples A-99.
A-96 to results and the like of 29] Structures, NMR fFigure and D-5.
Examples A-l-00 to A-102 and. the like of 1-O 30] SLructures, NMR results fFigure Examples D-5 and A-103 to A05. l-ike of 31] Structures NMR results and the [Figure Examples A-l-05 to A-109. lj-ke of NMR results and the 32] Structures, [Figure 1-5 Examples 4-110 to A-l-13. like of NMR results and the 33] Structures, [Figure Examples C-5 to C-6 and A-114 to A15. results and the l-ike 34] StrucLures, NMR [Figure Examples B-5, and A15 to 4'17. and the like of 35] Structures, NMR results [Figure Examples A-118 to A-l. and the like 36] Structures, NMR results lfigure Examples A-122 Lo A-I24 and C-8. the like of 37] Structures, NMR results and fFigure Examples C-9 and A-125 to A-127. like of NMR results and the 38] Structures, [rigure Examples A-L28 to A-130. results and the like 39] Structures, NMR [Figure A-l-33.
Examples A-131 to and the l-ike of 401 Structures, NMR results tFigure Examples 4-134 to A-l-35. and the like of 4L] SLructures, NMR results [Figure Examples A-137 and A-l-38.
I'stereochemistry in Figs. 1 to of AUX-H" described 4I is explained as foll-ows. the 5- alpha position from The stereochemistry of the (-G"-Gb-G"-Gd-G'-) by using membered ring can be introduced as a chiral auxiliary a chiral substituted 2-oxazolidinone (AUX-H) compounds of the reagent to obtain optically-active present or stereoselectively. 1-5 invention stereospecifically t'A-lrr chiral compound of Example For example, the (S) as an be obtained by using benzyloxazolidinone AUX-H. position from The above of the alpha 'tstereochemistry (-G" the -G' -; means t.he 5 -membered ring -Gb -G' -Gd arrow in the carbon indicated by an stereochemistry at the followinq formula: alFha LG]"^o.Gl -Go'*\r"' ,kl;./^\/o_** 4-benzyL by using the chiral For example, I'AUX-H" (Step method 28 as an in Preparation oxazolidinone (Step the Z) described below, Z) or Preparation method 4B can be obtained following Compound optically-active tIl rr tt chiral denotes a new stereoselectively. The symbol point induced by this procedure.
A^,-H \_/ o benzy I -2 benzy I -2 -oxazol idi none idinone -oxazol (o-'"' (\f"^vo-R. yd-!4J *o\---.Io' position atpha oVil-"" ,o1.eo zF** *-oioo,c" *o'n*oo "4,,. ,\i"/"yo_*. tt l the chiral 4-benzyl-oxazolidinone Besid,es, by usign rrAUX-Hrr (Step 38 3) described as an in Preparation method can be Compound below, the following optically-active tIl tr*rr denotes The symbol also obtained stereoselectively. procedure. new chiral point induced by this oo oro-e" ,-Y4 "\n\ r\9'*'t$'o"'o Rotr Rdt position alpha \-J* ov,il-"*(-|*" s1.co o-oi.^o.Gl- *our-\oo -"4,". following According to the above procedures, the can be optically-active compound and II-Cl-W] II-c2-W] obtained stereoselectivelv. *oL** *ol(*o' B" B" oril-v--[fn* o-lLv-{fn" e,..eo ee..eo Ru-G:.G'iVd *.--o:.o';" **n** **n** ,". ,n, fr*l ttl= ,\;"^yo-*" ,\i;"l"Yl-o-*" r-c2-w r-cl-w I I I I procedures, for example, According to the above following compound and optically-active lfV-CfJ IIV-C2] be also obtained stereoselectively. il{}*" 9.-n *oun*oo '\nt"-R' rv-c2] compound For example, dr optically-active IIV-C2 (R)benzyloxazolidinone as Wl may be obtained by using an AUX-H. o\'o-'.,<*" ll | | q^l/V qAu" \/-'+'LJ:- -6'r, \t^o^Ptt '"!_.t pri Ph H /:\ il N-1r /)-R*" *orn** tv-c2-oor-w descrj-bed in Figs.
The or Stereochemistry" "Materials 1 to 41 is explained as follows.
A-87, A-BB, and A-89, For example, in Examples A-86, the explanation 4-oxo-cyclopentane-trans-L,2- "Dimethyl means that. these dicarboxylate was used aS a material-" dimethyl 4-oxo- examples were prepared by using a material without cyclopentane-trans-A,2-dicarboxylate aS (AUX-H) in the using any chiral auxiliary reagent A-89 preparation for Examples A-86, A-8'/, A-88, and methods as below. described name in Figs. 1- to 4I whose compound Examples listed rrBrt trArr as follows. comprises symbol or are explained (excluding A-4 and A0) A-85 Examples Examples A-1 to were prepared by using 3-subst.ituted cyclobutane-carboxylic the catalytic hydrogenation acid obtained by [X-2ooA] according to the following scheme, reaction as showed in the preparation methods as described below. was carried out reaction The catalytic hydrogenation A-53, A7 in Example in Step A5 in Example A-82, Step be1ow.
Example A-75 as described t_5 and Step A7 in cooH cooH Pd/C or Rh/C RUH R^,AJ lx-200 prepared by usi-ng Examples B- 1 and B-2 were obtained acid substituted cyclobutane-carboxylic IX-2008] showed in the with zLnc as by the reduction reaction preparation meLhods following scheme, according to the described be1ow.
B1 was carried out in Step The reduction reaction described bel-ow. in Example B-1 as Zn, HCI . _-.cooH | :r-cooH ^a1./4 R^,}J x-200 is a stereoisomer of The above [X-2008] [X-200A]. cyclobutane-carboxylic By using the 3-substituted for example, Lhe prepared by the above methods, acids can be obtaj-ned f ollowing compound and IIV-82]-l ITV-8221 stereoselectivelv. cooH *"t-+"""rQQQH n /:\ ni //-R* R*AR* compound t_u For example, the following IIV002-W] ( catalYtic bY the cis-isomer may be obtained palladium on activated carbon hydrogenation reaction with or rhodium on activated carbon.
Rh,c R"<>cooH__** R"'-O-cooH il--()**" *oun** o-*" rv002-w1 name figs 1 to 4L whose comPound Examples listed in rrCrt rrDrr follows. or are explained as comprises symbol prePared bY using Examples C- l- t.o C- 9 were I'Preparation method of arylcarboxylic acid, according Example as described below.
C series" noOH 9H, fY'* I tr prepared by using Examples D-1 to D-6 were the reduction obtained by cyclohexanecarboxylic acid according phenylcarboxylic acid, reaction of a rrPreparation D series". method of Example as showed Weinreb amide intermediates A mixture of the and trans-isomer bel-ow was separated into cis-isomer gel column purification by sil-ica thereof through the chromatography. reduction ffoH ,^\t\./ --------------l> --------t ,o-H bioLogica- assay. 42] The results of the [Figure assay. 43] The results of the biologica- IFigure the biological assay. 44] The results of IFigure assay. 45 The results of the biological Lr,r_gure ) the biol-ogical assay. 46] The results of IFigure results of the biologica- assay. 471 The lFigure assay. 4e] The resul-ts of the biologica- IFigure 1_0 DESCRIPTION OF EMBOD]MENTS [00s3] may be of terms that The followinqs are definitions used in the specification. [00s4] phrase substituted" means to The be "may given substituent substituted with the given number of position(s) not to be substituted at any replaceable or (unsubstituted) phrase substituted" herein means . The 'tnot positions with hydrogen that all replaceable are occupied aLoms. may be For example, the phrase alkyl group which "Cr-6 l- to 5 substituents substituted with the same or different from bot.h cases where Cr-e alkyl selected Group Atr includes group different 1 to 5 may be substituted with the same or A at any replaceable substit,uents selected from Group group is not position(s) thereof and where Cr-e alky1 (unsubstituted) substituted . [00ss] for example, fluorine The term atom" includes "halogen atom, or iodine atom and chlorine atom, bromine atom, l-ike. [00s6] The term group" refers to a straight- "a1ky1 group, and includes branched-chain saturated hydrocarbon group, alkyl for example, Ct-tz a1kyl group, Cr-g alky1 Cr-e group, group, group, Cs-tz aIkyl C1-+ alkyl group, Cr-s alky1 group 1 L2 1 to 8, l- to 6 and Cs-e a1kyl which have to , 8 carbon atoms, to 4, 1- to 3, 5 to L2, and 5 to group preferred of aIky1 respectively. The examples t'Cr-: group", a1kyl include alkyl group", alkyl "Cs-tz "C1-6 group" group't includes, for and the like. The a1ky1 "Cr-3 group, propyl group, and example, methyl group, ethyl j-ncIudes, f or group" isopropyl group. The Cr-G alkyl giroup' group, isobutyl group, sec-butyl example, butyl group, neopentyl group, pentyl group, isopentyl tert-butyl group/ group, hexyl group, tert-pentyl group, 1-ethylpropyl group, 2,2-dimethylbutyl group, isohexyl L,1-dimethylbutyl group, group group 2-eLhylbutyl 3,3-dimethylbutyl , the above- group, besides 1,1-dimethylmethylpropyl group. The example of mentioned examples of Cr-: alkyI "Cs- decyl, group" heptyl, octyl, nonyl, l_0 alkyl incfudes, above-mentioned the 1ike, besides the undecyl, dodecyl and. branched- chain. examples, whj-ch may be a st.raight.- or [00s7] group" to a straight- The term refers "alkenyl group having one or hydrocarbon branched-chain unsaturated group, example, vinyl more double bonds, and includes for group, group, group, a11yl 1-propenyl isopropenyl (1--methylpropenyl group, 2-methyl- group methylpropenyl group, 2-butenyl 1--propenyl group and the like), 1-butenyl (1--methyl group group, group, methylbutenyl 3-butenyl group, 3-methylbutenyl group, 2-methylbutenyl butenyl group, group pentenyl group, methylpentenyl and the like), group like. hexenyl and the group't refers to a straight- The term alkenyl "Cz-3 2 to 3 group having hydrocarbon branched-chain unsaturated includes for example, carbon atoms and one double bond, and group, allyl group, group, isopropenyl vinyl l-propenyl group and the like t00s8l group groupt' refers to a bivalent The term "a1kylene alkyI, and derived from a straight,- or branched-chain alkylene group", includes for example, alkylene "Cr-+ "Cr--6 group". The preferred example of group" and alkylene "Cr-3 group by group bivalent derived alkylene includes a carbon removing each one hydrogen atom from both terminal includes, for example, atoms of straight-chain alkane, and (-Ctt, (-CHzCHz -), trimethylene methylene -;, ethylene dfl dtt dar \ f F1- remFl- hrrl ( -cH, CHz CHz CHz - \-rr2 urr2 vn2 ene ) , pentamethylene CH2 CHz CHz - hexamethylene -CHz CH2 ) CH2 CH2 CH2 CH2 CH2 CH2 -) and the like. a saturaLed hydrocarbon.
The term refers to "afkane" [00se] refers to a monocyclic The term ring" "cycloalkyl Cz-t includes, for example, saturated hydrocarbon, and 3 to 7 ring having cycloalkyl ring which means a cycl-oalkyl includes ring" carbon atoms. The example of "cycloalkyl ring, cyclopropane ring, cyclobutane ring, cyclopentane and the 1ike. cyclohexane ring, cyclohepLane ring group" refers to a monocyclic The term "cycloalkyl for example, Cz-t hydrocarbon group, and includes saturated group having 3 cycloalkyl group which means a cycloalkyl group" includes The of 7 carbon atoms. example "cycloalkyl group/ group, cyclopentyl group, cyclobutyl cyclopropyl group the like. cyclohexyl group, cycloheptyl and 0 61] ncycloalkylene group" refers to a bivalent The term group/ group above-mentioned cycloalkyl derived from the atoms for binding. which has any two available ring carbon carbon atom or different The carbons may be the same single grouprr The example of carbon atoms. "cycloalkylene grouptt whj-ch means includes cycloalkylene "C:-ro atoms. The group having 3 t.o l-0 carbon cycloalkylene group" for example, example of includes "cycloalkylene group, group, cyclopentylene cyclopropylene cyclobutylene group' group, group, cycloheptylene cyclohexylene group, group, cyclodecylene cyclooctylene cyclononylene for example, L,!- group like, and specifically, and the group, L,I- cyclopropylene group, 1-,2-cyclopropylene group, !,3- group, L,2-cyclobutylene cyclobutylene 4,4- group, group L,3-cyclopentylene cyclobutylene group, 4,5- group, 1-,4-cycLopentylene cyclohexylene group the 1ike. cyclooctylene and monocyclic or ring" refers to a The term aryl "Co-ro atoms having 6 to 1-0 carbon bicyclic aromatic hydrocarbon ring, and for example, benzene in the ring and includes naphthalene ring. to an aromat The term Cs-ro aryl group'r ref ers group 10 carbon atoms, and includes hydrocarbon having 6 to group, 2-naphthyl phenyl group, 1--napht.hyl for example, group and the 1ike. and Rd2, or Rd2 A specific aspect of the definition "Rdl fused form 3 Ce-ro aryl ring and Rd3 can be taken together to wherein to the benzene ring to which they are aI1 attached with the same the Co-ro aryl ring may be substituted Group Att 4 selected f rom dif f erent l- to substituents (such ring as naphthalene includes, for example, Cr6 ar1rl below: ring) and the like, ds described 'Roo Group A \\ /t [006s] a bivalent The term arylene groupt'refers to "CG-ro hydrocarbon group which monocyclic- or bicyclic-aromatic has 5 l-0 carbon atoms in the ring and has any includes, for available ring carbon atom for binding, and phenylene, and the 1ike, preferably example, naphthylene (o-phenylene, phenylene m-phenylene, p-phenylene), more preferably p-phenylene . group'includes The term spirocyclic cycloalkyl "Cs-rr group, spiro nonanyl group, spiro noneny1 .41 [4.4] group/ spiro .5] decanyl group, spiro decenyI [4.5] group, group, undecenyl spiro undecanyl spiro [5.5] [5.5] preferably spiro nonyl group and the like, t3.51 group. spiro . 5] nonyl group" refers Lo a The term heteroaromat,ic 'tmonocyclic group which heteroaromatic 3- to 7-membered monocyclic selected contains the same or different 1 to 4 heteroatoms from and sulfur atom, besides nitrogen atom, oxygen atom carbon atoms. g,roup" is When the term heteroaromat "monocyclic used of Y", the term as a definition "monocyclic group which has any two heteroaromatic group" is a bivalent The monocyclic available ring atoms for binding. het,eroaromatic group may be attached via any available ring. nitrogen or carbon atom in the group of monocyclic heteroaromatic The example pyrrolinylene, thi-enylene, includes for example, furylene, isothiazolylene, thiazolylene, oxazolylene, isooxazolylene, (L,2,5- imidazolylene, pyrazolylene, oxadiazolylene L,2, 4-oxadiazolylene), oxadiazolylene, L,3, 4-oxadiazolylene, (L,2,5-thiadiazolylene, L,3,4- thiadiazolylene triazolylene thiadiazolylene 1- 4-thiadiazolylene) , ,2 , (L,2,3-triazolylene, tetrazolylene, L,2, 4-tr:azol-ylene), pyrazLrrylene, pyridazinylene, t-0 pyridylene, pyrimidinylene, triazinylene and t,he Iike. heteroaromatic The preferred example of monocyclic group oxazolylene, thiazolylene, includes thienylene, (L,3,4- pyrazolylene, oxadiazolylene imidazolylene, (I,2,4- triazolylene oxadiazolylene, L,2,4-oxadiazolylene), pyridylene, pyrimidinylene Letrazolylene, tniazolylene), and the like. group which heteroaromatic The definition "monocyclic different 1 to may be substituted with the same or monocyclic A" means a substituents sel-ected from Group given have the group which may heteroaromatic atom(s) if or on nitrogen substituent(s) on carbon atom(s) ring. heteroaromatic it./they exist in the monocyclic in the monocyclic when nitrogen atom is contained quaternized atom may be heteroaromatic ring, the nitrogen to form a N-oxide with a substituent or mav be oxidized derivative thereof. a collective term for The t.erm disease" is "autoimmune immune wherein own d.iseases which relate to conditions cells or tissues reacts t.o own helthy system excessively for example, rheumatoid and attacks them, and includes such as psoriasis, inflammatory bowel disease arthritis, multiple sclerosis, Crohn's disease and ulcerative colitis, Behcet's disease, ankylosing systemic lupus erythematosus, type uveit.is, polymyalgia rheumatica, spondylitis, diabetes. [006e] I'allerqic a disease due to The disease" refers to particular antigen, and response to a excessive immune allergic rhinitis includes for example, atopic dermatitis, pollinosis, conjunctivitis, allergic such as allergic asthma, food gastroenteritis, asLhma, childhood bronchial like. aI1ergy, drug allergy, hives and the refers to a disease The diseaseI' term "metabolic relating turnover or a disease caused by abnormal metabolic for example, and includes to metabolic abnormality, type II diabetes. diabetes such as type I diabetes and 0 071] to a compound which The antagonist" refers "RORy receptor retinoid-related orphan inhibit a funct.ion of Y (RORy) or reduced. to make the activity therof disappear looT Tl-ra nraf g1Sgd in the eXampleS Of each substituent or are explained compounds represented by formula tIl tI-Wl as follows.
Fra I l+ -r9. "'b-U\ t_0 and t,he examples of R" and Rb includes: which are substituted with O.-n, /N*T A.FN \ o- \\ preferably Cs-e group, In one aspect, R" is Cs-rz a1ky1 same or group, with the 1_5 alkyI which may be substituted from Group A. different 1 to 5 substituents selected unsubstituted-C5-sa1ky1 The preferred R" includes an (CHE group, preferably CCHz CH2 CH2 - most ): [007s] In one aspect, Ra is wherein Y" is / \ a.i na] a ?ranA Drrry-Ls rr\Jrrur v! (ii) group/ C1-6 alkylene cycl-ic moiety U is with (i) group which may be substituted C:-z cycloalkyl from selected f erent l- to 5 substituents the same or dif Group A, (ii) group which may cycloalkyl Cs-rr spirocyclic 1 to 5 substi-tuents substituted with the same or different A, or selected from Group with the (fii) substituted 1_5 Co-ro aryl group which may be from Group selected same or different l- to 5 substituents In another aspect, R" is wherein zv Y" is single bond, or (ii) group/ C1-6 alkylene cyclic moiety U is (i) group substituted with C:-z cycloalkyl which may be selected from the same or different 1- to 5 substituents Group or (ii) group which may be Cs-rr spirocyclic cycloalkyl l- to 5 substituents substituted with the same or different selected from Group A.
The nreferred Yt includes single bond (ii) trimethylene; and methylene, ethylene, nraFarrorl va bOnd, methylene the more inClUdes Single and ethylene. 'l'ne preferred U includes cyclobutyl cyclic moiety with group group, which may be substituted or cyclohexyl selected from the same or different 1 to 3 substituents Group A; cyclobutyl the more preferred cyclic moiety U includes dr^tth v with group, may be substituted v! cyclohexyl which Ytvql/ group; and the same or different 1 to 3 Cr-o aIky1 moiety U includes the yet more preferred cyclic group, which may be group cyclohexyl cyctobutyl or 1 t.o 3 substituents substituted with the same or different.
(CH, (CH: (CUr CHCH2 CHz -, CCH2 -, selected from CHCH2 -, 1 ;2 ) 2 3 (CHr (cur;gCCHzcHz -, and -, )z cH3cH2c(cH3 -, )zCHC(CH: )zcHz cH3 cH2 cH Hs cHz - . [007e] moiety U includes Another preferred cycl-ic group/ group, spiro non-enyI spiro [4.4] 14.A1nonanyl group, deceny1 group, spiro spiro t4.51 decanyl [4.5] group, or group, undecenyl spiro undecanyl spiro t5.51 [5.5] with the group, which may be substituted spirot3.5lnonyl Group selected from same or different 1 to 5 substituents group which may be more preferably spiro nonyl t3.51 substituents or different l- to 5 substituted with the same sel-ected from Group A. phenyl U includes Another preferred cyclic moiety group with the same or different which may be substituted from Group A; to 5 substituents selected group which may be substj-tuted more preferably phenyl group; 1- to 3 Cr-e a1ky1 with the same or different phenyl group which may yet more preferably, (CH3 CHCH2 -. substituted with l- to 3 pref R" 'includes In another erred. aspect, followings: group. wherein R.1 is cr-o a1kyl group a1kyl Ro includes Cr-r In one preferred. aspect, which group the like, group isopropyl and such as ethyl and f 1 to 5 same or dif erent may be substituted with t.he from Group A; and substituents selected preferred incl-udes an unsubstituted-ethyl the more Rb group, group, trifluoromethYl group, hydroxyethyl group, and group, I,1-difluoro-ethyl difluoromethyl group unsubstituted- isopropyl .
Cz-t alkenyl Ro includes In another preferred aspect, group, group, I-propenyl group, preferably vinyl group, which may be substituted group, a]ly1 1_5 isopropenyl selected 1 to 5 substituents with the same or different from Group A; and an unsubstituted-vinyl the more r:referred Rb includes group. group and an unsubstituted-isopropenyl yet Rb includes Cr-z cycloalkyl In another aspect, group, group, group cyclopropyl cyclobutyl such as group group, and cyclopentyl group, cyclohexyl cycloheptyl with the same the like, which may be substituted Group A; substituents selected from different 1 to 5 group which preferred cyclopropyl the more Rb includes 1- to 5 may with the same or different be substituted A; and l-0 substituents selected from Group yet preferred Rb includes an unsubstituted- the more cyclopropyl group. [008s] In one aspect, R' is l-5 hydrogen atom, or (2) groupt group, preferably C1-3 alky1 C1-5 aIky1 hydrogen atom and the more preferred. Rc includes mal-hrr'l .
Jroup. bond.
In one aspect, Y' is single group which may alkylene In another aspect, Y' is Cr-e 1 to 5 same or different be substituted with the substituents selected from Group nrafarrorl v" group which may Cr-e alkylene the includes be substituted with same or different l- to 3 Cr-a alkyl group; and preferred - CH2 CH2 CHz - the more Y" includes -CHz -CHz , -, -cH2c(cH' -, -cH2cH2-, -cH(cH: -, -cHzcH(cH3 -, -c(cH3 )2 ;' wherein the -CH(CH3 CH2 -, -, and -CH2CH2CHz -, ) -C(CH3 ) zCHz terminal sides of these symbol - located on the t,he right chemicaL formulae indicates a single bond, and right and left moeities and left bonds are linked to adjacent Y", respectively. asner:f . Yc wherein Rcl is hyd.rogen In another is -NRc1- atom or C1-6 alkyl group; preferred Rc1 includes hydrogen atom the example of and C1-3 a1ky1 group; and preferred of Rc1 i-ncludes hydrogen the more example atrom. [008e] In another aspect, Y' is -O-. [00e0] rcnant vc gr6lgp CyCloalkylene SuCh In anOthe- is C:_ro group, as group cyclobutylene cycr_opropyrene group, cycloheptylene cyclopentylene group, cyclo hexylene may be group group the like, which and cyclooctylene and 1- to 5 substituents substituted with the same or different selected from Group A; Y' includes cyclobutylene the preferred example of group with the same or different which may be substituted to 2 substituents selected from Group A; and preferred of Y" includes the most example group . unsubstituted- cyc lobutylene [00e1] group such as Ce-ro arylene In one aspect, Y" is group and the like, which phenylene group and naphthylene l- to 5 same or different may be substituted with the substituents selected from Group A; and Y' includes unsubstituted'- the preferred example of phenylene group. [00e2] group Yc i s monocyclic heteroaromatic In one asneet. 1 to 5 or different which may be substit.uted with the same monocyclic A wherein the substituents selected from Group and the Same heteroaromatic rinq consists of carbon atoms selected from nitrogen or different 1 to 4 hetero atoms and is 3 to 7-membered; atom, oxygen atom and sulfur atom, includes thienylene, zv the preferred example of Y" pyrazoLylene, oxazolylene, thiazolylene, imidazolylene, (!,3,4-oxadiazolylene, L,2, 4-oxadiazolylene), oxadiazolylene (L, tetrazolylene, triazolyl-ene 2, 4 riazolylene), which may be pyridylene, pyrimid.inylene and the like, 1 to 3 substituents substituted with the same or different selected from Group A; and preferred of Y' includes the more examPle unsubst ituted- thiazolylene [00e3] bond. rn one aspect, Yut is single [00e4] may be group which rn one aspect, Yd1 is Cr-e alkylene l- to 5 substituents with the same or different substituted selected from Group A; Cr-: alkylene preferred example of Yd1 includes the same or different group which may be substituted with the to 5 Cr-: alkyl group; and includes - and more preferred example of Yd1 -CHz drr I Arr \ Lrl -. tur13 / [00es] wherein formula In one aspect, the compound of [I-W] other methine and be linked each both Yc and Yd1 mav be group form C:-z cycloalkyl directly or via Cr-+ alkylene to following formula ring includes compounds of the [I-Wc]: // H ----- ,\_'-"( .YLll LP)n"' tla:1^/ (qn., H----ll l-Wc wherein n'3 is integer selected from 0 or 1 to 4, provided that a the other symbols are as defined in l- to 4. selected from O or sum of n"l and nt is an integer [00e5] wherein of formula In one aspect, the compound tI-Wl each other Y' mav be methine and be linked both and Ydt group to form Cz-t cycloalkyl directly or via Cr-+ alkylene following formula Ir-WcS] ring includes compounds of the methylene to form a wherein Y' and Ydt are connected vj-a cyclopentane moiety: ,^,,t '^------,-6 ____,/ (.-c osrN-Y \\ // ,G"-'Go R?-G: ac H *) go--\__-..-C( wneret_n each symbol is as defined in t011. [00e7] rn one aspect, Yd' is a single bond. [00e8] group, alkylene aspect, Yd' is Cr-e In another preferably group, more preferably -CHz - Cr-: alkylene [00ee] same Run, and Rdu are the rn one aspect, Rut, Rd', Rut, (1) (7): group from the following or differenL selected hydrogen atom halogen atom, (3) group with the same Cr-e alkyl which may be substituted selected from Group or different 1 to 5 substituents (4) group wherein Rd10 is hyd.rogen atom or Cr-e alkyl -oRd10 with the same or different 1 to which may be substituted substituents from Group A, selected (5) atom or Cr-e a1ky1 -CooRd11 wherein Rdlr is hydrogen group/ (6) group may be substituted with the Cg-r cycloalkyl which Group A, selected from same or different 1 to 5 substituents cyano group, or alternatively can be taken together Rd1 and Rd', or Rd2 and Rd3 ring to which form a Ce-ro aryl ring fused to the benzene ring is wherein the Ce-ro aryl they are all attached different l- unsubstituted or substituted with the same or to 4 substi-tuents selected from Group [010 ] Rds are the rn another aspect, Rut, Ru', Ru', Run, and group from the following same or different selected (4): f 1) hrzdrncrcn atOm halogen atom, (3) with the same Cr-e alky1 group which may be substituted selected from Group or different 1 to 5 substituents group (4) or Cr-e alky1 -ORdrO wherein Rd10 is hydrogen atom which with same or different l- to 5 may be substituted the substituents selected from Group A, or alternatively be taken together to Rd1 and Rd', or Rd2 and Rd3 can form a Ce-ro aryl ring fused to the benzene ring to which aryl ring is they are at1 attached wherein the Co-ro with the same or unsubstituted or mav be substituLed Group A. different l- Lo 4 substituents selected from [01-0]-l Run, and Rds are rn the preferred aspect, Rut, Rd', Ru', group the following the same or different selected from hydrogen atom, atom, fluorine atom or chlorine (3) group with the same Cr-: alky1 which may be substituted wherein the specific or different 1 to 5 halogen atoms, example of Rdt, Rd', Rd', Run, and Rd5 includes unsubstituted- methyl, unsubstituted-ethyI, and trifluoromethyl, (4) group wherein Rd10 is hydrogen atom or Cr-s a1ky1 -oRdr-o different l- to 5 zv which may be substj-tuted with the same or A, wherein the specific substituents selected from Group group, example of said includes methoxy -oRd10 (5) atom or Cr-e alkyl -COORd11 wherein Rdrl is hydrogen group, preferably Rd11 is hydrogen atom, cyclopropyl group, (7) group. cyano [010 ] and' Rds Rut, Ru', Ru', Run/ rn another preferred aspect, from the following group selected are the same or different (1) (a) to : hydrogen atom, chlorine atom, fluorine atom or same (3) substituted with the Cr-: alkyl group which may be the specific halogen atoms, wherein or different 1- to 5 includes unsubstituted- 1_0 example of Rut, Rdt, Ru', Rdn, and Rds and trifluoromethyl, methyl, unsubstituted-ethyl, group Cr-: aIky1 (4) is hydrogen atom or -oRd10 wherein Rd10 1 to 5 the same or different which may be substituted with wherein the specific from Group A, substituents selected methoxy group. 1_5 example of said -ORdr'o includes [010 ] Rd2 and' Rd3 can fn aspect, Rut and Rd', or another to another ring fused taken together to form a benzene wherein they are al-1 attached benzene ring to which the same or with zv former benzene ring may be substituted from Group A, and selected different 1- to 4 substituents ring moieties for example, the following naphthalene provided: \\ // Group Group A 0104 In one aspect, R" is hydrogen atom, or group, or alternativelY Cr-: alkyl to form be taken together R' and Rd1, or R" and Rds can ^11-..1 ^-^ \4 cLJ-J\y rErrE . preferred of R" includes The example hydrogen atom, methyl group. [010 ] Rds can Rdt, or R' and' In the preferred aspect, Rt and for example, the to form ethylene, and be taken together provided: following ring moieties are o N- v \l Rd'l [010 ] the moiety the examPle of In formula or II-W] II], Y*' is attached benzene ring to which containing Yd' and the includes as follows: \-Ys? R.l2 t-Y4-) -vea-ftn" \-"n.O *"\- \-Y< -v(r)-n" ''\// ,*o' Y-vu{__r,)-n" \-fL\ O-*" *'\_ *o'\--1*o' \-"<l \-"<l RouT Ro'F *"\-- *'\ fo" J \-Yq, ,,!-Ro' \-"t-O "e{-}n" a** -\* [010 ] from 0 or 1 In D" is an integer selected one aspect, to 4, preferably 0 or 1. [010 ] selected from 0 In another aspect, r" is an integer preferably or 1 to 3, 0 or 1. [0110 ] selected from O or 1 In one aspect, fl"2 is an integer preferably 1. to 3, 0 or 0 111] selected from O or In one aspect, ild is an integer to 3, preferably 0. 0112 In A is one aspect, Group Cr-e alkyl group/ halogen atom, and (c) group. -oRA1 wherein RA1 is hydrogen at.om or C1-5 aIky1 0113 1-0 The pref erred Group A includes: (CHr;2CHCH2CHz-, (a) (CH:)zCHCH2-, (CHr)3CCH2-, CH:-, (cHi (CHs and cH3CH2C(CH3 )zCHC(CH: )z-, )zCHz-, )gCCHzCHz- , cH3 cHz cH Hs cHz ) -, fluorine atom and chlorine atom, (c) group. 1-5 and -oCr-: a1ky1 such as methoxy -oH, Iorr+1 formula The preferred aspect of compounds of tI-Wl formula: includes compounds of the following 'Roo RL-G: R- q"^fo-*" -A-w wherein P-ru '7-'^\ lisl in . the other symbols are as defined t01l [011s] of f ormula II-W] The pref ered aspect of compounds the following formulae: includes compounds of ,o.-H F"') R"H nr*YK ""-'r/o-'*" fiW] wherein the group selected from R'2 is ind.ependently consisting of: (a) group/ C1-5 a1ky1 halogen atom, group; (c) or C1-5 aIky1 -oRA1 wherein RA1 is hydrogen atom ; and from 0 or 1 to nt is an inteqer selected the other symbols are as defined t011. of formula preferred aspect of compounds tI-Wl Another formula: includes compounds of the following wnerel_n O or I Lo 4; and n"3 is an integer selected from provided the other symbols are as defined in integer selected from 0 that a sum of n'1 and n"3 is an 1 |'r: A 0117 preferred of compounds of formula [I-W] Another aspect includes compounds of the following formula: oYN-Y h.oo nlci 6c H -..-A 'nb-s\ i---\c, l-Wcs I ] )- wnerer_n each symbol is as defined in . 0118 formula Another preferred aspect of compounds of [I-W] includes compounds of the following formula: ,RO' il-Ys?<\ ,)-Ro' Rds' o-*" n"eo -c1-wI wherei-n nc3o is an integer selected from 1 to 5; in . the other symbols are as defined [01] 011e of formula Another preferred aspect of compounds [I-W] formulae: includes compounds of the following 'Roo rr -c51-w ,RO' F"){ 9-ru o*-N1 Rou' hd4 o-*" il -c53-w wherein j-ndependently group tI. from the r-s sel-ected consisting of: Cr-u aIkyl group/ (b)halogen atom, and (c) a1kyl group' RA1 is hydrogen atom or C1-5 -oRA1 wherein 1 to 5; and n" is an inteqer selected from O or as defined in the other symbols are t01l. formula preferred of compounds of II-W] Another aspect of the following formulae: includes compounds Ro1 Rot r -Aro-w Rd'1 r-Azo-w] wherein F*ru R"1 is Cr-o a1kyl group/ and defined in and the other symbols are as [Of1 t RO,I, Rd' F" A' >< f"') oy-t-Ys\ ;- 69 /L*o' ('F"i *oun*oo ,N"l^\!o-*" -A30-w wherein l.r._ ,"0*ttl group from the R'2 is ind.ependently selected consisting of: (a)Cr-. a1kyl group, (b)hatogen atom, and grouP, (c) alkyl RA1 is hydrogen atom or C1-5 -oRAl wherein na is integer sel-ected f rom 0 or 1 to 5; and the other srrmbols are as defined in . 0121] The preferred aspect of compounds of formula [I-W] i-ncludes compounds of the following formulae: *o\--*o' o*,il-"$*" \t --N 'rno Rq-G: *o'n*ou .--/"u4 , \{i;.rtiJ-o-*" tI-AI *ot\--.r** otil-ve{}n" ,o-,.r --\-[*-"'tf **n** (qsr".Nj|-o.-R" Illl 9..-N ""-y'o--*" "\-r-o--*. tl ttvl ilil1 -G*" n-n-o-*" rv-A2l ilv-Al I ,o.-n t"-n-o-*" rv-A4 P-ru ""--"-o'.-* rv-82 *o\-** ooil{-}*" *o'n*oo t"--.*-o'-*" "-)r.o--*" lv-822 rv-B21 I ] *o'\--r*o oo-ft{}*" ,o.-u *"'W *oun'*oo --n-"-R" "Yo'-o" il rv-c2l rv-c1 ,Ro' -{'lF*" *orn*oo o-"' lN-rxl rv-D6l rv-Dsl O-*r *'\ *'\ ,** ro' il-{'}*" il*{,}* *oufl* *oun** *-\,-o.-*" rvC1 \o'-o rvC2 *o'\---r*o' ooil-vt--/t ,N--r* fn" nlru'yzl.-*-y9{ nd *o'n*oo '\""f).o-*" *"\-J** ooil{-}*" ,N-.---i,r -:oL--J R*AR* ""--rn-o'-*" IV.B] ,*o' fi-G** o\", ,N..---.-tt n"!u}-il *oun** \-'l *o.\--*r*o' o*fi{-}*" fr-frF*" I--N *'-?-"\ol_ *o'-** **n** "Yo'-*" t v-821*C1 l *"'\-** *o\J*o' oofi1irln,. oo-t{-}*" n ,N_-N ,l{--N ,,'o{\rr( *"'-Q. RalF+*l n*An* J *osnpat ^lA, f-_u-o-_*" Yo'-*" tl vCr v*822*C2 t l t l wherein t( is C1-5 alkyl group, nLcl Ro ..r ^ and Ib , the other symbols are as defined in I01l loa22l The preferred of formul-a or aspect of compounds lI-Wl tIl formulae: includes compounds of the following *o\J*o' oW.**#A Fe..co h*o' R"-cl.
. ;. ,*J n. *oul1*oo 'Fo'"Y' ,\;.Al?o_*" ['{2-wr il-{r:,}*" *orn*oo *--r'o-*' lv-B2r-cz 0123 preferred of formula or The aspect of compounds tI-Wl tIl incl-udes following formulae: compounds of the *o\--,*o' oyil-ff*" n ,o-N Rou'hoo / {R)! Ro --y'o-*" rvC2-i01 rv-821*c2-s02 I ] i l loL24l preferred formula or The compound of II-W] III includes compounds of the following formulae; [Tab1e , 9H. os-N-,-\ f', o-n, H.c1 /^\--{. ii I ll I '_v/ \-r\.,, \Z-^, ||v"3 u l/\l.] I r3Y 13 g-trt I r3v u ?H. o *>/\ ,o-ru \\Z\.Ll \-Z\..r, vr 13 lTable H ?t. vr 13 ,Orru H.C, .%at.
,O-ru H ?H' ,, ,/"', ,r,r--ry ^ ^ "\.il-.s t'"1.
,"*' N: l.l-rrl-"r, O-*'ra, "ik-'P)-*0.,,.
H ?*' ,cH' N: ,,^J"' ,N=ry H,cQ "1.\A uyq.J '',.-Cc>-p)*D"*. [/_"* H ?l ,cH. o- ,,.tc,pJ*d",, *cik> SrJ*0** lTable H.C. q,'l f T:1-rl a rqv+v J ..r.{t*' "Y\A n."{k,p5-4 2..,,,r3-'uu \-\./ !"'l't Y* %"t.
H?r H9l o\".'N.-/\ oY-\a P-ru ,o-N G"*. 9"*, l*,o*' ll 1'otra lTable Huc.
I r3v lTable Itc.,cH, g*ru o\'NY\ ,N=ru N\zV \/' v-cH' t I 3 \'^ort H.C, ^t, o ufl" rr FH, g-ru o\.ft1{1 ,ru=ry -Y"V u"*, I I Il $or-t lTable o\-NY\ P-r.r '.llllll \Z\.r, \--^\-/ {o\ vrr3 "r tl H ?l ,cH, n ,."{{) {l-}:D-,_.
-'Ao* \.r' H.c-\ .*\r/ r.r l^lJ H.C, ^ ,"''3 ,cH, ' '3Y n3v f,:u lTable t_01- o\,,N-ri,\ ,trl=N NttilI \41'. vrr3 t:t1 P$d.-, l'-**oF6*, lTable H,C. 3v\ ^--Y os.*:'\ tilt lroH *,.{""^' "Y\A f-ii e'*' l^o* u n-< ,...{",^' ' '3v \ ./ \,.,,, i-il YL'L F\,/ \/ %'*' )',"0 !r-o* os-N'-z\ ii I lt I \r'\ \-\-, itY-CH.
,O-X H.C, "3{b,e{ -2sl may be any accept,able salts" "Pharmaceutically of fhe nr:esent for nontoxic salf invention compound, example, acj-d, organic include salts formed with inorganic like. acid, inorganic base, organic base, amino acid and the salts The inorganic acid salts include for example, formed with hydrochloric acid, nitric acid, sulfuric acid, phosphoric like. acid, hydrobromic acid and the The organic acid salts include for example, salts formed with fumaric oxalic acid, maleic acid, citric acid, acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic gluconic acid, trifluoroacetic acid, acid, ascorbic acid, methanesulfonic acid, p- acid, benzenesulfonic tol-uenesulf onic acid and the like.
The include for salts formed with inorganic base example, sodium sa1t, potassium sa1t, calcium sa1t, magnesium sa1t, ammonium salt and the like.
The salts formed with base include for example organic salts formed with methylamine, ethylamine, diethylamine, trimethylamine, diethanolamine, triethylamine, ethanolamine, triethanolamine ethylenediamine (hydroxymethyl trj-s methylamine, cyclohexylamine dicyclohexylamine, N,N' ethylenediamine, guanidine, -dibenzyl pyridine, picoline, the choline, cinchonj-ne, meglumine and 1ike.
The salts formed with amino acid include for example, salts formed glutamic with lysine, arginine, aspartic acid, acid and the l-ike.
Such salts can be formed by reacting compounds formula or with inorganic base, organic base, II-w] inorganic acid, organic acid, or amino acid according conventi-onal methods of formula The term refers to the compounds "solvate't or pharmaceutically acceptable salts thereof tr-wl or which coordinate to the solvenL molecules, and also preferably incl-udes are hydrates. Such solvates pharmaceutically acceptable solvates. Such solvate includes ethanol solvate, for example hydrate, dimethylsulfoxide solvate and the like of compounds of pharmaceutically salts formula or or acceptable II-W] tIl includes hemihydrate, thereof. The specific example monohydraLe, dihydrate or mono(ethanol) solvate of compounds of formula of sodium salt of or or monohydrate [I-W] tll (ethanol) compounds of formula or 2 3 solvate of [I-W] [I] / 1ike. Such solvates dihydrochloride of the same and the can be produced methods. according to conventional 101,271 or may In addition, the compounds of formula [I-W] tll have a variety of For example, the compounds "isomer'r.
Z forms or cis or formula or can exist in E or [I-W] tIl trans geometric Moreover, the isomers as isomers. asymmetric compounds of formula or which have [f-w] tIl diastereomers as carbon atoms include enantiomers and atoms. stereoisomers according to said asymmetric carbon or which have Besides, the compounds of formula tll [I-W] axial chiralitv include stereoisomers accordinq to said axial chirality. In some cases, tautomer may be included.
Therefore, the present invention includes all of these isomers and mixtures thereof. alpha o-*" t-wl When a specific configuration, especially, of geometrie of the isomer or of the asymmetric carbon atom position (-G--Gb-G"-Gd-G"-) alpha from the 5-membered. ring not indicated in the structural formula such as formula Wl or the formul-a includes [I], compounds of the structural alt of isomers such as geomet.ric isomers cis or trans isomers) mixtures and stereoisomers or z forms) and thereof. predictable based When the structure of compounds is on the starting material such as an optical-Iy-active process, compound, the intermediate or the synthesis such predictable structural structure . formula mean the -2el In addition, the compound of formula or [I-W] tll be labeled with more such as one or isotopes 'nC, and the like. Besides, the compound of formula or [I-W] wherein one tIl also includes an isotopic compound thereof or more are replaced with . [ot2e] The or or compounds of formula tI-Wl III pharmaceutically preferably acceptable salts thereof are purified pure, preferably 80? or to be substantively more nl lrar [013 ] According to the present invention, prodrugs of compounds of formula or may also be a useful II-W] tIl t'prodrug" medicine. herein ref ers to The as used j-nvention derivatives of the present compound having a chemically group, which show or metabolically decomposable the inherent pharmaceutical- activity upon hydrolysis, physiological solvolysis, or other decompositions under conditions in vivo, and may also be a complex connected ZU with bonds other than covalenL bonds or a salt. Prodrugs can of oral be used for example, for improving absorption administration or targeting the object site. A modified groups in the site includes highly reactive functional present giroup, invention compounds, such as hydroxyl group, group carboxyl amino group, thiol and the 1ike. group includes The group that modifies the hydroxyl group, propionyl group, isobutyryl specifically acetyl group, 4- group, pivaloyl group, palmitoyl group, benzoyl group, group, methylbenzoyl dimethylcarbamoyl dimethylaminomethylcarbonyl group, sulfo group, alany1 (sodium group, fumary group and the like. In addition, 3- (sodium group, 2- carboxylate) benzoyl also carboxylate)ethylcarbonyl group and the like are included. group The group that modifies the carboxyl includes cnaa'i f i r group, propyl group, r:aI1y methyl group, ethyl isopropyl group, group, isobutyl group, tert-butyl butyl group, group, pivaloyloxymethyl group, carboxymethyl (acetyloxy)ethyl group group 1-- dimethylaminomethyl 7-- , (ethoxycarbonyloxy) group, 1- l-5 ethyl Avnr rh i sopropyloxycarbonyloxy ethyl ) :,!vqy / (cyclohexyloxycarbonyloxy) (5-methyloxo-!,3- group, ethyl phenyl group/ o- di-oxolyI)methyl group benzyl group, rn t\z I .rrrrlrl1 N Lrl N- yr vqy morpholinoethyl group like. diethylcarbamoylmethyl group, phthalidyl and the group includes The group that modifies the amino group, specifically tert-buty1 group, docosanoyl pivaloylmethyloxy group, group, a1any1 group, hexylcarbamoyl pentylcarbamoyl group, 3 -methylthio- - (3-ethoxy (acetylamino)propylcarbonyl group, L-sulfo 1_10 hydroxyphenyl)methyl group, 5 2 l-, 3 -4 - -methyl - -oxo- -dioxol yl ( methyl group, 5 -methyl oxo- 1, 3 -dioxol-4 - yI)methoxycarbonyl group, giroup, tetrahydrofuranyl pyrrolidylmethyl group and the Iike. 013 ]_l The includes a term composition" "pharmaceutical mixture comprising one or more actj-ve ingredients and one or more pharmaceutically for example, acceptable carriers, preparations powder, oral such as tabl-et, capsule, granule, l_0 troche, syrup, emulsion suspension and the like or parenteral preparations preparation, such as external suppository, injection, eye drop, a preparation for transnasal preparation for lung administrat.ion and a administration and the 1ike. -321 present Pharmaceutical compositions of the invention can prepared be by mixing suitably the compounds of formula or pharmaceutically salts thereof II-w] or acceptable with at l-east one pharmaceutically acceptable carrier and the like in the art of according to conventional methods medicinal preparations. rate of the compounds of Content formula pharmaceutically salts or or acceptable If-w] tIl thereof pharmaceutical includes for the composition preferably weight. in example, 0.1 to l-00 +, 0.1 to 70 by ZJ the composition on dosage forms, while it varies depending 11_1 dosage amounts and the like. -331 The term acceptable carriersrl "pharmaceutically includes all sorts of organic or inorganic carriers which are commonly-used as a material for drug formulations, such as excipient, disintegrant, binder, fluidizer, lubricant and the preparations like for solid and solvent, solubilizi-ng agent, suspending agent, tonicity agent, buffering agent, soothing agent and the like for Iiquid preparatrr_ons. 1_0 preparations further Such may employ additives such as preservative, antioxidant, colorant, sweetening agent and the like as necessary. 0134 ava i ni anF terrn inClUdeS f Or eXample, laCtOSe, white soft sugar, D-mannitol, D-sorbitol, cornstarch, dextrin, microcrystalline cellulose, crystalline cellulose, carmellose, carmellose calcium, sodium carboxymethylstarch, substituted hydroxypropylcell-ulose, gufr arabj-c and the 1ike. [013s] The term includes for example, "disintegrant" carmellose, carmellose sodium, sodium calcium, carmellose carboxymethylstarch, croscarmell-ose sodium, crospovidone, 1ow ce 1 lulos e, substi-tuted hydroxypropyl hydroxypropylmethylcellulose, cel-lulose and the crystalline 1ike.
The term includes for example, "binder" hydroxypropyl ce 1 1u1 o s e, hydroxypropylme thyl c e 1 1u1os e, povidone, crystalline cellulose, white soft sugar, dextrin, starch, gelatin, gum carmellose sodium, arabic and the like. [013 ] The term includes for example, light "fluidizer" anhydrous silicic acid/ magnesium stearate and the like.
The term includes for example, magnesium "lubricant" stearate, calcium stearate, the like. talc and rn1"ql The purified term includes for example, "solvent" water, ethanol, propyleneglycol, macrogol, sesame oi1, corn oil, olive oil and the like. [01-40] j-ncludes The term agent" for example, "solubil:-z|ng propyleneglycol, D-mannitol, ethanol, benzyl benzoate, triethanolamine, sodium carbonate, sodium citrate and the like. 014 1] The term agent" includes for example, "suspending benzalkonium chloride, carmellose, hydroxypropylcellulose, propyleneglycol, glyceryl povidone, methylcellulose/ t_1_3 monostearate and the like. loL42l The term agent" includes for example, "tonicity glucose, the D-sorbitol, sodium chloride, D-mannitol- and like. term agent" includes for example, "buffering disodium hydrogen phosphate, sodium acetate, sodium carbonate, sodium citrate and the 1ike. l0r44l The term agent" includes for example, benzyl "soothing alcohol and the like. [014 ] The for example, met,hyl term includes "preservative" 1_5 parahydroxybenzoate, propyl ethyl parahydroxybenzoate, parahydroxybenzoaLe, sodium chlorobutanol, benzyl- alcohol, dehydroacetate, sorbic acid and the 1ike.
The term includes for example, sodium "antioxidant" sulfite, ascorbic acid and the like.
I'colorant" The food dye term includes for example, such as Food Red No. 2 and No. 3, Food Ye11ow No. 4 and No. g-carotene and the like, and the like.
The term agent" includes for example "sweetening saccharin sodium, dipotassium glycyrrhizate, aspartame and the Iike. -4Bl pharmaceutical present The compositions of the invention well as mammals can be administered to human as guinea pig, other than human such as mice, rat, hamster, rabbit, pig, the cat, dog, cattle, horse, sheep, monkey and Iike orally or parenterally such as loca1Iy, rectally and intravenously. While the dosage amount may vary depending on subj ect, dosage f orm, route of disease, s).mptom, administration and the like, for example when it is admj-nj-stered patient with autoimmune orally to an adult psoriasis, disease such as rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis and systemic (body lupus eryt.hematosus and the l-ike, or allergic disease weight: present about 50 kg) the dosage amount of the invention ranges generally compound of an active ingredient from about 1 mg to about 1- g per day, which can be administ.ered once to several times. -4el The compounds of formula or or tI-Wl tll pharmaceutically acceptable thereof can inhibit RORy, salts thereby they can be used as an active ingredient treating preventing as autoimmune dj-sease or a disease such such as rheumat.oid arthritis, psorj-asis, inf lammatory bowel disease such and ulcerative colitis, as Crohn's disease multiple sclerosis, systemic lupus erythematosus, ankylosing polymyalgia rheumatica, spondylitis, uveitis, and type I such as asthma; dry diabetes; allergic disease eye; fibrosis; and metabolic disease such as diabetes. [01s ] RORy" means that a function of RORy is "Inhibit inhibited or reduced. to make the activity therof disappear It includes, for function of RORy is inhibited example, the according to Biological assay 1- described hereafter. j-ncludes The preferred RORy" aspect of "fnhibit human RORy".
"Inhibit [01s The f or or compounds of ormula tI-Wl tIl pharmaceutically can be used in acceptable salts thereof j-naf (here combination with more medicament ter other one or (s) methods caI1ed additional medicament according to which is hereinafter commonly used in the art of medicine, called combination use. -s2l The of the compounds of timinq of administration pharmaceutically salts formula or or acceptable II-w] trl thereof is not l-imited and and additional.medicament(s) form of they may be administered to a subject in a combination drug or may be administered simultaneously at regular int,ervals. In addition, the compounds of formula pharmaceutically or or acceptable salts tI-Wl tIl thereof pharmaceutical- may be used as a kit comprising the composition present and additional of the invention medicament .
The dosage amount of the additional medicament may fol-low one practice, may employed in clinical and be determined appropriately depending on subject, disease, symptom, dosage f of orm, route of adminj-stration, timing t_0 admini-stration, combination and the like. The mode of additional (s) medicament is not limited as long as the present invention compounds or salts thereof and the additional medicament are combined.
The (s) additional- medicament include for example, a medicament preventing for treating or autoi-mmune psoriasis, disease such as rheumatoid arthritis, inflammatory bowel disease such as Crohn's disease and gpf i t- i e mrr'l l- ulcerative rple sclerosis, systemic lupus erythematosus, polymyalgia ankylosing spondylitis, uveitis, rheumatica, and type I diabetes; prevent.ing a medicament for t.reating or allergic disease such as asthma; a medicament for treating or preventing metaboli-c disease such as diabetes; 1,1,7 a medicament preventing eye; for treating or dry preventing a medicament for treating or fibrosis.
One t,o three medicament selected from the above to be employed in combination with the compounds of formula or or pharmaceutically acceptable salts Ir-w] trl thereof. 1_0 prevent.ing The medicament for treati-ng or autoimmune disease includes, for example, methotrexate t.o treat or prevent rheumatoid arthritis, and ciclospori-n A and methotrexate prevent psoriasis. to treat or -s3l Next, processes preparing some examples of for the compound of present as fo11ows. the invention are shown However, the processes for preparing the present invention compound should not be limited thereto.
It possible to modify the processes to carry out zv the preparation more effectivefy, for example, introducing a protecting group group foll-owed by into a functional deprotecting precursor it in a subsequent step; using a having group a functional in a step followed by converting it to the desired functional group in a subsequent step; exchanging the order of preparation methods or steps thereof, even though not mentioned in these examples. can be The workup after the reaction in each step carried out by a commonly-used method, wherein Lhe by a isolation and purification may be carried out conventional method selected from crystallization, recryst,allization, separating, silicagel distillation, oY a chromatography, preparative HPLC and the like, combination thereof, as appropriate.
A racemic form of the compound can be obtained using an material, ligand, or reagient, achiral compound as a or by mixing of enantiomers. [01s4] The followinq abbreviations are used in preparation methods and Examples herein: p-toluenesulfonyl (pTs), group methanesulfonyl group (Ms), (TBDMS) tert-butyldimethylsilyl group group (TBDPS) t.ert-butyldiphenylsilyl (TMS) trimethylsilyl group (TES) triethylsilyl group (OTf trif luoromethanesulfonyloxy group (eoc) tert-butoxycarbonyl group benzyl group (Bn) (Ph) phenyl group group (Ac) acetyl (nBu) n-butyl group (teu) tert-butyI group isopropyl group (iPr) (Et) ethyl group group (Me) methyl (LDA) Iithlum diisopropylamide diisobutylaluminum (DIBAL) hydride 1-ethyI-3 - carbodiimide hydrochloride -dimethylaminopropyl) (wsc.Hcl (HOBL'HzO) 1-hydroxy-lH-benzoLriazole monohydrate (TBAF) tetrabutylammonium fluoride (DBU) 1, 8-diazabicyclo . 0] undecene [5.4 (TFA) trifluoroacetic acid trifluoroacetic (TFAA) anhydride (TMDS L 3 - tetramethyldisiloxane ,I ,3, ) Dess-Martin (DMP) reagent lithium hexamethyldisilazide (LHMDS) 4 (DMAP) -dimethylaminopyridine (TEMPO) 2, 2, 6, 6-tetramethylpiperidinyloxy radical (DMSO) dimethylsulfoxide (DMF) lV, N-dj-methylf ormamide ]-20 (THF) tetrahydrofuran (nUal N, N-dimethylacetamide hexamethylphosphoric (HMPA) triamide 01ss In the following schemes, rrxtr group is a leaving such as halogen, and trifluoromethanesulfonyloX!, preferably iodj-ne; bromo, and rrpNl- A nrcrt ec,t- i ng is group for amine, and includes for example, group, and tert-butoxycarbonyl benzyloxycarbonyl group, preferably tert-butoxycarbonyl group. tr rr rr po po and is a protecting group f or hydroxyl group, and includes for example, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group, group, benzyl acetyl group and the like, preferably tert-butyldiphenylsilyl group, and group. benzyl rrpc group, is a protecting group for carboxyl and includes group, for example, methyl group, ethyl tert-butyl group, benzyl group and like, preferably methyl group/ group, tert-but.yl and benzyl group. rrAUX-Hrt includes is a chj-raI auxiliary reagent, and for (R) (S) example benzyl benzy:-- oxazolidinone, (S) oxazolidinone, (R)isopropyloxazolidinone, (4S, i sopropyl oxazo 1 idinone, 5R) -4 5 -phenyl -methyl- (4R,55) oxazol-idinone, methylphenyLoxazolidinone 1,21, (R) (S) and the like, preferably benzyloxazolidinone, benzvl . oxazolidinone group. is a chiral auxiliary "AUXrr trQrr is a group the like, comprising boron, zirtc, tin or and includes for example, boronic acid, dialkoxyboron, halogeno zLnc, and trialkyltin.
Each symbol is as defined in the above [01]. [01s6] Preparation method l- Preparation method *';t ** oYot otri-vc{__-,}-n" .ei.q. -a n4-v*-.fl_n" ^ft-g' Rt-c:cr.;\t".,,v'.Jr* .,G" 1no ^-u.. -y914J '9"--\a'' **n** *oun** (\l^jio.-n" (\ilffio.-n" x-021 I Rb Step l o x-01 R' Ro alkyl =G r+alkyl =c'-o **)<, *0, oril-*-{r}n" ,c1.eo *-oio,.i\-y'f **'\oo (\nffio-*, Step 2 Each 1 is of the steps in the above Preparation method as follows.
Io1s7] Step 1 (R' group) Compound Cr-s aIkyl can be obtained by reacting Compound. with Reactant in the tX-O1l [X-02] presence of a condensing agent in a solvent under the condition of a common ami-de bond formation reaction.
The solvent for the reaction includes for example, hydrocarbon solvent such as benzene, toluene, xylene, and hexane; halogenated solvent such as dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane; ethers solvent such as diethyl ether, tetrahydrofuran, 1_0 dioxane, I,2-dimethoxyethane, polar and diglyrne; and solvents such as N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, and acetone, which may be used alone or as a mixture of two or more. preferred solvent for the reaction includes methylene chloride, chloroform, and N,ff- dimethylformamide.
The condensing agent for the reaction includes for example, (WSC.HCl: water-soluble carbodiimide 1-ethyl dime thylaminopropyl carbodi imi de hydrochlorj-de) dicyclohexylcarbodiimide (DCC), diphenylphosphoryl azide (DPPA), (1- \-rJ cdrbonyldiimidazole r_ and O- \ ,/ , azabenzotriazoleyl) N,N' tetramethyluronium -I/, - ,N' , (HATU). hexafluorophosphate IH- As appropriate, 1--hydroxy- benzotriazol-e monohydrate tlvlt L rL2v 4- dimethylaminopyridine (DMAP), N,N-diisopropylethylamine and the like may preferred agent for be added. The condensing the reaction includes mixture of water- soluble 1-afhrr] /"- (WSC carbodiimide IlUJ- : -"- dimethylaminopropyl)carbodiimide hydrochloride) and l-- (HOBL hydroxy- J-H-benzotriazole monohydrate H2O) and a mixt.ure of O- -azabenzotriazoleyl) -N,N,N' ,N' ,- (HATU) and N, N- t.etramethyluronium hexaf luorophosphate di i sopropylethylamine .
The reaction generally ranges room temperature temperature to about L2O|C, preferably room t.emperature to 1_0 about 100oC.
The reaction generally ranges about 30 minutes to time preferably 3 days, about l- hr to 1 day.
Alternatively, in amidation reaction, the above (R' prepared compound Cr-e alkyl group) can be by the reaction mixed acid anhvdride of of an acid halide or compound with compound [X-01] [X-02].
The acid halide of compound can be derived [X-01] the reaction of compound with of an carboxylic acid [X-01] thionyl chloride, oxalyI chloride etc. wherein a catalytic amount of N,N-dimethylformamide may be added.
The mixed. of compound can be acid anhydride tX-O1l of compound derived by the reaction of a carboxylj-c acid with etc.
[X-01] ethyl chlorocarbonate [01s ] Step 2 can be obtained from Compound hydrogen) tIl = Compound Cr-e alky1 group) in a solvent under the The ester condition of a common ester hydrolysis reaction. hydrolysis the alkaline reaction may be carried out under or aci-dic condition. includes for The base for the alkaline condition example, metal hydroxide such ?il aqueous solution of alka1i potassium as lithium hydroxide, sodium hydroxide, and hydroxid.e. preferred reaction includes The base for the aqueous sodium hydroxide, and agueous lithium hydroxide. for example, The acid for the acidic condition includes hydrochloric acid, hydrobromic acid, sulfuric acid, and preferred reacti-on trifluoroacetic acid. The acid for the includes hydrobromic acid, and hydrochloric acid, t_5 trifluoroacetic acid. includes for example, The solvent for the reaction hydrocarbon solvent such as benzene, toluene, xylene, and ethanol-, hexane; alcohols solvent such as methanol, isopropyl a1cohol, halogenated solvent and tert-butanol; carbon zv such as methylene chloride, chloroform, solvent such tetrachl-oride, and 1, 2-dichloroethane; ethers !,2- as diethyl ether, tetrahydrofuran, dioxane, such as ethyl dimethoxyethane, and diglyne; esters solvent acetate, methyl butyl acetate; acetic acid, acetate, and preferred includes and water. The solvent for the reacti-on ]-25 methanol, ethanol, methylene chloride, chloroform, tetrahydrofuran, water. toluene, acetic acl-d, and generally The reaction temperature ranges about 0oC to I20oC, preferably room temperature to about 100oC.
The reaction time generally ranges about 30 minut.es to preferably 3 days, about t hr to 1 day. -sel Preparation method 2 The case of that the 5-membered rinq is isoxazole: -\r. co'-t\ Preoaration method 2A Preparation method 2 C nol, Ro' oo.fr-ffi** e"..co Ri-G:.^"-;l x,10 tn" *oun*o' ,\l^?o-^" Preparationmethod 2e R' a-r" Hrcr^,-\rr-r"--r" _ ,o*p"t o ttl R' 9('iT -----t> r\;^32o-*, -----> H,c/o .O1-go ,o{-f.l ,o_,f -"i;;'- x-28 x-20 I tl _601 Preparat.ion method 2A Preparat i on method 2 A *"A*'-cH' n"AoH Step 2 Step 1 -cHt x-101 x-l1 I I I n'-VBt *"A* Step 3 x-13 x-12 0151-] Step 1 Compound of can be obtained by the reaction [X-11] Compound 10] or with N, O-dimethylhydroxylamine hydrochloride thereof in the presence of a condensing agent in a solvent.
The solvent for the reaction includes for example, hydrocarbon xylene, and sol-vent such as benzene, toluene, hexane; halogenated solvent such as methylene chlorj-de, chloroform, carbon tetrachloride, and 1, 2-dichloroethane; ethers solvent such as ether, tetrahydrofuran, diethyl polar dioxane 7-, 2 -d.imethoxyethane, and diglyme; and solvents such as N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, and acetone, whj-ch may be used al-one or as a mixture preferred for the of two or more. The solvent reaction and N,N- includes methylene chloride, chloroform, dimethylformamide The condensing for the reaction includes for agent (WSC'HCl: (3- example, water-solubl-e carbodiimide 1-ethy1 N,N' dimethylaminopropyl)carbodiimide hydrochloride), - (DCC), dicyclohexylcarbodiimide diphenylphosphoryl azide (DPPA) (CDI) l-- and carbonyldiimidazole . As appropriate, (HOBL hydroxy- H2O) 4- 7H-benzotriazole monohydrate (DMAP) dimethylaminopyridine and the like may be added.
The preferred reaction includes a condensing agent for the (WSC'HCI: mixture of water-soluble carbodiimide 1--ethyl (3-dimethylaminopropyl)carbodiimide and 1- hydrochloride) (HOBL hydroxy- 7H-benzotriazole H2O) and a monohydrate (WSC' mixture of water-soIuble carbodiimide HCI : 1-ethyl (3-dimethylaminopropyl)carbodiimide hydrochloride) and 4- (DMAP) dimethylaminopyridine .
The generally ranges room reaction temperature temperature to about L2O,C, preferably room temperature to about. 1-00 The reaction time generally ranges about 30 m'inutes to preferably 3 days, about t hr to 1 day. l0r62l Step 2 Compound Compound can be obtained by reacting lK-l2l in the presence of a reducing agent in a solvent. [x-11] example, The solvent for the reaction includes for hydrocarbon and solvent such as benzene, toluene, xylene, hexane; halogenated as methylene chloride, solvent such chloroform, carbon tetrachloride, and 1,2-dichloroethane; and ethers solvent such as diethyl ether, tetrahydrofuran, dioxane, L,2-dimethoxyethane, and diglyme, which may be used alone or as a mixture of two or more. The creferred solvent for reaction toluene, methylene the includes chloride, chloroform, hexane, and tetrahydrofuran.
The includes for reducing agent for the reaction example, diisobutylaluminum hydride, and lithium aluminium hydride. preferred The reducing agent for the reactj-on includes diisobutylaluminum hydride. generally The reaction temperature ranges about -78oC to room temperature/ preferably to OoC. about -78oC The reaction time generally ranges about 30 minutes to 3 days, preferably about t hr to 1- day. -63l Step 3 Compound can be obtained by reacting Compound [X-13] presence with carbon tetrabromide in the of [X-12] triphenylphosphine in a solvent,.
The sol-vent. f or the reaction includes f or example, hyd.rocarbon xylene, and. solvent such as benzene, toluene, hexane; halogenated solvent such as methylene chloride, chloroform, carbon tetrachloride, and 1, 2-dichloroethane; and ethers solvent such as diethyl ether, tetrahydrofuran, dioxane, I,2-dimethoxyethane, which may be and diglyme, pref used alone or as a mj-xture of two or more. The erred solvent for the reaction incl-udes toluene, methylene chloride, and hexane.
The reaction temperature generally rangies about -30oC to 100oC, preferably about OoC to room temperature.
The reaction time generally ranges about 30 minutes to 3 days, preferably about 30 minutes to 1- day. _641 Preparation method 28 Preparation method 2B \$.*'r{}O-oc AUX-H x-231 tx-21'l n ,.o-Po1 (o-P"' Y ..1 HoA._-v=T ou"J.._,r{ x-2o Ex-221 Gep 1* Step 2 tx-241 (a-Po ou*\t'{ AUX)1-'.f{ 'q;,;.pb-u" '\*/Vo'R' Step 3 Step 4 x-26 x-251 (a-P e ro-t \-n4 H.c.ru&t'4 (\"' An'1o-*. *\"' li HrC'o '\r'Yo-*' At].
Step 5 Step 6 x-27 one examp le of AUX-H ax-z1t Y*-* [01-6s] Step l- reaction of Compound can be obtained by the lX-221 presence Compound with Reactant in the of a [X-20] lX-2]-l condensing agent in a solvent.
The solvent for the reaction includes for example, hydrocarbon solvent such as toluene, xylene, and benzene, hexane; halogenated solvent such as methylene chloride, chloroform, carbon 1, 2-dichloroethane; tetrachl-oride, and ethers solvent such as diethyl ether, tetrahydrofuran, dioxane, L,2-dimethoxyethane, polar and diglyme; and solvents such as N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, and acetone, which may be used alone or as a mixture of two or more. preferred for the The solvent reaction includes methylene chloride, chloroform, and N,N- dimethylformamide The condensing agent for the reaction includes for example, (WSC'HCI: (3- water-soluble carbodiimide 1-ethy1 dimethylaminopropyl)carbodiimide ff,N' hydrochtoride), - (DCC), dicyclohexylcarbodiimide diphenylphosphoryl azlde (DPPA), (CDI) and carbonyldiimidazole 1- . As appropriaLe, (HOBI hydroxy- 7H-benzotriazole monohydrate H2O) 4- dimethylaminopyridine (DMAP) and t,he like may be added.
Tha nraForrarl condensing agent for the reaction includes a mixture (WSC'HCI: of water-soluble carbodiimide 1-ethy1 (3-dimethylaminopropyl) and 1-- carbodiimide hydrochloride) (HOBL hydroxy- 7H-benzotriazole monohydrate HzO) and a mixture (WSC' of water-solubIe carbodiimide HCl : 1-et.hyl (3-dimethylaminopropyl)carbodiimide hydrochloride) and 4- dimethylaminopyridine (DMAP) The generally reaction temperature ranges room temperature preferably to about i-2OoC, room temperature to about 1-00 The reaction generally minutes time ranges about 30 to 3 days, preferably about t hr to 1 day. [016 ] Step 2 Compound can be obtained by the reaction of lX-241 Compound with presence of a Reactant in the lX-221 [X-23] base in a solvent. solvent f or t,he reaction includes f or example, hydrocarbon solvent such as benzene, toluene, xylene, and hexane; ethers solvent such as diethyl ether, tetrahydrofuran, and diglyme; dioxane, 1, 2-dimethoxyethane, polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, which may be used and acetone, preferred alone or as a mixture of two or more. The solvent for the reaction includes tetrahvdrofuran.
The base for the reaction includes for example, sodium hexamethyldisilazide, lithium hexamet.hyldisilazide, and (LDA). lithium diisopropylamide preferred base for the reaction includes sodium hexamethvldisilazi-de and lithium hexamethyldis i laz ide .
The reaction temperature generally ranges about -78oC to preferably 50oC, about -78oC to room temperat.ure. 1-3 3 The reaction time generally ranges about 30 minutes preferably 3 days, about 30 minutes to 1 day.
Step 3 removal of the Compound can be obtained by lx-251 protecting group Po1 from Compound in a solvent. lx-241 group, the When the protecting group Po1 is a benzyl protecting group removed by the catalytic may be pressure medium hydrogenation reaction under normal or pressure (for example, 3 atm).
The catalyst for the catalytic hydrogenation reaction carbon, includes for example, palladium on activated pref pallad.ium Raney nickel-. The erred hyd.roxide, and palladium activated catalyst for the reaction inc1udes on carbon, palladium hydroxide. reaction The sol-vent for the catalytic hydrogenation such as methanol, includes for example, alcohols solvent ethanol, isopropyl and tert-butanol; esters alcohol, and butyl solvent such as ethyl acetaLe, methyl acetate, acetate; such as diethyl ether, ethers sol-vent diglYme; tetrahydrofuran, dioxane, l-, 2-dimethoxyethane, and acetic which may be used alone or as acid, and water, pref f the mixture more. The erred sol-vent or of two or ethyl acetate, and reaction includes methanol, ethanol, tetrahvdrofuran. i nn f amna13l11gg The lggnf generall-y ranges room temperature to preferabl-y room to about 10OoC, temperature about 80oC.
The reaction generally time ranges about 30 minutes to 7 days, preferably about l- hr to 5 days.
Step 4 Compound can be obtained by introducing the lX-261 protecting group Po into Compound in a solvent. lx-251 group, When the protecting group Po is a sily1 Compound can be obtained by using silylation agent. lX-261 in the presence of a base. solvent f or the reaction includes f or example, esters solvent methyl and such as ethyl acetate, acetate, butyl acetate; ethers sol-vent such as diethyl ether, tetrahydrofuran, dioxane, !,2-dimethoxyethane, and diglyme; and polar solvents dimethyl such as N,N-dimethylformamide, sulfoxide, acetonitrile, and acetone, which may be used alone or as a mixture of or more. The preferred solvent for the reaction inc1udes N,N-dimethylformamide. j-ncludes base for the reaction for example, preferred triethylamine, pyridine, and imidazoJ-e. The base the reaction includes i-midazole.
The silvlation aqent for the reaction includes for example, tert butylchlorodiphenyl s i 1ane, tert- t_3 5 butylchlorodimethyl i lane, s and tert-butyldimethylsilyl trifluoromethanesul-fonate. The preferred silylation agent for the reaction includes tert-butylchlorodiphenylsilane.
The reaction temperature generally ranges room temperature to about 100oC, preferably room temperature to about. 80oC.
The reaction time generally ranges about 30 minutes to 3 days, preferably about t hr to 1 day. [016e] 1-0 Step 5 Compound hydrolysis reaction lx-Zll can be obtained by of Compound in a solvent under the commonly-used lX-261 condition. The hydrolysis may be performed under reaction the alkaline or acidic condition.
The base f includes f or or t.he alkaline condition example, dfl agueous solution metal hydroxide such of alkali as potassj-um lithium hydroxide, sodium hydroxide, and hydroxide; and inorganic peroxide as Iithium peroxide, such potassium peroxide, preferred. and sodium peroxide. The peroxi-de. zv base f or the reaction incl-udes lithium The acid for the includes for example, acidic condition hydrochloric sulfuric acid, acetic acid, hydrobromic acid, acid, p-toluenesulf acid trif luoroacetic acJ-d, and onic monohydrate. preferred includes The acid for the reaction hydrochloric p-toluenesulfonic acid, acetj-c acj-d, and acid monohydrate.
The solvent for the reaction includes for example, hydrocarbon solvent xylene, and such as benzene, toluene, hexane; alcohols solvent as methanol, eLhanol, such isopropyl aIcohol, and tert-butanol; halogenated solvent such as methylene carbon chloride, chloroform, tetrachloride, and 1, 2-dichloroethane; ethers solvent such as diethyl ether, dioxane, a,2- tetrahydrofuran, dimethoxyethane, polar such as N,N- and diglyme; solvents t_0 dimethylformamide, dimethyl sulfoxide, acetonitrile, and acetone; acetic acid, and water, which may be used alone or as a mixture preferred of two or more. The solvent. for the reaction includes tetrahydrofuran, and water.
The reaction temperature generally ranges about -30oC to 80oC, preferably room temperature. about OoC to The reaction time generally ranges about 30 minutes to 3 days, preferably about 30 minutes to 1- day. [017 ] Step Compound the reaction of can be obtained by [X-28] Compound witfr N,O-dimethylhydroxylamine or lX-27I hvdrochloride presence agenL thereof in the of a condensing in a solvent. solvent for the react,ion includes for example, hydrocarbon xylene, and solvent such as benzene, toluene, L3'7 hexane; halogenated solvent such as methylene chloride, chloroform, carbon tetrachloride, and 1, 2-dichloroethane; ethers solvent such as diethyl ether, tetrahydrofuran, polar dioxane I,2-dimethoxyethane, and diglyme; and solvents such as N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, and acetone, which may be used alone or as a mixture pref of two or more. The erred so1vent f or the reaction includes methylene and N,N- chloride, chloroform, dimethylformamide j-on j-ncludes The condensing agent f react f or or the (WSC'HC1: (3- example, water-soluble 1--ethy1 carbodiimide dimethylaminopropyl)carbodiimide hydrochloride), N,N' - (DCC), dicyclohexylcarbodiimide diphenylphosphoryl azide (DPPA), (CDI) and carbonyldiimidazole . As appropriate, 1- (HOBL hydroxy- J-H-benzotriazole monohydrate HzO) 4- dimethylaminopyridine (DMAP) and the like may be added. preferred The condensing for reaction includes a agent the (WSC' mixture of water-sol-uble carbodiimide HCl : 1-ethyl (3-dimethylaminopropyl)carbodiimide hydrochloride) and 1-- (HOBL hydroxy- 7H-benzotriazole H2O) and a monohydrate mixture (WSC'HCI: of water-soIubIe carbodiimide 1-ethy1 (3-dimethylaminopropyl) carbodiimide hydrochloride) and 4- (DMAP) dimethylaminopyridine .
The reaction generally ranges room temperature temperature to about A20oC, preferably room temperature to about 100oC.
The reaction generally about 30 minutes to time ranges preferably 3 days, about t hr to 1 day. [01-71] Preparation method 2C Preparation method 2C Ru-\'r-B' H3C-O,N o ,a-Po ro_t.
Et lt arl | )# IX-131 ./r/\-./.Ya:( ^"/-,(Yq {'-t [rr, bJ -t"-\oto' '\"/-Vo-n [x-z8l * lt.pi tx-3il x-30] -g-po (o-Po P-H a" P-!$ n"-o n"{\'."e4 n{A--v4 lx-33J I /l *f t\"-+\Por*' ,\.*po.o Step 3 step 4 x-34 x-321 o\,oH g-ru P-N roH -'-yvv4 o.J' \\ ,4 n ),-^.tr t(tn' '\".-*{,por*" '\'^Yo'*' G;;" Step 6 x,36 x-351 ,,*-*-fl-*o' *osn*an X-34 9-t't Step 7 Step 8 x-3BI alkyl =c1-n g9-co ,o-.1.1 -ouJ,-= loLt2l Step 1 Compound by the reaction of can be obtained [X-30] Compound presence with Compound in the of [X-28] [X-13] base in a solvent.
The solvent for the reaction includes for example, hydrocarbon solvent such as benzene, toluene, xylene, and hexane; halogenated solvent such as methylene chloride, chloroform, carbon tetrachloride, and 1, 2-dichloroethane; and ethers solvent such as diethyl ether, tetrahydrofuran, dioxane, !,2-dimethoxyethane, and diglyme, which may be preferred used alone or as a mixture of two or more. The j-ncludes solvent for the reaction toluene, tetrahydrofuran, methylene chloride, and hexane. base for the reaction includes for example, butyllithium, methyllithium, ethylmagnesium bromide, (LDA) lithium preferred diisopropylamide and the like. The base for the reaction includes butyllithium, and l-ithium diisopropylamide (LDA) The reaction generally ranges about temperature -78oC preferably to 50oC, about to room temperature. -7BoC The generally reactj-on time ranges about 30 minutes to preferably 3 days, about t hr to 1- day. [017 ] Step 2 Compound can be obtained by the reaction of [X-31] Compound with O-methylhydroxylamine or hydrochloride [X-30] thereof in a solvent. solvent for the reaction includes for example, alcohols solvent isopropyl such as methanol, ethanol, and alcohol; hyd.rocarbon solvent such as benzene, toluene, xylene, and hexane; halogenated solvent such as methylene chloride, chloroform, L,2- carbon tetrachloride, and dichloroethane; ethers solvent such as diethyl ether, tetrahydrofuran, d.ioxane L and diglyme; , ,2-dimethoxyethane, polar and solvents such N,N-dimethylformamide, dimethyl sulfoxide, pyridine, acetonitrile, and acetone; water, and which may be used alone or as a mixture of two or more.
The preferred solvent for the reaction includes methanol, ethanol, pyri-dine, methylene tetrahydrofuran, toluene, 1_5 chloride, and hexane.
The reaction generally temperature ranges about -l-OoC preferably to 50oC, about OoC to room temperature.
The reaction time generally ranges about 30 minutes to 3 days, preferably 1 about t hr to day. 1077 Step 3 Compound can be obtained by the cyclization [X-32] reactj-on of Compound in the presence of halogen or [X-31] organohalide in a solvent.
The solvent for the reaction includes for example, hydrocarbon solvent such as benzene, toluene, xylene, and hexane; halogenat,ed solvent as methylene chlorj-de, such chloroform, carbon tetrachloride, and L,2-dichloroethane; ethers solvent such as diethyl ether, teLrahydrofuran, dioxane, L,2-dimet,hoxyethane, and diglyme; polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide, acetonit,rile, and acetone, which may be used alone or as a preferred mixture of two or more. The solvent for the reaction includes acetonitrile, and methvlene chloride.
The halogen or organohalide for the reaction includes for example, bromine, iodine, N-bromosuccinimide, N- iodosuccinimide, preferred and iodine monochloride. The halogen or organohal-ide for the reaction includes iodine, and iodine monochloride. 1-5 The reactj-on generally temperature ranges about -l-OoC preferably to 50oC, about ooC room temperature.
The reaction generally time ranges about 30 mlnutes to 3 days, preferably about 30 minutes to 1 day. [017s] Step 4 Compound can be obtained by the reaction of [X-34] Compound presence with Compound in the of a [X-32] [X-33] metal catalyst in a sol-vent.
When Compound 3 3 is alkylboronic ac [X- ] arylboronic acid, the acid" moiety thereof "boronic boronic acid itself and preferably an or an ester thereof, ester thereof. As Compound an alkylzinc or [X-33], arylzinc reagent,, or arylmagnesium dil alkylmagnesium reagent or the like may be used.
The solvent for the reaction includes for example, hydrocarbon solvent toluene, xylene, and such as benzene, hexane; ethers sol-vent. such as diethyl ether, tetrahydrofuran, dioxane, and diglyme; L,2-dimethoxyethane, polar solvents such N,N-dimethylformamide, dimethyl sulfoxide, water, which may acetonitrile, and acetone; and be used alone or as a mixture of two or more. The pref erred solvent f or the react.ion includes N, N- dimethylformamide The metal catalvst for the reaction includes for example a palladium such as catalyst (triphenylphosphine)palladium(II) bis dichloride, and !,!' (diphenylphosphino) bis (rr) ferrocene-palladium dichloride, preferably ( ( bis palladium II d.ichloride . triphenylphosphine ) The metal catalyst for the reaction also includes a nickel as catalyst such lL,2- (diphenylphosphino) (II) bis ethanel nickel dichloride, and (II) nickel such as acetylacetonate, and an iron catalyst iron(III) chloride. may be As appropriate, a base or an inorganic salt added. 1,44 The base inorganic for the reaction includes or salt. for example, alkali metal phosphate such as tripotassj-um phosphate; as sodium carbonate, alkali metal carbonate such and potassium carbonate; alkali metal acetate such as sodium acetate; and fl-uoride salt such as cesium fluoride and preferably phosphate. the 1ike, tripotassium The reaction temperature generally ranges about -l-OoC to l-50oc, preferably about OoC to 100oC.
The reaction time generally ranges about 30 minutes t,o preferably 3 days, about t hr to 1 day.
Step 5 Compound by removal of the can be obtained [X-35] protecting presence group Po from Compound. in the of [X-34] (TBAF) tetrabutylammonium in a solvent. fluoride The for reaction includes for example, solvent the isopropyl alcohols solvent such as methanol, eLhanol, alcohol, solvent such as ethyl and tert-butanol; esters acetate, methyl acetate, and butyl acetate; hydrocarbon solvent xylene, and hexane; such as benzene, toluene, ethers solvent ether, tetrahydrofuran, such as diethyl polar solvents dioxane, L,2-dimethoxyethane, and diglyme; sulfoxide, such as N,N-dimethylformamide, dimethyl water, which acetonitrile, and acetone; acetic acid, and may two or more. be used alone or as a mixture of 1,45 preferred The solvent for the reaction includes methanol, acetic ethanol, ethyl acetate, tetrahydrofuran, acid, and water.
The reaction temperature generally rangles about -l-Ooc to 150oC, preferably about OoC to B0oC.
The reaction time generally ranges about 30 minutes to preferably days, about t hr to 3 days. l0r77l Step 6 l_0 Compound by the reaction of can be obtained [X-36] Compound in the presence of an oxidant in a solvent.
[X-35] The for example, oxidant for the reaction includes (TEMPO), 2,2,6,5-tetramethyl-piperidinyloxy radical potassium peroxide, permanganate, aqueous hydrogen pyridinium preferred dichromate, and oxide. The chromium oxidant for the reaction includes 2,2,6,6-tetramethyl- (TEMPO) piperidinyloxy radical Alt,ernatively, Compound can be prepared by [X-36] obtaining and the an aldehyde derj-ved from Compound [X-35] , pyridinium oxidant for t,he reaction includes for example, (PCC), (PDc), and dichromate pyridinium chlorochromate (DMSO) dimethyl sulfoxide by oxa1y1 chloride, activated Dess-Martin reagent, and sodium chlorite.
The for example, solvent for the reaction includes halogenated solvent methylene chloride, chloroform, such as ]-46 carbon tetrachlorj-de, and A,2-dichloroethane; ethers solvent such as tetrahydrofuran, dioxane, diethvt ether. 1,2-dimethoxyethane, and diglyme; polar solvents such as IV-dimethylf ormamide, dimethyl sulf oxide, acetonj-tri1e and acetone; and water, which may be used alone or as a preferred mixture of two or more. The solvent for the reaction includes methylene chloride, chloroform, tetrahydrofuran, acetonitrile, and water. generally The reactj-on temperature rangles about -10oC t_0 to l-50oc, preferably about to 80oC.
The reaction time generally ranges about 30 minutes to days, preferably about t hr to 3 days. [01-78] Step 7 Compound a1kyl group) can be obtained [x-38] Cr-e by the reaction of Compound with Reactant in [X-36] [X-37] the presence in a solvent under the of a condensing agent condition of a common amide bond formation reaction.
The for example, solvent for the reaction includes hydrocarbon solvent .such toluene, xylene, and as benzene, hexane; halogenated solvent such as methylene chlorj-de, chloroform, carbon and 1,2-dichloroethane; tetrachloride, ethers sol-vent such as diethyl ether, tetrahydrofuran, dioxane, polar solvents !,2-dimethoxyethane, and diglyme; such as dimethyl sulfoxide, N,IV-dimethylformamide, used alone or as a acetonitrile, and acetone, which may be preferred solvent for the mixture of two or more. The reaction chloroform, and N,N- incl-udes methylene chloride, dimethylformamide . reaction includes for The condensing agent for the (WSC'HCI: example, water-soluble 1-ethyl carbodiimide N,N' dimethylaminopropyl)carbodiimide hydrochloride), - (Dcc), azide dicyclohexylcarbod.iimide diphenylphosphoryl (DPPA), (cDI), (7- and O- cdrbonyldiimidazole azabenzotriazole- N' tetramethyluronj-um 1-yl) - N N N' - , , , , (HATU) hexafluorophosphate . As appropriate, 1-hydroxy-7H- (HOBL HzO) 4- benzotriazole monohydrate (DMAP), dimethylaminopyridine N,N-diisopropylethylamine and the like may be added. reaction The preferred condensing agent for the (WSC'HCI: includes a mixture of waLer-soIubIe carbodiimide 1 carbodiimide -ethyl 3 -dimethylaminopropyl hydrochloride) monohydrate and 1-hydroxy-J.H-benzoLrLazole (HOet' (7-azabenzotriazoleyt) - H2O) and a mixture of O- (HATU) N,N,N',N'r-tetramethyluronium hexafluorophosphate and N, N-di isopropylethylamine . [017 ] generally rangies room The reaction temperature preferably room temperature to temperature to about L20oC, za about l-00 1,48 The reactj-on generally rangies about 3 0 minutes to time 3 days, pref erably about l- hr to 1 day. [01-80] Step I Compound hydrogen) can be obtained from Compound group) in a solvent under Cr-e a1ky1 [X-38] the condition of a common ester hydrolysis reaction. The ester performed under the hydrolysis reaction may be alkaline or acidic condition. includes for The base for the alkaline condition example, metal hydroxide such dfl aqueous solution of alka1i potassium as lithium hydroxide, sodium hydroxide, and hydroxide. preferred for the reaction includes The base aqueous sodium hydroxide, and aqueous lit.hium hydroxide.
The includes for examPle, acid for t.he acidic condition hydrochloric acid, hydrobromic acid, sulfuric acid, and preferred reaction trifluoroacetic acid. The acid for the includes acid, and hydrochlorj-c acid, hydrobromic trifluoroacetic acid. for example, The solvent for the reaction includes hydrocarbon toluene, xylene, and solvent such as benzene, ethanol, hexane; alcohols solvent such as methanol, isopropyl halogenaLed solvent aIcohol, and tert-buLanol; carbon such as methylene chloride, chloroform, solvent such tetrachloride, and 1, 2-dichloroethane; ethers 1,49 as L,2- diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and sol-vent such as ethyl diglyme; esters polar acetate, methyl acetate, and butyl acetate; and preferred solvent such as acetic acid and water. The solvent for the reaction includes methanol, ethanol, methylene chl-oride, chloroform, tetrahydrofuran, toluene, acetic acid, and water.
The reaction temperature gienerally ranges about 0oC to 12OoC, preferably 1OOoC. room temperature to about The reaction t.ime generally ranges about 30 mj-nutes to preferably 3 days, about 1- hr to 1 day. [01-8]-l In Step 1 of Preparation method 28, a racemic form of may give hydrogen) [x-zr1 be used to Compound tI] product. which is in racemic form as a final Preparation method 3 The case of that the 5-membered ring is isoxazole: ,Gi-co Gb-'"\ The case of that Y' is singte bond or a1kylene.
Preparation A method 3 R".-\..Br R"/\oH Preparationmethod 3B eUXl On,^\)n"r *"\--** (\y;^i(,o'r" r Y" o\-11n"' o"fi-v*Qn" ,9:-co n"-al^rJ"r *osn*ue x-431 I -t'-t{ q$'y'Vjt o"o-Rc Rr-H ou,. . .9:'qo X44l -c'ooc\= [x47] tx45l -831 Preparation method 34' Preparat i on method A ---------------- n'Aog R"Att-cH.
Step 1 -CH, .-i: Step 2 Step 3 preparation performed in a The method 3A may be similar method 24. manner to that described in Preparation 0184 Preparation method 38 Preparation method 3 B "'\n"r {\s{io=ro V)n"z Step 1 lx4fl x.4o] o-ec O\,,o-Pc AUXA\ oux\t'-?rn' AUX.H I x42l )no I r\rir^\2o.tro (\yA\2o.tro -,YH x44l Step 2 x43] x45] oto-ec oYo-Pc il ,"1 nru-N-\.rf{ ,oA-","*; ($r-{2o-.o t$,{^}{2o:ro H,c'- Step x46] ax47l [018 ] Step Compound can be obtained by t.he reaction of [X-41] Compound with a benzyl halide in the presence of [X-40] base in a solvent.
The solvent for the reaction includes for example, hydrocarbon solvent such as benzene, toluene, xylene, and hexane; and ethers solvent such as diethyl ether, tetrahydrofuran, dioxane, L,2-dimeLhoxyethane, and diglyme, which mav be used alone or as a mi-xture of two or more. preferred The solvent for reaction includes toluene.
The base for t,he reaction includes for example, dfl aqueous solution such as lithium of alkali metal hydroxide hydroxide, sodj-um hydroxide, and potassium hydroxide. The preferred base for the reaction includes potrassaum hydroxide.
The reactj-on generally room temperature ranges temperature to about 180oC, preferably room temperature to about 150oC.
The reaction generally time ranges about 30 minutes to 3 days, preferably about t hr 1 day.
Step 2 Compound can be obtained by the reaction of [X-43] Compound presence al with Reactant in the of a lK- lX-421 condensing agent in a sol-vent. solvent for the reaction includes for example, hydrocarbon solvent xylene, and such as benzene, toluene, hexane; halogenated solvent such as methylene chloride, chlorof orm, carbon 1-, 2 tetrachloride, and -dichl-oroethane; ethers solvent such as diethyl ether, tetrahydrofuran, dioxane, polar 7-,2-dimethoxyethane, and diglyme; and solvents such N,N-dimethylformamide, sulfoxide, as dimethyl acetonitrile, and acetone, which may be used alone or as a Tha nrcfcrrgd mixture Of twO SOI-vent fOr the Or mgre. reaction includes methylene chloride, chloroform, and N,N- dimethylformamide The condensing agent for the reaction includes for (WSC'HCl: example, water-soluble carbodiimide 1-ethyl dimethylaminopropyl)carbodiimide hydrochloride), (DCC), dicyclohexylcarbodiimide diphenylphosphoryl azide (DPPA), (CDI) 1- and carbonyldiimidazole . As appropriate, (HOBL hydroxy- 4- 7H-benzotriazole monohydrate H2O) (DMAP) dimethylaminopyridine and the like may be added. preferred reaction The condensing agent for the (WSC'HCl: includes mixture carbodi-imide a of water-so]uble 1-ethy1 3 -dimethylaminopropyl carbodiimide hydrochloride) monohydrate and 1-hydroxy-lH-benzotriazole (HoBf .
T{-o) rrvv e LLzv and a mixture of water-soluble carbodiimide (WSC (3-dimethylaminopropyl) HCI : 1-ethyl carbodiimide (DMAP) hydrochloride) and 4-dimethylaminopyridine . nn famna64l111g The generally ranges room lgaafi temperature to about l-20oc, preferably room temperature to about 100oC.
The reaction generally ranges about 30 minutes to time preferably 3 days, about t hr to l- day. -871 Step 3 j-on react of Compound can be obtained by the [X-45] Compound with in the presence of a [x-43] Reactant lx-441 base in a solvent.
The for example, solvent for the reaction includes hydrocarbon solvent such as benzene, toluene, xylene, and hexane; ether, ethers solvent such as diethyl tetrahydrofuran, dioxane, 1, 2-dJ-methoxyethane/ and diglyme; polar and solvents such as N,JV-dimethylformamide, dimethyl sulfoxi-de, acetonitrile, and acetone, which may be used preferred alone or as a mixture of two or more. The solvent for the reaction includes tetrahyd.rofuran.
The base for the reaction includes for example, sodium hexamethyldisilazide, Iithium hexamethyldisilaz:-de, and (LDA).
Iithium diisopropylamide The preferred base for the reaction includes sodium hexamethvldisilazide and lithium hexamethyldi s i 1az ide .
The reaction temperature generally ranges about -78oC to 50oC, preferably about -78oC to room temperature.
The reaction time generally ranges about 30 minutes to preferably 3 days, about 30 minutes to 1 day. -8I l Step Compound by hydrolysis reaction can be obtained [X-46] of Compound in a solvent under the commonly-used [X-45] condition. performed under The hydrolysis reaction may be the alkaline or acidic condition.
The base for the al-kaline condition includes for example, dfl aqueous aIkali metal hydroxide such solution of potassium as lithium hydroxide, sodium hydroxide, and hydroxide; peroxide lithium peroxide, inorganic such as potassium preferred peroxide, and peroxide. The sodium r_5 5 peroxide. base for t.he reaction includes lithium The acid for the acidic condition includes for example, hydrochloric acid, acetic acid, hydrobromic acid, sulfuric acid, trif luoroacetic acid, and p-t.oluenesu1f onic acid monohydrate. preferred reaction includes The acid for the hydrochloric p-toluenesulfonic acid acid, acetic acid, and monohydrate.
The solvent for the reaction incl-udes for example, hydrocarbon solvent such as benzene, toluene, xylene, hexane; alcohols solvent such as methanol, ethanol, isopropyl alcohol, and tert-but.anol; halogenated solvent such carbon as methylene chloride, chloroform, tetrachloride, and 1, 2-dichloroethane; ethers solvent such as L,2- diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and polar solvents such as N,N- diglyme; dimethylformamide, dimethyl sulfoxide, acetonitrile, acetone; acetic water, which may be used alone or acid, and as a mixture of two or more. The preferred solvent for the reaction includes water. tetrahydrofuran, and The reaction temperature generally ranges about -30oC preferably to 80oC, about OoC to room temperature.
The reactj-on time generally ranges about 30 minutes to 3 days, preferably about 30 minutes to l- day. [018e] Step 5 l_5 6 Compound reaction of can be obtained by the lX-471 Compound or and N, O-dimethylhydroxylamine lx-451 hydrochloride presence thereof in the of a condensing agentr in a solvent.
The solvent for the reactj-on includes for example, hydrocarbon solvent such as benzene, toluene, xylene, and hexane; halogenated solvent such as methylene chloride, chloroform, carbon tetrachloride, and 1, 2-dichloroethane; ethers solvent such as diethyl ether, tetrahydrofuran, polar dj-oxane 7-, 2 -dimethoxyethane, and diglyrne; and solvents such as N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, which may be used afone or as a and acetone, mixture preferred of two or more. The solvent for the reaction N,ff- includes methylene chloride, chloroform, and dimethylformamide .
The for condensing agent for the reaction includes (WSC'HCl: (3- example, water-soluble 1-ethy1 carbodiimide dimethylaminopropyl)carbodiimide hydrochloride), N,N' - (DCC), dicyclohexylcarbodiimide diphenylphosphoryl azide (DPPA), zv (cDr) l-- and carbonyldiimidazole . As appropriate, hydroxy- (HOBL H2O) 4- 7H-benzotriazole monohydrate (DMAP) dimethylaminopyridine and the like may be added.
The preferced a condensing agent for the reaction includes (wsc'HCl: mixture water-soluble 1--ethy1 of carbodiimide (3-dimethylaminopropyl) 1-- carbodiimide hydrochloride) and (HOBL hydroxy- l-H-benzotriazole monohydrate HzO) and a (WSC' mixture of water-soluble carbodiimide HCI : 1--ethyl (3-dimethylaminopropyl)carbodiimide hydrochloride) and 4- (DMAP) dimethylaminopyridine .
The reaction generally room temperature ranges temperature to about 7-20oC, preferably room temperature to about 100oC.
The reaction time generally ranges about 30 minutes to 3 preferably days, about t hr to 1- day. [01-e0] Preparation method 3C Preparation method 3 c l{3c-o-N o"^r-t' [X-13 ] Pe q.rylorro lx4il Step 2 Step 1 x,511 x"50] ,O-N o\ro-Pc ,o-N nl-e --\&v-1#1pa x-53 Step 3 Step 4 ,$ry:o.ro njt9o-ro oYo-Pc o\.o-P y*a-Jy n. P{ 1no ,V^$o* $**q;oH Step 6 x.s6r Step x-551 oYoH .,o-N oro-r' --}\'-y'.!+l \ yd!--p nd ( Step \ncr -P-) Step ? '\$^Vor*" tx-ssr X.54 'd3 *:;t *" o*,H-trkl*., Gi.co *-oi'l;r*.},.. **\* .:ril-tf{":" Rou' hoo '--1:-,f 1A',yer=/ I 'V'47o-o" ,l*'1^n.,-o- Step 9 'VoVo'*' s6p-To rLeP I u tx-aol R":cr+alkyl _<li _"i':. coG\ )-\- 0]-e1l Step l.'rrr I h o Compound reaction of can be obtained [x-50] * f1^^ f II LIIS presence of Compound with Compound lX-47I [X-13] base in a solvent.
The solvent for the reaction includes for example, xylene, and hydrocarbon solvent such as benzene, toluene, hexane; halogenated as methylene chloride, solvent such chloroform, carbon tetrachloride, and 1, 2-dichloroethane; and tetrahydrofuran, ethers solvent such as diethyl ether, dioxane, L,2-dimethoxyethane, and diglyme, which may The preferred used alone or as a mixture of two or more. solvent for the reaction includes t.etrahydrofuran, toluene, for the reaction methylene chloride, and hexane. The base includes methyllithium, for example, butyllithium, (LDA) ethylmagnesium bromide, lithium diisopropylamide j-ncludes the preferred reaction like. The base for the (LDA) butyllithium, and lithium diisopropylamide . generally about The reaction temperature ranges -78oC to 50oC, preferably to room temperature. about -'78oC The reaction time generally ranges about 30 minutes preferably 3 days, about t hr to 1 day. _e2l Step 2 j-on Compound 51] can be obtained by the react Compound with o-methylhydroxytamine or hydrochl-oride [X-50] 1_6 0 thereof in a solvent. solvent for the reaction includes for example, alcohols solvent such as met.hanol-, ethanol, and isopropyl alcohol; hydrocarbon solvent such as benzene, toluene, xylene, methylene and hexane; halogenated solvent such as chloride, chloroform, carbon tetrachloride, and A,2- dichloroethane; ethers solvent such as diethyl ether, tetrahydrofuran, L,2-dimethoxyethane, and diglyme; dioxane, polar solvents dimethyl such as N,N-dimethylformamide, l_0 sulfoxide, water, and pyridine, acetonitril-e, and acetone; which may be used alone or as a mixture of two or more.
The preferred includes methanol, solvent for the reaction ethanol, pyridine, toluene, methylene tetrahydrofuran, chloride, and hexane.
The react.ion temperature generally ranges about -l-0oC preferably to 50oC, about OoC to room temperature.
The reactj-on generally about 30 minutes to time ranges 3 days, preferably about t hr to 1 day. 01e3 Ql-an 2 Compound can be obtained by the cyclization [x-52] reaction of presence of halogen or Compound in the [X-51] organohalide in a solvent.
The for example, solvent for the reaction inc1udes hydrocarbon toluene, xylene, and solvent such as benzene, hexane; halogenated solvent such as methylene chloride, chloroform, carbon tetrachloride, and 1, 2-dichloroethane; ethers sol-vent tetrahydrofuran, such as diethyl ether, polar dioxane, L,2-dimethoxyethane, and diglyme; and solvents such as N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, and acetone, which may be used alone or as a preferred mixture of two or more. The solvent for the reaction includes acetonitrile, and methylene chloride.
The halogen or organohalide for the reaction includes f or example, N- bromi-ne iodine, N-bromosuccinimide, iodosuccinimide, and iodine monochloride. The preferred halogen or halide for the reaction incl-udes iodine, and iodine monochloride.
The reaction temperature generally ranges about -l-Ooc to 50oC, preferably room temperature. about OoC to The reaction time generally ranges about 30 minutes to 3 preferably days, about 30 minutes to 1- day. 01e4 Step 4 Compound by the reaction of can be obtained [X-54] presence Compound with Compound in the of a [X-52] [x-53] metal catalyst in a solvent.
When or arylboronic Compound is alkylboronic [X-53] itself acid, these may be alkylboronj-c or arylboronic acid or an ester thereof is preferred. thereof, and the ester the Compound an alkylzinc or arylzinc reagent, [X-53], an alkylmagnesium or arylmagnesium reagent or the like may be used. j-on The sol-vent f or the react includes f or example, hydrocarbon solvent such as benzene, toluene, xylene, and hexane; ethers solvent as diethyl ether, such tetrahydrofuran, dioxane, 1, 2-dimethoxyethane, and diglyme; polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, and acetone; and water, which may be used alone or as a mixture of two or more. The preferred solvent N,N- for the reaction includes dimethvlformamide The metal catalyst for the reaction includes for example, palladium catalyst such as bis triphenylphosphine palladium A,!' II dichloride, and (diphenylphosphino) bis ( f errocene-palladium II dichloride, preferably (triphenylphosphine) ( bis palladium II dichloride.
The metal catal-yst f reaction also includes a or the ni-ckel Z- catalyst such LL r (diphenylphosphino) (II) bis ethanel nickel dichloride, and (II) nickel acetylacetonate, and an iron catalyst such as (III iron chl-oride .
As appropriate, a base or an inorganic sal-t may be added.
The base or inorganic for the reacLion includes salt for example, phosphate as trj-potassium al-kal-i metal such phosphate; alkaIi metal such as sodium carbonate, carbonate potassium and carbonate; alka1i metal acetate such as sodi-um cesium fluoride acetate; and f]uoride salt such as and the like, preferably cesium fluoride and tripotassium phosphate.
The generally ranges react.ion temperature about -10oC preferably to 150oC, about OoC to 100oC.
The generally minutes to reaction time ranges about 30 3 days, preferably about t hr to 1 day. -esl Step 5 Compound can be obtained by removal of the [X-55] protecting group in a solvent.
Po from Compound [X-54] group, When the protecting group P' is a benzyl the protecting group may be removed by the catalytic hydrogenation reaction under normal pressure or meoaum pressure (for example, 3atm). g4l3l rrcf f r:r f ha The reaCtiOn includeS f Or example, palladium on activated carbon, palladium hydroxide, and Raney preferred reaction nickel. The catalyst for the palladium includes palladium on activated carbon and hydroxide.
The solvent for reaction includes for example, isopropyl alcohols solvent such as methanol, ethanol, as ethyl alcohol, and tert-butanol; esters solvent such acetate, methyl acetate; ethers solvent acetate, and butyl such as diethyl ether, tetrahydrofuran, dioxane, !,2- dimethoxyethane, waLer, which and diglyme; acetic acid, and may be of two or more. The used al-one or as a mixture preferred solvent for the reaction includes methanol, ethanol, ethyl acetate, and tetrahydrofuran. generally The reactj-on temperature ranges room preferably to temperature to about 100oC, room temperature about 80oC. generally minutes to The reaction time ranges about 30 7 preferably days, about t hr to 5 days. [01e6] Ql-an C. v evv Compound can be obtained by the reaction [X-55] Compound presence in a solvent. in the of an oxidant [X-55] The oxidant for reaction includes for example, (TEMPO), 2,2,6,6-tetramethylpiperidinyloxy radical potassium permanganate, peroxide, agueous hydrogen pyridinium preferred dichromate, and chromium oxide. The -tetramethyl oxidant for the reaction includes 2,2,6, piperidinyloxy (TEMPO). radical Alternatively, Compound derived can be prepared by obtaining an aldehyde [x-55] from Compound for the reaction and the oxidant [X-55], (PDC), includes for example, pyridinium dichromate pyridinium (PcC) chlorochromate and dimethyl sulfoxj-de (DMSO) activated by oxaIyI chlorj-de, Dess-Martin reagrent, and sodium chlorite.
The solvent for the reaction includes for example, halogenated. solvent such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane; ethers solvent such as diethyl ether, tetrahydrofuran, dioxane, 1-,2-dimethoxyethane, may be and diglyme; and water, which preferred used alone or as a mixture of two or more. The j-on solvent f or t,he react includes methylene chloride, chloroform, tetrahydrofuran, water.
The reaction temperature generally ranges about -10oC to 150oC, preferably about OoC to 80oC.
The reaction time generally ranges about 30 minutes to 5 days, preferably about l- hr to 3 days. [01e7] Step 7 Compound alkylation reaction can be obtained by [X-57] of Compound in the presence of base in a solvent.
[X-56] The f example, sol-vent f or the reaction incl-udes or ethers solvent such as diethyl ether, tetrahydrofuran, dioxane and polar 7-,2-dimethoxyethane, and diglyme; solvents such as IV,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, and acetone, which may be used alone or as mixture f or the of t.wo or more. The nref erred solvent ]-66 reactrr-on includes N,N-dimethylformamide, and acetonitrile.
The base for the reaction includes for example, potassium carbonate, sodium carbonate, sodium hydrogen carbonate and the like. The nreferred base for the reaction includes potassium carbonate, and sodium carbonate. lTll^ I IIE^ alkylating agent for the reaction includes for example, methyl iodide, ethyl iodide and the like. The preferred alkylating agent for the reactj-on includes methyl iodide.
The reaction temperature generally ranges room temperature to about L2OoC, preferabty room temperature to about 100oC.
The reaction time generally ranges about 30 minutes to 3 days, preferably about 1- hr to 1 day.
Alternatively, Compound can be obtained by [X-57] reactr-ng presence Compound with an al-cohol in the of [X-56] a condensing agent, or by reacting Compound with [X-55] trimethyl s i lyldiazomethane . [01-e8] Step Compound can be obtained from Compound [X-58] [X-57] in a solvent under the acidic condition of ester hydrolysis reaction.
The acid for reaction includes for example, hydrochloric acid, hydrobromic acid, sulfuric acid, and 1,57 preferred trifluoroacetic acid. The acid for the reaction incl-udes hydrochloric acid, hydrobromic acid, and trifluoroacetic acid.
The solvent for the reaction includes for example, hydrocarbon solvent such as benzene, toluene, xylene, and hexane; halogenated solvent such as methylene chloride, chloroform, carbon tetrachloride, and 1-, 2-dichloroethane; ethers solvent such as diethyl ether, tetrahydrofuran, dioxane 1,2 esters solvent -dimethoxyethane, and digIyme,. such as ethyl acetate, methyl acetate, and butyl acetate; and polar The solvent such as acetic acid and water. preferred solvent for the reaction includes methylene chloride, chloroform, tetrahydrofuran, toluene, acet,ic acid, and water.
The generally reaction temperature ranges about 0oC tro L20oC, preferably room 100oC. temperature to about The reaction time generally ranges about l-0 minutes to 3 days, preferably about 3 0 mi-n. to l- dav.
Io]-eel Ql-an Compound group) obtained Cr-e alkyl can be [X-50] = the reaction of Compound with Reactant in [X-58] [X-59] the presence the of a condensing agent in a solvent under condition of a common amide bond formation reaction.
The for solvent for the reaction includes for exampl€, 1_5 8 exampl-e, hydrocarbon solvent such as benzene, toluene, xylene, such as and hexane; halogenated solvent dichloromethane, chloroform, carbon tetrachloride, and L,2- dichloroethane; ethers solvent such as diethyl ether, tetrahydrofuran, I,2-dimethoxyethane, and diglyme; dioxane, polar and solvents such as N,N-dimethylformamide, dimethyl sulfoxide, which may be used acet.onitrile, and acetone, pref al-one or as a mixture of two or more. The erred solvent for the reaction includes methvlene chloride, chlorof orm, and N, /V-dimethylf ormamide.
The condensing agent for the reaction incl-udes water- soluble (WSC carbodiimide HCl: 1-ethyl dimethylaminopropyl)carbodiimide hydrochloride), N,N' dicyclohexylcarbodiimide (DCC), azide diphenylphosphoryl / arnr \ (DPPA) (7- 1s carbonyldiimidazole and O- azabenzotriazole- 1-yI N, N, N', N', - tetramethyluronium (HATU) hexafluorophosphate 1--hydroxy-IH- . As appropriate, (HOBL benzotriazole monohvdrate H2O), 4- dimethylaminopyridine (DMAP), and N, JV-diisopropylethylamine the like may be added. The preferred condensing agent for t.he reaction includes a mixt.ure of waLer- soluble (wsc (3- carbodiimide .EILI : 1--ethy1 dimethylaminopropyl) carbodiimide hydrochloride) and (HOBL hydroxy- HzO) and a J-H-benzotriazol-e monohydrate mixture of O- -azabenzotriazole-yl) -NrN,N' ,N' ,- ]-69 tetramethyluronium hexaf luorophosphate and di i sopropylethytamine The reaction temperature generally rangies room temperature preferably to about L20oC, room temperature to about l-00oC.
The reactj-on time generally rangles about 3 0 minutes to 3 days, pr€ferably about t hr to 1 day.
Step 10 Compound hydrogen) can be obtaj-ned f rom Compound Cr-e a1ky1 group) in a solvent under [X-eO] the condit.ion hydrolysis reaction. The of a common ester ester hydrolysis reaction may be performed under the alkaline or acidic condition.
The base for the alkaline condition includes for example, such afl aqueous solution of a1kali metal hydroxide as lithium hydroxide, hydroxide, and potassium sodium hvdroxide. The preferred base for the reaction includes aqueous sodium hydroxide lithium hydroxide. and aqueous The acid for the acidic condition includes for example, hydrochloric and acid, hydrobromic acid, sul-furic acid, preferred trifluoroacetic acid. The acid for the reaction includes hydrochloric acid, hydrobromic acid, and trifluoroacetic acid.
The solvent for the reaction includes for example, hydrocarbon solvent such as benzene, toluene, xylene, hexane; methanol, ethanol, alcohols sol-vent such as isopropyl alcohol, and tert-butanol; halogenated solvent carbon such methylene chlori-de, chloroform, tetrachloride, and 1, 2-dichloroethane; eLhers solvent such L,2- diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, such as ethyl and diglyme; esters solvent polar acet,ate, methyl acetate, and butyl acetate; and like. sol-vent such as acetic acid, water and the preferred solvent for the reaction includes methanol, ethanol, methylene chloride, chloroform, tetrahydrofuran, toluene, acetic acid, water.
The reaction temperature generally rangies about 0oC 7-20oC, preferably 100oC. room temperature to about The reaction time generally ranges about 30 minutes to 3 preferably days, about t hr to l- day.
In Step 2 Preparation method 38, dD racemic form of may be used to give Compound hydrogen) lx-42J trl product. which is i-n racemic f orm as a f inal 02 01] Preparation method 4 The case of that the 5-membered ring is triazole: ,G1-co ,rN--|\l -\t. do,-"\ Preparation method 4 C Preparation method 4 A ^d K\ K ^& otil-v"-$n' RLN" ,N----* -:- *'-t'i'J-rt'!,"" R*AR* x-73 x-70 t I (\<ti!.r-Jro-R.
Preparation method 4 B tx-1061 -o-P" =c," a lky I -o-P6 \n!,". *o\-to' ,\n^ffo_, ,oA-r'tl o*il-v*(lf n* .Gl-eo x-801 R"-Gioo.e: *o'n*o' v4r"" x-e0 tl t\t""!\}or*" u:'*\ 102021 Preparation 44' method Preparation method 4 A pe-p/ n"AOn Step 1 tx-711 x.70 R"-N' RLNHz Step 2 t,r* x-73 lx-721 4A includes the The example of Preparation method following scheme: 1,7 2 fH." FH, t'"1-*r\-1o Hrcl ,boc ---> a-il Step 1 Compound can be obtained by the reaction of [X-71] (DPPA) Compound wit.h azide and AII [X-70] diphenylphosphoryl presence alcohol in the of a base in a solvent. solvent for the reaction includes for example, alcohols solvent such as methanol-, ethanol, isopropyl alcohol, as and tert-butanol; halogenated solvent such methylene chloride, chloroform, carbon tetrachloride, and l-,2-dichloroethane; ethers solvent such as diethyl ether, t.etrahydrofuran, and diglyme; dioxane, 1, 2-dimethoxyethane/ esters solvent such as ethyl acetate, methyl acetate, and butyl polar ff,N- acetate; and solvent such as dimethylformamj-de, and acetonitrile. The preferred solvent for and the reaction includes tert-butanol, toluene, tetrahydrofuran.
The base for the reaction includes for example, organic N,N- base such as triethylamine, diisopropylethylamine, pyridine and the like. The preferred base for the reaction includes triethylamj-ne. for example, The alcohol for the reaction includes methanol, tert-butanoI, benzyl ethanol, isopropyt aIcohol, alcohol and the like. The nreferred alcohol for the reaction includes tert-butanol. generally ranges about 0oC to The reaction temperature l-50oC, preferably room temperature to about 100oC. generally about 30 minutes to The reaction time ranges 3 days, preferably about t hr to 1 day. 102041 Step 2 of the Compound can be obtained by removal lx-721 protecting group in the presence Pt1 from Compound tX-711 of an acid in a solvent. for example, The solvent for the reaction includes isopropyl al-cohols solvent such as methanol, ethanol, and chl-oride, alcohol; halogenated solvent such as methylene chloroform, and L,2-dichloroethane; carbon tetrachloride, ethers solvent such as diet.hyl ether, tetrahydrofuran, esters solvent dioxane, !,2-dimethoxyethane, and diglyme; acetate; zv such as ethyl acetate, methyl acetate, and butyl polar solvent as N, N-dimethylf ormamj-de, such preferred acetonitrile; acid, and water. The acetic acetate, and solvent for the reaction includes ethyl dioxane. example, The acid f or t.he reaction includes f or hydrochloric acid, and acid, hydrobromic acid, sulfuric trifluoroacetj-c acid. The preferred acid for the reaction includes hydrochloric acid, and trifluoroacetic acid.
The reactj-on generally ranges about 0oC to temperature 150oC, preferably room temperature to about 100oC. generally The reaction time ranges about 30 minut.es to 3 days, preferably about l- hr to 1 day. [020s] Step 3 Compound can be obtained by the reaction of [x-73] Compound azide with imidazolesulfonv1 lX-721 hydrochloride in the presence of a base in a solvent.
The solvent for the reaction includes for example, alcohols solvent methanol, ethanol, and isopropyl such as alcohol; halogenated solvent such as methylene chloride, chloroform, I,2-dLchloroethane; carbon tetrachl-oride, and ethers solvent such as diethyl ether, tetrahydrofuran, dioxane, solvent L,2-dimethoxyethane, and diglyme; esters such as ethyl acetate, methyl acetate, and butyl acetate; polar and solvent such as N,N-dimethylformamide, and acetonitrile. preferred for the reaction The solvent incl-udes methanol. for example, The base for the reaction includes potassium carbonate, sodium carbonate and the like. The preferred potassium base for the reaction includes carbonate.
The reaction generally ranges about 0oC tro temperature preferably 150oC, room temperature to about 100oC.
The generally minutes tro reaction time ranges about 30 3 days, preferably about t hr to 1 day.
Preparation method 48 Preparation method 4B (o-,'"' llfi, fr .., l'o-'"' ou*A-Y*f ,ol-"*f Step 1 x-82 x-80 ( t}<;iJ-'t\io-*. o-*' x-83 'ft^if _--.-> Step 2 nux/\ -veiJ *}^fi,o-*" Step3 t*_rul g-po x-88 (o-'' 9 ao-'" ll",l yno ,..-\.',YH ,\ir^\ro_u, {t^Tror*" x-8e I ] x-eo The example Preparation method of Step 7 and Step B of 4B includes the followinq scheme: o',ooo" o-,oop" o',ooo" "..-\^( O\r'cH3 o.-acH. "rft H-C -.-> !':'' Ittt' 102071 Step Compound by the reaction of can be obtained [x-82] presence Compound with Reactant in the of a [X-80] [X-81] j-ng condens agent in a solvent.
The solvent for the reaction includes for example, hydrocarbon xylene, and solvent such as benzene, Loluene, hexane; halogenated as methylene chloride, solvent such chloroform, carbon tetrachlorj-de, and 1, 2-dichloroethane; ethers solvent tetrahydrofuran, such as diethyl ether, polar dioxane L,2-dimethoxyethane, and diglyme; and solvents such as JV,JV-dimethylformamide, dimethyl sulfoxide, acetonitril-e, and acetone, which may be used alone or as a preferred mixture for the of two or more. The solvent reaction and ff,N- includes methylene chloride, chloroform, dimethvl-f ormamide . includes for The condensing agent for the reaction (WSC'HCl: example, water-so1uble 1-ethyl carbodiimide dimethylaminopropyl carbodi imide hydrochloride) (DCC), dicyclohexylcarbodlimide diphenylphosphoryl azide (DPPA) (CDI) and carbonyldiimidazol-e . As appropriate, (HOBI hydroxy- l-H-benzotriazole HzO) 4- monohydrate (DMAP) dimethylaminopyridine and t.he like may be added. preferred The condensing agent for the reaction incl-udes a (WSC'HCl: mixture of water-soluble 1-ethy1 carbodiimide (3-dimethylaminopropyl) carbodiimide hydrochloride) and 1- (HOBL hydroxy- a l-H-benzotriazole monohydrate HzO) and (WSC'HCI: mixt,ure of water-soluble 1--ethyI-3 - carbodiimide -dimet.hylaminopropyl) hydrochloride) and 4- carbodiimide (DMAP) dimethylaminopyridine The reaction temperature generally ranges room temperature to about L20oC, preferably room temperature to about 100oC.
The reaction generally rangfes about 30 minutes to time pref 3 days, erably about 1- hr to 1 day.
Step 2 Compound can be obtained by the reaction of [X-84] Compound with in the presence of a Reactant [X-82] [x-83] base in a solvent.
The includes for example, solvent for the reaction hydrocarbon solvent such toluene, xylene, and as benzene, hexane; ether, ethers solvent such as diethyl tetrahydrofuran, and diglyme; dioxane, !,2-dimethoxyethane, and polar dimethyl solvents such as N,N-dimethylformamide, used sulfoxide, acetonitrile, and acetone, which may be preferred more. The alone or as a mixture of two or solvent for the reaction includes tetrahvdrofuran.
The base for the reaction includes for example, sodium hexamethyldisilazide, lithium hexamethyldisilazide, and (LDA). preferred lithium diisopropylamide The base for the reaction and lithium includes sodium hexamethvldisilazide hexamethyldis i 1a z lde . [020e] The reaction generally ranges about -78oC temperature to 50oC, preferably about -'7BoC to room temperature.
The reaction generally ranges about 30 minutes to time 3 days, preferably about 30 minutes to 1 day.
Step 3 removal of the Compound can be obtained by [X-85] protecting group in a solvent.
Pol from Compound [x-84] group, Lhe When the protecting group Po1 is a benzyl protecting group by the catalytic may be removed pressure medium hydrogenation reaction under normal or (for pressure example, 3atm).
The hydrogenation reaction catalyst for the catalytic carbon, includes for example, palladium on activated preferred palladium nickel. hydroxide, and Raney catalyst for palladium activated the reactj-on includes on carbon and palladium hydroxide.
The solvent for the catalytic hydrogenation reaction includes for as methanol, example, alcohols solvent such ethanol, isopropyl alcohol, and tert-butanol,' esters solvent such as ethyl acetate, methyl acetate, and butyl acetate; ethers diethyl ether, solvent such as tetrahydrofuran, dioxane, 1, 2-dimethoxyethane, and diglyme; acetic acid, or as a and water, which may be used alone pref mi-xture of two or more. The erred solvent for the reaction includes methanol, ethanol-, ethyl acetate, and tetrahydrofuran. generally The reaction temperature ranges room temperature 100oC, preferably room temperature to to about about 80oC.
The reaction generally minutes to time ranges about 30 preferably 7 days, about t hr to 5 days.
Step 4 Compound can be obtained by introducing [X-86] protecting group in a solvenL.
Po into Compound [X-85] group/ When the protecting group Po is a siIyl Compound can be obtained by using silylation agent [X-85] presence in the of a base.
The solvent for the reaction includes for example, 1_8 1 esters solvent such as ethyl acetate, methyl acetate, and butyl acetate; ethers solvent such as diethyl ether, tetrahydrofuran, dioxane, l;2-dimethoxyethane, and diglyme; and polar solvents such as IV,N-dj-methylformamide, dimethyl sulfoxide, acetonitrile, and acetone, which may be used alone or as mixture or more. The preferred a of two solvent for the reaction includes N,N-dimethylformamide.
The base for the reaction includes for example, preferred triethylamine, pyridine, and imidazole. The base for reaction the incLudes imidazole.
The silylaLion aqent for the reaction includes for example, 1- 1ane, tert- tert - butyl chlorodiphenyl s butylchlorodimethyl s i lane, and tert-butyldimethylsilyl preferred trifluoromethanesulfonate. The silylat.ion agent for the reaction includes tert-butylchlorodiphenylsilane.
The reaction temperature generally ranges room temperature preferably room temperature to to about l-00oc, about 80oC.
The generally 30 minutes to reaction time ranges about 3 days, preferably 1 about t hr to day. lo2r2l Step 5 Compound can be obtained by hydrolysis reaction of [X-87] Compound commonly-used 86] in a sol-vent under ttre condition. may be performed under The hydrolysis reactj-on the alkaline or acidic condition.
The base for the alkaline condition incl-udes example, metal hydroxide such dfl agueous solution of alkali as lithium hydroxide, hydroxide, and potassium sodium peroxide, hydroxide; inorganic peroxide such as lithium potassium peroxide, peroxide. The preferred and sodium peroxide. base for the reaction includes lithium for example, The acid for the acidic condj-tion includes hydrochloric acid, hydrobromic acid, sulfuric acetic acid, acid, trifluoroacetic acid, and p-toluenesulfonic acid monohydrate. preferred reaction includes The acid for the hydrochloric acid, acetic acid, and p-toluenesulfonic acid monohydrate.
The solvent for the reaction includes for example, hydrocarbon xylene, and solvent such as benzene, toluene, hexane; alcohols as methanol, ethanol, solvent such isopropyl alcohol, and tert-butanol; halogenated solvent such carbon as methylene chloride, chloroform, tetrachloride, and l-, 2-dichloroethane; ethers solvent such L 2- diethyl et.her, tetrahydrof uran, dioxane dimethoxyethane, polar such as N,N- and diglyme; solvents dimethylformamide, dimethyl sul-foxide, acetonitrile, acetone; may be used alone or acetic acid, and water, which preferred for the as a mixture of two or more. The solvent reaction includes tetrahvdrofuran and water.
The reaction generally ranges about temperature -30oC to 80oC, preferably about OoC to room temperature.
The reaction generally 30 mj-nutes to tj-me ranges about 3 days, preferably about 30 minut.es to 1 day. [0 ] Step 6 Compound can be obtained by the reaction of [x-88] Compound with N, O-dimethylhydroxylamine or [X-87] hydrochloride thereof in the presence of a condensing agent in a solvent.
The solvent for includes for example, the reaction hydrocarbon solvent such as benzene, toluene, xylene, and hexane; halogenated methylene chloride, solvent such as chloroform, carbon tetrachloride, and 1, 2-dichloroethane; 1_5 ethers solvent tetrahydrofuran, such as diethyl ether, polar dioxane, 1-,2-dimethoxyethane, and diglyme; and solvents such as N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, may used alone or as a and acetone, which be mixture of two or more. The preferred solvent for the zv reaction and N,N- includes methylene chloride, chloroform, dimethylformamide .
The includes for condensing agent for the reaction (WSC'HCl: (3- example, 1-ethy1 water-soluble carbodiimide dimethylaminopropyl)carbodiimide hydrochloride), N,N' - (DcC), dicyclohexylcarbodiimide azide diphenylphosphoryl ]-84 (DPPA), (CDI) and carbonyldiimidazole . As appropriate, 1- (HOBL hydroxy- 7f-benzotriazole monohydrate HzO) 4- dimethylaminopyridine (DMAP) the like may be added. j-ncludes The preferred condensing agent for the reaction a (WSC'HC1: mixture of water-soluble carbodiimide 1-ethyl (3-dimethylaminopropyl)carbodiimide hydrochloride) and 1- (HOBI hydroxy-lH-benzotriazole monohydrate HzO) and a (WSC'HCl: 1-ethyl mixture of water-so1uble carbodiimide (3-dimethylaminopropyl)carbodiimide hydrochloride) and 4- (DMAP) dimethylaminopyridine .
The reaction generally ranges room temperature temperature to about !20oC, preferably room temperature about l-00oC.
The reaction time generally ranges about 30 minutes 3 days, pref 1- day. erably about t hr to lo274l Step 7 Compound obtained by the reaction of can be [X-89] in a Compound in the presence of a reducing agent [x-88] solvent.
The solvent for the reaction includes for example, hydrocarbon toluene, xylene, and solvent such as benzene, hexane; halogenated such as methylene chloride, solvent 1-, 2-dichloroethane; chloroform, carbon tetrachloride, and ethers tet.rahydrofuran, solvent such as diethyt ether, may be dioxane, a,2-dimethoxyethane, and diglyme, which preferred more. The used alone or as a mixture of two or solvent for the reaction includes toluene, methylene chloride, chloroform, hexane, and tetrahydrofuran. f or The reducing agent f or t,he react ion includes example, diisobutylaluminum hydride, and lithium aluminium preferred reaction hydride. The reducing agent. for the incl-udes diisobutylaluminum hydride.
The reaction temperature generally ranges about -78oC to room preferably to OoC. temperature, about -7BoC The reaction time generally ranges about 30 minutes to preferably 3 days, about t hr to 1 day. [021s] Step 8 Compound obtaj-ned by the reaction of 90] can be (1,-diazo Compound 89] with dimethyl oxopropyl)phosphonate in a sol-vent.
The for reaction includes for example, solvent the isopropyl alcohols solvent such as methanol-, ethanol, alcohol, solvent such as and tert-butanol; halogenated methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane; such as diethyl ether, ethers solvent tetrahydrofuran, dj-oxane, a,2-dimethoxyethane, and diglyme; methyl acetate, and esters solvent such as ethyl acetate, polar such as N,N- butyl acetate; and solvent preferred solvent dimethylformamide, and acetonitrile. The the reaction includes met.hanol. 102L6) The gienerally ranges about 0oC tro reaction temperature 150oC, preferably room temperature to about l-00oc. generally The reaction time ranges about 30 minutes 3 days, preferably about l- hr to 1 day. l02t7l Preparati-on method 4C Preparat i on Re-Nr\f4 Re-N')=_"--i;,' r R"_N" RL._o ,$US'o-o" ('-11n.'^t^{n*,., tx-101 I tx.z3t x-e0 'R' ltep z s*r.
Y"-*" tx'1021 tx-lool oYoH N=u ,N=ru nlHi-fti R?-hif-...".rrJl* (r\ncr^fr{ncz.., (\n.' n"2^ Rb Rb' ' IzrI \yc^ Step 3 Yo-o. st.p4 Y"-R.
O ---, x-1041 x-103J no" Rot ,Gi.oo o*.-il-*'h;*" q1-6" 'Roo 'nu.c\.v{r--C Rds' R I G'G"-=*ysl+ ) )no (W'1,\* ifor*c x-l061 I Step 6 Step 5 =c.'aalkyl ,"=T -cio, oi -Ni \r'\- j-ncludes e of The examnl Preparation method 4A the following scheme: n-o9jlcir, t/ -b-tCH. cHt ot,ldp" o'rooo. "t"JcH' gH. ( ro-tbdo" ,N=\ ,N=\ x-s- H,c{_Q-',?Y x,c{_e_"Fy o-r"#'. "s,x: V"r?t" - cH.- ,*=n! (o' FH. lfr'h u"*too- FH. .,N=\ ;fi:ff#: ^ H,c'{-Q-n.)-1 H.c{:e,-it+ \"xcx: \"$.1:- HrN>A 9"", gH. "Y\A ,-=l "Yflt$ 9H. ,,=l n,c-\-e-"X1*e"", x,c{-Q-'f("S"* c{"t o Step l- Compound can be obtained by the reaction [X-100] Compound with Compound in a sol-vent.
[X-90] [X-73] The includes for example, solvent for the reaction 1-0 alcohols solvent such as methanol, ethanol, isopropyl alcohol, halogenated solvent such as and tert-butanol; methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane; as diethyl ether, ethers solvent such tetrahydrofuran, L,2-dimethoxyethane, and diglyme; dioxane, acetate, and esters solvent such as ethyl acetate, methyl 1-\r r Fr a aaf + 1 ''l polar such as N,N- vuuy! o-=.ot€; and solvent t_8 8 dimethylformamide, and acetonitrile. The preferred solvent for the reaction includes tetrahydrofuran.
The reaction gfenerally ranges about OoC to t.emperature preferably 150oC, room temperature t.o about l-00oc.
The reaction time generally ranges about 30 minutes to 3 days, preferably 1 about t hr to day. l021,el Step 2 Compound can be obtained by the reaction of [x-102] Compound in presence of a with Compound the [X-100] [X-101] metal catalyst in a solvent.
When Compound is alkytboronic or arylboronic [X-101] acid, these may arylboronic acid itself be alkylboronic or preferred. or an ester thereof, and the ester thereof is As the or ary1-zinc reagent, Compound an alkylzinc [X-10]-1 , an alkylmagnesium or arylmagnesium reagent or the like used.
The includes for example, solvent for the reaction hydrocarbon solvent such as benzene, toluene, xylene, and ofhar hexane; diethyl ethers solvent such as t.etrahydrofuran, dj-oxane, L,2-dimethoxyethane, and diglyme; polar dimethyl solvents such as N,N-dimethylformamide, sulfoxide, and water, which may acetonitrile, and acetone; '1'ne be used alone or as a mixture of two or more. pref incl-udes N, N- erred solvent f or the reaction dimethylformamide .
The metal catalyst for the reaction includes example palladium catalyst such as (triphenytphosphine) (II) bis palladium d.ichloride, and L,!' (dlphenylphosphino) (If) bis ferrocene-palladium dichloride, preferably bis triphenylphosphine palladium II dichloride .
The metal catalvst for the reaction also incl-udes a nickel as catalyst such lL,2- (diphenylphosphino) (II) bis ethanel nickel dichloride, and (II) 1-0 nicket iron catalyst such as acetylacetonat,e, and an rnn/TTT\ vrr+! \r!+/ ^hrOfide.
As appropriate a base or an inorganic salt may added. includes The base or inorganic salt for the reaction for example, metal phosphate such as tripotassium alkali phosphate; alkali metal carbonate such as sodium carbonate, potassium such as and carbonate; alkali metal acetate sodium acetate; fluoride such as cesium fluoride and salt phosphate. and t,he like, preferably tripotassium The generally ranges about -10oC reaction temperature to 150oC, preferably about OoC to 100oC. generally about 30 minutes to The reaction time ranges 3 days, preferably t hr l- day. about to to220l Step t_90 Compound by removal the can be obtained [X-103] protecting group presence of from Compound in the [X-102] (TBAF) of tetrabutylammonium in solvent. fluoride a The solvent for the reaction includes for example, alcohols solvent such as methanol, ethanol, isopropyl alcohol, and as ethyl tert-butanol; esters solvent such acetate, methyl acetate, and butyl acetate; hydrocarbon sol-vent such as xylene, and hexane; benzene, toluene, ethers solvent such as diethyl ether, tetrahydrofuran, dioxane L,2-dimethoxyethane, polar and diglyme; and solvents such as N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, and acetone, which may be used alone or as a preferred mixture of for the two or more. The solvent reacti.on includes tetrahvdrofuran.
The reaction generally ranges about -l-0oC temperature to 150oC, preferably about 0oC to B0oC.
The reactj-on t,ime generally ranges about 30 minutes to days, preferably about l- hr to 3 days. lo22rl Step 4 Compound by the react,ion of [x-104] can be obtained Compound presence in a solvent. in the of an oxidant [X-103] The oxidant includes f or example, f or t.he reaction (TEMPO), 2,2,6,6-tetramethylpiperidinyloxy radical potrassr_um permanganace, hydrogen peroxide, aqueous pyridinium dichromate, and chromium oxide. The preferred oxidant for the reaction includes 2,2,6,5-tetramethyl piperidinyloxy (TEMPO) radical prepared Alternatively, Compound can be by [X-]-041 obt.aining and an aldehyde derived from Compound [X-103], the oxidant for reaction includes for example, pyridinium (PDC), dichromate pyridinium chlorochromate (PCC), (DMSO) and dimethyl activated by oxa1y1 sulfoxide chloride, Dess-Martj-n reagent, and sodium chlorite.
The for example, solvent for the reaction includes halogenated solvent chlorj-de, chloroform, such as methylene carbon tetrachloride, and 1-,2-dichloroethane; ethers solvent such as tetrahydrofuran, dioxane, diethyl ether, 1,2-dimethoxyethane, and diglyme; polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, and acetone; and water, which may be used alone or as a mixture of two or more. preferred The for the reaction includes solvent methylene chloride, chloroform, tetrahydrofuran, zv acetonitrile, and water.
The reaction temperature generally rangies about -10oC to l-50oc, preferably about OoC to 80oC.
The reaction generally ranges about 30 minutes to time preferably days, about l- hr to 3 days. lo222l ]-92 Qian Compound 105] Cr-e alkyl group) can be obtained by the reaction of Compound with Reactant [X-104] in presence [X-]-051 the of a condensing agent in a solvent under the condition of a common amide bond formation reaction.
The sol-vent f includes f or the reaction or example, hydrocarbon solvent such as benzene, toluene, xylene, and hexane; halogenated solvent such as methylene chloride, chloroform, carbon tetrachloride, and 1, 2-dichloroethane; ethers solvent such as diethyl ether, tetrahydrofuran, dioxane, 7-,2-dimethoxyethane, and diglyme; and polar solvents such as N,N-dimethylformamide, dimet.hyl sul-foxide, acetonitrile, as a and acetone, which may be used alone or preferred mixture of two or more. The solvent for the reaction includes met,hylene chloride, chloroform, and N,N- dimethylformamide . condensinq aqent for the reaction incl-udes for (WSC'HC1: (3- example, water-sol-uble 1-ethyl carbodiimide dimethylaminopropyl) carbodiimide hydrochloride) N,N' - dicyclohexylcarbodiimide (DCC), diphenylphosphoryl azide (DPPA) (7 (CDI) carbonyldiimidazole and O- - azabenzotriazol-e yI -l/, N, N', N' - teLramethyluronium (HATU). hexafluorophosphate 1--hydroxy- IH- As appropriate, (HOBL benzotriazole monohydrate HzO) 4- (DMAP), dimethylaminopyridine and N, N-diisopropylethylamine the like may be added. The preferred condensing agent the reaction incl-udes mixture of water-soluble (WSC carbodiimide rlU-L: r -afhrrl verrJ+ -"- J dimethylaminopropyl)carbodiimide hydrochloride) and (HOBL hydroxy- H2O), and a LH-benzotriazole monohydrate (7-azabenzotriazol-e-y1) mixture of O- -N,N,N' ,N' ,- (HATU) and N, N- tetramethyluronium hexaf l-uorophosphate di i sopropylethylamine . generally ranges room The reaction temperat.ure temperature L20oC, preferably room temperature to to about about 100oC.
The generally ranges about 30 minutes to reaction time 3 days, pr€ferably about l- hr t.o 1 day. 102231 Step 6 (R' obtained from Compound hydrogen) can be Compound group) in a solvent under Cr-e alkyl [X-1.06] = the condition of a common ester hydrolysis reactj-on. performed under the ester hydrolysis reaction may be alkaline or acidic condition. includes for The base for the alkaline condition example, alkal-i met.al- hydroxide such dfl aqueous solution of potassium as lithium hydroxide, sodium hydroxide, and z5 preferred reaction includes hydroxide. The base for the aqueous sodium hydroxide and aqueous lithium hydroxide.
The acid for the acidic condition includes for example, hydrochloric hydrobromic acid, sulfuric acid, and acid, trifluoroacetic acid. The preferred acid for the reaction includes hydrochloric acid, hydrobromic acid, and trifluoroacetic acid.
The solvent for the reaction includes for example, hydrocarbon toluene, xylene, and solvent such as benzene, hexane; alcohols solvent such as methanol, ethanol, isopropyl halogenated solvent a1cohol, and tert-butanol; such methylene chloroform, carbon as chloride, tetrachloride, and L,2-dichloroethane; ethers solvent such as dioxane, L,2- diethyl ether, tetrahydrofuran/ dimethoxyethane, and diglyme; esters solvent such as ethyl polar acetate, methyl butyl acetate; and acetate, and preferred solvent such as acetic acid and water. The methanol, ethanol, solvent for the reaction includes methylene toluene, chloride, chloroform, tetrahydrofuran, acetic acid, and water.
The generally ranges about OoC to reaction temperature 1-20oC, preferably room temperature to about 100oC. generally 30 minutes to The reaction time ranges about 3 days, preferably l- day. about t hr to 102241 In method 48, dfl racemic form of Step 1 of Preparation give hydrogen) may be used to Compound lX-811 tIl = which is in racemi-c final product. form as a [0225) Preparation method The case of that K has the followinq sLructure wherein the cyclic moiety U is cyclobutane rj-ng: Preparation method 5 t*-/ n"r--\ Step 1 x,190 tx-1e1 l sten z ;Ao^t'.
R"ta'--\O *^'F*J Step 3 x-le2 x.1e3 Step 4 R"AoH Step 5 A, x-10 RutT x.1e4] s;;E-- x-200B lo226l Step Compound can be obtained by amidation reaction [X-191] of Compound piperidine presence with in the of a [X-190] condensing agent in a solvent.
The solvent for the reaction includes for example, hydrocarbon xylene, and solvent such as benzene, toluene, hexane; halogenated solvent such as methylene chloride, chloroform, carbon tetrachloride, and 1-,2-dichloroethane; ethers sol-vent tetrahydrofuran, such as diethyl ether, polar dioxane, !,2-dimethoxyethane, and dlglyme; and solvents such as lV,/V-dimethylformamide, dimethyl sulfoxide, acetonitrile, and which may be used alone or as a acetone, mixture preferred of two or more. The solvent for the reaction N,N- includes methylene chl-oride, chloroform, and dimethylformamide .
The reaction includes for condensing agent for the (WSC'HCl: (3- example, water-soluble carbodiimide 1--ethyl dimethylaminopropyl)carbodiimide hydrochloride), N,N' - (DCC), dicyclohexylcarbodiimide diphenylphosphoryl azide (DPPA), (CDI) 1- and carbonyldiimidazole . As appropriate, (HOBL hydroxy- HzO) 4- 7H-benzotriazole monohydrate (DMAP) dimethylaminopyridine and the like may be added. j-ncludes The preferred reaction a condensing agent for the (WSC'HCl: mixture of water-soluble 1-ethyl carbodiimide (3-dimethylaminopropyl) and l-- carbodiimide hydrochloride) (HOBI hydroxy- HzO) and a |-H-benzotriazole monohydrate ]-97 mixture (WSC' of water-solubIe carbodiimide HC1 : 1--ethyl (3-dimethylaminopropyl) carbod.iimide hydrochloride) and 4- dimethylaminopyridine (DMAP) The reaction generally ranges room temperature temperature to about 7-20oC, preferably room temperature to about l-00 The reaction generally minutes to time ranges about 30 preferably 3 days, about t hr to 1 day. 10227) Step 2 Compound can be obtained by the reaction of lX-1,921 Compound with 1-, I, 3-tetramethyldisiloxane in the [X-191] 3, presence (Ph3P)IrC1(CO) of in a solvenL.
The for example, solvent for the reaction includes hydrocarbon solvent such as benzene, toluene, xylene, and hexane; halogenated solvent such as methylene chloride, chlorof orm, carbon tetrachl-orj-de, and 1-, 2 -dichloroethane; ethers solvent such as diethyl ether, tetrahydrofuran, dioxane 1-, 2 and diglyme; and polar -dimethoxyet,hane, solvent such as acet.onitrile, which may be used alone or as preferred a mixture for the of two or more. The solvent reacti-on includes toluene. generally to The reaction temperature ranges about 0oC 7-2OoC, preferably room temperature to about 100oC.
The reaction time generally ranges about 30 minutes 2 days, preferably about 30 min. to 1 day. 10228) Step 3 Compound can be obtained by the reaction of [X93] Compound with ethyl acrylate in a solvent. lX-1,921 The solvent for includes for example, the reactj-on hydrocarbon solvent such as benzene, toluene, xylene, and hexane; chloride, halogenated solvent such as methylene chloroform, carbon and 1,2-dichl-oroethane; tetrachloride, ethers solvent such as diethyl ether, tetrahydrofuran, dioxane, 1-,2-dimethoxyethane, diglyme; and polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, alone or as a and acetone, which may be used mixture of two or more.
The preferred reaction includes solvent for the acetonitrile. The reaction temperature generally ranges room preferably room temperature to about 150oC, temperature to about 120oC.
The reaction time generally ranges about 30 minutes to zv 2 days, preferably about t hr to 1- day. lo22el Step 4 Compound by quaternizing the can be obtained [X-194] amino group of Compound with p-toluenesulfonate and [X-193] the like quaternized Compound followed by reactiing the lx- 1931 with a base.
The base for reaction includes for example, dfl aqueous solution of alkali metal hydroxide such as lithium hydroxide, potassium The sodium hydroxide, and hydroxide. preferred base for the reaction includes an aqueous potassium solution of hydroxide.
The reaction generally rangfes room temperature temperature preferably to about l-50oc, room temperature to about l-20oC.
The reaction time generally ranges about 30 minutes to 2 preferably days, about t hr to 1 day.
Step 5A 3-substituted can cyclobutanecarboxylic acid [X-200A] be obtained by the catalytic hydrogenation reactj-on of Compound pressure in a solvent under normal [X-]-941 (for medium pressure example, 3atm).
The catalyst for the catalytic hydrogenation reaction includes for example, palladj-um on activated carbon, rhodium on activated carbon, palladium hydroxide, and Raney nickel. preferred The catalyst for the reaction includes palladium on activated carbon, and rhodium on actj-vated carbon.
The solvent for hydrogenation reaction the catalytic includes for example, alcohols solvent such as methanol, ethanol, isopropyl and tert-butanol; esters a1cohol, solvent such as ethyt acetate, methyl acetate, and butyl acetate; as diethyl ether, ethers sol-vent such tetrahydrofuran, dioxane, !,2-dimethoxyethane, and diglyme; acetic acid, and water, which may be used alone or as a mixture preferred solvent for the of two or more. The reaction includes methanol, and tetrahydrofuran.
The generally ranges room reaction temperature temperature to about 100oC, preferably room temperature to about BOoC.
The generally about 30 minutes to reaction time ranges 7 days, preferably about t hr to 5 days.
Step 58 3-substituted cyclobutanecarboxylic acid [X-200B] be obtained by reduction reaction of Compound using [X94] presence zinc in the of hydrochlori-c acid in a solvent. (cis-trans compound is a st.ereoisomer [X-200B] isomer) of the compound lX-200A1. for example, The solvent for the reaction includes ethers solvent such ether, tetrahydrofuran, as diethyl acetic acid, and dioxane, !,2-dimethoxyethane, and diglyme; water, which as a mixture of two or may be used alone or includes more. The preferred solvent for the reaction tetrahydrofuran, and water.
The reaction temperature generally ranges room temperature preferably to about l-50oC, room temperature to about l-20 The reaction time generally ranges about 30 minutes to 3 days, preferably about t hr to 1 day. lo232l Preparation methods 2, 3, and 4, Compound rrllarr wherein has the following structure can be prepared by using the compounds or obtained in [X-200A] [X-200B] preparation method acid compound as the carboxylic tX-1Ol and the like. *o'\--** o ooil**e(}n* 0 ,G?.oo y{tl)no R*flR* 1---^ot R"AoH fnlorc".
R"''- ,1.^", , -l -.^ x-I01 x-200A o ,,lu?t^Ii'o-*" "41={-+4 .-Ao* *'-() Re"t- x-2008 "'-o \"'-++l 7 \"'-+;i7 lvz55 J Preparation method 6 *"\-** r,-te-{*;** Oy,ott oY,n .c1-c" ,Gi.eo p1-6r i .- J N- f.{ -' /|** n'-G] . ." n^r*J1n. **n** 'Go'-\,/ Go'Gvfrld *o'n** (\y,H$7olo. (\y,N\io.r*. x-02w I ] Rb Step 1 lx{11 II.W] R.:cr_ualkyl :C.'-u alkYl *"\---r** otrt-ve{r}n" g1.qo n"-c1oo.e\,,,y*i1"' *o'l-\** ,\rr'\Zo.*" Step 2 tt-wl The followings in Preparation explain the each step method 6. 102341 Step 1 (R' group) Compound Cr-e a1ky1 can be obtained [I-W] by the reaction with in of compound compound [X-02W] [X-01] presence the of a condensing agent in a solvent under the condition reaction. of a common amide bond formation The solvent for reaction, the reaction temperature, the reaction of Step 1 of time are similar to those Preparation method reaction, Alternatively, in the above amidation compound group) be prepared by Cr-e a1kyl can [I-W] the reaction of an acid halide or mixed acid anhydride of compound with compound .
[X-01] [X-02W] The can be derived by acid halide of compound [X-01] the reaction a acid of compound with of carboxylic [X-01] thionyl chloride, oxalyl chloride etc. wherein a catalytic amount of N,N-dimethylformamide may be added.
The mixed of compound can be acid anhydride [x-01] of compound derived by the reaction of a carboxylic acid with etc.
[X-01] ethyl chlorocarbonate [023s] Step 2 Compound hydrogen) can be obtained from tI-Wl (R' group) in solvent under compound Cr-e a1kyl a [I-W] the condition of ester hvdrolvsis reaction. reaction temperature, The solvent for the reaction, the the reacti-on those of Step 2 of time are similar to Preparation method 1.
Example preparation methods, the According to the above compounds were prepared. listed in Figs. L illustrate the The following working Examples serve to present which does not intend invention more specifically, to limit t,he nresent invention. was measured using the The specific optical rotation following instrument.
(RUPOT,PU INSTrumenI: AUTOPOL V RESEARCH ANALYTICAL) lo237l (2-Chloromethylphenylcarbamoyl) Example A-82: 4- - cyclopropyl - 5 3 - isobutylcyclobutyl isoxazol [4 - ) butanoic acid 82 - lMethyl - 1-piperidin- 1-ytpentan- 1-one 9H, f1 t..^to* ,-.r.{r'--.,1ilt-/ (238 (833 1_0 4-Methylvaleric acid g) and DMF mL) were (233 mixed. After an addition of piperidine mL), HOBL'HzO (30r g) (452 g) mixture at ice and wsc HCI to the temperature, the resulting mixture was stirred at (1-000 overnight. water mL) at To the reaction was added ice temperat.ure and the resulting mixture was extracted with (500 layer was washed toluene mL x 2). The organic (500 with aqueous 10 w/v Z sodium carbonate mL + 300 mL) (500 and water mL x 2). The organic layer was concentrated (41,4.29 in vacuo give g) as a crude to the title compound product. l023el I- 1 piperidine \r\z) -Methyl - -pentenyl ) ---.* ?', ar HrcA'-^yN'-- *^".\--\rN--,,, (372.4 g) 4-Methyl-piperidinylpentanone and (1000 toluene mL) were mixed. To the mixt.ure was added (Ph3 (Co) (633 P) Ircl mg) . In a water-bath, I,I,3 (eZl tetramethyldisiloxane mL) was added dropwise to the mixture. The resultinq mixture was stirred at RT for 2 }:rr. give The reactj-on mixture was concentrated in vacuo to the (B++ title compound g) product. as a crude 102401 (A3) Ethyl 3 - isobutyl--2 -piperidin cyc lobutanecarboxylate Ao'-cH, cH- a' lo ) ,../\.'\-NJ r r3v ,..Fi1 \----l ( (a++ L- g) -Methylpentenyl)piperidine (443 acetonitrile mL) were mixed. The ethyl acrylate (447 mL) and hydroquinone to the mixuture. mg) were added The resulting mixture was stirred aL 95 overnight. The reaction in vacuo to give the mixture was concentrated (994.09 title compound g) product. as a crude l024Ll (A4) acid 3-rsobutylcyclobutenecarboxylic Ethyl 3 - isobutyl - 2-piperidin (994 ylcyclobutanecarboxylate g) methyl p- (ffZ toluenesulfonate mL) were mixed. The mixture was (1-100 stirred at 1l-0 for 2 hr water mL) was added to the mixture. The resulting mixture was washed with tert- (600 butyl methyl l- mL) and hexane ether hexane I / = / (600 mL). To the aqueous layer was added potassium (503 hydroxide g) at ice temperature. The resulting mixture was stirred at for 4 hr. The reaction aflrar /500 mixture was washed with 6fjaf1-rrr1 mL) and diethyl (500 ether hexane l- t mL). To the aqueous layer was / = / (Alz added concentrated hydrochl-oric acid mL) at ice temperature.
The mixture was extracted with ethyl acetate L x 2). The layer was washed with combined organic water (500 (500 mL x 2) and brine mL) t.hen dried over sodium was filtered off and sulfate. The sodium sul-fate qive the filtrate was concentrated in vacuo to the title (240 compound g) product. as a crude lo242l (A5) 3-Isobutylcyclobutanecarboxylic acid \\ \\ roH roH H^c t*TI l-].V r l-----ll )--/ H.c Hrc (l-88 3-Isobutylcyclobutenecarboxylic acid and (2OOO was tetrahydrofuran mL) were mixed. To the mixture (5.64 added 5 w/w Z rhodium carbon g) . The on activated resulting mixture was stirred at RT for 7 hr under hydrogen atmosphere The w/w rhodium on activated carbon atm) . 5 ? was filtered off and the filtrate was concentrated in vacuo to give (134.05 g) crude product. the title compound as a 102431 (A6) l_0 N-Methoxy-N-methyl i s obutyl cyc lobutanecarboxamide v-cH3 H"Q bH. ')--r u^ t-.t a\ I r3v I r3v (62.1 g) and DMF 3-Isobutylcyclobutanecarboxylic acid (500 mL) mixture were added N,O- were mixed. To the (46.9 g), dimethylhydroxylamine hydrochtoride triethylamine (83.9 (92.3 (73.8 g) g) . The mL) HoBt ' Hz O and WSC' Hc1 resulting mixture was at RT overnight. To the stirred (SOO reaction mf,). The mixture was mixture was added water (250 extracted with hexane I 1 mL x 2). ethyl acetate / = / (250 The with water mL), combined. organic layer was washed (250 (250 aqueous mL) water mL) l-0 w/v Z sodium carbonate , (500 1 N hydrochloric water, saturated aqueous acid mL), (250 (250 sodium bicarbonate mL) and then brine mL). The organi-c The layer was dried over magnesium sulfate. magnesium and the filtrate was sulfate was filtered off give (87.5 g) concentrated in vacuo to the title compound product. as a crude lo244l 82 - 7 3 - IsobutylcyclobuLanecarbaldehyde O-nu vr 13 HuQ nsY 1-0 N-methoxy-N-methyl a solution of isobutylcyclobut.anecarboxamide (ll g) chloride in met.hylene (235 (1.0 mL) was hydride added dropwise diisobutylaluminum M (+73.2 The mixture in methylene chloride) mL) at -78 was stirred After an addition of l-.5 M at -78 for 2 hr. (530 was sulfuric acj-d mL) at ice temperature/ t.he mixture organic extracted with methylene chloride. The combined layer was washed with 1.5 M sulfuric acid, water and brine, sulfate then dried over magnesium sulfate. The magnesium was filtered comprising the title off and the filtrate compound was used in the next step. 1024s1 (A8) (2, L- 2-Dibromovinyl) -:-isobutylcyclobutane (1-68 g) To a solution of tetrabromide in carbon (252 methylene chloride mL) was added dropwise a solution (266 (350 of g) triphenylphosphine in methylene chl-oride mT,) af i r-e f amnar:t- lrrF rrr! The miXtUre was Stirred at iCe temperature was then added for 20 min. To the mixture dropwise a solution in of 3-j-sobutylcyclobutanecarbaldehyde methylene chloride at ice temperature. The mixture stirred After an addiLion at ice temperature for 20 min. of aqueous 10 w/v sodium carbonate L) dropwise to the mixture, methylene chlorj-de the mixture was extracted with (200 mL x 2). The combined organic layer was washed with water sul-fate. The and brine, then dried over magnesium magnesium sulfate was filtered off and the filtrate was concentrated in vacuo. To the resultant residue were added (750 (750 hexane ge1 mL) chloroform r 1 mL), silica (900 and hexane mL). The mixture was filtered and the filtrate To the resul-tant was concentrated in vacuo. (500 residue was mL). The mixture was added hexane vacuo. The flltered and the filtrate was concentrated in resultant. purified silica ge1 column residue was by (Eluent: give compound chromatography hexane) to the t.itle (76.21 21,0 102461 (Ae) (S) ( oxazo1idin-2 - -4 -Benzyl-3 benzyloxybutyryL) *ol-o-n ^)-T-"^o (238 (S) 4-Benzyloxybutyric g) acid benzyl (2L7 (1-3OO oxazol-idinone g) and chloroform mL) were mixed.
After g) and an addition of 4-dimethylaminopyridine (282 WSC'HCl g) mixture at ice temperature/ the to the resulting mixture was stirred at RT overnight. The 1_0 reaction mixture was in vacuo and toluene concentrated poured L) was into the residue. The mixture was washed (f.S with 1 N aqueous hydrochloric acid L), saturated (Z (1.5 sodium bicarbonate L) and brine L), then dried over sodium sulfate. The sodium sulfate was fil-tered off the filtrate was concentrated in vacuo to give the titl-e (424.e compound g) as a crude product. lo247l (A10) ( (S) tert-Buty1 3- benzyloxooxazolidine carbonyl - S -benzyloxyvalerate 2L1, oaa-r oa/'\ \^,,,11.--r^t.-o.-,,\-J "\lA-r-o--,,\.i a YoY"*' I E*:*' \-/ d -4 -Benzyl - : - 4 oxazolidin-2 -one -benzyloxybutyryl ) (41-0 (f g) and l) were mixed. To the tetrahydrofuran . A mixture was added dropwise sodium hexamethyldisilazane (:a (approximately (702 1-.9 mol L) in tetrahydrofuran) mL) at -78oC. The reaction temperature was rose to -50oC and to stiired at the same temperature. After cooling (275 78 tert-but.y1 bromoacetate mL) was added dropwise to gradually rose the mixture. The react,ion temperature was (L20 to mL) was -15 and N,N,l/'-trimethylethylenediamine added dropwise to the mixture. After stirring at the same (f.e temperature, water poured into the reaction ice l) was (2.+ and the mixture was excracted with toluene l,) . The organic acid layer was washed with aqueous 20 w/v % citric (2.+ (1.5 L), water L), saturated aqueous sodium (Z (1.6 bicarbonate l,) and brj-ne L), then dried over sodium sulfate. off and the The sodium sulfate was filtered give filtrate was concentrated in vacuo t,o a residue(548.8 (2260 g). g mL) 555 of the residue was mixed with methanol and activated carbon g). The resulting mixture was stirred at 75 for 2 hr. The activated carbon filtered off and the filtrate was concentrated in vacuo to product. give (559.9 the title compound g) as a crude lo248l ( (S) 82 - 11) tert-Butyl 3- benzyloxooxazol-j-dine carbonyl) hydroxyvalerate oa/'\ o\tfa*o* "\lAt-o.-,,\-,lJ Voxt* a Voxll' 6 i*?" o cHl"s ( (S) tert-Buty1 f - -4 -benzyl-2 -oxooxazolj-dine-3 - (500 (750 carbonyl) benzyloxyvalerate g) ethyl acetate (1510 mL) and mixed. To the tetrahydrofuran mL) were (SO g) mixture was added 20 w/w palladium hydroxide . The mixture was stirred for 4.5 hr under hydrogen atmosphere .Fha hydroxide was f lltered of f and the =l- .Y ^al_l_adium qive filtrate was concentrated in vacuo to the title (455.76 compound g) product. as a crude l024eJ (AL2) ( (S) tert-Buty1 3- benzyloxooxazolidine carbonyl) S tert valerate - - -butyldiphenylsilanyloxy) o9 oA \-',,I(=,^..--ot "\dr^orBDPS *..+ 1 YoY"" 1Y"xlX: d i*?" o cH; \-/ \-/ f arl- rr'l g ( (S) -Rrrf -oxooxazolidine-3 - - -4 -benzyl-2 (2000 (401 g) DMF mL) were carbonyl)-s-fryAroxyvalerate and (160 g) mixed. To the mixture were added imidazole and (287 tert-butylchlorodiphenylsilane mL) at ice temperature. pouring The mixt.ure was stirred at RT f or l- hr. Af ter (1.2 water l,) into the reaction, the mixture was extracted (2.3 was washed with with tol-uene l,) . The organic layer ,o (Z (1.6 l-0 aqueous 20 w/v citric acid L), water l,) and w/v (f.0 sulfate. The Z brine L), then dried over sodium sodium sulfate was fittered off and the filtrate was (744.2 concentrated in vacuo to give the title compound as a crude product. [02s0] )-l)-/l-orl-- (A13) l_5 4 ev5 e 4-rerr-Butyl La \ butyldiphenylsilanyloxy) succinate ethyll o\l/-r-orBDPS u,14./^t\.-OTBDPS VoY'* Vo-\<'cH3 ---+ I i*?*' I 6;?', (sA g), Lithium hydroxide monohydrate tetrahydrofuran (1300 (500 mL) and water mL) were mixed. To the mixture (256 peroxide was added dropwise aqueous 30 w/w hydrogen mL) at ice was stirred aL the temperature. The mixture same temperature for 1- a solution of tert-butyl 3- hr and (S) (tert- - 4-benzyL-2 -oxooxazolidine-3 -carbonyl) -s - (744 butyldiphenylsilanyloxy)valerate g) in tetrahydrofuran (1200 mL) was added to this mixture at ice dropwise temperature. sodium After stirring at RT for 2 hr, aqueous (ZlZ (1.3 hydrogen sulfite g) L) was added dropwise to the reaction mixt.ure was mixture at ice temperature. The (3.5 extracted The organic layer with ethyl acetate L) . was washed with water L) and 10 w/v saline solution (706.79) L) then give a residue . concentrated in vacuo to (3.5 After combining the oil, hexane L) and aqueous 1 M (2.8 sodium layer was extracted carbonate L), the aqueous (1.5 and washed with hexane To the resulting aqueous (865 mL) at Iayer was added dropwise 6 N hydrochloric acid ice temperature was extracted with ethyl and the mixture (2.2 acetate L) . The organi-c layer was washed with water (2.2 (r.s L) then dried L) and 10 w/v Z saline solution over sodium sulfate was filtered off sulfate. The sodium vacuo. After an and the filtrate was concentrated in (l-.6 addition L) and hexane L) to of diisopropyl ether .r resultant the residue, the mixture was stirred at RT. The l'rrr rirr'ration precipitate to give the titl-e was collcatarr (437 compound g) .4 . [02s1] (Al-4) (tert-butyldiphenylsilanyloxy) tert-But,yl 5- -:- me thoxyme thyl c arbamoylva l- e rat. e OTBDPS u/1/!/^t.-.,OTBDPS H^C'"'N vo \z ll l\nu o iHl"t (tert tert - lgt- 2- (437 butyldiphenyl s i lanyloxy ethyl succ inate .4 ) I , (I7l (2000 triethylamine mL) and DMF mL) were mixed. To the mixture were added N, O-dimethylhydroxylamj-ne (ll- (l (201- hydrochloride g) ' g) WSC ' HC1 HOBL Hz O and at ice temperature. After stirring at RT overnight, (800 water poured and the mL) was into the reaction mixture mixture was extracted with hexane .4 L) . The organj-c (a.2 layer l-0 w/v Z saline was washed with water L) and (I.2 solution L). The aqueous layer was extracted with (2.+ hexane L) once again and the combined organic layer was dried The sodium sulfate was over sodium sulfate. filtered off and the filtrate was concentrated in vacuo to give (a25.L product. the title compound as a crude lo2s2l (A- (tert 15 tert-Buty1 3- ) [2- butyldiphenylsilanyloxy) isobutylcyclobutyl ethyll - ) oxohexvnoate OTBDPS u n.O.xrl\,. /< --OTBDPS ">-r Voxll' o cHf,"' r"x:l: (2,2-Dtbromovinyl) (+O 1- g) -:-isobutylcyclobutane and (280 tetrahydrofuran mL) were mixed. To the mixture was (2.66 (fO+ added n-butyllithium M in hexane) mL) dropwise at -78 The mixture was stirred at ice temperature and t- art (tert-butyldiphenylsilanyloxy) a solution of -l.rrrr-rr'l 5- - (5+ g) 3-methoxymethylcarbamoylvalerate in tetrahydrofuran (100 mL) was added mixture. After stirring dropwise to the at ice temperature for t hr, saturated aqueous ammonium chloride (180 (l-00 were to the mL) and water mL) added j-on react mixture. The mj-xture was extracted with ethyl (500 acetate mL), washed with saturated aqueous ammonium (fgO chloride mf, and 400 mL) and dried over sodium sulfate.
The was sodium sulfate was filtered off and the filtrate concentrated of silica gel in vacuo. After an addition g) (500 and ethyl acetate 1 20 mL) into the hexane / = / resultant RT for l- hr. residue, the mixture was stirred at The silica gel was filtered and the filtrate was (60.09 concentrated vacuo to give the title compound as a crude product. 02s3 (4'15) (tert- tert-Butyl 12- butyldiphenylsilanyloxy) 6 3 isobutylcyclobutyl - + - ethyll - - - ) me thoxyimino hexynoate OTBDPS OTBDPS roxll' "xix: A A.ung v vr13 (tert-butytdiphenylsilanyloxy) tert-Buty1 3- ethyll - (3-isobutylcyclobutyl) (58.1 6- g) and - -oxohexynoate (300 methanol mL) were mixed. To the mixture were added sodium (21,.55 g) pyridine (:O sulf ate mL) and O- (I2 g) methylhydroxylammonium chl-oride .67 at ice temperature.
The mixture was stirred at RT overnight and the resultant precipitate was removed by filtration. After (350 concentration of the filtrate in vacuo, tofuene mL) was poured into was washed with l- the residue. The mixture (150 N hydrochloric (300 (:OO acid mL) water mf,) and brine mL), then The sulfate dried over sodium sulfate. sodium was filtered off and the filtrate was concentrated in vacuo.
After (80 g) an addition of silica gel and ethyl acetate (600 hexane r 20 mL) residue, the mixture was to the stirred at RT for t hr. The silica was filtered off and the vacuo to give the fil-trate was concentrated in (55.54 title compound g) as a crude product. 102541 (Al-7) (tert-butyldiphenylsilanyloxy) tert-Buty1 - [4- iodo- ( isobutylcyclobut.yl) isoxazol-yll valerate 21,8 OTBDPS OTBDPS oxll' "x3x: ' '3v crf,ns (tert-butyldiphenylsilanyloxy) tert-Buty1 3- ethylJ - (3-isobutylcyclobutyl) (53. 64-methoxyiminohexynoate g) (ZzO and acetonj-trile mL) were mixed. To the mixture (49.6 was added iod.ine g) at ice temperacure and the pouring reaction mixture was stirred for 3 hr. After the mixture into 20 w/v Z sodium the solution of aqueous (380 thiosulfate mL) at ice temperature, the mj-xture was extracted with chloroform l) and dried over magnesium sulfate. The maqnesium sulfate was filtered off and the filtrate was concentrated in vacuo. After an addition (eo (500 silica gel g) hexane 1 20 and ethyl acetate / = / mI.\ fn flra rrr!/ lvl-^Sidue, the mixtUre waS Stirred at RT fOr t hr.
The ge1 the filtrate was silica was filtered off and concenLrated in vacuo. The residue was purified twice by gel (Eluent: silica column chromatography et.hyI acetate hexane 7 + + 45) to give the title / 60 7 50 L / (38.2 compound g) . [02ss] (A18) (t.ert-butyldiphenylsilanyloxy) tert-Buty1 5- ( valerate cyclopropyl 3 - isobutylcyclobutyl) isoxazol--3 -y1l H,C.
OTBDPS zCH. OTBDPS [_j'cH, v.o_/cH3 roxl* I ti,?*. o cHi"s (tert-butyldiphenylsilanyloxy) iodo- tert-Buty1 5- -g - - (:-isobutylcyclobutyl) (37 - isoxazol-y1J valerate '44 9) 2 - cyclopropyl - 4, 4, 5, 5 -tetramethyl- (262 g) mL) were mixed. [1,3,2]dioxaborolane(17.58 and DMF After the resulting solution was degassed by bubbling argon, (PPh3)2 phosphate (33.32 g) g) tripotassium and PdCl2 G.67 were added to the mixture. The mi-xuture was stirred at (200 poured 80 overnight. After water mL) was into the reaction, resultant precipitate was removed by (600 fil-tration and the filtrate was extracted with Loluene (200 mL) . water mL x 2, The organic layer was washed with (150 320 mL) and brine mL), then dried over sodium sulfate.
The was sodium sulfate was filtered off and the filtrate geI (+S t_5 concentrated in vacuo. After of silica an addition g) (400 and ethyl acetate hexane r 20 mL) to the / = / residue, mixture was RT. The silica ge1 was the stirred at filtered off and the filtrate was concentrated in vacuo. purified gel column The residue was by silica (El-uent: + zv chromatography ethyl acetate hexane 7 80 1 / = / + (20.2 g). / 60 7 50) to give the title compound [02s6] (A- ( 82 - 19 tert-Butyl 3 - - - - ) 14-cyclopropyl isobutylcyclobutyl isoxazo1-yIl hydroxyvalerate OTBDPS rroxll' "xix: 6 cH:-' tert-Butyl ( - tert-butyldiphenylsilanyloxy) -3 - - cyclopropyl 5 3 isobutylcyclobutyl) isoxazoL- 3 valerate - - - -yll (a7.62 g) (106 and tetrahydrofuran mL) were mixed. After (2.45 an addition 1, mL) and of acetic acid water 4 / = / (f (39.2 tetrabutylammonium fluoride M in tetrahydrofuran) mr.l t- n l-l.ra .OlUtiOn .\rE at iCe temperature, the mixture was stirred at RT overnight. The reaction mixture was concentrated purified geI in vacuo and by silica column (Eluent: chromatography hexane I 6 1 ethyl acetate / / 2) give (l-l-.82 g) to the title compound . lo2s7l (A-82 -20 Mono-tert-buty1 3 -cyclopropyl-5 - - ) - [4 isobutylcyclobutyl glutarate isoxazol-y]l 9-rrr a1l-.1 *-cH3 Lr"x:X: &?*. tert-Butyl l4-cyclopropyl (ff g), isobutylcyclobutyl) isoxazol-3 -y11 hydroxyvalerate (27.5 acetonitrile (110 mL) mL) and M phosphate buffer were mixed. To the mixture were added 2,2,5,6-tetramethyl- (438 1--piperidinyloxy (TEMPO) radical mg) and sodium (5.08 chlorite g) at RT. After an addition of aqueous sodium hypochlorite mL) dropwise t.o the the mixture at l-5 min. ice temperature, the mixture was stirred at RT for (200 Aqueous 20 w/v Z sodium mL) was added to thj-osulfate the reaction at ice temperature, the mixture was extracted (400 with ethyl acetate mL). The organic layer was washed (200 with aqueous 5 w/v Z potassium hydrogen sulfate mL), (200 water (l-00 dried over mL) and brine mL), then magnesium sulfate. The magnesium sulfate was filtered off give and the filtrat.e was concentrated in vacuo to the (1-2.2 title compound g) as a crude product. 02s8 (A2I) (2-chloromethylphenylcarbamoyl) - tert-Buty1 4 - - isobutylcyclobutyl) isoxazol-3 - 14-cyclopropyl-5 butanoate 9-r'r ,O-ru r"xil: Mono- tert 3 - 3 - -butyl 14-cyclopropyl zu isobutylcyclobutyl) glutarate B3 g) and DMF isoxazolyll mL) were mixed. an addition of 2-chl-oro After ( (1 g) WSC'HC1 methylphenylamine 1- . l-84 HOBL'Hz O . 2B and (1.50 g) the mixture was stirred to the resultant solution, at RT for was added 2 davs. To the reaction mixture saturated agueous and the mixture was sodium bicarbonate, extracted with ethyl acetate. The organic layer was washed with saturated water and brine, aqueous sodium bicarbonate, then dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated in vacuo.
The resultant purified gel column residue was by silica (Eluent: chromatography ethyl acetate hexane 1 t5 1 + give (7.241 q) / I / 8) to the title compound . [025e] (A22) (2-Chloromethylphenylcarbamoyl) 4- -3 - - cyclopropyl- 5 3 isobutylcyclobutyl isoxazol-- 3 butanoic - - -ylJ acid ,tr,srrr, 'il];r"' cl//'v ctr'v oxll' cnf,-s (2-Chloromethylphenylcarbamoyl) tert-Buty1 4- cyclopropyl- 5 isobutylcyclobutyl isoxazo]-- 3 butanoate -yl1 (1.09 g) (3.2 and toluene mL) were mixed. To the mixture was (z.z added trif l-uoroacetic acid mL) at ice temperature and the mi-xture was stirred at RT for 30 min. After water poured ice mL) was into the reaction mixt,ure dropwise at temperature, 4 N hydroxide was added to the aqueous sodium mixture dropwise and the mixture was extracted with ethyl- acetate. The organic layer was washed with brine and dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate in vacuo. The resultant was concentrated residue was purified by silica gel column chromatography /nlrronf- afhrrl : e err y ! acetate hexane rrvz:srre i 7 5 I 3 1 / 2 2 \.H+svr.e. / / / t / - - - t + to give the title / methanol chLoroform I / 8) (905 compound mg). The title compound was analyzed using a chiral title compound col-umn. The retenti-on time of the was 5.6 min., and the optical purlty thereof was 94.8 Z ee. column The condition for the analysis using the chiral as follows: performance Instrument: HPLC System Shimadzu High liquid chromatography Prominence Column: DAICEL CHfRALPAK AD-3R 0.46 cm x 15 cm Co1umn temperature: 40 Mobile phase: solution) 10 mM phosphate buffer 2.6) solution) acetonitrile phase: A solution : B solution Composition of Mobile ?n . 1i Flow rate: 0.5 mL / min (220nm) Detection: IIV (Z-ChIoromethylphenylcarbamoyl) Example A-15 : 4- [4- ( butanoic cyclopropyl 3 - isobutylcyclobutyl isoxazol-ylJ acid 2 51] (A1) (2-chloromethylphenylcarbamoyl) tert-Buty1 4- - - -cyclopropyl-5 isobutylcyclobutyl) isoxazoL-3 - butanoate \\Z\^u rroxll' o cHf,"' Mono- tert -butvl 3 - -cyclopropyl-5 (245 isobutylcyclobutyl) isoxazoLyll glutarate mg) and DMF 2-chloro mL) were mixed. After an addition of (Al WSC'HCI methylphenylamine mg) HOBL'HzO mg) and (fOe mg) to t.he mixture, the reaction mixture was stirred at RT. mixture and the Wat.er was added to the reaction mixture was extracted with ethyl acetate. The organic layer bj-carbonate, was washed with saturated aqueous sodium water and brine, over sodium sulfate. The then dried sodium sulfate was filtered off and the filtrate purified concentrated residue was in vacuo. The resultant (Eluent: by preparative chromatography ethyl acetate hexane give mg). 1 4) to the title compound / 1r:r 10262) (A2) (2-Chloromethylphenylcarbamoyl) 4- cyclopropyl isoxazol-- 3 butanoic 3 - isobutylcyclobutyl) -yIl acid *\i\ \z\^, o__<-cH3 licH, vr 13 (2-chloromethylphenylcarbamoyl) tert-Butyl 4- cyclopropyl 3 - isobutylcyclobutyl) isoxazo:-"y1l butanoate (1-31 (0.8 mg) and water mL) were mixed. After an addition (L.54 mL) to of 25 w/w Z hydrogen bromide in acetic acid the reaction was stirred at RT for 1.5 mixture, the mixture hr. Sodium acetate and water were added to the reaction mixture acetate. and the mixture was extracted with ethvl The organic layer was washed with water and brine, then was filtered dried over sodium su]fate. The sodium sulfate off and in vacuo. the filtrate was concentrated purified preparative resultant resr_oue was by (Eluent: chromatography I 9) to methanol chloroform / = / give (97.3 the title compound mg) . The specific optical rotation was +32.7o value of the title compound [cx]o" = 1.00, methanol). The title compound was analyzed using a compound chiral column. The retention time of the title was purity was 95.1 Z ee. .8 min., and the optical thereof The condition for the analysi-s using the chiral column as follows: performance Instrument: HPLC System Shimadzu High liquid chromatography Prominence Column: DAICEL CHIRALPAK AD-3R 0.46 cm x 15 cm Column temperature: 40 Mobile phase: (A phosphate (pH solution) fO mM buffer 2.6) solution) - acetonit.ril-e Composition of Mobile phase: A solution:Bsolution= : 70 Flow rate: 0.5 mL min (ZZOnm) Detection: (Potassium Example of Crystallization salt of Example A-15) (0.5 Example g) A-16 was dissolved in ethanol(5.0 mL), (1.06mL) and aqueous l- mol/L KOH was added into the mixture at ice temperature.
The mixture was 1-0 minutes, then the stirred at RT for 1_5 solvent pressure give was removed under reduced to potassium (0.539 salt g). The of Example A-l-5 as a solid (O.OSO g1 (0.2 solid was dissolved in isobutyl acetate mL), and the The mixture was stirred at RT for 2 davs. precipitated solid was collected on a filter and dried (0.01-0 zv under pressure give g) reduced at RT to a crystal . 102641 Example A-53: 4 2- {4-Cyclopropyl dimethylpropyl cyclobutyl-l isox azolyl) - S - 2 4 - ) t , dimethylphenylcarbamoyl valeric ac id (A1-) 4,4-Dimethylpentenoj-c acid 22'7 Hrc-A,, Hrc--\A..,, vr I ' '| Hrc-tH.
H.c-tu. (1,.02 To 20 was ethyl * sodium ethoxide in ethanol L) added (515 diethylphosphonoacetate mL) dropwise at ice temperature. After the mixture was stirred at ice temperature of 2,2- for 1.5 hr, a solution (510 (250 dimethylpropionaldehyde mL) in tet.rahydrofuran mL) was The added to the mixture at ice temperature. mixture was stirred at RT for 3.5 hr and aqueous 4 N sodium (885 hydroxide ice mL) was added to the mixture at temperature. After the mixture was stirred overnight at RT, N (802 reaction hydrochloric acid mL) was added to the mixture ice was extracted with at temperature. The mixture ethyl acetate L), washed with water L x 5) and brine (500 mL) The magnesj-um then dried over magnesium sulfate. sulfate was filtered off and the filtrate was concentrated (289 in give g) vacuo to the t.itIe compound as a crude product.
In addition, the title compound was also prepared product using 2,2- as a crude zv (SO way as dimethylpropionaldehyde mL) in the same described above. lo26sJ (A2) 4,4-Dimethylvaleric acid I'lxJo,, ngu x:86r"- (343 g), 4,4-Dimethylpentenoic acid methanol (1240 (150 mL) were tetrahydrofuran 3 1 mL) and ethanol mixed. After 10 w/w palladium on an addition of (:f was activated carbon g) to the mixture, the mixture stirred RT hydrogen atmosphere atm). at for 10.5 hr under The 10 wfw palladium on activated carbon was filtered off vacuo to giye the and the filtrate was concentrated in (354 titl-e compound g) product. as a crude 53 3 4 4 1 1 1 - one - -Dimethyl - -piperidin- -ylpentan- ._.--.----i> I'l>+o* x::6rO tt3- vl 13 (:+A g), piperidine(29L mL) 4,4-Dimethylvaleric acid and DMF l,) were mixed. To the mixture were added (450 (553 g) HOBL'HzO g) and WSC'HCl at ice temperature.
(L.7 After RT overnight, water the mixLure was st,irred at t,) was added to the reaction mj-xture at ice temperature and (500mL, and 400 mL x the mixture was extracted with t,ol-uene z). The was washed with agueous 10 w/v Z organic layer (f (f then concentrated sodium carbonate L) and water L), (SOe in vacuo give g) as a crude to the title compound product. lo267l (A-s3-4) (4, l- 4 1 piperidine -Dimethyl - -pentenyl ) x::6v-O :':>-^---J\N1 .t.r CH, (, (508 4, 4-Dimethyl-piperidinylpentanone and (*220 to]uene mL) were mixed. After an addition of (Ph3 (CO) (802 P) IrCl mg) to the mixture L,L,3 , ,3- (795 tetramethyldisiloxane to the mL) was added dropwise reaction under water-coolinq. The mixture was stirred at RT for give the title 3 hr, then concentrated in vacuo to (LL7I compound g) as a crude product.
(A-s3-s) (2, Ethyl 1- 2 -dj-methytpropyl) piperidin- cyc lobutanecarboxylate o/-cH. ____-> r:fo (LL46 g) 1,-(4,4-Dimethylpentenyl)piperidine and (91-0 acetonitrile mL) were After an addition of mixed. (549 (553 ethyl acrylate mL) and hydroquinone mg) to the mj-xture, overnight. The the mixture was stired at 90 give reactj-on mixture was in vacuo to the concentrated title (1470 g) product. compound as a crude l026el (A6) (2, 3- 2-Dimethylpropyl) -cyclobutenecarboxylic acid Aoz.-cH, H-c n Htc'!n*-r Hrc3 Ethyl 3 2-piperidin -dimethylpropyl) (147 y1 cyc lobutanecarboxylate g) and methyl p- (4L7 toluenesulfonate mL) were mixed. After the mixture (2100 was stirred mL) was poured at 1-05 for 2 hr, water into the reaction mixture and the aqueous layer was extracted.
The aqueous layer was washed with tert-butyl (S00 (500 methyl ether hexane f 1 mf,) and hexane mL) . / = / (663 To potassium g) the aqueous layer was added hydroxide j-ce oC at was at l-00 temperature and the mixture stirred for 2 hr. After the reaction mixture was washed with tert- (500 butyl methyl L mL x 2), ether hexane 1 / = / (500 concentrated hydrochloric acid mL) and 6 N hydrochlori-c (606 layer acid mL) were added. to the aqueous at ice temperature. The mixture was extracted with ethyl (500 was acetate mL x 2) . The combined organic layer (f (500 washed with mL), then dried waLer L x 2) and brine over magnesium sulfate. The maqnesium sulfate was filtered qive off and the filtrate was concentrated in vacuo to the title compound g) as a crude product. fnt?nl Jv t 3 2 \-r t - -Dimethylpropyl cyclobutanecarboxylic acid nrc-V (2,2-Dimethylpropyl) cyclobutenecarboxylic acid (153 g) (l-300 and tetrahydrofuran mL) were mixed. After an addition (e.Z g) of 5 w/w Z rhodium on activated carbon to the mixture, the mj-xture was at RT for 35 hr under stirred l_0 hydrogen (f atmosphere atm). The 5 w/w t rhodium on activated carbon was was filtered off and the filtrate concentrated give (l-75.56 g) in vacuo to the title compound as a crude product tlt-NMR(+OOltUz, DMSO-d6) 0.83 9H) 1-.26(d, J 5.95 Hz, (m, (m, 2H) 1.68-1.78 (m, 2H) 2.19-2.29 3H) 2.8]--2.93 1H) , , , , 11- . 95 1H) lo27rl (A8) (2,2- N-Methoxy-N-methyt-3 - dimethylpropyl cyclobutanecarboxamide O*nu vr 13 H.C3 (2, (75 3- 2-Dimethylpropyl) cyclobutanecarboxylic acid .2 g) (600 and DMF mL) were mixed. After an addition of N,O- (51.7 dimethylhydroxylamine g), hydrochloride triethylamine (92.4 (8I.2 (101-.6 mL) HOBI'Hz O g) and WSC'HC1 g) to the mixture, Water the mixture was stirred at RT overnight. poured was into the reaction and the mixture was extracted with ethyl acetate hexane I 1-. The organic layer was / = / washed with l- N hydrochloric water, agueous 10 w/v acid, sodium carbonate and water, then dried over sodium sulfate.
The was sodium sulfate was filtered off and t.he filtrate (95.2 qive g) concentrated in vacuo to the title compound as a crude product. fn.)r.'l I ZJ (A9) (2, 3- 2-Dimethylpropyl) cyclobutanecarbaldehyde o-ctt^ H.C -----'-+ Ltn-\ tt3-) H.c! To a sol-ution of N-methoxy-N-methyl-3 - (95.2 dimethylpropyl)cyclobutanecarboxamide g) in toluene (330 (1.0M mL) was added diisobutylaluminum hydride in (+e0 toluene) After the mixture mL) dropwise at -78 (648 was stirred at for 3 hr, 1.5 M sulfuric acid mL) was added dropwise to the mixture at ice temperature.
The mixture and the combined was extracted with toluene organic layer was washed with l- M sulfuric acid, water and brine, then dried over sodium sulfate. The sodium sulfate was filtered comprising the title off and the fj-ltrate compound was used in the next step. 102731 (A10) (2,2-Dj-bromovinyl) (2,2- l- -:- dime thylpropyl cyc lobutane ,L* -=-( r---f H.qllBr Lrrl | | + rr?Y n'c-V n'cV (205 g) in To a solution of carbon tetrabromide methylene (600 a solution of chloride mL) was added (325 (3so triphenylphosphine g) in methylene chloride mL) was stj-rred dropwise at ice temperature. After the mixture at ice min, a solution of 3-(2,2- temperature for 45 was added dimethylpropyl) cyclobutanecarbaldehyde in toluene The mixture was to the reaction at ice temperature. w/v Z stirred at ice temperature for t hr and agueous 10 (0oo dropwise sodj-um carbonate mr,; was added to the mixture precipitate was at the The resultant same temperature. filtered off and the filtrate was extracted with chloroform. organic layer was washed with water and brine, then dried over addition of silica gel sodium sulfate. After an to the mixture, the mixture was stirred at RT. The sodium sulfate filtrate and silica were filtered off and the was concentrated in vacuo. The resultant residue was (Eluent: purified ge1 by silica column chromatography (1-20.33 hexane) to give g) . the title compound 1027 fa-c?-1 1 \ c-Renzyloxyvaleric acid (sOO (50 g) mixed.
-Valerol-act,one and toluene mr,) were (158 To the mixture were potassium hydroxide g) and added (178 benzyl bromide ml,) . The mixture was stirred at 125 (350 overnight. was water To the reaction mixture added mL) at ice temperature. The organic layer was removed, and ether the aqueous layer was washed with tert-butyl methyl (150 mL x 3). To resulting aqueous layer were added concentrated hydrochtoric acid mL) and 6 N hydrochloric acid was extracted mL) at ice temperature. The mixture (250 with ethyl acetate ffiL, 100 mL). The combined organic (l-00 over layer was washed with brine mL), then dried magnesium sul-fate. The maqnesium sulfate was filtered off qive and the f iltrat.e was in vacuo to "orrJ"rrarated (79.2 title compound g) as a crude product. (8.11 In addition, Lhe title compound was also prepared (S as a crude product 6-valerolactone g) in using the same way as described above. 1027 (A12) (R) (5-benzyloxypentanoyl) oxazolidin- Benzyl 2 -one o\*,,['-.,"-.--^o-\-\ Hok"^o (87.9, g), (R) -Benzyloxyvaleric acid benzyL (74.8 (eeO t0 oxazolidinone g) mL) were mixed. and chloroform (51-.5 To the mixture were added 4-dimethylaminopyridine and wSC.HcI g). for 2.5 The mixture was stirred at RT hr. The reaction mixture was concentrated in vacuo. To (360 the resul-tant mL). To residue was added ethyl acetate (2LL the mixture were added 2 N hydrochloric acid mL) and water (100 mL), and the mixture was extracted with ethyl (180 acetat.e was washed with 2 N mL) . The organic layer (105 (gO hydrochloric acid mL), water mL), saturated (90 (gO aqueous brine mL), sodium bicarbonate mL x 2) and then dried over magnesium The magnesium sulfate sulfate. was in vacuo filtered off and the filtrate was concentrated (l-48 to give g) crude product. the titl-e compound as a 1021 (A-53 ( (R) tert-Butyl 4 2 -oxooxazolj-din-3 - -13 3 - - -benzyl- carbonyl benzyloxyhexanoate A solution of benzyl 12," cr) benzyloxypentanoyl oxazot idin one ) \LJ' JI (660 tet.rahydrofuran mL) was added dropwise to a mixture of (702 (1.9 sodium hexamethyldisilazarre M in tetrahydrofuran) (660 mL) and tetrahydrofuran mL) at -78 The reaction temperature was rose to To the mixture was added dropwise mL) at The tert-butyl bromoacetate -78 mixture reaction temperature was rose to -35 To the was mL) added dropwise N,N,.1// -trimethylethylenediamine at ice temperature. And then, to the mixture were added (SgO wat.er (660 layer was mL) and hexane mL) . The aqueous removed, and the layer was washed with aqueous 20 organic (650 (560 w/v Z citric acid mL x 3), water mL), saturated (660 (550 agueous brine mL), sodium bicarbonate mL) and then dried over magnesium sulfate. The maginesium sulfate zv was in vacuo fil-tered off and the filtrate was concenLrated (L96 to gj-ve the title g) as a crude product. compound lo277l (a-E?-14) (3-benzyloxypropyl) 4 -tert-Butyl 2- succinate \.,, *oA-r-o-\A ........-...* !.o=*r. ffilo I E'?" Lithium hydroxide monohydrate t.25.6 (694 (522 were mixed. To tetrahydrofuran mL) and water mL) the mixture was added dropwise agueous 30 w/w Z hydrogen peroxide (139 was mL) at ice temperature. The mixture ( (R) stirred for 30 min. and of tert-butyl 3- a solution benzyl 3 carbonyl 6 -benzyloxyhexanoate -oxooxazolidine - ) - (I72.73 g) (347 was added dropwise in tetrahydrofuran mL) to the mixture at ice temperature. The mixture was stirred 3 hr. To the reaction mixture was then added dropwise (794 (206 g) a solution of sodium hydrogen sulfite in water mL) hexane. at ice temperature. To the mixture was added The organi-c layer was layer was removed, and the aqueous (500 washed with tert-butyl methyl ether mL x 2). To the agueous 25 w/v Z potassium layer were added aqueous (2OO (5OO hydrogen sulfate mL), ethyl acetate mL) and (470 mL). The aqueous 25 w/v % potassium hydrogen sulfate organic layer was removed, and the aqueous layer was (170 extracted with ethyl acetate mL). The combined organic then dried over layer was washed with brine, magnesium sulfat.e. The mag'nesium sulf ate was f iltered of f and the give filtrate was concentrated in vacuo to the title compound g) as product. The title a crude compound was analyzed using a chiral column. The retention time of the the optical title compound was L3.4 min., and purity thereof was 94.L ? ee. condition for the analysis using the chiral column was as follows: performance Instrument: HPLC System Shimadzu High liquid chromatography Prominence 1-0 p Column: DAICEL CHIRALPAK AD-3R 0.46 cm x 15 cm Column temcerature: 40 (A (pH Mobile phase: solution) fO mM phosphate buffer 2.6) solution) acetonitrile Composition Mobile phase: A : B solution of solution 1555245 Flow rate: 0.5 mL min (22Onm) Detection: W 1027 (A15) tert-Butyl 5-benzyloxy (methoxymethylcarbamoyl hexanoate *o?o-)f\ ,.r'o-ryAfgln ------.-+ Vo*9*' YoXll, o I li?t, cul"s (3-benzyloxypropyl) (eO g) 4-tert-Butyl 2- succinate (48.4 (400 To triethylamine mL) and DMF mL) were mixed. the mixture were added N, O-dimethylhydroxylamine (31.5 (45.6 (57.1 hydrochloride g), g) WSC'HCI HOBL'HzO and g) at RT at ice temperature. The mixture was stirred (4OO overnight. was added water To the reaction mixture (480 mL), and the mixture was extracted with hexane RL, 480 was washed with hL, 240 mL). The combined organic layer (240 aqueous 10 w/v mL x 3), aqueous l-0 Z sodium carbonate (240 (240 potassium water mL) w/v Z hydrogen sulfate mL), (240 and brine magnesi-um sulf ate. The mL) then dried over magnesium sulfate was filtered off and the filtrate (84.1 give g) concentrated in vacuo to the tit.le compound as a crude product. 1027 (2,2- (A15) (3-benzyloxypropyl) tert-Buty1 -e - 3- 13- dimethylpropyl cyclobutyll - -oxohexynoate nc'o'u\rYo-\,/\ H.c b' f-l + ' nse>-/ !.o.*.cH. fl:u J;?'. (2, (2, 1,dibromovinyl) -: 2-dimethylpropyl) cyclobutane g) (50 mixed. To the and tetrahydrofuran mL) were (ZO.S (1.55 hexane) mixture was added n-butyllithium M in zv at ice mL) dropwise at -78 The mixture was stirred of tert-butyl 5- temperature for 30 min. and a solution (methoxymethylcarbamoyl) (4. g) in benzyloxy hexanoate 13 (ZS to the mixture. tetrahyd.rofuran mL) was added dropwise za.v After 20 min., saturated stirring at ice temperature for aqueous ammonium chloride was added to the reacti-on mixt,ure.
The The organic mixture was extracted with ethyl acetate. layer was washed dried over magnesi-um with brine, then sulfate. The maqnesium sulfate was filtered off and the filtrate was concentrated in vacuo. The resultant residue (Eluent: was purified geI by silica column chromatography give ethyl acetate hexane I 20) to the title compound / = / (3.4s (A17) (2,2- (3-benzyloxypropyl)-A- tert-Butyl 3- dimethylpropyl cyclobutyll 5 -hexynoate -a -methoxyimino- ',t-oltf\ n-\, z^ ill o\<'cq Lt r\ \/ r,3v -atl Au""3 l-arl- (3-benzyloxypropyl) (2,2- 3- -A- -Prrl-rr'l 13- g) and dimethylpropyl) cyclobutyll -a-oxohexynoate .44 methanol mL) were mixed. To the mixture were added (2.r5 (9. a- sodium sulfate g) pyridine s mL) and (L.26 methylhydroxylammonium g). The mixture was chloride f ilt.ered, stirred at RT overnight. The mixture was then vacuo. To the and the filtrate was concentrated in resul-tant residue was add.ed water, and the mixture was washed extracted with ethyl acetate. The organic layer z.+ r with water and brine, then dried over magnesium sulfate.
The magnesium sulfate was filtered filtrate was off and the concentrated in vacuo. To the resul-tant residue was added silica ge1 g), and the mixture was stirred at RT for l-0 mrn. The silica was filtered off and the filtrate was concentrated give (3.38 g) in vacuo to the title compound as a crude product.
(A18) (2,2- tert-But.yl 6-benzyloxy dimethylpropyl) cyclobutyll -4 - iod.oisoxazol -3 -yl )hexanoate i-arf rr'l (3 (2, -Drrf DsvI L 3 -benzyloxypropyl) -A- 2- dimethylpropyl) cyclobutyll -a -methoxyiminohexynoate . 37 g) (lO and methylene chloride mL) were mixed. To the mi-xture was added iodine monochloride M in methylene chloride) mL) at ice The mixture was 0.ae temperature. stirred at ice temperature for 1- hr, and then to the mixture was The added aqueous solution of sodium sulfite. mixture was extracted with chloroform. The orqanic layer was washed with water and brine, then dried over magnesium sulfate. The maqnesium was fil-tered off and the sulfate qive filtrate was concentrated in vacuo to the title (4.2I compound g) product. as a crude 102821 (A19) tert-Buty1 5-benzyloxy {4-cyclopropyl 2 dimethylpropyl hexanoate - cyclobutyl isoxazol--3 -yIl u a )""3 o'\rcH.
J \ /\ ^o-\r\ B-O cH.
X::'V l- orl- rrl (2,2- -P.rrf 6-benzyloxy dimethylpropyl cyclobutyl 3 hexanoate -4 - iodoisoxazoL- -y1 (4.20 2 -cyclopropyl - 4, 4, 5, 5-tetramethyl - (2.34 (5.92 g), phosphate lL,3,2l dioxaborolane tripotassium g), (go (ro DMF mL) and water mL) were mixed. The mixture was gas. mixture was degassed by bubbling argon To the (PPh3 added PdCl2 mg) The mixture was stirred at. )2 ],l34 . 80 was ethvl for l- hr. To the reaction mixt.ure added acetate, and was filtered. The aqueous then the mj-xture layer was removed, and the organic layer was washed with water sulfate. The and brine, then dried over magnesium magnesium sul-fate was filtered off and the filtrate was purified concentrated was in vacuo. The resultant residue (Eluent: by silica gel ethyl acetate column chromatography (980 zv give mg). A hexane I 25) to the title compound (L.24 mixture thereof of the title compound and impurities was also obtained.
(A20) (2,2= tert-Butyl 3- - {4-cyclopropyl dimethylpropyl cyclobutyl isoxazol yl hydroxyhexanoate ) l J H.C. 9-t't I 13v tert-Butyl 6-benzyloxy-3 - 2- i4-cyclopropyl (980 dimethylpropyl) mg) cyclobutyll isoxazol-yll hexanoate (10 (: methanol ml,) and tetrahydrofuran mL) were mixed. To palladium the mixture was added 7.5 w/w Z on activated (200 carbon mg). The mixture was stirred at RT under hydrogen atmosphere atm) for 5 hr. The catalyst was freshened up, and the mixture was stirred at RT under hydrogen atmosphere aLm) overnight. The 7.5 w/w Z palladium on activated carbon was filtered off and the filtrate was concentrated in vacuo. purifled ge1 The resultant residue was by silica column (Eluent: hexane 1 chromatography et.hy1 acetate / = / + (700 L 4) to give the title compound mg). tert- (2,2- Butyl 6-benzyloxy - {4-cyclopropyl dimethylpropyl)cyclobutyll isoxazoLyllhexanoate with (L.24 impurites thereof g) which is obteind in the foregoing in similar way to the step was also reacted a above, and purified by gel column chromatography to silica give (ZSg the t.itIe compound mg) . lo284l (A21) (2,2- l--tert-Buty1 3- - {4-cyclopropyl dimethylpropyl cyc lobutyl isoxazol-3 -y1 adipate Hrc, I r3v "ul: (2,2- tert-Buty1 3- - {4-Cyclopropyl-s- dimethylpropyl cyclobutyll isoxazol-yIl hydroxyhexanoate (I.42 g) phosphate acetonitrile mL), and 0.1 M buffer mL) were added 2,2,6,5- were mixed. To the mixture (TEMPO) (l-59 tetramethylpiperidinyloxy radical mg) and (1-.1-5 g) was added sodium chlorite at RT. To the mixture dropwise aqueous sodium hypochlorite mL) at ice temperat.ure. The mixture was stirred for 2 hr, and then (12- the mixture hydrogenphosphate were added disodium (2-hydrate) hydrate) fe mg) and sodium dihydrogenphosphate (3L2 RT for 50 min. To mg). The mixture was stirred at the mixture was added aqueous 20 w/v Z sodium thiosulfate with mL) at ice temperature. The mixture was extracted ethyl acetate. The organic layer was washed with aqueous 5 magnesJ-um w/v Z citric acid and brine, then dried over sulfate. filtered off and the The maqnesi-um sulfate was qive filtrate was concentrated in vacuo to the title (1.45 g) product. compound as a crude [028s] (A22) 1-tert-Buty1, 6-methyl 3 - - [3 {4-cyclopropyl- 2 2 -dimethylpropyl cyclobutyll isoxazo:-.yI adipate "Xil: o.cH, (2,2- 1--tert-Butyl 3- - {4-cyclopropyl (1OO dimethylpropyl) cyclobutyll isoxazol-y1)adipate mg) and DMF mL) were mixed. To the mixture were added (0.0287 (+f.S methyl iodide mL) potassium carbonate mg) at ice temperature. The mixture was stirred at RT for t hr, and then mixture 5 w/v ? potassium to the was added aqueous hydrogen sulfate at ice temperature. The mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, over magnesium sulfate. then dried The magnesium sulfate was filtered off and the filtrate (l0 concentrated in vacuo to give t.he title compound mg) product. as a crude l_5 2 tert -Butv1 3- -cyclopropyl-s- [3- (1. g) dimethylpropyl) isoxazo:--yI)adipate 35 cyclobutyll were added and DMF mL) were mixed. To the mixture (0.388 (559 methyl iodide mL) potassium carbonate mg) t hr, at ice temperature. The mixture was stirred at RT for and then water at ice temperature. to the mixture was added product The mixture was mixed with the crude of 1-tert- (2,2- butyl, methyl Z-{+-cyclopropyl [3 (110 dimethylpropyl) isoxazolyl)adipate mg) cyclobutyll previously. obtained The resulting mixture was extracted with toluene. The orqanic laver was washed with water and brine, then dried over magnesium sulfate. The magnesium sulfate was filtered off and the filtrate was concentrated in vacuo give (1-.53 g) to the title compound as a crude nrnAr r af y! vssg u .
(A-s3-23) (2,2- 6-Methyl 3- - t4-cyclopropyl dimethylpropyl cyc lobutyl isoxazol y1 adipate t'3Y o oxll' ,o-N u r\- I r3v cHY-' /un3 o.cH3 (2,2- 1-t.ert-Butyl 6-methyl 3- - , [3 {4-cyclopropyl dimethylpropyl) (1. g) cyclobutyll isoxazo1yl)adipate 5O and chloroform was mL) were mixed. To the mixture added trifluoroacetic acid mL) at ice temperature. The mixture was stirred at. RT overnj-ght. The reaction mixture was concentrated in vacuo, twice with and then azeotroped toluene give (1,.43 g) to the title compound as a crude product. lo287l (A- (2,2- 53 24 Methyl- - 4-{4-cyclopropyl - ) [3 dimethylpropyl cyclobutyll 2 4- ) isox azoLyl - S - t dime thylphenyl carbamoyl valerate | ,3v o,",'g (2,2- -Methyl 3- - {4-cyclopropyf dimethylpropyl-) (100 cyclobutyll isoxazoLy1)adipate mg), (0.0379 (f 2,A-dimethylphenylamine mL) and DMF mL) were (0.0354 mixed. To the mixture were added triethylamine mL), HOBL'HzO (58.8 mg) and WSC'HCI mg) at ice temperature.
The mixture was stirred To reaction at RT overniqht. the mixture was added saturated aqueous sodi-um bicarbonate at ice temperature.
The mixture was extracted with ethyl acetate.
The organic layer was washed with water and brine, then dried over magnesium su1fat.e. The magnesium sulfate was filtered off and the filtrate was concentrated in vacuo.
The resultant purified preparative residue was by (Eluent: chromatography hexane I 4) to ethyl acetate / = / give (ffS the title compound mg).
(A-s3-2s) (2,2- t3 - {s-Cyclopropyl-s- dimethylpropyl cyclobutyll isox azoLyl - S - 2 4- ) t , dimethylphenylcarbamoyl valeric acid },. ^u \.,.\ t1 a Y\ , !3v \z- \Z\^, v, 13 vr 13 o/vr OH (2,2- Methyl 4- - {4-cyclopropyl dimethylpropyl) cyclobutyll isoxazo:--yl 2, 4- (115 dimethylphenylcarbamoyl)valerate mg) acid and acetic (I.2 mL) were mixed. To the mixture was added 47 Z hydrobromic (0.6 was acid mL) at 10 The mixture stirred at RT at. 60 To the and further stirred (492 reacti-on mixture was added sodium acetate mg) at ice temperature. The mixture was extracted with ethyl acetate.
The organic layer was washed with water and brine, then dried over magnesium sulfate. The magnesium sulfate was filtered off was in vacuo. and the filtrate concentrated preparati-ve The resultant residue was purified by chromatography (Eluent: acetic acid methanol chloroform (rog r 20 0.05) t.o give the tit.le compound mg) . The resulting titLe compound was analyzed using a chiral column.
The retention time of title compound was 24.7 min., and purity the optical thereof was 94.9 Z ee.
The the chj-ral column condition for the analysis using was as follows: performance Instrument: HPLC Syst.em Shj-madzu High Iiquid chromatography Prominence Column: DAICEL CHIRALPAK AD-3R 0.46 cm x 15 cm Col-umn temperature: 40 Mobile phase: (A (plt phosphate 2.6) solution) 10 mM buffer solution) acetonitrile Gradient: phase was changed from The mobile constantly A solution : B solution 60 : 40 to A solution : B solution mobile phase z 70 over 20 min., and then the of A solution : B : 70 was hold for 5 min. solution 30 The mobile phase was then changed from A solution : B solution 50 z 40 : 70 to A solution : B solution over 1 min., and then the mobile phase of A solution : B solution 50 : 40 was hold for 4 min.
Flow rate: 0.5 mL min (ZZOnm) Detectj-on: W [028e] (+-Chloromethylphenylcarbamoyl) Example A-79: 5 -+- cyclopropyl- isoxazo!-3 - 2-dimethylpropyl cyclobutyl] [3 ) y1)valeric acid [02e0] (A1) (4-chloromethylphenylcarbamoyl) Methyl cyclopropyl - 2-dimethylpropyl cyclobutyl] isoxazol-3 - [3 ) )valerate o'cH' o--, (2,2Methyl 3- - {4-cyclopropyl-s- (100 dimethylpropyl) mg), cyclobutyll isoxazol-yl)adipate (43.5 (f were 4-chloromethylphenylamine mg) and DMF mL) WSC' mixed. To the mixture were added HOBL'HzO mg) and (58.8 HCI mg) at ice temperature. The mixture was stirred at RT, and further stirred at 70 To the reaction mi-xture was added sodium bicarbonate at saturated aqueous ice temperature. The mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over magnesium The magnesium sulfate sulfate. was filtered off and the filtrate was concentrated in vacuo.
The resultant purified by preparative residue was (Eluent: chromatography ethyl acetate hexane 1 4) to / = / give the (72.8 titl-e compound mg) .
Io2e1] (A-7 (4-Chloromethylphenylcarbamoyl) 9-2) 5- -+- cyclopropyl-5 2-dimethylpropyl) cyclobutyl] isoxazol-3 - yI)valeric acid H.C, ,o*ru 9*N H,C r ,3v a\lJ (4-chloro-2 Methyl - + - -methylphenylcarbamoyl ) cyclopropyl - 2-dimethylpropyl cyclobutyl] isoxazol--3 - [3 ) (zz.s (0.725 y1)valerate mL) were mixed. mg) and acetic acid (0.363 To the mixture was added 48 w/v Z hydrobromi-c acid mL) and then to at RT. The mixture was stirred at 60 (287 the reaction mixture was acetate mg) at added sodium ice with ethyl temperature. The mixture was extracted acetat.e. with water and brine, The organic layer was washed 251, then dried over magnesium sulfate. The magnesj-um sulfate was filtered in vacuo. off and the filtrate was concentrated preparative The resultant residue was purified by (Eluent: chromatography acid methanol chloroform acetic (49.t r 20 0.05) to give the titte compound mg) . The = / / specific optical rotation value of the title compound was +32 . The title compound . Oo 1. oo, methanol) Icx]o'u = = was analyzed using a chj-ral column. The retention time of purity the title compound was 26.8 min. and the optical t0 thereof was 94.8 Z ee.
The condition for the analysis using the chiral column was as follows: performance Instrument: HPLC System Shimadzu Hlgh liquid chromatography Prominence Column: DAICEL CHIRALPAK AD-3R 0.46 cm o x 15 cm Column temnerature: 40 (A (pH Mobile phase: sol-ution) f O mM phosphate buf f er 2.6) solution) acetonitrile Gradient: The mobile phase was constantly changed from A solution : B solution 60 : 40 to A solution : mobile phase solution 30 : 70 over 20 min., and then the min. of A solution : B solution 30 z 70 was hold for 5 phase : B The mobile was then changed from A solution soluti-on 70 A : B solution 50 : 40 : to solution phase over 1 min. and then the mobile of A solution solution 60 : 40 was hold for 4 min.
Flow rate: 0.5 mL min Detection: W 2 Onm) l02e2l (Example Example of Crystallization A-79) (O.S Example A-79(0.1 g) was dissolved in acetonitrile mL) . The give solvent was evaporat.ed in the air at RT to a crystal. [02e3] (2-Chloro-4 Example A-58: 5- -methylphenylcarbamoyl ) -+- cyclopropyl 2-dlmethylpropyl cyclobutyll isoxazol [3- ) yI)valeric acid. lo2e4l (A-s8-l-) (2-chloro-4 Methyl - -methylphenylcarbamoyl - (2, cyclopropyl 2 dlmethylpropyl cyclobutyll isoxazoL- 3 [3- - - ]valerate 9-rrr figu o.",'g (2,2Methyl 3-{4-Cyclopropyl-s- - dimethylpropyl) (1OO cyclobutyll isoxazolyl)adipate mg), zv (0.0377 (f 2-chloromethylphenylamine mL) and DMF mL) were mixed. To the mixture were added triethylamine (0.0354 (SA.e (+l ice mL), HOBL.HzO mg) and WSC.HCl mg) at temperature. The mixture was stirred at RT overnight. To the reaction agueous sodium mixture was added saturated bicarbonate at ice temperature. The mixture was extracted with was washed with ethyl acetate. The organic layer water, 1 N hydrochloric and brine, then dried over acid magnesium sulfate. The magnesium sulfate was filtered off The resultant and the filtrate was concentrated in vacuo.
(Eluent: residue was purified preparative chromatography give compound ethyl acetate hexane f 8) to the title (53.3 mg) . [02es] (A2) (2-Chloromethylphenylcarbamoyl) - -+- cyclopropyl - 5 2-dimethylpropyl cyclobutyl] isoxazol--3 - - [3 - ) yl)valeric acid (2-chloro-4 + Methyl 5 - - - - -methylphenylcarbamoyl ) cyclopropyl isoxazoL-3 - - 2-dimethylpropyl cyclobutyl] [3 ) (63.3 (O.e y1]valerate mg) and acetic acid mL) were mixed. (0.3 To the mixture was added 48 w/v ? hydrobromic acid at 10 at RT, and further The mixture was stirred were added stirred at 50 To the reaction mixture (250 sodium ice temperature. The acetate mg) and water at mixture was extracted twice with ethvl acetate. then dried organic layer was washed with water and brine, over magnesium sulfate. The maqnesium sulfate was filtered off and the filtrate was concentrated in vacuo. resultant resr_o.ue was purified by preparatrr-ve (E1uent: chromatography methanol chloroform aceiuie acid (56.7 give mg) r 20 0.1) to the title compound .
= / / Thc ...'oeific optical rotation value of the title . The compound was +20.6o(c 1.00, methanol) Icx]o'u = title was a chiral- column. The compound analyzed using retention time of the title compound was 26.4 min., and the optical purity thereof was 95.9 Z ee.
The condition for the analysis using the chiral- column was as follows: Instrument: High performance HPLC System Shimadzu liquid chromatography Prominence Column: DAICEL AD-3R 0.46 cm x 15 cm CHIRALPAK e Column temperature: 40 phase: (A phosphate buffer Mobile solution) fO mM 2.6) solution) acetonitrile from Gradient: The mobile phase was constantly changed A solution 40 to A solution : B : B solution 50 ; phase solution 30 : 70 over 20 min., and then the mobile of A was hold for 5 min. solution : B solution 30 : The mobile phase was then changed from A solution 60 : 40 solution 30 : 70 to A solution : B solution over phase of A solution : B 1- min., and then the mobile solution 60 : 40 was hold for 4 mi-n.
FIow rate: mL min Detection: I.rV Onm) l02e6l Example (Example of Crystallization A-58) (O.f Example compound A-58 g) was dissolved l_n isobutyl (0.3mf,) (0. mL) was acetate at 5O'C, then heptane added to the mixture. The mixture was stirred at 4O.C for l-.5 precipitated hr, and stirred at RT overnight. The l_0 solid was collected on a fil-ter at RT and dried under reduced pressure (0.0639). to give a crystal lo2e7l (Z-Chloromethylphenylcarbamoyl) Example A-75 : 4- -:- cyclopropyl (Z-ethylbutyl) - cyclobutyl] isoxazol-3 - yl)butanoic acid [02e8] (A1) Ethyl 4-ethy1hexenoate r,a"\ t'at-hfo\-,cH3 *rcJ-"ro (35.5 g) in Potassium tert-butoxide was suspended (400 tetrahydrofuran mL). To the suspension was added (62.8 dropwise a solution of ethyl diethylphosphonoacetate (300 mL) in tetrahydrofuran ice temperature. The mL) at mixture was stirred at RT for 30 min., and then to the mixture was added dropwise a solution of 2- (Zl (SO ethylbutylaldehyde mL) in tetrahydrofuran mL) at temperature. The mixture was stirred at RT for 90 min., (100 and then to the mixture was added water mL). The mixture was extracted with ethyl acetate. The organic layer was (200 washed with water brine I 1 mL) and / = / (100 brine mL), then dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated (55.3 in vacuo to give g) the title compound as a crude product.
Io2eel (A2) 4-Ethylhexanoic acid #r,;)---o=cH3 + *,\r, '',J)--"ot-,cH3 Eethyl (55.3 g) 4-ethyIhexenoate was dj-ssolved in a mixture (150 (j-50 of tetrahydrofuran mL) and ethanol mL).
To the palladium solution was added 5 w/w Z on activated (5.5 carbon g). The mixture was at RT for 3.5 hr stirred under (f palladium hydrogen atmosphere atm). The 5 w/w % on activated carbon was fil-tered off usins Celite. To the zv filtrate (111 was added aqueous 4 N sodium hydroxide mL). mixture was stirred at RT overnight. The reactj-on mixture was washed with hexane. To the agueous layer was added (l-13 4 N hydrochloric acid mL) . The mixture was '7 extracted with ethyl acetate. The organic layer was washed with (300 (150 water brine I 1 mL) and brine mL), / = / then dried was over sodium sulfate. The sodium sulfate fil-tered off and the filtrate was concentrated in vacuo tro give (41.0 the title compound g) as a crude product. 75 - 3 a -Ethyl 1 1 -ylhexanone ) - -piperidin- t't) *ut-r Hsc-._y'-_-,,.\,oH + t.t.--r-.--^1-NJ (47.0 a-Ethylhexanoic g) was dissolved in DMF acid (1-90 (34.0 mL) . To the solution were added piperidine mL) (52.7 HOBL 'Hz g) (66 g) O and WSC'HCI .I . The mj-xture was stirred at RT overnight. To the reaction mixture were (300 (100 added ethyl acid acetate mL) and 1 N hydrochloric mL) at ice temperature. The aqueous layer was removed and the organic layer was washed with saturated aqueous (150 (100 sodium bicarbonate mL x 2) mL x 2) and brine then dried over sodium sulfate. The sodium sulfate was filtered in vacuo to off and the filtrate was concentrated give (59.8 the title compound g) as a crude product. 03 01] (A- (4-Ethy1 7s I piperidine -4 ) - hexenyl *'t) NJ a) Hrc:,,\.-\-NJ ------> (59.8 g) -Ethy1- 1--piperidin- 1-ylhexan- 1-one was dissolved (500 in toluene mL). To the solution was added (ph3 (co) (95.9 rrCl mg) To the mixture was added !,L,3, (82.3 3-tetramethyldisiloxane mL) in a water-bath.
The mixture was in water-bath for 3 hr. The st.irred a qi-ve reaction mixture was concentrat,ed in vacuo to the (98.1 title compound g) product. as a crude (A-7s-s) l-0 Ethyl (2-ethylbutyl 2 1 3 - - -piperidin- - cyc lobutane carboxylat e t't) H.C..r.,,\..-\,,,NJ (+-Ethy1 (e8.1 I - 1 piperidine and - -hexenyl ) 9) acetonitrile (zO were mL) were mixed. To the mixture added (53.0 (2'71 ethyl acrylate mL) hydroquinone mg) . The mixture was stirred at 100 overniqht. The reaction qive mi-xture was vacuo to the title concentrated in (L32 compound g) as a crude product.
(A6) (2-Ethylbutyl) zv 3- acid cyclobutenecarboxylic __--> Ethyl 3 - ethylbutyl piperidin- 1- - ylcyclobutanecarboxylate (1-32 g) p- and methyl (4L.0 toluenesulfonate mL) were mixed. The mixture was stirred at l-OO waLer for 3.5 hr. After an addition of mL) the mixture was washed with tert-butyI methyl ether (l-20 heptane 1 1, mL) . To the aqueous layer was (140 added aqueous potassium mL). The I N hydroxide mixture was stirred at 105 for 3 hr. The reaction (l-50 mixture was washed with mL) . tert-butyl methyl ether The organic layer was extracted with water mL). To the combined aqueous layer was added concentrated hydrochloric (105 acid mL) at ice temperature. The aqueous layer was extracted (250 with ethyl acetate mL x 2) . The combined (100 (l-00 organic layer was mL) and brine washed with water mL), t.hen dried over sodium sulfate. The sodium sulfate was filtered in vacuo off and the filtrate was concentrated (39.0 to give the titl-e g) as a crude product. compound (A7) (2-Ethylbutyl) 3- acid cyclobutanecarboxylic --_--> H.C H,C (2-Ethy1butyl) (39. 3- g) cyclobutenecarboxylic acid 0 (200 was dissolved in tetrahydrofuran mL). To the solution was (S.S g). added 5 w/w Z palladium on activated carbon The mixture was stirred at RT overnight under hydrogen atmosphere (r atm). The 5 w/w Z palladium on activated carbon was filtered off usinq Celite and the filtrate was concentrated in vacuo. The residue was purified by silica ge1 (Eluent: column chromatography ethyl acetate hexane (25.2 1_0 1 4 I 2) to give the title compound g) . [030s] (A8) N-Methoxy-N-methyl-3 - e thylbutyl cyc lobutanecarboxamide ..o-cH^ lJ a- l r3v f,gu (2-Ethylbutyl) (l-0. 3- acid 0 g) cyctobutanecarboxylic (100 and chloroform mL) were mi-xed. To the mixture were (5.36 g), added N,O-dimethylhydroxylamine hydrochloride (11.3 (L2.5 N,N-diisopropylethylamine mL), WSC'HCI g) and 4-dimethylaminopyridine (7.96 g) at ice temperature. The mixture was stirred RT After an addition of at overnight.
N hydrochloric acid mL) at ice temperature/ the 261, aqueous layer was removed. The organic layer was washed with (SO (SO 1 N hydrochloric acid mL), water mL), saturated (50 (SO aqueous sodium bicarbonate mL) and brine mL) then dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was in vacuo concentrated to give (L3.2 the title compound g) as a crude product.
(A9) (2-Ethylbutyl) 3- cyclobutanecarbaldehyde N.O-CH' To a (2- sol-ut.ion of N-methoxy-N-methyl ethylbutyl)cyclobutanecarboxamide (L3.2 g) in methylene chloride mL) was added dropwise diisobutylaluminum (1.0 hydride (Ze.O M in methylene chloride) mL) at After stirring at -78 for 2.5 hr, l- M sulfuric acid was added dropwise to the mixture. mixture was The stirred at ice temperature for 20 min. The organic layer was removed, and the aqueous layer was with methylene chloride extracted mL x 2). The combined organic layer was washed with 0.5 N sulfuric (SO (SO acid mL x 2), water mL) and brine, zv then dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate comprising the title compound used in the next sten.
(Al-0) (2, ( I- 2-Dlbromovinyl-) ethylbutyl cyc lobutane -: ) H,c\ --------------.> -r/a nrc-){ (27.0 g) To a solution of carbon tetrabromide in methylene chloride ml,) was added dropwise a solution of (42.8 (8S triphenylphosphine g) in methylene chloride mL) at ice temperature. was at ice The mixture stirred t.emperature for 20 min., and then to the mixture was added dropwise a solution of ethylbutyl)cyclobutanecarbaldehyde in methylene chloride aL l_0 ice temperature. 40 After stirring at ice temperature for (250 min., saturated agueous bicarbonate mL) was sodium added dropwise to the mixture. The aqueous layer was removed, and the organic layer was washed with water mL) (50 and brine mr,), then dried over sodium sulfate. The sodium sulfate was filtrate was filtered off and the concent.rated in vacuo. To the residue were added hexane chloroform (100 gel (so g) hexane 1 L mL) sil-ica and = / , (300 mL). The mixture was and the filtrate was filtered concentrated in vacuo. To the residue was added hexane (300 mL), and the mixture filtered. The filtrate was purified concentrated in vacuo. The resultant residue was (Eluent: by silica gel hexane) to column chromatography give (9.78 t,he titl-e g) compound .
Il-arl-- (A1-l-) tert-Buty1 5- butyldiphenylsilanyloxy) - ethyll ethylbutyl cyclobutyll -oxo- 5 ) -4 -hexynoate OTBDPS ".O."/\.--.-OTBDPS H.c r''oxll' '"' Yoxll' o cHl"' o cnf,-, (2, (2-ethylbutyl) (9 l- cyclobutane .78 2-Dibromovinyl) -g- g) (100 and tetrahydrofuran mL) were mixed. To the mixture (1-.55 hexane) was added dropwise n-butyllit,hium M in mL) at mixture was stirred under ambi-ent -78 The temperature. To the mj-xture was added dropwise a solution Iarl- rrl of - : - -l.rrrf 5 - tert -butyldiphenylsilanyloxy) (10.6 g) methoxymethylcarbamoylvalerate in tetrahydrofuran mL) ice After stirrinq at ice at temperature. temperature for 2 hT. saturated aqueous ammonium chloride (150 The mixture mL) was added to the reaction mixture. (150 was extracted with RL, l-00 mL). The ethyl acetate mL) and combined organic layer was washed with water brine over sodium sulfate. The ffiL, 50 mL), then dried sodi-um sulfate was filtered off and the filtrate purified concentrated residue was in vacuo. The resul-tant (Eluent: by sj-lica gel ethyl acetate column chromatography + + give the title / hexane L 40 7 30 I 20) to / / / (9.70 compound g) l-arf rr'l (tert- -Prrf 3- butyldiphenylsilanyloxy) (z- ethyll - ethylbutyl cyclobutyll -4 -methoxyiminohexynoate OTBDPS OTBDPS n /tlJ Il l-nu o-<cH3 cH;'3 /-cH. vr 13 (tert-butyldiphenylsllanyloxy) tert-Buty1 3- ethylJ - 6- (z-ethylbutyl)cyclobutyll (g.70 - g) t3 oxohexynoate and methanol- mL) were mixed. To the mixture were added (4.57 sodium sulfate pyridine (7.0 mL) and O- methylhydroxylammonium (2.69 g). chloride The mixture was stirred at RT overniqht was and filtered. The fil-trate purified concentrated in vacuo. The resultant residue was (Eluent: by silica gel column chromatography et,hyl acetate / hexane: L 30 I 20) to give the title compound (7.8s r_s g) ]_0l (A13 (tert-butyldiphenylsilanyloxy) tert-Buty1 5- -:- s- (2-ethylbutyl t3 - cyctobutyll -4 - iodoisoxazol-3 -y1 )valerate (tert-butyldiphenylsilanyloxy) tert-Buty1 3 - ethyll - (z-ethylbutyl) - - cyclobutyl] -4 -methoxyiminohexynoate (7.50 g) (60 and acetonitrile mL) were mixed. To the mixture (7.54 g) ice was added iodine was added at temperature. The mixture was for 4.5 hr, and then stirred to the mixture were added aqueous 5 w/v Z sodium (50 (200 thiosulfate 5 mL), ethyl acetate mL) and aqueous w/v Z sodj-um thiosulfate ffiL, 150 mL) at ice temperature.
The was aqueous layer was removed, and the organic layer washed with saturated bicarbonate brine aqueous sodium (roo (sO I l- mL) and brine mL) then dried over sodium sulfate. The was filtered off and the sodium sulfate filtrate was concentrated in vacuo. The resulLant residue was purified gel twice by silica column chromatography (El-uent: ethyl acetate hexane I 50 1 40 I 20) / = / glve (7.A g) to the title compound . [031-]-l (A14) (tert-butyldiphenylsilanyloxy) tert-Butyl 5- -:- cyclopropyl-5 (2 isoxazol-3 - - -ethylbutyl) cyclobutyl] - zv yI )valerate I 13y H a ,""3 "'l\"*.
.Orlr OTBDPS Tf"X::: o cnf", (tert.-butyldiphenylsilanyloxy) tert-Butyl -:- - t3- -ethylbutyl) cyclobutylJ iodoisoxazol- 4 - -yl )valerate (4.e6 2 -cyclopropyl - 4, 4, 5, 5 - tetramethyl- (l-. (5. 3, 2] dioxaborolane g), phosphate 66 [1, 6B tripoLassium g), (PPh3 (468 (so PdCl2 mg) and N,N-dimethylacetamide mL) were mixed. The mixture was stirred at 80 for 5 hr.
To the reaction mixture were ethyl acetate mL) added and Celite at RT, and the mixture was filtered. The collected sol-id was washed with ethyl acetate mL x 2). (100 The filtrate was washed with water br:-ne 1 t mL x 2) and brine mL), then dried over sodium sulfate.
The sodium sulfate was filtered off and the filtrate was purified concentrated in vacuo. The resultant residue was (Eluent: by silica gel column ethyl acetate chromatography /hexane L/ 50+I/40 L/30+I/20)togivethe titl-e g) compound . {2.86 (A15) (z- tert-Butyl 3- - {4-cyclopropyl-s- ethylbutyl cyclobutyll isoxazol 3 s ) - -yI - -rryaroxyvalerate I r3v ' '3v OTBDPS OH oxll' cHl"a r"X;x: To tetrabutvlammonium fluoride M in (0.0725 zv (6.2G tetrahydrofuran) mL) were added water mL) (0.29 (tert- acetic acid tert-butyl 5- mf,) and a solution of butyldiphenylsilanyloxy) - [3 {4-cyclopropyf-s- (2.76 ethytbutyt) g) cyclobutyll isoxazolyI)valerate in tetrahydrofuran The mixture mL) at. ice temperature. was stirred at RT overniqht. The reaction mixture was concentrated purified in vacuo. The residue was by sllica (Eluent: gel column chromatography acetate hexane et,hyl (7.12 g).
L 6 I 4 L 2) to give the title compound / / / (A16) Mono-tert-butyl 3-{4-Cyclopropyl-s- - ethylbutyl glutarate cyclobutyll isoxazol yI o\.,cH3 oxll' N^,, nrt-3 v, ,3 CHf,-a l- orf rr'l -Rrrf 3- [3 {4-cyclopropyl-s- ethylbutYl cyclobutyll isoxazol yI hydroxyvalerate (I.72 (:S g), acetonitrile M phosphate buffer mL) and 0.5 mL) were mi-xed. To the mixture were added 2 Q7 ,2 ,5 ,6- (TEMPO) (60.4 tetramethylpiperidinyloxy mg) radical- (1.31 sodium chlorite g) and aqueous sodium hypochlorite (8.5 mL) at RT. The mixture was stirred for t hr, and then to the mj-xture 5 w/v Z sodium were added agueous thiosulfate mL) and aqueous l-0 w/v Z citric acid mL) wlth at ice temperature. The mixture was extracted (fOO ethyl acetate mL). The organic layer was washed with The sodium brine mL), then dried over sodium sulfate. sulfate was filtered off and the filtrate was concentrated (l- g) in vacuo to give the tit.l-e compound . 78 as a crude nraArraF y!vuqvu.
(Al-7) (2-chloromethylphenylcarbamoyl) - tert-Buty1 4- (Z-ethylbutyl) :- cyclobutyll isoxazol {+-cyclopropyl )butanoate f1 | \4..'-., v, ,3 o\-,cH3 Aruns Mono- tert. -buty1 3- - {4-cyclopropyl-s- (1s0 ethylbutyl) cyclobutyll mg) and isoxazolyl)glutarate (1.5 DMF mL) were mixed. To the mixture were added HOBL' (63.5 (79.6 Hz o mg) and 2-chloro mg) wsc HcI (0.0512 methylphenylamine mL) . The mixture was stirred at RT was ethyl overnight. To the reaction mixture added acetate. The mixture was washed with aqueous l-0 w/v Z citric acid, water, saturated aqueous sodium bicarbonate and brine, sulfate. The sodium then dried over sodium sulfate was filtered off and the flltrate was concentrated purif 4rr vauuu. was ied by The resul-tant resi-due preparative (Eluent: chromatography ethyl acetate hexane give (L22 1, 6) to the title compound mg) . [031s] (A18) (2-chloro-4 4- -methylphenylcarbamoyl) -3 - (Z-ethylbutyl) cyclopropyl-5 - - cyclobutyl] isoxazol-3 - y1)butanoic acid *>/\ %"t. ox91' A.ung vr 13 (2-chloromet,hylphenylcarbamoyl) tert-Butyl 4- -:- (Z-ethylbutyl) cyclopropyl-5 - - cyclobutyl] isoxazol-3 - yl)butanoate (l-22 (o.z mg) water mL) were mixed. To the mixture was added a solution of 25 w/w Z hydrogen bromide in (1.4 ice After acetic acid mL) at temperature. (1.65 stirring at RT for 2 hr, aqueous 4 N sodj-um hydroxide mL) was added to the reaction mixture at ice temperature.
The mixture was extracted with ethyl acetate. The organic layer was washed with water and brj-ne, then dried over magnesium sulfate. The magnesium sulfate was filtered off and the filtrate was concentrated in vacuo. The resultant (Eluent: residue was purified preparative by chromatography give methanol chloroform acetic acid 1 20 0.1) to / / = / / the (56.7 was title compound mg) . The title compound analyzed using a chiral The retention time of the column. purity title compound was 8.2 min. and the optical thereof was 90.5 Z ee.
The condition for the analysis using the chiral column was as follows: performance Instrument: HPLC System Shimadzu High liquid chromatography Prominence Column: DAICEL CHIRALPAK AD-3R 0.46 cm x 15 cm Co1umn temperature: 40 (A (pH Mobile phase: solution) fO mM phosphate buffer 2.6) solution) acetonitrile Composition of Mobile phase: A solution : B solution : 70 Flow rate: 0.5 mL min (220nm) Detection: IrV (3-isobutylcyclobutyl) Example A-27 : 3- -lH- [5-Cyclopropyl 2, 3l triazol-a -yIJ - 4-dLmethylphenylcarbamoyl) butyric It, -4 acid [0 ] (A-21 ( carbamate -a) tert -Butyl 3 - isobutylcyclobutyl ,cH, ,N-r"fcn. cH,- H,c b )---/ (3.00 g) 3-Isobutylcyclobutanecarboxylic acid and tert-butanol To the mixture were added mL) were mixed. (5.38 (4.28 triethylamine mL) and diphenylphosphoryl azlde mL) at. 95 overnight, at ice temperature. After stirring the reacti-on mi-xture was in vacuo. To the concentrated resultant residue was added ethvl acetate. The mixture was washed with water and brine, then dried over magnesium sulfate. The masnesium was filtered off and the sulfate filtrate was concentrated in vacuo. The resultant residue was purified gel (Eluent: by silica cofumn chromatography ethyl acetate hexane 1- 40) to give the title compound / = / (2.er (A-27 -2) 3 - Isobutylcyclobutylamine hydrochloride .fr-"o-ftt. cHr- H"c ll ..'......................* J\ -)--r )--/ (3-isobutylcyclobutyl) (2.90 tert-Buty1 g) carbamate and dioxane mL) were mixed. To the mixture was ad.ded a solution of 4 N hydrochloric in mL) at acid dioxane 10oC. The mixture was stirred at RT overniqht. The reaction give mixture was concentrated in vacuo to the (1.91 title compound g) product. as a crude [031-e] (A-27 Imidazole-l--sulfonyl -3) azide hydrochloride HruAru --'---+ ttAtt -"ini (200 zv (l-3.0 g) were Sodium azide and acetonitrile mL) mixed. To chloride the mixture was added dropwise sulfuryl (16.1 mL) at ice temperature. The mixture was stirred at imidazole RT overnight, and then to the mixture was added (25.9 g) The mixture was stirred at RT at ice temperature. acetate. for 4 hr, and then to the mixture was added ethyl (400 mL x 2) and The mixture was washed with water (400 saturated bicarbonate mL x 2), then aqueous sodium dried over magnesium sulfate. The magnesium sulfate filtered To filtrate was added a solution off. the hydrochloric acid in ethyl acetate at ice temperature. give precipitated on a fil-ter to the solid was collected title g) compound .l .
(A-27 4) 1 isobutylcyclobutane - -Azide o //J H"Q H^C II -"'----+ + ll -)--r c.nt\) H.C' (555 mg), 3-Isobutylcyclobutylamine hydrochloride (O.S copper(II) pentahydrate mg) and methanol sul-fate potassium mL) were mixed. To the mixture were added (1,.49 g) imidazolesulfonyl azide carbonate and (1.01 mixture was hydrochloride g) at ice temperature. The added zv t.o the mixture were stirred at RT overnight, and then 1- N and brine at ice temperature. hydrochloric acid, water, The mixture was extracted with tetrahydrofuran. with 1 N hydrochloric acj-d organic tayer was washed brj-ne, then dried The magnesium over magnesium sulfate. sul-f ate was f iltered of f and the f iltrate comprJ-sing the title compound was used in the next step.
(A5) (tert-butyldiphenylsilanyloxy) tert-Butyl 5- -g- formvlvalerate Hrc-N OTBDPS HA7r'OTBDPS _-----+ \'o\<'cH3 I r3v r"xiil: I E;?*' f arf -Rrrl-rz'l 5 - tert -butyldiphenylsilanyloxy) - - methoxymethylcarbamoylvalerate 61, g) and tetrahydrofuran mL) were dropwise mixed. To the mixture was added (1.O (fg.f diisobutylaluminum hydride M in toluene) mL) at oC. oC hr. To -78 The mixture was stirred at -78 for l-.5 (0.51-5 the mixture was acid mL). added dropwise acetic After an addition of aqueous Rochelle salt at -20 the mixture The organic was extracted with ethyl acetate. layer washed with water, then dried over magnesium sulfate.
The was magnesium sulfate was filtered off and the filtrate purified concentrated residue was in vacuo. The resultant gel (Eluent: by silica column chromatography ethyl acetate (2.50 zv hexane give g).
I 25) to the title compound / = / 103221 (A-27 -6) tert-Buty1 3-ethynylhexanoate ttor-^:ot::tt ll O O ^Thhh^ IEUrD g-O-CH.
H.^y,'-\,.u ll u.c,,Y. ---........--.> \"r'o cH3 .* Vo-\<'cH3 ll l-nH o cH;'r T h.*. l- ari rr'l -Prrl- - : tert -butyldiphenylsilanyloxy) (2 (I-dtazo formylvalerate .20 g) dimethyl (0.899 (ZZ oxopropyl)phosphonate mL) were mL) and methanol potassium (L.31 mixed. To the mixture was added carbonate g) at 2 hr, ice temperature. After stirring at RT for saturated aqueous was added to the sodium bicarbonate reaction was mixture at ice temperature. The mixture extracted with layer was washed ethyl acetate. The organic with water and brine, then dried over magnesium sulfate.
The magnesj-um was sulfate was filtered off and the fil-trate purified concentrated in vacuo. The resulLant residue was (Eluent: by silica gel acetate column chromatography ethyl hexane: I 10 + L to give the title compound / / / 50) (1,.L2 g) (A-27 (tert-butyldiphenylsilanyloxy) -7) tert-Buty1 5- iodo- 1- -isobutylcyclobutyl) -l-H- 2, 3] trr:-azol-- 4- rr'l I rr:'l arrIa *or,.r.--orBDps ' 1_-a>- H"C ll )-'/ v\/vr 13 l-nu Y"xix: nu"' 's (1.10 tert-Buty1 3-ethynylhexanoate the solution of 1-azideisobutylcyclobutane which in tetrahydrofuran (A4) was prepared in described above, and the step as tetrahydrofuran mL) were mixed. To the mixture was (0.878 added ITll, N- N,N-diisopropylethylamine (493 (52e bromosuccinimide mg) and copper(I) iodide mg) at temperature. The mixture was stirred at RT overnight.
The reaction mixture and the filtrate was was filtered, concentrated in vacuo. After an addition of aqueous 10 w/w * ice t.emperatrure, ammonia to the resultant residue at the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over magnesium sulfat.e. The magnesium sulfate was filtered off and the filtrate was concentrated in vacuo. The resul-tant residue was purified gel chromatography by silica column (Eluent: : + give ethyl acetate hexane I 40 I 12) to / / / (353 the title compound mg). lo324l (A8) (tert-butyldiphenylsilanyloxy) tert-Butyl 5- cyclopropyl- 1- isobutylcyclobutyl) 2, 3] LriazaL- 4- - -lH- [1-, valerate , ,Nr-r.r n,.i|-*[,-=orror. 3" ^-i* \-<)'-Ny/.._r.*.orBDps V"x* YoxlX' cn;'t o cn;: o (tert-butytdiphenylsilanyloxy) tert-Buty1 5- -f - [5-iodo- l-- - isobutylcyclobutyl) 2, 3] triazol-4 -yll valerate -l-H- [L, mg) 2 G+o -cyclopropyl -4 -tetramethyl- , ,4 ,5 ,5 (0 (403 3, 2] dioxaborolane . l-6 mL) tripotassium phosphate mg) N, (3 (0 N-dimethylacet.amide .+ mL) and water . B5 mL) were mixed. The mixture was by bubbling argon gas. degassed (PPh3 (SO To the mixture was added PdCl2 mg) . The mixture was stirred at 80 for t hr. To the reaction mixture was added et.hy1 at ice temperaLure, and acetate then the mixture was filtered. The filtrate was washed with water and brine, masnesium sulfate. then dried over The magnesium sul-fate was filtered off and the fj-l-trate was purified concentrated in vacuo. The resultant residue was (Eluent: by silica gel col-umn chromatography ethyl acetate (238 hexane give 1 20) to the titl-e compound mg) . / = / [032s] (A-27 (3 l-s - -9) tert-Buty1 3 - -cyclopropyl isobutylcyclobut,yl l-H- - L, 2, 3f triazolyIl hydroxyvalerate H.c\-1!N OTBDPS ---------t- r"x:l: l- crl- rrl (tert-butyldiphenylsilanyloxy) -Rrrl- 5- -3 - zv cyclopropyl- 1- - isobutylcyclobutyl) - 1H- 2, 3] triazol-+ - yIl (233 (3.0 valerate mg) and tetrahydrofuran mL) were mixed.
To the mixture were added tetrabutylammonium (f (0.444 fluoride M in tetrahydrofuran) mL) and 80 v/v aqueous (0.045 acetic acid mL) at ice temperature. The mixture was st.irred at RT overni-qht. Af ter an addition of brine at, ice temperature, the mixture was extracted with ethyl acetate. The was washed with brine, organic layer then dried over magnesium sulfate. The magnesium sulfate filtered off and the filtrate was concentrated in vacuo.
The resultant residue was purified by silica ge1 column (Eluent: chromatography 2) ethyl acetate hexane 1 to / = / give (107 the title compound mg).
(A10) (3- tert-Butyl [s-cyclopropyl isobutylcyclobutyl) - l-H- 2, 3] triazol- 5 -oxovalerate [L, -yll ,N*-ry ' '3v ^---( Ny/--r"r.t-,,oH \,-1 )-N oxll' Voxll. cnl"e 6 *tf,ne (3-isobutylcyclobutyl) tert-Butyl 3- - [5-cyclopropyl (106 1H- triazol-+-yll mg) and [L,2,3] hydroxyvalerate chloroform mL) were mixed. To the mixture was added Dess-Martin (130 After reagent mg) at ice temperature. stirring at RT for t hr, saturated aqueous sodj-um bicarbonate and ethyl acetate were added to the mixture at ice temperat.ure. The mixture was extracted with ethyl acetate. The orqanic laver was washed with saturated aqueous sodium bicarbonate, water and brine, then dried over magnesium sulfate was filtered sulfate. The magnesium qive off and the filtrate was concentrated in vacuo to the (fOe title product. compound mg) as a crude lo327l (A-27 ( 1-) Mono-tert-butyI 3 - -cyclopropyl isobutylcyclobutyl) -lH- 2, 3] triazol -+-yl-lglutarate HrC-\ t'tk* /.\_ --\./ -.-.--.-.------- "X:x: r"xix: (3-isobutylcyclobutyl) tert-Butyl 3- - [5-cyclopropyl-r- l-0 (105 1H- triazol - 5 mg) [I ,2 ] -+-yIJ -oxovalerate , (f (0.2 tetrahydrofuran To mL) and water mL) were mixed. (+e. the mixture were added sodium dihydrogenphosphate A mg) and (35.8 The amj-dosulfuric acid mg) at ice temperature. mixture was stirred. RT for 5 mi-n., and then to the mixture was added dropwise a solution of sodium chlorit,e (39.8 mg) in water (O.Z temperature. After mL) at ice stirring at RT for t hr., aqueous sodium thiosulfate and brine were added to the mixture at ice temperature. mixture was extracted with ethyl acetate. The organic layer was washed with brine, then dried over magnesi-um sulfate. The was filtered off and the maqnesium sulfate (11 filtrate was concentrated in vacuo the title compound give mg) to as a crude product.
(A12) (3- tert-Butyl [5-cyclopropyl isobutylcyclobutyl) 2, 3] triazol-4 -y1l 4- -1H- [L, dime thylphenyl carbamoyl butyrate oYot Hrc-\ --\./ /\- "..{"'-^.r-*n=l N t,*)A "-\,/ e"*.
Y"Xll: Mono-tert-butyf 3 1 [5-cyclopropyl- (l-06 isobutylcyclobutyl) -1H- 2,3] triazol -a-yllglutarate (0.0356 (1 mg), 2,4-dimethylphenylamine mL) and DMF mL) were (48.2 mixed. To the mixture were added HOBL'HzO mg) (50.3 and WSC'HCI mg) at ice temperature. After stirring at RT overnight, saturated agueous sodium bicarbonate was added to the reaction The mixture at ice temnerature. mixture was extracted with ethvl acetate. The orsanic layer was washed with water brine, then d.ried over sodium sulfate. The was filtered off and sodium sulfate the filtrate was concentrated in vacuo. The resultanL (Eluent: residue was purified preparative by chromatography ethyl acetate hexane I 2) to give the title compound / = / (10s mg) . [032e] (A-27 -L3) 3 - -isobutylcyclobutyl) -rH- [5-Cyclopropyl 2,31 butyric la, triazol-a -ylJ 4 -dimethylphenylcarbamoyl) acid n ?H, ,."-{k>-W '."{O=-W \z\.., %at. vr 13 oxll' A'..,uns (3-isobutylcyclobutyl) tert-Butyl 3- - [5-cyclopropyl-f- (2,4- fU- triazol-+-ylJ [1-,2,3] -+- dimethylphenylcarbamoyl)butyrate (100 mg) and chloroform B mL) were mixture was added mixed. To the (0.2 trifluoroacetic acid mL) at ice temperature. After stirring was at RT for 5 hr, Lhe reaction mixture concentrated in vacuo. The resultant residue was purified (Eluent: 1_0 by preparative chromatography chloroform methanol- acetic 1, 0.f) to give the title acid 20 / = / / compound (79.5 mg) . (2-Chloromethylphenylcarbamoyl) Example B-l- : 5- -+- (2,2- {+-cyclopropyl dimethylpropyl) cyclobutyll isoxazol--3 -y] acid )valeric 3 31] (B1) (2, acid 3- 2-Dimethylpropyl) cyclobutanecarboxylic Aot Aot -------------i> H"C H"q l--l H.c\,-- H3c'+_J-- H,C H,C (2, acid 3- 2-dimethylpropyl) cyclobutenecarboxylic 28]- (10 g), (l-00 tetrahydrofuran mL) and 5 N hydrochloric acid (100 mL) were mixed. To the mixture was added z:-nc g) at ice temperature.
The mj-xture was stirred at 7 0 overnight. After an hydrochloric addition of 6 N acid and water the mixture was filtered. The filtrate was extracted with (150 ethyl acetate ffiL, 1OO mL). The organic (l-00 layer was washed with brine mL), then dried over sodium sulfate.
The sodium sulfate was filtered off and qive the filtrate was concentrated vacuo the title in to compound (1-1.6 g) product. as a crude 1H-tuMR (40oMHz, DMSo-d6) 0.82(s, 9H) 1.34(d, t 7.2sHz, (m, (m, (m,1H) 2H) 1.81-1.90 2H) 2.I9-2.29 2H) 2.40-2.49 , , , (brs, 2.81 -2.96(m, lH), L2. 02 lH) (B2) (2-chloromethytphenylcarbamoyl) - -+- cyclopropyl isoxazol-3 - 2-dimethylpropyl) cyclobutyl] - y1)vateric acid The (318 prepared title compound mg) was by using 3- 2-dimethylpropyl) cyclobutanecarboxylic acid prepared in (Bl-) t,he step described above according to the step (A8) described in Example subsequent A-53 and the sEeps (2-Chloromethylphenylcarbamoyl) Example A-85 : 4- (2-ethylbutyl) + -cyclopropyl 3 - cyctobutyll isoxazol-3 - vl- lbutanoate sodium N.;.,\ V\^. + vr 13 - Chloro-4 -methylphenylcarbamoyl - : - + -cyclopropyl - (z-ethytbutyl) - - cyclobutyl] isoxazolyl]butanoic acid (28.9 mg) and ethano] mL) were mixed. To the mixt,ure (0.0577 was added aqueous mL) at ice 1 N sodium hydroxide temperature. The mixture was stj-rred at ice temperature 20 min., give and then the solvent was evaporated to the title (30.4 compound mg) as a crude product.
Example A-78 The compound is a typical example of compounds wherein Y" is C:-ro group may substituted cycloalkylene which be with the same or different. 1 t.o 5 substituents selected from Group A, for example, cyclobutane ring. *"*, t-sl-\ o 0,,cF|3 wscHcl eq't Fl]Bt l{20 f'-) oYoxKL Ethyl acrylate ct-L n CFL -r#r Qtr'r ,.":c*-\tr {Ph3P}zlrcl{co} 4c Hydroquinone l-tg -p*o*c4 ''."."".."..-"'-.- A To I uene T.t.l o+.t ,r.cr*ffi/ MeCN OvCf{3 A \-r *\o'-*' H,N*A' *cH, wsc Hcl 7.5%PdtC HOBI H2O EtOH o_c4 il..-(' 2N NaOH aq. :cH, *a*, MeOH o-ffis [033s] Example A-65 wherein The compound is a typical example of compounds Y" is monocyclic group which may be heteroaromatic substituted with the same or different 1 to 5 substituents heteroaromatic selected from Group A wherein the monocyclic rinq consists of carbon atoms and the same or di-fferent to 4 hetero atoms atom selected from nitrogen atom, oxygen and sulfur atom, and is 3 to 7-membered, for example, thiazole. 94 P-N NH4Cr, WSC HCI c|,[ HOEt H2O r,,"{-{;r1\1otn rtc-L4Fffi Ets'ltl L*oH t*NFl {j lt Hz(tarmI P*,c *.",f1 r#-*' t4n_-.i!,,.*",*,, :"'of;" l$eOH, THF, 2NftCtaq Clt 0 -N *rJ-"orr, Laeres son'sReag*trH. HBC oTBDps _{ <-<XA/*oTBDPs --1^-<A/.* , ! t( MS4A. EtOH rHF A \Nq ".ZLaorr* TBAF, AcOH TEMFo, Naclo2, ruacloaq H2OTTHF Phosphate buffer, nnecu co2H **rr, Flrx.nlx.' V-., Plt P-tf ,il---* bn3 ^ - H ./:\ I NNaOHaq, rc{_dr\\y gFt, g* f{-{, /-cH, EIOH, THF H,c{-h\^{ qc/- il;-* -l1o 9rA^r., rg - HoBtHzo n t'llrr HZrJ CO?EI AtH Dl!tr s*"or, Example TFAA BnoH> BH3 slurez ^,. -^\-rr-OH lll fYo.,,}'" fl\^o^y^yo" oHo THF VoH L(-)-Ii4al ic acid .: O CH". r'_,uotf} TBDPS.CI ,l'laH il \-/ Et3N, DMAP o\.--t--o'sf cs^ r=-Jt" CH?CE flftx, -'i"1" MeNHOMe HCI P(yc A' HOBt HzO wsc Hcl E(|N "..-o',tYvo',{.r, ixr-d MeOH: AE-. \--l ?*,^A^ H"cf" HrC.,rr^11 BuLi VB- H2NOMe HCI Py, MeOH Na2504 ,..4"r, -CH.- ,o*ru ,o-{-i^.
K3Po4, PdClz(PPh3)2 , P-H ".^4"t" _CH., DMF, H2O ,..4.*.
"CH.' NaCl02 TBAF in THF NaH2PO4 NaHCO3 AcOH H2NSO3H Dess-Martin _------> ..........--..-..--.._-'- -..---.---..,i> cHcl3 HrN\r'\ %at.
H ?t.
N)i\ HOBt H2O wsc Hct 9.*, --;* "A"t;:' Example A-10 Pd(oH)2 nr'.eayoBn ^ Hrco,^:-z^.r",oH Hsc.y.'\'?o !sf€yo'-r\/ n'c'fH, tr.'lr, /, ;=;:;Tr.- o rHF CH30NHCH3 wsc Hcl CBr4, PPh3 Br o'cH' DIBAL HOBt H20 x:!6#" t36-^y--*. c|dzctz CH2CI2 H2N.o-CH3 o'il r^ *:u" Y.r.
Na2GO3 '3i-(cir. ov,cH3 H,G \-,/ tig*.
\.,, * P-fcrt. l2--B.^-!o+. rr\ cHr- x.ciH' Pdcr2(PPh3)2 i(i:o K3PO4 DMF, H2O u,cjH' Dess-Martin NaCtO, H2NSO3H periodinane NaH2PO4 .+.....'-.........,# tBuOH, H2O CHZCI? Hrc- 9-tl u fH, *l'\ WSC HCI 25o/o HBr HOBt H2O %"t.
Example A-32 The compound is a typical example of compounds wherein Y' group with the is Cr-o alkylene which may be substituted same from Group A, or different l- to 5 substituents selected group with methyl for example, C;.-e alkylene substituted group. o il#, 9"*. co2H :T'** cHcr3 ','te4vo'F"tsa> r.o,, t"f#u. 1) BnBr )r-v d :Ph dioxane ...* -...------------ 2) NaOHaq. cozH wsc Hcl MeOH DMAP cHct3 L|OH H2O LHMDS H2O2aq HMPA.THF aPh s) .........---..---'- H2 (latm) Pd/c Hrc \) THF, MeOH 1) DMP HrN:A NaHCO3 ill H 9H. .%cH. cHcl3 HrG s) 9cH, -_--+ 2) NaClO2 wsc CO'Me NaH2PO4 HOBI H2O H2NSO3H THF, H2O il#' % HBr-AcOH .--._-.--+ .9cH. c02H [033 Example A-52 Thc cnmn611nd another typical example of compounds wherein Y' is Cr-e alkylene group which may be substituted with the same or different 1 to 5 substituents selected from Group A, for example, group substituted Cr-o alkylene with methyl group. co2H TfOH H,C. ,cH3 H-c .cH. ccrfo^en toaro'.r.
H,C. en--,oi\,-o.,^, + ,CH, LiBr-t4 It -'13._ Ph o\-xv,oH o Et20 PhrPaYoEt H-C CH- Et3N H"C CH.
Ph-_-oi,.KAserE1 ......€ nn-_.o-,X-b DMSO, CHaCI? I To I uene NaBH4 CoCl 1N NaOH 6H2O H.C CH- H-C CH- Ph.-oi.Y..-A66rg Ph..-oi.X-A6srs1 MeOH, o^l'tx illl 6^Hffoen onN' ar^corteu wsc Hcl DMAP cHct3 cat KOtBu Pd/c ?^l-t*, To I uene -cortBu 9H' |y-YBr H,CV n-BuLi NH20Me -oTBDPS H3C CH3 Jl|eOH.
Pvridine u^ t .3v cortBu NH20Me HlC CH! OTBDPS HlC CH3 pyridine MeOH, cortBu N ,o-fcfi, P-".^-!"*, 1 M TBAF " cH, 80% AcOH H3C CH3 DMF, H2O cortBu Pdcr2(PPh3)2 K3P04 ,^ 9Ht Dess Martin nll)sr"'ru' NaClO, HZNSO3H o.GH, periodinane H3C CH3 NaH2pO4 H'C nleox Tol uene, cortBu Ct12Cl2 tBuOH, H2O t"JA I 9H' .-l\cH, .%"", HOBI H2O O'GH' H3C CH! CO2Me :l.--...-* co2H DMF H 9Ht N\,\ %HBr 9at. co2H AcOH HrC CH, Example A-9 Boc20 HOOC* 1N NaOHaq -,^1 Hooc-,^-.oH tt Y- NH, OH NHBoc GH3CN L-HOmOSenne (MeO)MeNH Et3N wsc Hcl TBDPS-CI HOBI HzO imid. ?*' 3 HOOCV,.!,OTBDPS O-T?OTBDPS t'lHgoc cHct3 CH, NHBoc )BrCH2COOtBu,iPr2NEt ?H, ? CH3CN o-rar-orBDPS TFA/CHCI3 ?*, fr 2)Boc2O,iP12NEt ,Y--orBDPs tt',/t) cH, NH, GootBu Hrc'r-GH. H3C-O\N H2NOMe HCl,Na2SO4 OTBDPS OTBDPS pyr.,MeOH OtBu s11s, x"c"J-*cx, r2,cH3cN,, +H3c-\__</,io. ^ft, lloor"u ^rtl;oTBoPs DMP,NaHGO3 TBAF,THF cHct3 80%AcOHaq ___-__> H'N-(\ NaClO2.NaH2P04 wsc Hcl H2NSO3H,THF/H2O \/-CH3 FiOBt H2O ilb"*, NJ "H.t CootBu o"Jllo*, :l:,,.{}q$y1fib.,. rro*3",,,,"-t3d24k hsu r--^':'z ril\ il]lo* 034 1] Preparatj-on Example of A-86, A-87, A-88, and A-89 9-Borabicyclo Hrc02c."_Jc02cH3 if3c02c.. (1.2eq. 3. 1] nonan Ph3PCH3Br ,c02cH3 ) JooA Hz,z KOtBu 2eq. i\ ) ueq./ Na0Ac/H20 THF, reflux,4Smin tHF, ooc*rt overn i ---.......-..r-'-***-.> Racemi c form H3c02ci1c02cH3 lmidazole Zeq. ) lnzc.r{cozcn3 H3c02ci{co2cH3 (1.2eq.
T:li IBDPSCI iT.
*''H,THF* DMF. rt.5. 5h Y V rt, overni*n, TBgpS'-/ ,rOOrOl ||10/ 2N Na0H irle0NHlde HC I . 5eq. ltt|Cs, DMAP, iPrZNEt -,J*-'f, '--.*-..'- ,,*:h' --.._-.-..--..1 [|eOH, Iilt CHC I 3. rt-75"C n,"|oyo-,t, 1.01[| DIBAL tt-l*coztnu "nt c0rtBu (Zeq, ^,*-",'.." f,:u THF, -78'c*0"c Toluene,l20"C V TBDPSO, -./\ ll Br ")-r Dess-Mart i ne (0.7 eq. ) reagent {4_"hco,tBu n{r-cortnu 2eq. (2. ) nBuLi 1eq" ...-....---.--.> IHF, -78"C-0'C cHc | 3, 0"c TBDPSO, .cHt vt I, . (3eq. tt{eONH2 HCI (3eq.
Na2C03 ) *.-{"' r>-4.r-co,tBu \--\-/ H,C 'r3v Et0H. 80'c. 1. 5h TBDPSO'- %*"* n,c}-0" H,c7-o' (2eq.
H,C I C0rtBu lltl| ICI 2eq. )_,, K3P04(4eq. 7\ (0. ^ltn, Pdc l2 2 15eq.
PPh3) ) HtC-\-r-"/ t*7 I ^r--\) \-0TBDPS DMF/H20.80'c 0"C-rt. 2h H,ct-oj}'S* -\-oTBDPs III IBAF co,tBu p-{, p-{, (1. 2eq. cH. lo,tBu n,,-to]-'Q r,r-\-ffi'f) THF,0"c*70'c -\-orBDPS \-oH 40mi n.
TEldP0 3eq, (3eq- f,la0 | 02 p-{' pr, NaCi0 il3??l'3il eH, fo,tBu A ,?-tr io:tBu -.{',D-V'fi H"c-\--Q-f'{) '""V DMF. rt,80min.
U I { crfiN.* Phosphate buffer ^tso.nu vrt3 rt.100min. o // \\ H"N-( )-CH" a \-t leq' ) lllsO HC | 2eq. ) TFA .
H08t 1"120(1. 2eq, ) (2v) ,,rt:.o+d DMF, rt, overnight cHct 3 Forn, rt*50oC, 2h40m in. nltl "Y.)n 'fi%*, >-0.
Hd,, l--0.. 0 CH, Separating with Chiral (Et0H co I umn AD so I vent) ,,Hrcr_ ,*,'i- oyN_\_/_cH, cH. o-*^1il{}*, H,c{-Qf,,,,o qcffi J-0,. ]to',^" vl 13 0-|l'Y" o_*oy*1_icH, .,t-a "tr0 o cH3 0 cH3 purified The above 4 stereoisomers were isolated and (EA-85, by recycle preparative HPLC EA-87, EA-88, EA-89 in the order of retention tj-me from shortest to longest). purification The was as follows: condition for the (,Japan Instrument: recycle preparative HPLC LC908 type Analyt.ical Industry) Column: DAfCEL CHIRALPAK AD 2cmax25cm phase: Mobile ethanol '7.OmL/ Flow rate: mi-nutes (254nm) Detection: W Each of the isolated and purified stereoisomers was analyzed by using a chiral column. The retention time of EA-85 methyl A-85) was 1"L.'7 minutes. ester of Example The retention time of compound EA-87 methyl ester of time of Example A-87 A) was L2.0 mj-nutes. The retention compound EA- 88 methyl of Example A- 88 was l-4 . 5 ester ) l-0 minutes. (a methyl ester of The retention time of EA-89 Example A-89) is 1-5.7 minutes.
The condj-tj-on for the analysis using the chiral col-umn was as follows: performance Instrument: HPLC System Shimadzu High liquid chromatography Prominence 46cmrox25em Column: DAICEL CHIRALPAK AD 0 Column temperature: 3 O'C phase: Mobile ethanol Flow rate: 0.5mL/ minutes Detection: trV(254nm) 3 01_ H"'">:t H")n oYN-\--rhcH' o=rN-\-/-cH' o-,,, ,iJAttt,,1\ H,c-\-_(/-Y" nrcffi }-0. a )-o.. 'cH: 1.1t''"F^ ,o_*o1NfufcH' Y,,"O "r*(l 0 cH3 (Compound EA-86, EA-87, EA-88, EA-89) (5v) HBr/Ac0H Ac0H 0v) rt*50'C, l. 5h s\,'N-\-/-cH, Hrcffi ->o* ff,c.
H,C, l.i )-\ fq' uY" olzN-\i-cH, e___,.li{_fcH, ,o-[{ /t-Un 'r'011 (Compound A-86, A-87, A-BB, A-89) give EA-85, EA-87, EA-88, and EA-89 were hydroLyzed to carboxylic acids A-86, A-87, A-88, and A-89, respectively.
The resulting carboxylic acids were analyzed by using a A-86, chiral column. The retention time of carboxylic acids A-87, A-88, was minutes, 7.0 minutes, 7.9 and A-89 8.0 minutes, and II.2 minutes, respectively. The optical purity thereof was >99.5 €e 71- * €€, >99.5 3 €€, and 89 Z €€, respectively.
The condition for the analysis using the chiral column as f oll-ows: Instrument:HPLC Shimadzu High performance System Iiquid chromatography Prominence cm cpxl! cm Column: DAICEL CHIRALPAK AD-3R 0.46 Column temperature: 40C phase: 10 mM phosphate buffer Mobile solution) (pH=2. (e ), solution) acetonitrile Composition phase: : B solution 30 : of Mobile A solution Flow rate: 0.5mL/ min (22Onm) Detection: 103421 Preparation A-118 of Example AL2, A-l-13, and p-l{ H,c-toT' Separating with Chiral (Et0H co I umn AD so I vent) ,t'2= *t'q 0Y*1-/-cH' QH,. .o-11 cH" 'yli-(J}cH' H3.{-OY""O H,cffi ?o,* ?o.rn, t';- oy*a_/-cH, NfuL-cH, o_^, n,c{--$/",,fi *{'.r, 7\ h,,e.l f a procedure by recycle preparative HPLC 1,ulr!-cation gave of EA- 112 EA- l-l-3 and EA- 118 which is a mixture (s) EA-l3. enantiomer of EA-l2 and enantiomer of The condition for the purification was as follows: (Japan Instrument: recycle preparative HPLC LC908 type Analytical tndustry) Column: DAICEL CHIRALPAK AD 2cmpx25cm phase: Mobile ethanol Flow rate: 7. OmL/ min (25+nm) Detection: Each compound was analyzed by using a chiral column.
The retention methyl ester of time of EA-112 Example A-lI2) was I4.9 minutes. The retention time of EA- 113 methyl ester of Example A- 1-13 was L6 .2 minutes .
The retentj-on Example A- time of SA18(a methyl ester of 118) was L9.4 minutes.
The column condition for the analysis using the chiral was as follows: performance Instrument: HPLC System Shimadzu High liquid chromatography Prominence Co].umn: DAICEL CHIRALPAK AD O.46cm<px25cm Column temperature: 3 O"C phase: Mobile ethanol- Flow rate: 0.5mL/ min (254nm) Detection: W ,, \_ oyil{},H, o-*ooil{}*, ,,"1) n,cffi *}0., lr-0, 'CH: 0 CH3 tl HFr olNa-/_cH' {-}cH, gH, ,o-N H,c{*ryY O *jro,rn, wr 13 (Compound EA-112, EA-l13, EA-l18) (5v) HBrlAc0H AoOH 0v) rt*50'C. 1. 5h t';= t';- o-*o*il{-}'n' .o-*'1'ilfu|cH' cH^ n,c-\--Q^/O n,cffi )-ot ir )r o1'NVcH' n,c-\ffi"'.fi *'ron (Carboxylic is 4 acids A7-2, A- l_lJ ano A-118 which mixture of enantiomer A-]-L2 and enantiomer(s) of A- r_13 hydrolyzed Compound EA- 112 EA- l-13 and EAl-8 were give carboxylic and A-118 which is a acids A-LL2, A3, mixture of enantiomer(s) of A-LL2 and enantiomer(s) of 113, respectively.
Preparation method of Example C series WSC'HCI HOBt,H2O DIBAL (MeO)MeNH'HCl I uene iPr2NEt n! /&COOH CH3CN/DMF ?H, fi\(*f'"'*, i'3 ti cl-t u"A-,/\y' up& "'Y*' il iF#.*un' cBr4,PPh3 cFr. r\/\H CH2cr2,0"c -78oc qq f^\a N' ---------------- ---------------- 4c/'-r/-t/ *,")tAy' **)tAy' oYoxll' nBuLi,THF qc-*A/ cH;'r -78'C-0"C u -.2/\nn^ J,cH3 MeONH2'HCl N^,.
Na2CO3 Arw: v,,3 cH2Cl2 o-69 EtOH,80"C ..."............- \J *--+ H,c-l--',.
" I R----a I u n,--1'-^/' rr3v K3P04.PdCt2(PPh3)2 DMF.80'C oxT' Pd(oH)2 THF andlor Alcohol "nI' H2{l -4atm) OBn r..-....._-.--.
NaClO2 TFMPO NaClOaq.
CH3CN oxfl' Phosphate buffer oxT' K2CO3 ,o-N 0"G to ri HrC Mel cHi' Arun: ^u'3 o'"' cHct3 -_.> Example C-1 rctl socr2 Ani I ine ilY\ fl3u %*r, ----i> O-""s O--'s [034s] Example WSC.HCI HOBt.H20 am i ne'HC I Et3N /-'dc4" r_.(l 2N NaOHaq MeOH/THF o'^. -_-'' Example D-1, D-3 Preparation Example D series method for wsc.Hcl gH. (YT"'.*, HOBt. HCI PtO2 cx'{' (MeO)MeNH'HCl Hp-\y'J AcOH iPr2NEt H2(4atm) OH CH3CN flY-* .........................* u n)'t-/--y' t'i'ot#t" as showed A mixture of the Weinreb amide intermediates and trans-isomer below was separated into cis-isomer j-on column purif icat by silica thereof through the chromatography.
CB14 DIBAL N'-'cH.
PPh3 ?" a+- To I uene cH2Cr2 H3C'^\/\'/' -79'c er, /Yry'o'o. lll F .J^' un1u"'\./ ,.\""V oxT' oYox3' cH:"' H.cr*Al crtr = $oBn H.c'o MeONH2.HCI Na2SO4 nBuU,THF Me0H/Pvridine -79'c to 0'c -\<'-;- -CH^ ru"'3 MeOIN O cH2Cr2 -------------t- v'.{-aH D-'1 o-tcH' vr 13 K3PO4,PdC12(PPh3)2 DMF,8O"C O ,O-n "x3X: ffi.' ilY\ %cH, /1t-l ...'+ ,o-r'r Preparati-on of Example A-l-05 and A-105 Example A-105 MeB(OH)2 H,Nt Pyridine, Dioxane - \ tt,v ll I -lr-l ^'N-r\ reflux "ilI \Z\..,, V\nu vl vl l3 t-|J \ ,-o, o'cte 2N NaOH MeOH,0"C* [034e] Preparation of Example A-105 ,.*}, I g-N SOCI2, DMA u.*, HNl.\ o'*, o-cH, %t", 2N NaOH MeOH,0"C [03s0] Preparation of Exampl-e A- 110 FSO2CF2CO2Me u-\-uH3 cat. Cul ,O-ru ,o-r"l uf,r n!.1 vr 13 DMF-HMPA,8O.c l^t.t o,"'.s O'""s 1) TFA, Toluene r-r A 2) HATU. DIPEA DMF un .,:Y N{r ;FCH^ \__/ HrN\z\ o-cH. %"t. 2N NaOH-MeOH 9-r.r t-t 0"n, I r3v rn"ql l Formulation examples of the present invention include 3]-2 example the following, but which should not construed as limitative.
(Preparation Formulation example 1 of capsule) Compound of Example A 5U mg Microcrystalline 10 mg cellulose Lactose LA mg Magnesium 1 mg stearate (1) (2), (3) (4) gelatin and are mixed and filled in a a:ncrrl a (Preparation Formulation example 2 of tablet) Compound of Example A !vY Lactose sog Corn starch Carmellose calcium 449 Magnesium 1g stearate (1), (2)and (3) g (4) The entire amounts of and 30 of granulated. are mixed with water and dried in vacuo and then The granulated powder is mixed with t4 g of and l- g of and tableted by a tableting machine. In this wdy, 1-000 l-0 ms of tablets can be obtained, each of which contains Compound of Example A-1. [03s2] Biological assayl- Pharmacological effects of the typical compounds of 3 1_3 present the invention were observed. [03s3] In vitro assay of inhibitory effect against RORy t.ranscriptional activity Inhibitory effect on transcript.ional of test article activity of RORy was measured by means of the following luciferase gene reportor assay. i nrr hrrm:11 A cDNA 6:nr.nrl and mOuSe RORy ligand binding (lenl domain were obtained based on the reported sequences (Genebank asseccion number and sequence: human, NM 005060.3 and f rom Ser253 to Lys51-8,. mouse, NM 0LL28L.2 and f rom I1e251 to Lys516) hrrm:n PoPrr The cDNA or mouse RORy was incerted into (Strategene), pFA-CMV GAL4-DNA vector which expresses binding domain fusion protein. plasmids The resulting are hereinafter referred to as GAL4-hRORy plasmid plasmid, respectively. and GAL4-mRORy Human or mouse GAL4-RORv olasmid was transientlv co- (CHO transfected cell-s cells) into Chinese hamster ovary with pGL5-Luc plasmid a reporter plasmid express5-ng f iref ly l-ucif erase depending on GAL4.
(Mirus) to TransIT CHO transfection reagent was used co-transfect plasmid into CHO human or mouse GAL4-RORy cel1s with pGL5-Luc plasmid.
One day before the assay, CHO cells were suspended v/v Z fetal bovine HAM F-L2 Nutrient medj-um containing 1-0 serum and seeded at 6 x 105 cells I75 cm' cell culture I J-CL:'J1. . reagent was Fifty four micro litters of Transit-CHO added into a l-5 ml tube contai-nins 1.16 mI of HAM F-L2 Nutrient medium without fetal bovine serum and incubated room temperature for l-0 min.
A total 35 uL plasmid solution containing the GAL4- (9000 hRORy plasmid (400 pGL-Luc plasmid ng) and ng), (8600 pcDNA3 plasmid ng) were into the tube and mixed added gently. (250 plasmid In case of mouse assay, the GAL4-mRORy (s750 (9OOO plasmid ng) ng), pGL-Luc plasmid ng) and pcDNA3 were added.
The mixture was incubated at room temperature for ml_n.
Reagent was then added Nine micro litters of CHO Mojo int.o each tube and mixed gently. The mixture was incubated at room temnerature for 10 mi-n.
The resultant reagent was applied to the transfection ceIl culture.
"C COz f or 4hr, the Af ter incubat.ion at 37 5eo treatment. transfected CHO cells were harvested by a trypsin in HAM F-I2 The col-l-ected cel-l-s were resuspended Nutrient v/v Z fetal bovine medium supplemented with 10 serum and plated into a plate at 8,000 384-welI-white cells/5Oul/we11 .
The plate was for 1hour incubated at room temperature and then further incubated. 5% COz f or 3hours. at 3'7oC The test articles were dissolved in dimethvlsulfoxide (DMSO) to l-0 mmol/L. The obtain a concentration of just resulting solution was diluted with the medium before use and plate t.o prepare 8 added to the ce1ls in the different concentrations of the test article.
The v/v Z. After final concentration of DMSO was 0.1 the addition of the test articles, the ce11s were incubated at 37"C 5Z Coz for 2days.
Ce11 viability was fluorescence method tested by a (invitrogen) usj-ng Resazurin .
Two the test article, days after the addition of Resazurin was dilut.ed with culture medium to make the 20umo1 /L resazurin solut,ion. 10uL of the diluted resazurin solution was added into the 384-well-plate.
Then, immediately at 615 the fluorescence was measured (Ohr nm with the excitation wavelength of 570 nm reading).
After incubation at 37"C 5*COz for 2hr, the f l-uorescence was measured at 515 nm with excitation wavelength of (2hr 570 nm again reading). 3 1_6 The (2hr-Ohr) fluorescence counts were calculated by subtracting the Ohr readings from 2hr readings.
The luminescence count in the cells treated with 0.1- Z DMSO alone was viability in defined as 100 Z, and the cell the test article was calculated as a percentage of control-) based on the value of 0.1- ? DMSO aIone. judged When the cell viability is 70 or 1ess, was that the test article has cytotoxicity.
RORy transcrj-ptional was detected as the activity intracellular luciferase activity using St.eadylite HTS Reporter (Perkin Gene Assay System Elmer).
Stedylite Reagent was diluted five-fo1d into a solution containing 1OmM Tricine 0.2 t w/v BSA, 0.02 * v/v Tween-20 to obtain the luciferase substrate solution.
After the measurement of the cel1 viability using Resazurin, the well-p1ate were culture media in the 384 removed. Then the Luc subsLrate solution was added into each well.
After the incubation room temperature for 10 minutes, a luminescence of each well was measured by microplate reader.
The luciferase activitv derived from the luminescence count in l- Z DMSO the vehicle-control well treated with 0. alone was defined as 1-00 the luciferase activity in 4, and the test article was calculated as a percentage - of control) based on the value of t.he vehi-c1e-control.
EC50 value of test was calculated bv curve article fitting with GraphPad Prism.
The luminescence counts at the concentration of the test article where the cytotoxicity was observed were excluded from the data analvsis.
The results are in Fiqs . 42-48. shown In Figs . 42-48, t.he values with Z is the activity of the test article which was as a percentage calculated of control) based on the value of the vehicle-control (100 treated with 0.1 ? DMSO alone %).
The activiti-es of Examples A-34 and A-41 in human which percentage were calculated as a - of control) based on the value of the vehicl-e-control treated with (100 0.1- ? DMSO alone Z) were 50 ? and 78 Z, respectively.
Industrial Applicability [03s4] The present in or invention is useful treating preventing zv autoimmune as rheumatoid arthritis, disease such psorj-asis, inflammatory bowel disease such as Crohn's disease and multiple sclerosis, ulcerative colitis, systemic lupus erythematosus, ankylosing spondylitis, uveitis, polymyatgia I diabetes; rheumatica, and type allergic disease dry eye; fibrosis such as such as asthma; 3 1_8 pulmonary ^-,l fibrosis and pri-mary biliary cirrhosis; atru metabolic disease such as diabetes.

Claims (62)

The claims defining the invention are as follows:
1. A compound of formula [I-W]: d1 d2 O N Y R G d5 c d1 ( ) n R R b ( ) n ( ) n R c c [ I-W ] wherein is ; R is (1) C alkyl group which may be substituted with the 5-12 10 same or different 1 to 5 substituents selected from Group A, (2) wherein Y is (i) single bond, or (ii) C alkylene group, cyclic moiety U is 5 (i) C cycloalkyl group which may be substituted with the same or different 1 to 5 substituents selected from Group A, (ii) C spirocyclic cycloalkyl group which may be 5-11 substituted with the same or different 1 to 5 substituents 10 selected from Group A, or (iii) C aryl group which may be substituted with the 6-10 same or different 1 to 5 substituents selected from Group R is a group selected from the following (1) to (3): 15 (1) C alkyl group which may be substituted with the same or different 1 to 5 substituents selected from Group A, (2) C alkenyl group which may be substituted with the same or different 1 to 5 substituents selected from Group A, (3) C cycloalkyl group which may be substituted with the 20 same or different 1 to 5 substituents selected from Group R is (1) hydrogen atom, or (2) C alkyl group; 25 Y is a group selected from the following (1) to (7): (1) single bond, (2) C alkylene group which may be substituted with the same or different 1 to 5 substituents selected from Group A, C1 C1 (3) -NR - wherein R is hydrogen atom or C alkyl group, 5 (4) -O-, (5) C cycloalkylene group which may be substituted with 3-10 the same or different 1 to 5 substituents selected from Group A, (6) C arylene group which may be substituted with the 6-10 10 same or different 1 to 5 substituents selected from Group A, (7) thiazolylene group which may be substituted with the same or different 1 to 5 substituents selected from Group Y is 15 (1) single bond, or (2) C alkylene group which may be substituted with the same or different 1 to 5 substituents selected from Group A; or alternatively c d1 both Y and Y may be methine and be linked to each 20 other directly or via a C alkylene group to form C 1-4 3-7 cycloalkyl ring; Y is (1) single bond, or (2) C alkylene group; d1 d2 d3 d4 d5 25 R , R , R , R , and R are the same or different group selected from the following (1) to (7): (1) hydrogen atom (2) halogen atom, (3) C alkyl group which may be substituted with the same 5 or different 1 to 5 substituents selected from Group A, d10 d10 (4) -OR wherein R is hydrogen atom or C alkyl group which may be substituted with the same or different 1 to 5 substituents selected from Group A, d11 d11 (5) -COOR wherein R is hydrogen atom or C alkyl 10 group, (6) C cycloalkyl group which may be substituted with the same or different 1 to 5 substituents selected from Group A, (7) cyano group, or alternatively d1 d2 d2 d3 R and R , or R and R can be taken together to 15 form a C aryl ring fused to the benzene ring to which 6-10 they are all attached wherein the C aryl ring may be 6-10 substituted with the same or different 1 to 4 substituents selected from Group A; R is 20 (1) hydrogen atom, or (2) C alkyl group, or alternatively e d1 e d5 R and R , or R and R can be taken together to form C alkylene; n is an integer selected from 0 or 1 to 4, 25 n is an integer selected from 0 or 1 to 3, n is an integer selected from 0 or 1 to 3, Group A is selected from the group consisting of (a) C alkyl group, (b) halogen atom, and A1 A1 5 (c) -OR wherein R is hydrogen atom or C alkyl group, or a pharmaceutically acceptable salt thereof.
2. The compound of formula [I-W] according to claim d1 d2 O N Y d5 d4 c d1 ( ) n R R c1 c2 ( ) n ( ) n [ I-W ] wherein is ; R is (1) C alkyl group which may be substituted with the 5-12 15 same or different 1 to 5 substituents selected from Group A, (2) wherein Y is (i) single bond, or (ii) C alkylene group, 5 cyclic moiety U is (i) C cycloalkyl group which may be substituted with the same or different 1 to 5 substituents selected from Group A, or (ii) C spirocyclic cycloalkyl group which may be 5-11 10 substituted with the same or different 1 to 5 substituents selected from Group A; R is a group selected from the following (1) to (3): (1) C alkyl group which may be substituted with the same or different 1 to 5 substituents selected from Group A, 15 (2) C alkenyl group which may be substituted with the same or different 1 to 5 substituents selected from Group A, (3) C cycloalkyl group which may be substituted with the same or different 1 to 5 substituents selected from Group 20 R is (1) hydrogen atom, or (2) C alkyl group; Y is a group selected from the following (1) to (7): (1) single bond, (2) C alkylene group which may be substituted with the same or different 1 to 5 substituents selected from Group A, C1 C1 (3) -NR - wherein R is hydrogen atom or C alkyl group, 5 (4) -O-, (5) C cycloalkylene group which may be substituted with 3-10 the same or different 1 to 5 substituents selected from Group A, (6) C arylene group which may be substituted with the 6-10 10 same or different 1 to 5 substituents selected from Group A, (7) thiazolylene group which may be substituted with the same or different 1 to 5 substituents selected from Group Y is 15 (1) single bond, or (2) C alkylene group which may be substituted with the same or different 1 to 5 substituents selected from Group Y is 20 (1) single bond, or (2) C alkylene group; d1 d2 d3 d4 d5 R , R , R , R , and R are the same or different group selected from the following (1) to (4): (1) hydrogen atom 25 (2) halogen atom, (3) C alkyl group which may be substituted with the same or different 1 to 5 substituents selected from Group A, d10 d10 (4) -OR wherein R is hydrogen atom or C alkyl group which may be substituted with the same or different 1 to 5 5 substituents selected from Group A, or alternatively d1 d2 d2 d3 R and R , or R and R can be taken together to form a C aryl ring fused to the benzene ring to which 6-10 they are all attached wherein the C aryl ring may be 6-10 substituted with the same or different 1 to 4 substituents 10 selected from Group A; n is an integer selected from 0 or 1 to 3, n is an integer selected from 0 or 1 to 3, n is an integer selected from 0 or 1 to 3, R is hydrogen atom, 15 Group A is selected from the group consisting of (a) C alkyl group, (b) halogen atom, and A1 A1 (c) -OR wherein R is hydrogen atom or C alkyl group, or a pharmaceutically acceptable salt thereof.
3. The compound of formula [II] according to claim wherein each symbol is as defined in claim 1, or a pharmaceutically acceptable salt thereof. 5
4. The compound of formula [III] according to claim wherein each symbol is as defined in claim 1, or a pharmaceutically acceptable salt thereof.
5. The compound of formula [IV] according to claim 4: wherein R is C alkyl group, and the other symbols are as defined in claim 1, or a pharmaceutically acceptable salt thereof.
6. The compound of formula [IV-D1] according to claim 5: wherein R is C alkyl group, and the other symbols are 10 as defined in claim 1, or a pharmaceutically acceptable salt thereof.
7. The compound of formula [IV-D2] according to claim 5: wherein R is C alkyl group, and the other symbols are as defined in claim 1, or a pharmaceutically acceptable salt thereof.
8. The compound of formula [IV-D3] according to claim 5: wherein R is C alkyl group, and the other symbols are 10 as defined in claim 1, or a pharmaceutically acceptable salt thereof.
9. The compound of formula [IV-D4] according to claim 5: wherein R is C alkyl group, and the other symbols are as defined in claim 1, or a pharmaceutically acceptable salt thereof.
10. The compound of formula [V] according to claim 1: wherein each symbol is as defined in claim 1, or a pharmaceutically acceptable salt thereof.
11. The compound according to any one of claims 1 to 10 wherein: R is C cycloalkyl group which may be substituted with the same or different 1 to 5 substituents selected 15 from Group A, or a pharmaceutically acceptable salt thereof.
12. The compound according to any one of claims 1 to 11 wherein: R is cyclopropyl group, 5 or a pharmaceutically acceptable salt thereof.
13. The compound according to any one of claims 1 to 12 wherein: the cyclic moiety U is C cycloalkyl group which may 10 be substituted with the same or different 1 to 5 substituents selected from Group A, or a pharmaceutically acceptable salt thereof.
14. The compound according to any one of claims 1 to 15 13 wherein: the cyclic moiety U is cyclobutyl group which may be substituted with the same or different 1 to 5 substituents selected from Group A, or a pharmaceutically acceptable salt thereof.
15. The compound according to claim 1 or claim 2 which is selected from the group consisting of the following formulas or a pharmaceutically acceptable salt thereof:
16. The compound according to claim 1 or claim 2 which is selected from the group consisting of the following formulas or a pharmaceutically acceptable salt thereof:
17. The compound according to claim 1 or claim 2, which is or a pharmaceutically acceptable salt thereof.
18. The compound according to claim 1 or claim 2, 5 which is or a pharmaceutically acceptable salt thereof.
19. The compound according to claim 1 or claim 2, 10 which is or a pharmaceutically acceptable salt thereof.
20. The compound according to claim 1 or claim 2, 5 which is or a pharmaceutically acceptable salt thereof.
21. The compound according to claim 1 or claim 2, 10 which is or a pharmaceutically acceptable salt thereof.
22. The compound according to claim 1 or claim 2, 5 which is
23. The compound according to claim 1 or claim 2, which is 10 .
24. The compound according to claim 1 or claim 2, which is
25. The compound according to claim 1 or claim 2, which is 10
26. The compound according to claim 1 or claim 2, which is
27. The compound according to claim 1 or claim 2, which is
28. A pharmaceutical composition comprising the compound according to any one of claims 1 and 17 to 21 or a pharmaceutically acceptable salt thereof, and a 10 pharmaceutically acceptable carrier.
29. A RORγ antagonist comprising the compound according to any one of claims 1 and 17 to 21 or a pharmaceutically acceptable salt thereof.
30. A medicament for treating or preventing a disease selected from the group consisting of autoimmune disease, allergic disease, dry eye, fibrosis, and metabolic disease, 5 comprising the compound according to any one of claims 1 and 17 to 21 or a pharmaceutically acceptable salt thereof.
31. The medicament according to claim 30 wherein the autoimmune disease is selected from the group consisting of 10 rheumatoid arthritis, psoriasis, inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, uveitis, polymyalgia rheumatica, and type I diabetes. 15
32. The medicament according to claim 31 wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis.
33. The medicament according to claim 30 wherein the 20 allergic disease is asthma.
34. The medicament according to claim 30 wherein the fibrosis is pulmonary fibrosis or primary biliary cirrhosis. 25
35. The medicament according to claim 30 wherein the metabolic disease is diabetes.
36. The medicament according to claim 35 wherein the diabetes is type I diabetes or type II diabetes.
37. A pharmaceutical composition comprising the compound according to any one of claims 22 to 27, and a pharmaceutically acceptable carrier. 10
38. A RORγ antagonist comprising the compound according to any one of claims 22 to 27.
39. A medicament for treating or preventing a disease selected from the group consisting of autoimmune disease, 15 allergic disease, dry eye, fibrosis, and metabolic disease, comprising the compound according to any one of claims 22 to 27.
40. The medicament according to claim 39 wherein the 20 autoimmune disease is selected from the group consisting of rheumatoid arthritis, psoriasis, inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, uveitis, polymyalgia rheumatica, and type I diabetes.
41. The medicament according to claim 40 wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis. 5
42. The medicament according to claim 39 wherein the allergic disease is asthma.
43. The medicament according to claim 39 wherein the fibrosis is pulmonary fibrosis or primary biliary cirrhosis.
44. The medicament according to claim 39 wherein the metabolic disease is diabetes.
45. The medicament according to claim 44 wherein the 15 diabetes is type I diabetes or type II diabetes.
46. Use of the compound according to any one of claims 1 and 17 to 21 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the 20 inhibition of RORγ in a mammal.
47. Use of the compound according to any one of claims 1 and 17 to 21 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the 25 treatment or prevention of a disease selected from the group consisting of autoimmune disease, allergic disease, dry eye, fibrosis, and metabolic disease.
48. The use according to claim 47 wherein the 5 autoimmune disease is selected from the group consisting of rheumatoid arthritis, psoriasis, inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, uveitis, polymyalgia rheumatica, and type I diabetes.
49. The use according to claim 48 wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis. 15
50. The use according to claim 47 wherein the allergic disease is asthma.
51. The use according to claim 47 wherein the fibrosis is pulmonary fibrosis or primary biliary cirrhosis.
52. The use according to claim 47 wherein the metabolic disease is diabetes.
53. The use according to claim 52 wherein the 25 diabetes is type I diabetes or type II diabetes.
54. Use of the compound according to any one of claims 22 to 27 for the manufacture of a medicament for the inhibition RORγ in a mammal.
55. Use of the compound according to any one of claims 22 to 27 for the manufacture of a medicament for the treatment or prevention of a disease in a mammal selected from the group consisting of autoimmune disease, allergic 10 disease, dry eye, fibrosis, and metabolic disease.
56. The use according to claim 55 wherein the autoimmune disease is selected from the group consisting of rheumatoid arthritis, psoriasis, inflammatory bowel disease, 15 multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, uveitis, polymyalgia rheumatica, and type I diabetes.
57. The use according to claim 56 wherein the 20 inflammatory bowel disease is Crohn's disease or ulcerative colitis.
58. The use according to claim 55 wherein the allergic disease is asthma.
59. The use according to claim 55 wherein the fibrosis is pulmonary fibrosis or primary biliary cirrhosis.
60. The use according to claim 55 wherein the 5 metabolic disease is diabetes.
61. The use according to claim 60 wherein the diabetes is type I diabetes or type II diabetes. 10
62. The compound of any one of claims 1 to 27, substantially as hereinbefore described with reference to any one of the examples and/or figures.
NZ618372A 2011-04-28 2012-04-27 Amide compound and pharmaceutical application therefor NZ618372B2 (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
JP2011-100331 2011-04-28
JP2011100331 2011-04-28
US201161482418P 2011-05-04 2011-05-04
US61/482418 2011-05-04
PCT/JP2012/061352 WO2012147916A1 (en) 2011-04-28 2012-04-27 Amide compound and pharmaceutical application therefor

Publications (2)

Publication Number Publication Date
NZ618372A NZ618372A (en) 2015-06-26
NZ618372B2 true NZ618372B2 (en) 2015-09-29

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