TWI670262B - Novel heteroaryl butanoic acid derivatives - Google Patents

Abstract

The present invention describes novel heteroarylbutyric acid derivatives, particularly among the excellent drug candidates for leukotriene A4 hydrolase (LTA4H). The invention also relates to pharmaceutical compositions comprising such novel heteroaryl butyric acid derivatives, methods of using the same to treat various diseases and conditions, and processes for preparing such novel compounds.

Description

Novel heteroaryl butyric acid derivatives

The present invention describes novel heteroarylbutyric acid derivatives, particularly among the excellent drug candidates for leukotriene A4 hydrolase (LTA4H). The invention also relates to pharmaceutical compositions comprising such novel heteroaryl butyric acid derivatives, methods of using the same to treat various diseases and conditions, and processes for preparing such novel compounds.

The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, and to the use thereof for inhibiting LTA4H. Thus, the compounds of the invention are useful in the treatment of diseases and/or conditions associated with LTA4H. Such diseases and/or conditions generally include acute and chronic inflammatory and autoinflammatory inflammatory conditions (eg, inflammatory bowel disease), neutrophilic skin diseases, allergies, fibrotic diseases, vasculitis, arthritic rash, heart Vascular disease (including atherosclerosis, myocardial infarction, and stroke) and cancer. The invention further relates to pharmaceutical compositions comprising the novel (I) heteroaryl butyric acid derivatives, methods of using the same to treat various diseases and conditions, and processes for preparing such novel compounds.

Leukotriene A4 hydrolase (LTA4H) catalyzes the hydrolysis of LTA4 to produce LTB4. LTB4 stimulates a range of pro-inflammatory responses, for example, which may involve leukocyte chemotaxis or interleukin release. Inhibition of LTA4H additionally enhances the biosynthesis of anti-inflammatory and regressive lipoxygen A4, which promotes the regression of chronic inflammation. Therefore, LTA4H inhibition may be beneficial in which chronic non-regressive inflammation may be a key component of pathology and seems to include numerous species Diseases of inflammatory and autoimmune diseases (see, for example, Anne M Fourie, Current Opinion in Invest. Drugs 2009, 10, 1173-1182).

The present invention relates to a novel compound of formula (I) and/or a pharmaceutically acceptable salt thereof and its use in inhibiting LTA4H, and may further comprise treating diseases and/or conditions such as: allergy, lung disease, fibrosis Diseases, inflammatory diseases, cardiovascular diseases (including atherosclerosis, myocardial infarction and stroke) and cancer.

More specifically, in Example 1, the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof;

Wherein R1 is OH or NH ₂ ; Y is O, S or CH ₂ ; X ₁ , X ₂ , X ₃ and X ₄ are N; or X ₁ , X ₂ , X ₃ and X ₄ are selected from N, NH. , C, CH and O, provided that at least two of X ₁ , X ₂ , X ₃ or X ₄ are N or NH; R 2 is optionally substituted by phenyl C ₁ -C ₆ alkyl; C ₃ -C ₆ cycloalkyl group; a phenyl group which is optionally substituted with halo, cyano, optionally substituted with halogen or C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy group or containing 1 to 3 heteroatoms selected from N a 5- to 6-membered heteroaryl ring of a hetero atom of O and S; or a 5 to 10 membered monocyclic or bicyclic heteroaryl group having 1 to 4 hetero atoms selected from N, O and S, The aryl group is optionally substituted by a halogen-substituted C ₁ -C ₆ alkyl group, a cyano group or a halogen.

The inner ring in the 5-membered ring shown in formula (I) means the ring-based aromatic ring, and thus the members X ₁ , X ₂ , X ₃ and/or X ₄ must therefore be selected so as not to hinder aromaticity. .

The 3-amino-butyrate side chain (e.g., in Formula (I), (II), (III), (IV), or (V)) as shown throughout the present invention typically contains a chiral center (carrying) Amine based carbon atom). If not otherwise indicated, the compound of formula (I) encompasses racemic and/or chiral ( S )-form or ( R )-form.

In the broadest embodiment of the invention (Example 1), the invention relates to a compound of formula (I) and/or a pharmaceutically acceptable salt thereof as set forth above in the Summary of the Invention.

Embodiment 2 of the present invention relates to a compound of the formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 is OH or NH ₂ ; Y is O; X ₁ , X ₂ , X ₃ and X ₄ are N; and R 2 a phenyl group, optionally a halogen, a cyano group, a halogen-substituted C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, or 1 to 3 heterogeneous groups selected from N, O and S a 5- to 6-membered heteroaryl ring of an atom; or R2 contains 5 to 10 membered monocyclic or bicyclic heteroaryl groups of 1 to 4 heteroatoms selected from N, O and S, the heteroaryl optionally being Substituted by halogen-substituted C ₁ -C ₆ alkyl, cyano or halogen.

Embodiment 3 of the present invention relates to a compound of the formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 is OH or NH ₂ ; Y is CH ₂ ; X ₁ , X ₂ , X ₃ and X ₄ are N; R 2 is a phenyl group which may optionally be a halogen, a cyano group, a halogen-substituted C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group or 1 to 3 selected from N, O and S. 5 to 6 membered heteroaryl ring of a hetero atom; or R 2 is a 5 to 10 membered monocyclic or bicyclic heteroaryl group having 1 to 4 hetero atoms selected from N, O and S, the heteroaryl group The condition is optionally substituted with a halogen-substituted C ₁ -C ₆ alkyl group, a cyano group or a halogen.

Embodiment 4 of the present invention relates to a compound of the formula (I) or a pharmaceutically acceptable salt thereof; wherein R1 is OH or NH ₂ ; Y is O; X ₁ , X ₂ , X ₃ and X ₄ are selected from N, NH, C, CH and O, provided that at least two of X ₁ , X ₂ , X ₃ or X ₄ are N or NH; and R 2 is a phenyl group, which is optionally halogen, cyano, or optionally a halogen-substituted C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group or a 5- to 6-membered heteroaryl ring containing 1 to 3 hetero atoms selected from N, O and S; or an R 2 -containing group 1 to 4 monocyclic or bicyclic heteroaryl groups selected from hetero atoms of N, O and S, the heteroaryl optionally substituted by halogen, C ₁ -C ₆ alkyl, cyanide Substituted by halogen or halogen.

Embodiment 5 of the present invention relates to a compound of the formula (I) or a pharmaceutically acceptable salt thereof; wherein R1 is OH or NH ₂ ; Y is CH ₂ ; X ₁ , X ₂ , X ₃ and X ₄ are selected from N , NH, C, CH and O, provided that at least two of X ₁ , X ₂ , X ₃ or X ₄ are N or NH; and R 2 is a phenyl group, which may optionally be halogen, cyano, or optionally Halogen-substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or 5 to 6 membered heteroaryl ring containing 1 to 3 heteroatoms selected from N, O and S; or R 2 a 5- to 10-membered monocyclic or bicyclic heteroaryl group containing from 1 to 4 heteroatoms selected from N, O and S, the heteroaryl optionally substituted by halogen, C ₁ -C ₆ alkyl, Replacement with cyano or halogen.

Embodiment 6 relates to any one of embodiments 1 to 5, or a pharmaceutically acceptable salt thereof, wherein the Y is attached in the para position of the phenyl moiety.

Embodiment 7 relates to any one of embodiments 1 to 5, or a pharmaceutically acceptable salt thereof, wherein the Y system is attached at a position between the phenyl moiety.

Embodiment 8 of the present invention relates to a compound of the formula (I) or a pharmaceutically acceptable salt thereof; wherein R1 is OH or NH ₂ ; Y is O; X ₁ , X ₂ , X ₃ and X ₄ are N; and R 2 A C ₁ -C ₆ alkyl group substituted by a phenyl group; or a C ₃ -C ₆ cycloalkyl group.

Embodiment 9 of the present invention relates to a compound of the formula (I) or a pharmaceutically acceptable salt thereof; wherein R1 is OH or NH ₂ ; Y is CH ₂ ; X ₁ , X ₂ , X ₃ and X ₄ are N; Department of R2 is optionally substituted by a phenyl C ₁ -C ₆ alkyl group; or a C ₃ -C ₆ cycloalkyl.

Embodiment 10 of the present invention relates to a compound of the formula (I) or a pharmaceutically acceptable salt thereof; wherein R1 is OH or NH ₂ ; Y is O; X ₁ , X ₂ , X ₃ and X ₄ are selected from N, NH, C, CH and O, provided that at least two of X ₁ , X ₂ , X ₃ or X ₄ are N or NH; and R 2 is a C ₁ -C ₆ alkyl group optionally substituted by a phenyl group; Or C ₃ -C ₆ cycloalkyl.

Embodiment 11 of the present invention relates to a compound of the formula (I) or a pharmaceutically acceptable salt thereof; wherein R1 is OH or NH ₂ ; Y is CH ₂ ; X ₁ , X ₂ , X ₃ and X ₄ are selected from N , NH, C, CH and O, provided that at least two of X ₁ , X ₂ , X ₃ or X ₄ are N or NH; and R 2 is optionally substituted by phenyl C ₁ -C ₆ alkyl Or C ₃ -C ₆ cycloalkyl.

Embodiment 12 relates to any one of embodiments 8 to 11 or a pharmaceutically acceptable salt thereof; wherein the Y is attached at the para position of the phenyl moiety.

Embodiment 13 relates to any one of embodiments 8 to 11 or a pharmaceutically acceptable salt thereof; wherein the Y system is attached at a position between the phenyl moiety.

Embodiment 14 relates to the compound of Example 1, which is a compound of formula (II) or a pharmaceutically acceptable salt thereof,

Wherein the variables R1, R2 and Y have the meanings as defined in embodiment 1.

Embodiment 15 relates to the compound of Example 1, which is a compound of formula (III) or a pharmaceutically acceptable salt thereof,

Wherein the variables R1, R2 and Y have the meanings as defined in embodiment 1.

Embodiment 16 relates to the compound of Example 1, which is a compound of formula (IV) or a pharmaceutically acceptable salt thereof,

Wherein the variables R1, R2 and Y have the meanings as defined in embodiment 1.

Embodiment 17 relates to any one of embodiments 14 to 16 or a pharmaceutically acceptable salt thereof, wherein the Y is attached in the para position of the phenyl moiety.

Embodiment 18 relates to any one of embodiments 14 to 16 or a pharmaceutically acceptable salt thereof, wherein the Y system is attached at a position between the phenyl moiety.

Based on Example 19 as described in Examples 14 to 18 of any of the one or a pharmaceutically acceptable salt thereof, wherein R2 via the lines phenyl optionally substituted with C ₁ -C ₆ alkyl; C ₃ -C ₆ cycloalkyl, or alkyl.

Based on Example 20 as in Example 14 to 18 of any of the one or a pharmaceutically acceptable salt thereof, wherein R2 based phenyl, which is optionally substituted with halo, cyano, optionally substituted with halogen or C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or 5 to 6 membered heteroaryl ring containing 1 to 3 hetero atoms selected from N, O and S; or R 2 containing 1 to 4 selected from N 5 to 10 membered monocyclic or bicyclic heteroaryl groups of the hetero atom of O and S, which are optionally substituted by halogen-substituted C ₁ -C ₆ alkyl, cyano or halogen as appropriate.

The compound of any one of embodiments 14 to 18, wherein the R2 contains 5 to 10 membered monocyclic rings of 1 to 4 hetero atoms selected from N, O and S, or a pharmaceutically acceptable salt thereof. Or a bicyclic heteroaryl group which is optionally substituted by halogen-substituted C ₁ -C ₆ alkyl, cyano or halogen as appropriate.

Embodiment 22 relates to any one of embodiments 1 to 21, or a pharmaceutically acceptable salt thereof, wherein R1 is OH.

Embodiment 23 relates to a compound of the formula (I) as in Examples 1 to 13 or a pharmaceutically acceptable salt thereof; wherein the amine group has the (R)-configuration.

Embodiment 24 relates to a compound of the formula (I) as in Examples 1 to 13 or a pharmaceutically acceptable salt thereof; wherein the amine group has the (S)-configuration.

The compound of any one of embodiments 14 to 18, wherein the amine group has the (R)-configuration, or a pharmaceutically acceptable salt thereof.

The compound of any one of embodiments 14 to 18, wherein the amine group has the (S)-configuration, or a pharmaceutically acceptable salt thereof.

Embodiment 27 is a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to Example 1, which is a compound of formula (V) or a pharmaceutically acceptable salt thereof;

Wherein variables R1, R2 and Y have the meanings embodiment defined in Example 1; or wherein R1 lines OH; Y line O; and R2 optionally halogen-based, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy Substituted phenyl.

Embodiment 28 relates to the compound of Example 27, or a pharmaceutically acceptable salt thereof; wherein the Y is in the para position.

Embodiment 29 relates to the compound of Example 28, or a pharmaceutically acceptable salt thereof; wherein the primary amine group in the side chain of the butyryl group attached to the tetrazole moiety of formula (V) has an ( S )-configuration.

Embodiment 30 relates to the compound of Example 28, or a pharmaceutically acceptable salt thereof; wherein the primary amine group of the butanyl side chain attached to the tetrazole- moiety of formula (V) has a ( R )-configuration.

Embodiment 31 relates to the compound of the formula (I) as in Example 1 and/or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: ( R )-3-amino-4-(5-(4- (benzo [d] thiazol-2-yloxy) phenyl) -2 H - tetrazol-2-yl) butanoic acid; (R) -3- amino-4- (5- (4 - (( 5-chloro-pyridin-2-yl) oxy) phenyl) -2 H - tetrazol-2-yl) butanoic acid; (R) -3- amino-4- (5- (4 - ((5- chloro-3-fluoropyridin-2-yl) oxy) phenyl) -2 H - tetrazol-2-yl) butanoic acid; (R & lt) -3- amino-4- (5- (4- (4 - (oxazol-2-yl) - phenoxy) phenyl) -2 H - tetrazol-2-yl) - butanoic acid; (R) -3- amino-4- (5- (3- ( 4-chlorophenoxy) phenyl) -2 H - tetrazol-2-yl) butanoic acid; (R) -3- amino-4- (5- (4- (4-chlorophenoxy) - phenyl) -2 H - tetrazol-2-yl) butanoic acid; (R) -3- amino-4- (5- (4- (4-fluorophenoxy) - phenyl) -2 H - Tetrazol-2-yl)butyric acid; ( R )-3-amino-4-(5-(4-(3-chloro-4-fluorophenoxy)phenyl)-2 H -tetrazole-2 - yl) butanoic acid; (R) -3- amino -4- (5- (4- (p - tolyloxy) phenyl) -2 H - tetrazol-2-yl) butanoic acid; (S )-3-amino-4-(5-(3-phenoxyphenyl)-2 H -tetrazol-2-yl)butyric acid; ( S )-3-amino-4-(5-( 4- (benzo [d] thiazol-2-yloxy) phenyl) -2 H - tetrazol-2-yl) Butyric acid; (S) -3- amino-4- (5- (4- (4-chlorophenoxy) - phenyl) -2 H - tetrazol-2-yl) butanoic acid; (R & lt) - 3-amino-4- (5- (3-phenethyloxy-phenyl) -2 H - tetrazol-2-yl) butanoic acid; (R) -3- amino-4- (5- (4 - phenethyloxy) -2 H - tetrazol-2-yl) butanoic acid; (R) -3- amino-4- (5- (4- (benzyloxy) phenyl) -2 H -tetrazol-2-yl)butyric acid; ( R )-3-amino-4-(5-(3-(benzyloxy)phenyl)-2 H -tetrazol-2-yl) acid; (R) -3- amino-4- (5- (4-butoxy-phenyl) -2 H - tetrazol-2-yl) butanoic acid; (R) -3- amino-4 (5- (4- (pentyloxy) phenyl) -2 H - tetrazol-2-yl) butanoic acid; (R) -3- amino-4- (5- (3 - ((5- (trifluoromethyl) pyridin-2-yl) oxy) phenyl) -2 H - tetrazol-2-yl) butanoic acid; (R) -3- amino-4- (5- (4- ( (5- (trifluoromethyl) pyridin-2-yl) oxy) phenyl) -2 H - tetrazol-2-yl) butanoic acid; (R) -3- amino-4- (5- ( 3- (benzo [d] thiazol-2-yloxy) phenyl) -2 H - tetrazol-2-yl) butanoic acid; (R) -3- amino-4- (5- (3- (3,5-difluorophenoxy)phenyl)-2 H -tetrazol-2-yl)butyric acid; ( S )-3-amino-4-(5-(4-( p -methylphenyl) oxy) phenyl) -2 H - tetrazol-2-yl) butanoic acid; (R) -3- amino-4- (5- (4- (4-fluorophenoxy) phenyl) -1 , 3,4- Oxadiazol-2-yl)butyric acid; ( R )-3-amino-4-(5-(4-(4-chlorophenoxy)phenyl)-1,3,4-oxadiazole- 2-yl)butyric acid; ( R )-3-amino-4-(3-(4-(4-chlorophenoxy)phenyl)-1,2,4-oxadiazol-5-yl) Butyric acid; ( R )-3-amino-4-(3-(4-(4-chlorophenoxy)phenyl)-1,2,4-oxadiazol-5-yl)butanamine; ( S )-3-amino-4-(4-(4-(4-chlorophenoxy)phenyl)-1 H -pyrazol-1-yl)butyric acid; and ( S )-3-amine -4- (5- (4 - ((5-chloro-3-fluoropyridin-2-yl) oxy) phenyl) -2 H - tetrazol-2-yl) butanoic acid.

Embodiment 32 relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of embodiments 1 to 31 and one or more pharmaceutically acceptable carriers.

Embodiment 33 is a combination comprising a therapeutically effective amount of a compound of any of embodiments 1 to 31, or a pharmaceutically acceptable salt thereof, and one or more therapeutic active agents.

Embodiment 34 is a method for modulating LTA4H activity in an individual, wherein the method comprises administering to the individual a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof.

Embodiment 35 is a compound according to any one of embodiments 1 to 31, or a pharmaceutically acceptable salt thereof, for use as a medicament for specifically inhibiting LTA4H activity.

Embodiment 36 is the compound of Embodiment 27 or a pharmaceutically acceptable salt thereof; wherein R2 is a 5- to 10-membered monocyclic or bicyclic heteroaryl group having 1 to 4 hetero atoms selected from N, O and S; The heteroaryl group is optionally substituted with a halogen-substituted C ₁ -C ₆ alkyl group, a cyano group or a halogen, as the case may be.

Embodiment 37 relates to the compound of Example 36, or a pharmaceutically acceptable salt thereof; wherein the Y is in the para position.

Embodiment 38 relates to the compound of Example 37, or a pharmaceutically acceptable salt thereof; wherein the primary amine group in the side chain of the butyl group attached to the tetrazole moiety of formula (V) has an ( S )-configuration.

Embodiment 39 relates to the compound of Example 37, or a pharmaceutically acceptable salt thereof; wherein the primary amine group in the side chain of the butyryl group attached to the tetrazole moiety of formula (V) has a ( R )-configuration.

Embodiment 40 relates to the compound of Example 27 or a pharmaceutically acceptable salt thereof; R1 is OH; Y is O; and R2 is a pyridyl ring optionally substituted by a cyano group or a halogen.

definition

As used herein, the term "C ₁ -C ₆ alkyl" means having up to 6 carbon atoms fully saturated branched or unbranched hydrocarbon moiety. Unless otherwise provided, it refers to a hydrocarbon moiety having from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, or from 1 to 2 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, tert-butyl, n-pentyl, isuf Base, neopentyl, n-hexyl and the like.

As used herein, the term "C ₁ -C ₆ alkoxy" refers to alkyl-O-, wherein alkyl is as defined above. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, cyclo Propoxy-, cyclohexyloxy- and the like. Typically, the alkoxy group has from about 1 to 6 carbon atoms, from 1 to 4 carbon atoms or from 1 to 2 carbon atoms.

As used herein, the term "C ₁ -C ₆ alkyl optionally substituted by halogen" refers to a C ₁ -C ₆ alkyl group, as defined above, which may be substituted by one or more halogens. Examples include, but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, 3 -Bromo-2-fluoropropyl and 1-bromomethyl-2-bromoethyl.

As used herein, the term "di-C _1-6 alkylamino" refers to a moiety of the formula -N(R _a )-R _a wherein each R _a is C _1-6 alkyl, which may be the same or different, As defined above.

As used herein, the term "C ₃ -C ₆ cycloalkyl" means a saturated monocyclic hydrocarbon radical having 3 to 6 carbon atoms. A cycloalkyl group may also be referred to as a carbocyclic ring and vice versa, with the exception of the number of carbon atoms present. Unless otherwise provided, a cycloalkyl group means a cyclic hydrocarbon group having 3 to 6 ring carbon atoms or 3 to 4 ring carbon atoms. Exemplary monocyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

As used herein, the term "halogen" or "halo" refers to fluoro, chloro, bromo and iodo.

As used herein, the term "heterocyclyl" refers to a heterocyclyl group which is saturated or partially saturated and preferably monocyclic or polycyclic (in the case of polycyclic, in particular bicyclic, tricyclic or spiro) And having from 3 to 24, more preferably from 4 to 16, most preferably from 5 to 10 and most preferably from 5 or 6 ring atoms; one or more, preferably from 1 to 4, especially 1 One or two ring atomic heteroatoms (the remaining ring atoms are therefore carbon). The bond ring (i.e., the ring attached to the molecule) preferably has from 4 to 12, especially from 5 to 7, ring atoms. The term heterocyclyl does not include heteroaryl. The heterocyclic group can be attached to a hetero atom or a carbon atom. Heterocyclyl groups can include fused or bridged rings as well as spiro rings. Examples of the heterocyclic ring include tetrahydrofuran (THF), dihydrofuran, 1,4-dioxane, morpholine, 1,4-dithiane, hexahydropyrazine, hexahydropyridine, and 1,3-dioxolane. , imidazolium, imidazoline, pyrroline, pyrrolidine, tetrahydropyran, dihydropyran, oxygen sulfur Disulfide , 1,3-dioxane, 1,3-dithiane, oxathiane, thiomorpholine, and the like.

The substituted heterocyclic group is a heterocyclic group independently substituted with 1 to 4 (for example, 1 or 2 or 3 or 4) substituents.

As used herein, the term "heteroaryl" refers to a 5- to 14-membered monocyclic- or bicyclic- or tricyclic-aromatic ring system having from 1 to 8 heteroatoms. Typically, the heteroaryl is a 5 to 10 membered ring system (eg, a 5 to 7 membered single ring or an 8 to 10 membered two ring) or a 5 to 7 membered ring system. Typical heteroaryl groups include 2-thienyl or 3-thienyl, 2-furyl or 3-furyl, 2-pyrrolyl or 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl or 5-imidazolyl, 3-pyrazolyl, 4-pyrazolyl or 5-pyrazolyl, 2-thiazolyl, 4-thiazolyl or 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl or 5-isothiazolyl , 2-oxazolyl, 4-oxazolyl or 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl or 5-isoxazolyl, 3-1,2,4-triazole Or 5-1,2,4-triazolyl, 4-1,2,3-triazolyl or 5-1,2,3-triazolyl, tetrazolyl, 2-pyridyl, 3-pyridine Or 4-pyridyl, 3-pyridazinyl or 4-pyridazinyl, 3-pyrazinyl, 4-pyrazinyl or 5-pyrazinyl, 2-pyrazinyl and 2-pyrimidinyl, 4- Pyrimidinyl or 5-pyrimidinyl.

The term "heteroaryl" also refers to a group in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic or heterocyclyl rings, wherein the attached group or point is in a heteroaromatic On the ring. Non-limiting examples include 1-, 2-, 3-, 5-, 6-, 7- or 8-pyridazinyl, 1-, 3-, 4-, 5-, 6- or 7-isodecyl , 2-, 3-, 4-, 5-, 6- or 7-fluorenyl, 2-, 3-, 4-, 5-, 6- or 7-carbazolyl, 2-, 4-, 5- -, 6-, 7- or 8-mercapto, 1-, 2-, 3-, 4-, 6-, 7-, 8- or 9-quinolizinyl, 2-, 3-, 4-, 5- -, 6-, 7- or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl, 1-, 4-, 5-, 6- , 7- or 8-pyridazinyl, 2-, 3-, 4-, 5- or 6-naphthyridinyl, 2-, 3-, 5-, 6-, 7- or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7- or 8- Orolinyl, 2-, 4-, 6- or 7-acridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-4aH carbazolyl, 1-, 2 -, 3-, 4-, 5-, 6-, 7- or 8-carbazolyl, 1-, 3-, 4-, 5-, 6-, 7-, 8- or 9-carbolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-cyridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- , 8- or 9-Acridine, 1-, 2-, 4-, 5-, 6-, 7-, 8- or 9-naphthyldiazepine, 2-, 3-, 4- , 5-, 6-, 8-, 9- or 10-phenanthroline, 1-, 2-, 3-, 4-, 6-, 7-, 8- or 9-phenazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenothiazine, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9 -or 10-phenoxazinyl, 2-, 3-, 4-, 5-, 6- or 1-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10- Benzoisoquinolyl, 2-, 3-, 4- or thieno[2,3-b]furanyl, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10 -or 11-7H-pyrazino[2,3-c]oxazolyl, 2-, 3-, 5-, 6- or 7-2H-furo[3,2-b]-pyranyl, 2-, 3-, 4-, 5-, 7- or 8-5H-pyrido[2,3-d]-o-oxazinyl, 1-, 3- or 5-H-pyrazolo[4 , 3-d]-oxazolyl, 2-, 4- or 5-4H-imidazo[4,5-d]thiazolyl, 3-, 5- or 8- Pyrazino[2,3-d]pyridazinyl, 2-, 3-, 5- or 6-imidazo[2,1-b]thiazolyl, 1-, 3-, 6-, 7-, 8 -or 9-furo[3,4-c] Orolinyl, 1-, 2-, 3-, 4-, 5-, 6-, 8-, 9-, 10- or 11-4H-pyrido[2,3-c]oxazolyl, 2-, 3 -, 6- or 7-imidazo[1,2-b][1,2,4]triazinyl, 7-benzo[b]thienyl, 2-, 4-, 5-, 6- or 7 - benzoxazolyl, 2-, 4-, 5-, 6- or 7-benzimidazolyl, 2-, 4-, 4-, 5-, 6- or 7-benzothiazolyl, 1- , 2-, 4-, 5-, 6-, 7-, 8- or 9-benzoxazinyl, 2-, 4-, 5-, 6-, 7- or 8-benzoxazinyl, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10- or 11-1H-pyrrolo[1,2-b][2]benzazepine. Typical fused heteroaryl groups include, but are not limited to, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 1-, 3-, 4-, 5-, 6- , 7- or 8-isoquinolyl, 2-, 3-, 4-, 5-, 6- or 7-fluorenyl, 2-, 3-, 4-, 5-, 6- or 7-benzene And [b]thienyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 2-, 4-, 5-, 6- or 7-benzimidazolyl and 2-, 4 -, 5-, 6- or 7-benzothiazolyl.

The substituted heteroaryl group is a heteroaryl group containing one or more substituents.

As used herein, the term "aryl" refers to an aromatic hydrocarbon group having from 6 to 20 carbon atoms in the ring portion. Usually, an aryl group has a single ring, a bicyclic ring of 6 to 20 carbon atoms or Tricyclic aryl. Further, as used herein, the term "aryl" refers to an aromatic substituent which may be a single aromatic ring or a polyaromatic ring fused together. Non-limiting examples include phenyl, pharmaceutically or tetrahydronaphthyl.

The substituted aryl is an aryl group substituted with 1 to 5 (e.g., 1 or 2 or 3) substituents independently selected from the group consisting of: hydroxy, thiol, cyano, nitro, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkenyl, C ₁ -C ₄ -alkynyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -thioalkyl, C ₁ -C ₄ -alkenyloxy, C ₁ -C ₄ -alkynyloxy, halogen, C ₁ -C ₄ -alkylcarbonyl, carboxy, C ₁ -C ₄ -alkoxycarbonyl, amine, C ₁ -C ₄ -alkylamino, di-C ₁ -C ₄ -alkylamino, C ₁ -C ₄ -alkylaminocarbonyl, di-C ₁ -C ₄ -alkylaminocarbonyl, C ₁ -C ₄ -alkylcarbonylamino, C ₁ -C ₄ -alkylcarbonyl(C ₁ -C ₄ -alkyl)amine, sulfonyl, sulfonyl, alkylamine sulfonyl, C ₁ -C _{a 4} -alkylaminosulfonyl group, wherein each of the above hydrocarbon groups (for example, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group) may be independently present at each occurrence by one or more The residue selected from a halogen, a hydroxyl group or a C ₁ -C ₄ -alkoxy group is further substituted.

As used herein, the term "salt or salts" refers to an acid or base addition salt of a compound of the invention. "Salt" includes specifically "pharmaceutically acceptable salts". The term "pharmaceutically acceptable salts" refers to salts which retain the biological effectiveness and properties of the compounds of the invention and which are generally not biologically or otherwise undesirable. In many cases, the compounds of the invention are capable of forming acid and/or base salts by virtue of the presence of an amine group and/or a carboxyl group or a similar group thereof.

Inorganic acids and organic acids can be used to form pharmaceutically acceptable acid addition salts, for example, acetate, aspartate, benzoate, besylate, bromide/hydrobromide, hydrogencarbonate Salt/carbonate, hydrogen sulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlorophylline, citrate, ethanedisulfonate, fumarate, glucoheptonate, glucose Acid salt, glucuronate, horse urate, hydroiodide/iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, propylene Acid salt, mandelic acid salt, methanesulfonate, methyl sulfate, naphthalate, naphthalene sulfonate, nicotinic acid Salt, nitrate, octadecanoate, oleate, oxalate, palmitate, bamotate, phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate, propionate , stearates, succinates, sulfosalicylic acid salts, tartrates, tosylates and trifluoroacetates.

Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, and methanesulfonic acid. Acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like. Inorganic bases and organic bases can be used to form pharmaceutically acceptable base addition salts.

Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from rows I to X of the Periodic Table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium, and magnesium salts.

Organic bases from which salts can be derived include, for example, primary, secondary and tertiary amines, substituted amines including naturally substituted amines, cyclic amines, basic ion exchange resins, and the like. Certain organic amines include isopropylamine, benzathine, cholate, diethanolamine, diethylamine, lysine, meglumine, hexahydropyrazine, and tromethamine.

The pharmaceutically acceptable salts of the present invention can be synthesized from the basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting the compounds in free acid form with a stoichiometric amount of a suitable base such as Na, Ca, Mg or K hydroxide, carbonate, bicarbonate or the like, or It is prepared by reacting the compounds in free base form with a stoichiometric amount of the appropriate acid. These reactions are usually carried out in water or an organic solvent, or a mixture of the two. Generally, if feasible, it is desirable to use a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile. A list of other suitable salts can be found, for example, in "Remington's Pharmaceutical Sciences", 20th Edition, Mack Publishing Company, Easton, Pa., (1985); and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

Any of the formulae given herein are also intended to indicate unlabeled forms as well as isotopically labeled forms of such compounds. Isotopically labeled compounds have structures depicted by the formulas given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes which may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ F, respectively. , ³¹ P, ³² P, ³⁵ S, ³⁶ Cl, ¹²⁵ I. The invention includes various isotopically labeled compounds described herein, such as those in which a radioisotope (e.g., ³ H and ¹⁴ C) is present or in which a non-radioactive isotope (e.g., ² H and ¹³ C) is present. The isotopically labeled compounds can be used in metabolic studies ( ¹⁴ C), reaction kinetic studies (eg, ² H or ³ H), detection or imaging techniques (eg, positron emission tomography (PET) or single photon emission computers) Tomography (SPECT), including drug or matrix distribution analysis or radiotherapy for patients. In particular, ¹⁸ F or labeled compounds may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or can be suitably labeled with isotopes by processes similar to those described in the accompanying examples and preparations. The reagent is prepared in place of the previously used unlabeled reagent.

In addition, the use of heavier isotopes, particularly guanidine (i.e., ² H or D) substitutions, may provide certain therapeutic advantages due to greater metabolic stability, such as prolonged in vivo half-life or reduced dosage requirements or improved therapeutic index. It will be appreciated that in this context oxime is considered to be a substituent of the compound of formula (I). The concentration of this heavier isotope (specifically 氘) can be defined as the isotope enrichment factor. As used herein, the term "isotopic enrichment factor" means the ratio of the isotope abundance of a given isotope to the natural abundance. If the substituent in the compound of the present invention is represented by hydrazine, the isotope enrichment factor of each of the specified ruthenium atoms of the compound is at least 3500 (52.5% 氘 at each designated 氘 atom), at least 4000 (60% 纳入 included) , at least 4500 (incorporated with 67.5% 氘), at least 5,000 (incorporating 75% 氘), at least 5,500 (incorporating 82.5% 氘), at least 6,000 (incorporating 90% 氘), at least 6333.3 (incorporating 95% 氘), at least 6466.7 (incorporated 97% 氘), at least 6600 (incorporating 99% 氘) or at least 6633.3 (including 99.5% 氘).

The pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent can be substituted with an isotope such as D ₂ O, d ₆ -acetone, d ₆ -DMSO.

The compound of the invention (i.e., the compound of formula (I)) containing a group capable of functioning as a donor and/or acceptor for hydrogen bonding may be capable of forming a co-crystal using a suitable co-crystal former. Such co-crystals can be prepared from compounds of formula (I) by known co-crystal formation procedures. The procedures include grinding, heating, co-liming, co-melting or contacting a compound of formula (I) with a co-crystal former in a solution under crystallization conditions and isolating the co-crystal formed thereby. Suitable co-crystal formers include those described in WO 2004/078163. Accordingly, the present invention further provides a cocrystal comprising a compound of formula (I).

As used herein, the term "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives known to those skilled in the art (eg, Antibacterial agent, antifungal agent), isotonic agent, absorption delaying agent, salt, preservative, drug, drug stabilizer, binder, excipient, disintegrator, lubricant, sweetener, flavoring agent, dye And the like and combinations thereof (for example, Remington's Pharmaceutical Sciences, 18th Edition, Mack Printing, 1990, pp. 1289-1329). In addition to any conventional carrier that is incompatible with the active ingredient, the invention encompasses its use in therapeutic or pharmaceutical compositions.

The term "therapeutically effective amount" of a compound of the invention refers to the invention that enables an individual to produce a biological or medical response (eg, reduce or inhibit enzyme or protein activity) or to ameliorate symptoms, alleviate the condition, slow or delay disease progression, or prevent disease, and the like. The amount of the compound. In one non-limiting embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the invention that is effective when administered to an individual: (1) at least partially alleviates, inhibits, prevents, and/or ameliorates (i) Mediated by LTA4H, or (ii) associated with LTA4H activity, or (iii) characterized by LTA4H a condition (normal or abnormal) condition or disorder or disease; or (2) reducing or inhibiting LTA4H activity; or (3) reducing or inhibiting the performance of LTA4H. In another non-limiting embodiment, the term "therapeutically effective amount" refers to an activity that, when administered to a cell, or tissue, or a non-cellular biological material or medium, is effective to at least partially reduce or inhibit the activity of LTA4H; or at least in part Or the amount of the compound of the invention which completely reduces or inhibits the expression of LTA4H.

As used herein, the term "individual" refers to an animal. Typically, the animal is a mammal. For example, an individual also refers to a primate (eg, a male or female human), a cow, a sheep, a goat, a horse, a dog, a cat, a rabbit, a rat, a mouse, a fish, a bird, and the like. In certain embodiments, the system is a primate. In still other embodiments, the system is human.

As used herein, the term "inhibiting, inhibiting, or inhibiting" refers to reducing or suppressing a given condition, symptom or condition or disease, or significantly reducing the baseline activity of a biological activity or process.

As used herein, the term "treat, treating, or treating", in one embodiment, refers to amelioration of the disease or condition (ie, slowing or preventing or reducing the progression of the disease or at least one of its clinical symptoms). ). In another embodiment, "treat, treating, or treating" refers to alleviating or ameliorating at least one physical parameter (including those that may not be recognized by the patient). In yet another embodiment, "treat, treating, or treating" refers to modulating a disease or condition on the body (eg, stabilizing a recognizable symptom), physiologically (eg, stabilizing a body parameter), or both. In yet another embodiment, "treat, treating, or treating" refers to preventing or delaying the onset or progression or progression of a disease or condition.

As used herein, an individual "needs" the treatment if it can benefit from treatment in terms of biology, medicine, or quality of life.

The term "a", as used herein, is used in the context of the present invention (especially in the context of the claims), unless otherwise indicated herein or otherwise clearly contradicted by the context. An), "and" and similar terms shall be taken to include both singular and plural.

All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by the context. The use of any and all examples or example language, such as "such as", is intended to be <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt;

Any asymmetric atom of the compounds of the invention (e.g., carbon or the like) may exist in the form of a racemic isomer or a mirror image isomer, such as ( R )-, ( S )- or ( R,S )- Configuration. In certain embodiments, each asymmetric atom has at least 50% of the image isomer excess, at least 60% of the mirror image isomer excess, and at least 70% of the mirror image in the ( R )- or ( S )-configuration. An excess of the construct, at least 80% of the enantiomers in excess, at least 90% of the enantiomers of the enantiomers, at least 95% of the enantiomers of the enantiomers or at least 99% of the enantiomers of the enantiomers. Substituents having an unsaturated double bond on the atom may exist in the cis-(Z)- or trans-(E)- form if possible.

Thus, as used herein, a compound of the invention may exist in one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, for example in a substantially pure geometry (shun Or an isoform, a non-image isomer, an optical isomer (enantiomer), a racemate or a mixture thereof. For the sake of clarity, the term "possible isomers" shall not include positional isomers.

Any resulting mixture of isomers may be separated into pure or substantially pure geometric or optical isomers, diastereomers, by physicochemical differences in their constituents, for example, by chromatography and/or fractional crystallization. Racemic isomer.

Any of the resulting racemic isomers of the final product or intermediate can be resolved into the optical antipodes by known methods, for example, by separation of the diastereomeric salts thereof obtained using an optically active acid or base. And release optically active acidic or basic compounds. Specifically, an optically active acid (for example, tartaric acid, benzopyrene tartaric acid, diterpene tartaric acid, di- O, O'-p-toluene) can be used by, for example, fractional crystallization of a basic portion. Salts formed from mercapto tartaric acid, phenylglycolic acid, malic acid or camphor-10-sulfonic acid) are split into the optical enantiomers of the compounds of the invention. The racemic product can also be resolved by a palm chromatography (e.g., high pressure liquid chromatography (HPLC)) using a palmitic stationary phase.

Further, the compounds of the present invention (including salts thereof) may also be obtained in the form of their hydrates or include other solvents for their crystallization. The compounds of the invention may be inherently or designed to form solvates with pharmaceutically acceptable solvents, including water; therefore, it is contemplated that the invention encompasses both solvated and unsolvated forms. The term "solvate" refers to a molecular complex of a compound of the invention, including a pharmaceutically acceptable salt thereof, with one or more solvent molecules. These solvent molecules are commonly used in the medical field and are known to be harmless to the recipient, for example, water, ethanol, and the like. The term "hydrate" refers to a complex of solvent molecules that are water.

The compounds of the invention, including their salts, hydrates and solvates, may be inherently or designed to form polymorphs.

In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier. The pharmaceutical compositions can be formulated for specific routes of administration, such as oral administration, parenteral administration, and rectal administration. Furthermore, the pharmaceutical compositions of the present invention may be prepared in solid form (including but not limited to capsules, troches, pills, granules, powders or suppositories) or in liquid form (including but not limited to solutions, suspensions or emulsions). Got it. The pharmaceutical composition can be subjected to conventional pharmaceutical operations (eg, sterilization) and/or can contain conventional inert diluents, lubricants or buffers, and adjuvants (eg, preservatives, stabilizers, wetting agents, emulsifiers, buffers, etc.) .

In general, the pharmaceutical composition comprises a lozenge or gelatin capsule containing the active ingredient together with a) a diluent such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) Lubricants, such as cerium oxide, talc, stearic acid, magnesium or calcium salts thereof and/or polyethylene glycol; for tablets, also include c) binders such as magnesium aluminum silicate, starch paste , gelatin, tragacanth, methyl fiber , sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if necessary, d) a disintegrant such as starch, agar, alginic acid or its sodium or effervescent; and/or e) absorbent , colorants, flavors and sweeteners.

Tablets can be film coated or enteric coated according to methods known in the art.

Compositions suitable for oral administration include an effective amount of a compound of the invention in the form of a lozenge, a lozenge, an aqueous or oily suspension, a dispersible powder or granule, an emulsion, a hard or soft capsule or a syrup or elixir. Compositions intended for oral use can be prepared according to any of the methods known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives. A group of reagents to provide a pharmaceutically elegant and palatable preparation. Tablets may contain a mixture of the active ingredient in admixture with a pharmaceutically acceptable non-toxic excipient. For example, the excipients are inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin or A gum arabic; and a lubricant such as magnesium stearate, stearic acid or talc. Such tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period of time. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. Formulations for oral use may be presented in the form of a hard gelatin capsule in which the active ingredient is mixed with an inert solid diluent (for example, calcium carbonate, calcium phosphate or kaolin); or it may be in the form of a soft gelatin capsule The ingredients are mixed with a water or oil medium (for example, peanut oil, liquid paraffin or olive oil).

Certain injectable compositions are isotonic aqueous solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions. The compositions may be sterilized and/or contain adjuvants such as preservatives, stabilizers, wetting or emulsifying agents, solubilizing agents, salts for regulating osmotic pressure and/or buffers. In addition, it may also contain other therapeutically valuable substances. The compositions are prepared according to conventional mixing, granulating or coating methods and contain from about 0.1% to 75%. Or contain about 1% to 50% of the active ingredient.

Compositions suitable for transdermal administration comprise an effective amount of a compound of the invention and a suitable carrier. Carriers suitable for transdermal delivery include absorbable, pharmaceutically acceptable solvents to aid passage through the skin of the host. For example, the transdermal device is in the form of a bandage comprising a backing member; a reservoir containing the compound, optionally with a carrier; and optionally a speed control barrier to deliver the compound to the controlled predetermined rate for a prolonged period of time to Host skin; and components that secure the device to the skin.

Compositions suitable for topical administration (e.g., application to the skin and eyes) include aqueous solutions, suspensions, ointments, creams, gels, or sprayable formulations such as those delivered by aerosol or the like. Such topical delivery systems will in particular be suitable for dermal administration to, for example, treat skin cancer, for prophylactic use, for example, sunscreens, lotions, sprays, and the like. Thus, it is particularly suitable for topical application, including cosmetic formulations well known in the art. These formulations may contain solubilizers, stabilizers, penetration enhancers, buffers, and preservatives.

Topical administration, as used herein, may also be in the case of inhalation or intranasal administration. It can be delivered in dry powder form (single delivery; in a mixture, for example as a dry blend with lactose; or in the form of mixed component particles, for example mixed component particles with phospholipids), conveniently delivered from a dry powder inhaler, or as an aerosol The spray form is presented from a pressurized container, pump, nebulizer, atomizer or ejector with or without the use of a suitable propellant.

The invention further provides anhydrous pharmaceutical compositions and dosage forms comprising the compound of the invention as an active ingredient, as water promotes degradation of certain compounds.

The anhydrous pharmaceutical compositions and dosage forms of the present invention can be prepared using anhydrous or low moisture containing ingredients under conditions of low moisture or low humidity. Anhydrous pharmaceutical compositions can be prepared and stored to maintain their anhydrous nature. Thus, anhydrous compositions are packaged using known materials to prevent exposure to water so that they can be incorporated into suitable formula sets. Examples of suitable packaging include, but are not limited to, hermetic sealing foils, plastics, unit dose containers (eg, vials), blister packs, and strip packs Installed.

The invention further provides pharmaceutical compositions and dosage forms that comprise one or more agents that reduce the rate of decomposition of the compounds of the invention as the active ingredient. Such agents referred to herein as "stabilizers" include, but are not limited to, antioxidants (e.g., ascorbic acid), pH buffers or salt buffers, and the like.

Method for synthesizing heteroarylbutyric acid derivatives

The agent of the present invention (for example, a compound according to formula (I)) can be prepared by the reaction sequence of Reaction Scheme A, which relates to the synthesis of an amino acid building block of Formula 1 , which is usually carried out by The commercially available protected amino acid Boc-Asp(O t Bu)-OH is activated or activated at a low temperature (for example, -20 ° C or the like) in the presence of a solvent with a reducing agent (for example, NaBH ₄ ). The reaction is obtained after the acid group. By looking at the stereochemistry of the starting material, ( S )- or ( R )-3-(t-butoxycarbonylamino)-4-hydroxybutyric acid tert-butyl can be obtained in the form of a chiral building block of formula 1 . ester. The variables in Schemes A through D correspond to the definitions provided in Example 1. Further, the term "PG" means a protecting group such as a tert-butyloxy-carbonyl group or a Boc.

The constitutive unit of formula 1 is reacted with sulfinium chloride in a solvent in the presence of a suitable base such as imidazole and then further reacted with an oxidizing agent such as a periodate and usually in a catalyst such as cesium halide. When it is used, when the chiral starting material of Formula 1 is used, it will obtain a cyclical building unit of the formula 2 of the chiral building unit as the case may be.

As another construction unit for synthesizing the compound of the present invention, the formula R2 can be made by using a solvent such as DMF in the presence of a base such as potassium carbonate in the solvent (for example, DMF) and if necessary at an elevated temperature (for example, higher than 100 ° C). The commercially available substrate of -Hal is reacted with an appropriately substituted benzonitrile (Y=O) to obtain a so-called nitrile 3 . Alternatively, the nitrile 3 can be obtained by reacting a commercially available fluorine-substituted nitrile with a commercially available substituted alcohol such as a phenol.

The nitrile 3 is then typically reacted with an azide (e.g., azidotrimethylnonane) and is typically carried out in the presence of a catalyst such as dibutyltin oxide (IV) to provide a tetrazole of formula 4 ( See Scheme B), in a Mitsunobu condition, with a suitable electrophile, typically with an activated alcohol of formula 1 (eg, methanesulfonate or toluene, or otherwise activated (eg, in situ) The reaction, or alternatively, is such that it reacts with the activated cyclic building unit of formula 2 to provide the intermediate compound of formula 5 (Scheme C). In addition to " t Bu", the alkyl moiety of the ester group in compounds 1 , 2 and 5 is alternatively selected to be Bn, Me or Et or another suitable protecting group.

The intermediate compound 5 is then typically reacted with an acid or base (e.g., hydrochloric acid or TFA, or, for example, with hexahydropyridine as a base) in a solvent such as dioxane or dichloromethane to give according to Scheme D. A compound of the formula (I) of the invention wherein R1 = OH. To obtain R1 = NH ₂ compound of, formula 5 may be in the ester group is cleaved to give the acid, which is then activated and reacted with ammonia or an ammonia equivalent. Followed by treatment with an acid, of formula (I) Amides (R1 = NH _2).

Alternative pathways for the synthesis of the compounds of the invention

The nature of the building blocks or matrices employed as starting materials for the preparation of the compounds of the invention may be required to deviate from the general reaction sequence provided above. These deviations are detailed in the following sections of the experimental section.

Experimental part abbreviation:

2-MeTHF 2-methyltetrahydrofuran

Asp aspartate

Aq water

Bn or Bzl benzyl

Boc tert-butoxycarbonyl

Br wide peak

Saline saturated aqueous NaCl solution

d double peak

Dd double peak

DCM dichloromethane

DIAD diisopropyl azodicarboxylate

DIPEA diisopropylethylamine

DME 1,2-dimethoxyethane

DMF N,N-dimethylformamide

DMSO dimethyl hydrazine

EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

ESI electrospray ionization

EtOAc ethyl acetate

EtOH ethanol

Eq equivalent

Ex instance

Fmoc fluorenylmethyloxycarbonyl

Gln bran acid

Glu glutamic acid

h hours

HATU 1-[bis(dimethylamino)methylene]-1 H -1,2,3-triazolo[4,5- b ]-pyridinium-3-oxide hexafluorophosphate

HOBT hydroxybenzotriazole

HPLC high performance liquid chromatography

iPrOH isopropanol

I.vac. in vacuum

LC liquid chromatography

m multiple peaks / milli, depending on the context

MeOH methanol

Mg mg

Min minute

MS mass spectrometry

mL ml

Mmmol millimole

m/z mass-to-charge ratio

NMR nuclear magnetic resonance

Ppm parts per million

q quadruple peak

Quint

Rt room temperature

Rt retention time

s single peak

t triplet

TBAF tetrabutylammonium fluoride

TBME third butyl methyl ether

TBS tert-butyl dimethyl decyl

tBu third butyl

TFA trifluoroacetic acid

THF tetrahydrofuran

TLC thin layer chromatography

Tos toluenesulfonyl, p-toluenesulfonyl

UPLC ultra performance liquid chromatography

Analysis details

NMR: In ^{Bruker Ultrashield TM 400 (400MHz),} Bruker Ultrashield TM 600 (600MHz), with or without the (500MHz) spectrometer 400MHz DRX Bruker CryoProbe (400MHz) or 500MHz DRX Bruker CryoProbe trimethyl Silane as an internal standard to implement Measure. The chemical shift (δ-value) is reported in the ppm low field region from tetramethylnonane, which is designated as a single peak ( s ), a double peak ( d ), a triplet ( t ), and a quadruple peak ( q ). ), quint , quasi- multiple, unresolved or overlapping signal ( m ), broad peak signal ( br ). Deuterated solvents are given in parentheses.

LC-MS: UPLC-MS condition a:

System: Waters Acquity UPLC with Waters SQ detector.

Column: Acquity HSS T3 1.8 μm 2.1 × 50 mm, column temperature: 60 ° C.

Gradient: 5% to 98% B, within 1.4 min, A = water + 0.05% formic acid + 3.75 mM ammonium acetate, B = acetonitrile + 0.04% formic acid, flow rate: 1.0 mL/min.

UPLC-MS condition b:

System: Waters Acquity UPLC with Waters SQ detector.

Column: Acquity HSS T3 1.8 μm 2.1 × 50 mm, column temperature: 60 ° C.

Gradient: 5% to 98% B, within 9.4 min, A = water + 0.05% formic acid + 3.75 mM ammonium acetate, B = acetonitrile + 0.04% formic acid, flow rate: 1.0 mL/min.

HPLC condition c:

System: Jasco LC-2000 Series with MD-2015 detector.

Column: Chiracel OZ 5μm 5×250mm, column temperature: rt.

85% heptane, 15% i PrOH + 0.05% TFA, flow rate: 1 mL/min.

HPLC condition d:

System: Jasco LC-2000 Series with MD-2015 detector.

Column: Chiralpak IC 5μm 5×250mm, column temperature: rt.

60% heptane, 40% EtOH + 0.1% TFA, flow rate: 0.5 mL/min.

HPLC condition e:

System: Jasco LC-2000 Series with MD-2015 detector.

Column: Chiralpak IC 5μm 5×250mm, column temperature: rt.

50% heptane, 50% EtOH + 0.1% TFA, flow rate: 0.5 mL/min.

HPLC condition f:

System: Agilent 1200 Series with DAD detector.

Column: Chiralpak AD-H 5μm 4.6×250mm, column temperature: rt.

60% heptane, 40% EtOH, flow rate: 0.7 mL/min.

HPLC condition g:

System: Jasco LC-2000 Series with MD-2015 detector.

Column: Chiralpak IC 5μm 5×250mm, column temperature: rt.

85% heptane, 12% i PrOH, 3% EtOH + 0.1% TFA, flow rate: 0.5 mL/min.

HPLC condition h:

System: Agilent 1100 Series with DAD detector.

Column: Chiralpak IC 5μm 5×250mm, column temperature: rt.

80% heptane, 10% EtOH, 10% MeOH + 0.1% HNEt ₂ + 0.1% TFA, flow rate: 1.0 mL/min.

Preparation method: Flash chromatography system:

System: Teledyne ISCO, CombiFlash Rf.

Column: Pre-filled RediSep Rf cartridge.

The sample is usually adsorbed onto Isolute.

All reagents, starting materials and intermediates used in these examples are obtained from commercial sources or are readily prepared by methods known to those skilled in the art.

Synthesis of Amino Acid Derived Construction Units

The alcohols 1a-1d were prepared by a method similar to that described by J. Martinez et al., Tetrahedron Letters 1991 , 32 , 923-926.

( S )-3-((t-butoxycarbonyl)amino)-4-hydroxybutyric acid tert-butyl ester (1a)

Thereby a rate (86 mL) in the cold to successively added Boc-L-Asp (O t Bu) -OH (25.0g, 86.0mmol) in DME N- methylmorpholine (10.1mL, 90.0mmol) and Isobutyl chloroformate (12.2 mL, 91.0 mmol) was maintained at a temperature below -10 °C. After 30 minutes, the precipitated N-methylmorpholine hydrochloride was removed by filtration, washed with DME (25 mL), and the filtrate and washings were combined in a flask in an ice salt bath. Was slowly added NaBH ₄ (4.14g, 108mmol) in the aqueous solution (30mL), followed by addition of water (70mL), maintaining the temperature between -15 ℃ and -30 ℃. The suspension was filtered and washed thoroughly with water. (4 × 50mL) and the filtrate was extracted with EtOAc, and combined organic layers were washed with brine, dried over Na ₂ SO _4, and concentrated under reduced pressure. The crude product was purified by EtOAc EtOAc m.

M/z = 276.2 [M+H] ⁺ , Rt = 3.04 min (UPLC-MS condition b), Rt = 6.83 min (HPLC condition g), ¹ H NMR (400 MHz, CDCl ₃ ) δ = 5.22 (s, br , 1H), 3.87-4.03 (m, 1H), 3.68 (d, 2H), 2.39-2.63 (m, 2H), 1.35-1.54 (m, 18 H) ppm.

The alcohol 1b-d was prepared similarly to the alcohol 1a .

Sulfalides 2a and 2b are prepared by a method similar to that described in AGJamieson et al., Journal of the American Chemical Society 2009 , 131 , 7917-7927.

( S )-4-(2-(Tertidinoxy)-2-oxoethyl)-1,2,3-oxathiazolidin-3-carboxylic acid tert-butyl ester 2,2-di Oxide (2a)

Step 1: A solution of the imidazole (16.0 g, 235 mmol) in 2-MeTHF (150 mL). Thionium chloride (4.29 mL, 58.8 mmol) was added dropwise. After 10 minutes, ( S )-3-((t-butoxycarbonyl)amino)-4-hydroxybutyric acid tert-butyl ester ( 1a , 6.0 g) was added dropwise in 2-MeTHF (30 mL). , 19.6 mmol). The cooling was removed and the RM was stirred for 2 h at rt, after which it was filtered through a pad of Celite ^TM. All volatiles were removed in vacuo and residue was partitioned between DCM (lOmL) The organic layer aqueous phase with aqueous HCl (10%, 20mL) and brine (20mL) of the washed, dried (MgSO ₄₎ concentrated and extracted with DCM (2 × 50mL) and.

Step 2: The residue was dissolved in MeCN (100mL), cooled to 0 ℃, ₃ and monohydrate (177mg, _{0.784mmol). 4} and NaIO4 (6,29g, 29.4 mmol) was treated with solid section RuCl, followed by dropwise addition Water (50 mL). After stirring at 0&lt;0&gt;C for 2 h, the mixture was partitioned between EtOAc (EtOAc) The aqueous phase of the combined organic layer was washed with saturated NaHCO ₃ (50mL) and brine (50mL) and extracted with EtOAc (2 × 50mL) and. The organic phase was gray plug of Celite ^TM, Na ₂ SO ₄ and filtered continuous silicon dioxide, up until a clear and colorless. The title compound 2a was obtained as a colorless solid.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ = 4.77 (dd, 1H), 4.56-4.64 (m, 1H) 4.53 (dd, 1H), 3.02 (dd, 1H), 2.76 (dd, 1H), 1.58 (s , 9H), 1.48 (s, 9H) ppm.

( R )-4-(2-(Tertidinoxy)-2-oxoethyl)-1,2,3-oxathiazolidin-3-carboxylic acid tert-butyl ester 2,2-di Oxide (2b)

Sulfonactone 2b was prepared starting from alcohol 1b similar to 2a .

¹ H NMR (400 MHz, CDCl ₃ ) δ = 4.78 (dd, 1H), 4.56 - 4.63 (m, 1H) 4.52 (dd, 1H), 3.02 (dd, 1H), 2.77 (dd, 1H), 1.58 (s , 9H), 1.48 (s, 9H) ppm.

Synthesis of nitrile intermediates 4-(benzo[d]thiazol-2-yloxy)benzonitrile (3a)

Heating a suspension of 4-hydroxybenzonitrile (6.55 g, 55.0 mmol), 2-chlorobenzothiazole (6.51 mL, 50.0 mmol) and K ₂ CO ₃ (7.60 g, 55.0 mmol) in DMF (20 mL) To 120 ° C and hold for 18 hours. The reaction mixture was cooled to rt, with heptane: EtOAc (1: 1,300mL) was diluted and washed with ₂ CO ₃ (50mL) and brine (50mL) with 0.2N NaOH (200mL), saturated Na. Dried over Na ₂ SO _4, filtered and concentrated to dryness to give the crude product by crystallization (heptane: EtOAc) which was purified to give the desired ether as a beige solid 3a.

M/z = 253.1 [M+H] ⁺ , Rt = 1.13 min (UPLC-MS condition a), ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 7.98-8.05 (m, 3H), 7.69-7. m, 3H), 7.46 (dd, 1H), 7.38 (dd, 1 H) ppm.

4-((5-chloropyridin-2-yl)oxy)benzonitrile (3b)

The nitrile 3b was prepared analogously to the nitrile 3a starting from 2,5-dichloropyridine and 4-bromobenzonitrile and was obtained as a colorless solid after trituration with MeOH.

M/z = 230.9 [M+H] ⁺ , Rt = 1.07 min (UPLC-MS condition a), ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.26 (d, 1H), 8.05 (dd, 1H) , 7.91 (d, 2H), 7.36 (d, 2H), 7.24 (d, 1 H) ppm.

4-((5-chloro-3-fluoropyridin-2-yl)oxy)benzonitrile (3c)

The nitrile 3c was prepared at a reaction temperature of 90 ° C starting from nitrile 3a starting from 5-chloro-2,3-difluoropyridine and 4-hydroxybenzonitrile. The title compound was obtained as a colorless solid, which was obtained from EtOAc.

M/z = 249.2 [M+H] ⁺ , Rt = 1.10 min (UPLC-MS condition a), ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.30 (dd, 1H), 8.13 (dd, 1H) , 7.93 (d, 2H), 7.43 (d, 2H) ppm, ¹⁹ F NMR (376 MHz, DMSO - d ₆ ) δ = 133.7 (d, 1F) ppm.

4-(4-(oxazol-2-yl)phenoxy)benzonitrile (3d)

4-(oxazol-2-yl)phenol (200 mg, 1.24 mmol), 4-fluorobenzonitrile (301 mg, 2.48 mmol) and K ₂ CO ₃ (515 mg, 3.72 mmol) in DMF (1.2 mL) The suspension was heated to 100 ° C for 16 hours. The reaction mixture was concentrated in vacuo and by chromatography on a flash column (0.1% TFA aqueous solution: MeCN, 9: 1 to 0: 1) RP18 silicon dioxide to give a colorless powder of the title compound 3d.

M/z = 263.1 [M+H] ⁺ , Rt = 1.07 min (UPLC-MS condition a), ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.23 (s, 1H), 8.06 (d, 2H) , 7.90 (d, 2H), 7.39 (s, 1H), 7.28 (d, 2H), 7.23 (d, 2H) ppm.

Synthesis of tetrazole intermediates

The compounds of the invention are typically synthesized via intermediates of formula 4a to formula 4o (see also Schemes B and C). In the following, such compounds are typically presented in the form of one tautomer (e.g., 1 H -tetrazol-5-yl). Likewise, the corresponding chemical names of such intermediates are provided for only one tautomeric form. However, such a tautomer may also be present in another tautomeric form (for example as a 2 H -tetrazol-5-yl tautomer). Thus, any tautomeric form can be encompassed in the intermediate of formula 4 ( 4a to 4o ), even if only one specific form is shown.

2-(4-(1 H -tetrazol-5-yl)phenoxy)benzo[ d ]thiazole (4a)

Purging 4-(benzo[ d ]thiazol-2-yloxy)benzonitrile ( 3a , 1.51 g, 6.00 mmol) and dibutyltin oxide (IV) (0.149 g, 0.600 mmol) in anhydrous A suspension in toluene (9.0 mL). Azido trimethyl decane (1.59 mL, 12.0 mmol) was added, after which the vial was sealed and heated to 110 ° C for 8 hours. The reaction mixture was cooled to rt, treated with MeOH (5mL) and concentrated in vacuo. Washed with MeCN (50mL) and pentane (15mL), to give the desired tetrazole as a beige solid 4a.

M/z = 296.1 [M+H] ⁺ , Rt = 0.91 min (UPLC-MS condition a), ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 16.6-17.3 (s, br, 1H), 8.17 ( d, 2H), 7.99 (d, 1H), 7.70-7.76 (m, 3H), 7.46 (d, 1H), 7.37 (d, 1H) ppm.

5-(4-(4-chlorophenoxy)phenyl)-1 H -tetrazole (4f)

4-(4-Chlorophenoxy)benzonitrile ( 3f , 1.43 g, 6.23 mmol) and dibutyltin oxide (IV) (0.155 g, 0.623 mmol) in hexane (9.0 mL) Suspension. Azido trimethyl decane (1.65 mL, 12.5 mmol) was added, after which the vial was sealed and heated to 100 ° C for 17 hours. The reaction mixture was cooled to EtOAc EtOAc m. Washed with MeCN (15mL) and heptane (15mL) to give the desired tetrazole as a colorless solid 4f.

M/z = 273.0 [M+H] ⁺ , Rt = 0.99 min (UPLC-MS condition a), ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 16.8 (s, br, 1H), 8.06 (d, 2H), 7.50 (d, 2H), 7.23 (d, 2H), 7.17 (d, 2H) ppm.

Other tetrazole (e.g., tetrazole 4b-j ) is prepared analogous to tetrazole 4a . Reaction parameters and analysis (characterization of the compounds) are provided in the table below.

Synthesis of substituted tetrazole intermediates Method A: (R) -4- (5- (4- ( benzo [d] thiazol-2-yloxy) phenyl) -2 H - tetrazol-2-yl) -3 - ((tert-butoxy Carbonyl)amino)butyric acid tert-butyl ester (5a)

A solution of triphenylphosphine (3.67 g, 14.0 mmol) and DIAD (1.70 mL, 8.75 mmol) in THF (10 mL) was cooled to 0 ° C then slowly transferred to 2-(4-( 1H -4) Zyrid-5-yl)phenoxy)benzo[ d ]thiazole ( 4a , 2.07 g, 7.00 mmol) and ( R )-3-((t-butoxycarbonyl)amino)-4-hydroxybutyric acid A stirred suspension of the third butyl ester ( 1b , 2.12 g, 7.70 mmol) in THF (10 mL). After 1 hour at rt, the reaction mixture was concentrated in vacuo. RP18 on silicon dioxide by flash column chromatography (0.1% TFA aqueous solution: MeCN, 9: 1 to 0: 1) to give the crude product as an orange oil of the title compound 5a.

M/z = 553.3 [M+H] ⁺ , Rt = 6.28 min (UPLC-MS condition b), ¹ H NMR (400 MHz, DMSO- d ₆ ) δ=8.17 (d, 2H), 7.98 (d, 1H) , 7.73 (d, 1H), 7.67 (d, 2H), 7.45 (t, 1H), 7.36 (t, 1H), 7.02 (d, 1H), 4.86 (dd, 1H), 4.66 (dd, 1H), 4.26-4.37 (m, 1H), 2.65 (dd, 1H), 2.41-2.54 (m, 1H), 1.41 (s, 9H), 1.25 (s, 9H) ppm.

Method B: ( R )-3-((Tertibutoxycarbonyl)amino)-4-(5-(4-(4-chlorophenoxy)phenyl)-2 H -tetrazol-2-yl) Acid (5f)

A solution of triphenylphosphine (5.77 g, 22.0 mmol) and DIAD (2.67 mL, 13.8 mmol) in 2-MeTHF (20 mL) was cooled to 0 ° C then slowly transferred to 5-(4-(4- Chlorophenoxy)phenyl)-1 H -tetrazole ( 4f , 3.00g, 11.0mmol) and (R)-3-((t-butoxycarbonyl)amino)-4-hydroxybutyric acid benzyl A stirred suspension of the ester ( 1d , 3.74 g, 12.1 mmol) in 2-MeTHF (20 mL). After 30 min at rt, 2N NaOH (45.8 mL, &lt;RTI ID=0.0&gt;&gt; The reaction mixture was diluted with heptane:EtOAc (1:1, 400 mL) andEtOAc. The combined aqueous extracts were carefully acidified to pH = 3 using EtOAc (EtOAc (EtOAc) The combined organic extracts were dried over Na ₂ SO _4, filtered and concentrated in vacuo. By crystallization (heptane: EtOAc) The crude product was purified to give the desired acid as a colorless solid 5f.

M/z = 474.2 [M+H] ⁺ , Rt = 5.09 min (UPLC-MS condition b), Rt = 8.51 min (HPLC condition c), ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 12.4 (s) , 1H), 8.06 (d, 2H), 7.49 (d, 2H), 7.19 (d, 2H), 7.15 (d, 2H), 6.99 (d, 1H), 4.86 (dd, 1H), 4.66 (dd, 1H), 4.23-4.33 (m, 1H), 2.61 (dd, 1H), 2.47-2.54 (m, 1H), 1.24 (s, 9H) ppm.

Method C: ( S )-3-((Tertibutoxycarbonyl)amino)-4-(5-(4-(4-chlorophenoxy)phenyl)-2 H -tetrazol-2-yl) Tert-butyl acid ester (5m)

Treatment of 5-(4-(4-chlorophenoxy)phenyl)-1 H -tetrazole ( 4f , 200 mg, 0.733 mmol) and ( S )-4-(2- with DIPEA (0.384 mL, 2.20 mmol) (t-butoxy)-2-oxoethyl)-1,2,3-oxathiazolidin-3-carboxylic acid tert-butyl ester 2,2-dioxide ( 2a , 330 mg, 0.880 mmol The solution in DMF (5 mL) was stirred at rt for 18 h. The reaction mixture was concentrated in vacuo and by chromatography on a flash column (0.1% TFA aqueous solution: MeCN, 9: 1 to 0: 1) RP18 silicon dioxide residue was purified to give the title compound as a colorless semisolid 5m.

M/z = 530.2 [M+H] ⁺ , Rt = 6.69 min (UPLC-MS condition b), ¹ H NMR (400 MHz, MeOD- d ₄ ) δ = 8.13 (d, 2H), 7.42 (d, 2H) , 7.15 (d, 2H), 7.08 (d, 2H), 4.89 (dd, 1H), 4.76 (dd, 1H), 4.45-4.53 (m, 1H), 2.67 (dd, 1H), 2.53 (dd, 1H) ), 1.49 (s, 9H), 1.34 (s, 9H) ppm.

Preparation of alkylation product 5b-1 similar to 5a, 5f or 5m

Synthesis of substituted tetrazole intermediates via phenol 6 and 7 (R) -3 - ((tert-butoxy carbonyl) amino) -4- (5- (4-hydroxyphenyl) -2 H - tetrazol-2-yl) butyric acid tert-butyl ester ( 6)

Step A: 5-(4-((Tertiarybutyldimethylmethyl)oxy)phenyl)-1 H -tetrazole (4n)

The tetrazole 4n was prepared analogously to the tetrazole 4a and was obtained as a colorless powder after recrystallization from heptane:EtOAc.

M/z = 277.4 [M+H] ⁺ , Rt = 1.18 min (UPLC-MS condition a), ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 16.42 (s, br, 1H), 7.71 (d, 2H), 6.83 (d, 2H), 0.73 (s, 9H), 0.00 (s, 6H) ppm.

Step B: (R)-3-((Tertidinoxycarbonyl)-amino)-4-(5-(4-((t-butyldimethylmethyl)-oxy)phenyl) -2 H -tetrazol-2-yl)butyric acid tert-butyl ester (5n)

An alkylated tetrazole 5n was prepared analogously to Method A.

M/z = 534.2 [M+H] ⁺ , Rt = 1. 58 min (UPLC-MS condition a).

Step C: (R) -3 - ( ( tert-butoxy carbonyl) amino) -4- (5- (4-hydroxyphenyl) -2 H - tetrazol-2-yl) butanoic acid t-butoxide Base ester (6)

(R)-3-((Tertidinoxycarbonyl)-amino)-4-(5-(4-((t-butyldimethylmethyl)-oxy)phenyl)-2 A solution of H -tetrazol-2-yl)butyric acid tert-butyl ester ( 5n , 2.14g, 4.00mmol) in THF (10 mL) was cooled to 0 ° C then TBAF in THF (1N, 4.40 mL) , a solution in 4.40 mmol). After 1 hour at this temperature, the reaction mixture was concentrated in vacuo. By flash column chromatography on RP18 silicon dioxide (0.1% TFA aqueous solution: MeCN, 9: 1 to 0: 1) The crude compound was purified product was obtained as a colorless powder of the title 6.

M/z = 420.4 [M+H] ⁺ , Rt = 1.07 min (UPLC-MS condition a), ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 9.95 (s, 1H), 7.86 (d, 2H) , 6.98 (d, 1H), 6.92 (d, 2H), 4.75 (dd, 1H), 4.59 (dd, 1H), 4.20-4.35 (m, 1H), 2.35-2.65 (m, 2H), 1.39 (s) , 9H), 1.25 (s, 9H) ppm.

(R)-3-((t-butoxycarbonyl)amino)-4-(5-(3-hydroxyphenyl)-2 H -tetrazol-2-yl)butyric acid tert-butyl ester ( 7)

Step A: 5-(3-((Tertiarybutyldimethylmethyl)oxy)phenyl)-1 H -tetrazole (4o)

A colorless powder was obtained after a tetrazole 4o was prepared similarly to the tetrazol 4a and was subjected to flash column chromatography (heptane:EtOAc, 1:0 to 1:1).

M/z = 277.1 [M+H] ⁺ , Rt = 1.16 min (UPLC-MS condition a), ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.65 (d, 1H), 7.55 - 7.59 (m, 1H) , 7.41 (t, 1H), 7.03 (dd, 1H), 1.00 (s, 9H), 0.23 (s, 6H) ppm, tetrazole-N H was not detected.

Step B: (R)-3-((Tertidinoxycarbonyl)amino)-4-(5-(3-((t-butyldimethyl)methyl)oxy)phenyl)-2 H -tetrazol-2-yl)butyric acid tert-butyl ester (5o)

An alkylated tetrazole 5o was prepared analogously to Method A.

M/z = 534.3 [M+H] ⁺ , Rt = 1.55 min (UPLC-MS condition a).

Step C: (R) -3 - ( ( tert-butoxy carbonyl) amino) -4- (5- (3-hydroxyphenyl) -2 H - tetrazol-2-yl) butanoic acid t-butoxide Base ester (7)

6 was prepared similar to phenol and phenol 7 is obtained as a colorless powder.

M/z = 420.2 [M+NH ₄ ] ⁺ , Rt = 1.07 min (UPLC-MS condition a), ¹ H NMR (400 MHz, MeOD- d ₄ ) δ=7.52-7.62 (m, 2H), 7.28-7.36 (dd, 1H), 6.90-6.95 (dd, 1H), 4.90 (dd, 1H), 4.75 (dd, 1H), 4.42-4.56 (m, 1H), 2.65 (dd, 1H), 2.52 (dd, 1H) ), 1.48 (s, 9H), 1.34 (s, 9H) ppm.

Method D: (R) -3 - ((tert-butoxy carbonyl) amino) -4- (5- (3-phenethyloxy-phenyl) -2 H - tetrazol-2-yl) butanoic acid t-butoxide Base ester (5p)

Treatment of (R)-3-((t-butoxycarbonyl)amino)-4-(5-(3-hydroxyphenyl)-2 H -tetrazol-2-yl with DIAD (111 μL, 0.572 mmol) a solution of tert-butyl butyrate ( 7 , 80 mg, 0.191 mmol), 2-phenylethanol (46 μL, 0.381 mmol) and triphenylphosphine (150 mg, 0.572 mmol) in 2-MeTHF (10 mL) Stir at rt for 4 hours. All the volatiles were removed in vacuo and the residue was purified by flash column chromatography (0.1% aqueous TFA:MeCN, 9:1 to 0:1) to give colorless viscous oily ether 5p .

M/z = 524.4 [M + H] ⁺ , Rt = 1.44 min (UPLC-MS condition a).

Method E: (R) -4- (5- (4- ( benzyloxy) phenyl) -2 H - tetrazol-2-yl) -3 - ((tert-butoxy carbonyl) amino) butyric acid of Tributyl ester (5r)

The (R) -3 - ((tert-butoxy carbonyl) amino) -4- (5- (4-hydroxyphenyl) -2 H - tetrazol-2-yl) butyric acid tert-butyl ester in the (6, 90mg, 0.215mmol), benzyl bromide (77μL, 0.644mmol) and _{K 2 CO 3 (89mg, 0.644mmol} ) in DMF (0.72mL) was suspended in 65. Stir at ° C for 5 hours. All the volatiles were removed in vacuo and the residue was purified by flash column chromatography (0.1% aqueous TFA:MeCN, 9:1 to 0:1) to afford yellow viscous oily ether 5r .

M/z = 510.2 [M + H] ⁺ , Rt = 1.35 min (UPLC-MS condition a).

Method F: (R)-3-((t-butoxycarbonyl)amino)-4-(5-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)- 2 H -tetrazol-2-yl)butyric acid tert-butyl ester (5v)

Would (R) -3 - ((tert-butoxy carbonyl) amino) -4- (5- (4-hydroxyphenyl) -2 H - tetrazol-2-yl) butyric acid tert-butyl ester (7, 100mg, 0.238mmol), in the 2-fluoro-5- (trifluoromethyl) pyridine (88μL, 0.715mmol) and _{K 2 CO 3 (99mg, 0.715mmol} ) in DMF (0.8mL) suspension of Stir at 65 ° C for 5 hours. All volatiles were removed in vacuo and the residue was purified by flash column chromatography (0.1% aqueous TFA:MeCN, 9:1 to 0:1) on RP18 cerium oxide to give yellow viscous oily ether 5v .

M/z = 565.4 [M+H] ⁺ , Rt = 1.37 min (UPLC-MS condition a).

Preparation of ether 5q-y similar to 5p, 5r or 5v

Example 1 Method G: (R)-3-amino-4-(5-(4-(benzo[d]thiazol-2-yloxy)phenyl)-2H-tetrazol-2-yl)butyric acid

Will 4N HCl in the (R) -4- (5- (4- ( benzo [d] thiazol-2-yloxy) phenyl) -2 H - tetrazol-2-yl) -3- ( A solution of (t-butoxycarbonyl)amino)butyric acid tert-butyl ester ( 5a , 414 mg, 0.749 mmol) in dioxane (1.87 mL, 7.49 mmol) was warmed to 40 &lt;0&gt;C for 3 h. The resulting suspension was filtered, and the crude product was washed with acetone, to give a colorless solid hydrochloride salt of the desired product (Example 1).

M/z = 397.0 [M+H] ⁺ , Rt = 2.61 min (UPLC-MS condition b), Rt = 8.80 min (HPLC condition e), ¹ H NMR (400 MHz, MeOD- d ₄ ) δ = 8.31 (d , 2H), 7.83 (d, 1H), 7.68 (d, 1H), 7.60 (d, 2H), 7.45 (dd, 1H), 7.35 (dd, 1H), 5.16 (d, 2H), 4.29 (five Peak, 1H), 2.95 (d, 1H), 2.79 (dd, 1 H) ppm.

Example (Ex.) 2-23 was prepared analogously to Example 1 (Method G) and the hydrochloride salt was obtained.

Example 24 ( R )-3-Amino-4-(5-(4-(4-fluorophenoxy)phenyl)-1,3,4-oxadiazol-2-yl)butyric acid

Step A: 2-(4-(4-Fluorophenoxy)benzylidene)carboxylic acid tert-butyl ester (8a)

4-(4-Fluorophenoxy)benzoic acid (5.5 g, 23.69 mmol), tert-butyl phthalate (3.13 g, 23.7 mmol), HOBT (5.44 g, 35.5 mmol), Et ₃ N (4.92) mL, 35.5 mmol) and EDC x HCl (6.81 g, 35.5 mmol) were dissolved in DCM (90 mL). The brown reaction mixture was stirred at rt for 5 h. The reaction mixture was concentrated in vacuo and partitioned between water (15 mL) (2 × 30mL) and the aqueous layer was extracted combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo with DCM. The crude product was purified by flash column chromatography (0-100% EtOAc in hexanes). The purified product was triturated with diethyl ether and a colorless solid was obtained.

M/z = 345.2 [MH] ⁺ , Rt = 1.03 min (UPLC-MS condition a), ¹ H NMR (400 MHz, DMSO - d ₆ ) δ = 10.13 (br s, 1H), 8.88 (br s, 1H) , 7.88 (d, 2H), 7.30 (dd, 2H), 7.15-7.20 (m, 2H), 7.02 (d, 2H), 1.43 (s, 9H) ppm.

Step B: 4-(4-Fluorophenoxy)benzoindole (9a)

HCl (4N, 30.3 mL, 121 mmol) in dioxane was added to the tert-butyl 2-(4-(4-fluorophenoxy) benzhydryl) hydrazide ( 8a , 2.80 g, 8.08 Mix in mmol) and stir at rt for 1.5 hours. The reaction mixture was evaporated in vacuo.

M/z = 247.1 [M+H] ⁺ , Rt = 0.78 min (UPLC-MS condition a), ¹ H NMR (400 MHz, DMSO- d ₆ ) δ=11.55 (br s, 1H), 10.43 (br s, 2H), 7.96 (d, 2H), 7.32 (dd, 2H), 7.2 (m, 2H), 7.07 (d, 2H) ppm.

Step C: (R)-3-((Tertidinoxycarbonyl)amino)-5-(2-(4-(4-fluorophenoxy)benzylidene)indolyl-5-side Benzyl valerate (10a)

4-(4-Fluorophenoxy)benzoindole ( 9a , 1.51 g, 4.74 mmol), ( R )-5-(benzyloxy)-3-((t-butoxycarbonyl)amine 5-)-oxo-valeric acid (1.6 g, 4.74 mmol), HOBT (0.944 g, 6.17 mmol), Et ₃ N (1.32 mL, 9.49 mmol) and EDC×HCl (1.36 g, 7.11 mmol) were dissolved in In DCM (18 mL). The brown reaction mixture was stirred at rt for 16 h. The reaction mixture was then diluted with water (15 mL) The combined organic layers were dried over Na ₂ SO _4, and evaporated under reduced pressure. The crude product was purified by flash column chromatography (EtOAc-EtOAc)

M/z = 566.2 [M+H] ⁺ , Rt = 1.16 min (UPLC-MS condition a), ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 10.27 (br s, 1H), 9.93 (br s, 1H), 7.89 (d, 2H), 7.25-7.40 (m, 7H), 7.19 (m, 2H), 7.04 (m, 2H), 5.08 (d, 2H), 4.21 (brm, 1H), 2.70- 2.75 (dd, 1H), 2.37-2.55 (m, 3H), 1.38 (s, 9H) ppm.

Step D: (R)-3-((Tertibutoxycarbonyl)amino)-4-(5-(4-(4-fluorophenoxy)phenyl)-1,3,4-oxo Benzyl-2-yl)butyric acid benzyl ester (11a)

(R)-3-((Tertidinoxycarbonyl)amino)-5-(2-(4-(4-fluorophenoxy)benzylidene)indolyl-5-sideoxy acid benzyl ester (10a, 2.10g, 3.71mmol) and TosCl (0.779g, 4.08mmol) was dissolved in DCM (35mL), Et ₃ N was then added in 2 minutes (0.772mL, 5.57mmol). The reaction mixture was stirred at rt for 16 h. The reaction mixture was then quenched with water and extracted three times with DCM. The combined organic layers were washed with brine, dried over Na ₂ CH ₄ By flash column chromatography (0-50% EtOAc in cyclohexane) to give the crude product as a colorless foam to afford 11a on the silicon dioxide.

M/z = 548.2 [M+H] ⁺ , Rt = 1.33 min (UPLC-MS condition a), ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 7.94 (d, 2H), 7.25-7.40 (m, 6H), 7.15-7.25 (m, 2H), 7.14 (d, 2H), 7.05 (m, 1H), 5.09 (s, 2H), 4.28 (br m, 1H), 3.17 (dd, 1H), 3.01 ( Dd, 1H), 2.75 (dd, 1H), 2.70 (dd, 1H), 1.28 (s, 9H) ppm.

Step E: (R)-3-Amino-4-(5-(4-(4-fluoro-phenoxy)phenyl)-1,3,4-oxadiazol-2-yl)butyric acid benzyl Base ester (12a)

(R)-3-((Tertibutoxycarbonyl)amino)-4-(5-(4-(4-fluorophenoxy)phenyl)-1,3,4-oxadiazole- 2-Benzyl benzyl butyrate ( 11a , 1.50 g, 2.74 mmol) was dissolved in 4N HCl (13.7 mL, 54.8 mmol) in dioxane and stirred at rt for 1.5 h. Then, the reaction mixture was evaporated under reduced pressure. The residue was triturated with ether to give a colorless solid of the title compound 12a, which was used without further purification in the next step.

M/z = 448.3 [M+H] ⁺ , Rt = 0.95 min (UPLC-MS condition a), ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.43 (br s, 2H), 7.98 (d, 2H) ), 7.30-7.40 (m, 7 H), 7.20-7.25 (m, 2H), 7.13 - 7.15 (m, 2H), 5.12 (s, 2 H), 4.00 (m, 1H), 3.57 (d, 2H) ), 3.40 (d, 1H), 2.96 (d, 1 H) ppm.

Step F: (R)-3-Amino-4-(5-(4-(4-fluorophenoxy)phenyl)-1,3,4-oxadiazol-2-yl)butyric acid (example) twenty four)

Benzyl (R)-3-amino-4-(5-(4-(4-fluoro-phenoxy)phenyl)-1,3,4-oxadiazol-2-yl)butyrate ( 12a , 200 mg, 0.447 mmol) was dissolved in MeOH (5 mL) and was then taken to EtOAc EtOAc EtOAc The mixture was degassed and purged three times with hydrogen. The reaction mixture was stirred under an atmosphere of hydrogen for 3 hours at rt. The reaction mixture was filtered through a pad of Celite and evaporated under reduced pressure. No further purification is required.

M/z = 358.2 [M+H] ⁺ , Rt = 0.71 min (UPLC-MS condition a), ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.00 (d, 2H), 7.26-7.35 (m, 2H), 7.03-7.26 (m, 4H), 4.11 (m, 1H), 3.8 (m, 1H), 3.17 (m, 1H), 2.79 (d, 2H) ppm.

Example 25 ( R )-3-Amino-4-(5-(4-(4-chlorophenoxy)phenyl)-1,3,4-oxadiazol-2-yl)butyric acid

Steps A to D: (R)-3-((t-butoxycarbonyl)amino)-4-(5-(4-(4-chlorophenoxy)phenyl)-1,3,4- Oxadiazol-2-yl)butyric acid benzyl ester (11b)

This compound was synthesized in four steps starting from compound 11a starting from commercially available 4-(4-chlorophenoxy)benzoic acid.

M/z = 564.2 [M+H] ⁺ , Rt = 1.39 min (UPLC-MS condition a), ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 7.96 (d, 2H), 7.51 (d, 2H) , 7.30-7.40 (m, 5H), 7.15-7.20 (m, 4H), 5.09 (s, 2H), 4.28 (br m, 1H), 3.16 (dd, 1H), 3.02 (dd, 1H), 2.7 ( Dd, 1H), 2.70 (dd, 1H), 1.28 (s, 9H) ppm.

Step E: (R)-3-((Tertidinoxycarbonyl)amino)-4-(5-(4-(4-chlorophenoxy)phenyl)-1,3,4-Ethylene Zin-2-yl)butyric acid (13b)

(R)-3-((Tertibutoxycarbonyl)amino)-4-(5-(4-(4-chlorophenoxy)phenyl)-1,3,4-oxadiazole- 2-Base) Benzyl butyrate ( 11b , 420 mg, 0.745 mmol) was dissolved in MeOH (8 mL) and EtOAc was evaporated from EtOAc EtOAc. The mixture was degassed and purged three times with hydrogen. The reaction mixture was stirred under a hydrogen atmosphere at rt for 3 hr. The reaction mixture was filtered through a pad of celite and evaporated under reduced pressure. Product 13b was used in the next step without further purification.

M/z = 474.1 [M+H] ⁺ , Rt = 1.13 min (UPLC-MS condition a), ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 12.29 (s, br, 1H), 7.98 (d, 2H), 7.51 (d, 2H), 7.13-7.22 (m, 4H), 4.21 (m, 1H), 3.14 (m, 1H), 3.01 (m, 1H), 2.54-2.57 (m, 2H), 1.28 (s, 9H) ppm.

Step F: (R)-3-Amino-4-(5-(4-(4-chlorophenoxy)phenyl)-1,3,4-oxadiazol-2-yl)butyric acid (example) 25)

This compound was synthesized from 13b analogously to 12a . The product was purified by flash column chromatography (methanol: EtOAc, from 0:1 to 2:1).

M/z = 374.1 [M+H] ⁺ , Rt = 0.78 min (UPLC-MS condition a), ¹ H NMR (400 MHz, DMSO- d ₆ ) δ=8.01 (d, 2H), 7.51 (d, 2H) , 7.17-7.22 (m, 4H), 3.80 (m, 1H), 3.65 (m, 1H), 2.89 (m, 1H), 2.79 (d, 2H) ppm.

Example 26 ( R )-3-Amino-4-(3-(4-(4-chlorophenoxy)phenyl)-1,2,4-oxadiazol-5-yl)butyric acid

Step A: 4-(4-Chlorophenoxy) -N '-hydroxybenzhydrazide (14)

A solution of 4-(4-chlorophenoxy)benzonitrile (1.00 g, 4.35 mmol) in EtOH (15 mL) was taken from EtOAc (EtOAc) hour. The reaction mixture was concentrated and the residue was recrystallized from EtOH at reflux, to give the desired product 14 as a colorless solid in vacuo.

M/z = 263.3 [M+H] ⁺ , Rt = 0.82 min (UPLC-MS condition a), ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 9.60 (s, 1H), 7.70 (d, 2H) , 7.45 (d, 2H), 7.07 (d, 2H), 7.02 (d, 2H), 5.80 (s, 2H) ppm.

Step B: (R)-3-((((9H-茀-9-yl)methoxy)carbonyl)amino)-4-(3-(4-(4-chlorophenoxy)phenyl) -1,2,4-oxadiazol-5-yl)butyric acid tert-butyl ester (15)

A suspension of Fmoc-β-Glu(O t Bu)-OH (250 mg, 0.588 mmol), HATU (246 mg, 0.646 mmol) and DIPEA (0.205 mL, 1.18 mmol) in 2-MeTHF (5 mL) Stir for 1 hour. 4-(4-Chlorophenoxy) -N '-hydroxybenzimidamide ( 14 , 170 mg, 0.646 mmol) was added and the vial was capped and heated to 90 ° C for 17 h. All volatiles were removed in vacuo and the residue was purified by flash column chromatography (0.1% aqueous TFA:MeCN, 9:1 to 0:1) on RP18 ceria to give a pale yellow viscous oily Diazole 15 .

M/z = 652.1 [M+H] ⁺ , Rt = 1.56 min (UPLC-MS condition a).

Step C: ( R )-3-((((9H-茀-9-yl)methoxy)carbonyl)amino)-4-(3-(4-(4-chlorophenoxy)phenyl) -1,2,4-oxadiazol-5-yl)butyric acid (16)

Treatment of ( R )-3-(((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(3-(4-(4-chlorophenoxy)) with TFA (4 mL) A solution of phenyl)-1,2,4-oxadiazol-5-yl)butyric acid tert-butyl ester ( 15 , 233 mg, 0.339 mmol) in DCM (6 mL). All volatiles were removed in vacuo and by chromatography on a flash column (0.1% TFA aqueous solution: MeCN, 9: 1 to 0: 1) RP18 The residue was purified silicon dioxide, to give acid 16 as a yellow foam.

M/z = 596.1 [M+H] ⁺ , Rt = 1.36 min (UPLC-MS condition a).

Step D: ( R )-3-Amino-4-(3-(4-(4-chlorophenoxy)phenyl)-1,2,4-oxadiazol-5-yl)butyric acid (example) 26)

Treatment of ( R )-3-(((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(3-(4-(4) with hexahydropyridine (0.511 mL, 5.16 mmol) A solution of chlorophenoxy)phenyl)-1,2,4-oxadiazol-5-yl)butanoic acid ( 16 , 205 mg, 0.344 mmol) eluted elute All volatiles were removed in vacuo and the residue was purified by flash column chromatography (EtOAc EtOAc EtOAc EtOAc EtOAc Product ( Example 26 ).

M/z = 374.0 [M+H] ⁺ , Rt = 3.14 min (UPLC-MS condition b), ¹ H NMR (400 MHz, DMSO- d ₆ ) δ=8.03 (d, 2H), 7.50 (d, 2H) , 7.18 (d, 2H), 7.16 (d, 2H), 3.50-3.61 (m, 1H), 3.18 (dd, 1H), 3.11 (dd, 1H), 2.41 (dd, 1H), 2.26 (dd, 1H) )ppm.

Example 27 ( R )-3-Amino-4-(3-(4-(4-chlorophenoxy)phenyl)-1,2,4-oxadiazol-5-yl)butanamine

Step A: ( R )-(4-Amino-1-(3-(4-(4-chlorophenoxy)phenyl)-1,2,4-oxadiazol-5-yl)-4- Tert-butylbutan-2-yl)carbamic acid tert-butyl ester (17)

This compound was synthesized analogously to 15 from 14 and commercially available Boc-β-Gln-OH.

M/z = 473.0 [M+H] ⁺ , Rt = 1.17 min (UPLC-MS condition a).

Step B: ( R )-3-Amino-4-(3-(4-(4-chlorophenoxy)phenyl)-1,2,4-oxadiazol-5-yl)butanamine ( Example 27)

( R )-(4-Amino-1-(3-(4-(4-chlorophenoxy)phenyl)-1,2,4-oxadiazol-5-yl)-4-side oxygen A solution of the butyl butyl carbamate ( 17 , 91.8 mg, 0.194 mmol) in EtOAc (EtOAc) All volatiles were removed in vacuo and the residue was purified by flash column chromatography (0.1% aqueous TFA:MeCN, 9:1 to 0:1). The product containing fractions were treated with 0.1 N HCl (4 mL) and concentrated in vacuo. The residue was triturated and collected by filtration washed with acetone (2mL) and heptane (2mL), to give the hydrochloride as a colorless powder of Example 27.

M/z = 373.1 [M+H] ⁺ , Rt = 2.68 min (UPLC-MS condition b), ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.22 (s, br, 3H), 8.05 (d, 2H), 7.69 (s, br, 1H), 7.51 (d, 2H), 7.22 (s, br, 1H), 7.15-7.21 (m, 4H), 3.92-4.01 (m, 1H), 3.40 (d, 2H), 2.60-2.67 (m, 2H) ppm.

Example 28 ( S )-3-Amino-4-(4-(4-(4-chlorophenoxy)phenyl)-1 H -pyrazol-1-yl)butyric acid

Step B: 4-(4-(4-Chlorophenoxy)phenyl)-1 H -pyrazole (18)

1-Bromo-4-(4-chlorophenoxy)benzene (170 mg, 0.600 mmol), 4-pyrazole Acid pinacol ester (140 mg, 0.719 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (42.1 mg, 0.060 mmol) and K ₂ CO ₃ (2N, 0.749 mL, 1.50 mmol) in n-propanol (5 mL) The suspension was heated to 100 ° C in the microwave for 90 minutes. Diluted with EtOAc (30mL) and the reaction mixture was washed with saturated Na ₂ CO ₃ (15mL), water (15mL) and brine (20mL). The dried organic phase was ₂ SO ₄ Na, filtered and concentrated in vacuo. By chromatography on a flash column (0.1% TFA aqueous solution: MeCN, 9: 1 to 4: 6) RP18 silicon dioxide to give a colorless solid pyrazole 18.

M/z = 271.1 [M+H] ⁺ , Rt = 1.10 min (UPLC-MS condition a), ¹ H NMR (400 MHz, MeOD- d ₄ ) δ = 7.94 (s, 2H), 7.60 (d, 2H) , 7.35 (d, 2H), 7.03 (d, 2H), 7.00 (d, 2H) ppm.

Step C: ( S )-3-((Tertibutoxycarbonyl)amino)-4-(4-(4-(4-chlorophenoxy)phenyl)-1 H -pyrazole-1- Tert-butyl butyrate (19)

4- (4- (4-chlorophenoxy) phenyl) -1 H - pyrazole (18, 200mg, 0.739mmol) was cooled at the 2-MeTHF (2.4mL) to -78 ℃. Solid sodium hydride (60% in mineral oil, 35.5 mg, 0.813 mmol) was added followed by 2a (305 mg, &lt;RTI ID=0.0&gt; The reaction mixture was allowed to warm to rt over a period of 1 hour. The reaction mixture was partitioned between EtOAc (EtOAc) (3 × 30mL) aqueous layer was extracted with EtOAc and the combined organic extracts were washed with brine, dried over Na ₂ SO _4, filtered and concentrated in vacuo. By chromatography on a flash column (0.1% TFA aqueous solution: MeCN, 9: 1 to 0: 1) RP18 silicon dioxide residue was purified to obtain sufficient purity of the title compound 19 as a yellow solid (about 70%) for The next step.

M/z = +529.2 [M+H] ⁺ , Rt = 1.45 min (UPLC-MS condition a).

Step D: ( S )-3-Amino-4-(4-(4-(4-chlorophenoxy)phenyl)-1 H -pyrazol-1-yl)butanoic acid (Example 28)

Intermediate 19 was deprotected similarly to Method G. Purification by flash column chromatography (0.1% aqueous TFA: MeCN, 9:1 to 0:1) on RP18 ceria to give the desired compound, which was suspended in a minimum amount of acetone and stored in Et ₂ O Treatment with HCl (2N, 1 mL, 2 mmol). The hydrochloride salt of Example 28 was collected by filtration and a pale yellow powder was obtained.

M/z = 372.2 [M+H] ⁺ , Rt = 3.08 min (UPLC-MS condition b), ¹ H NMR (400 MHz, MeOD- d ₄ ) δ=8.02 (s, 1H), 7.94 (s, 1H) , 7.60 (d, 2H), 7.36 (d, 2H), 7.04 (d, 2H), 7.00 (d, 2H), 4.45-4.60 (m, 2H), 4.04-4.11 (m, 1H), 2.77 (dd , 1H), 2.65 (dd, 1H) ppm.

Example 29 (S) -3- amino-4- (5- (4 - ((5-chloro-3-fluoropyridin-2-yl) oxy) phenyl) -2 H - tetrazol-2-yl) butyrate acid

Step A: ( S )-3-((Tertibutoxycarbonyl)amino)-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl) )-2 H -tetrazol-2-yl)butyric acid tert-butyl ester (5aa)

Intermediate 5aa was prepared from tetrazole 4c analogously to Method C and a colorless foam was obtained.

M/z = 549.3 [M+H] ⁺ , Rt = 6.26 min (UPLC-MS condition b), ¹ H NMR (400 MHz, DMSO- d ₆ ) δ=8.28 (dd, 1H), 8.10-8.14 (m, 2H), 8.09 (s, br, 1H), 7.41 (d, 2H), 7.01 (d, 1H), 4.85 (dd, 1H), 4.65 (dd, 1H), 4.27-4.36 (m, 1H), 2.63 (dd, 1H), 2.45 (dd, 1H), 1.40 (s, 9H), 1.25 (s, 9H) ppm, ¹⁹ F NMR (376 MHz, DMSO - d ₆ ) δ = -134.0 (d, 1F) ppm.

Step B :( S) -3- amino-4- (5- (4 - ((5-chloro-3-fluoropyridin-2-yl) oxy) phenyl) -2 H - tetrazol-2 Butyl acid (Example 29)

The intermediate 5aa was deprotected analogously to Method G to give the colorless powdery salt of Example 29 .

M/z = 393.1 [M+H] ⁺ , Rt = 2.47 min (UPLC-MS condition b), Rt = 14.85 min (HPLC conditions h), ¹ H NMR (400 MHz, MeOD- d ₄ ) δ = 8.24 (d) , 2H), 7.98 (d, 1H), 7.91 (dd, 1H), 7.36 (d, 2H), 5.17 (d, 2H), 4.25-4.34 (m, 1H), 2.96 (dd, 1H), 2.80 ( Dd, 1H) ppm, ¹⁹ F NMR (376 MHz, MeOD- d ₄ ) δ = 135.7 (d, 1F) ppm.

Biological part

The compound of formula (I) or a pharmaceutically acceptable salt thereof exhibits valuable pharmacological properties (e.g., properties sensitive to LTA4H), for example, as indicated in the tests provided in the next section, and thus Suitable for the treatment associated with LTA4H.

a) Human LTA4H enzyme analysis:

The leukotriene A4 hydrolase (LTA4H) catalyzes the epoxidation of epoxidized leukotriene A4 (LTA4) to become a pro-inflammatory mediator LTB4. LTA4H is also capable of catalyzing the hydrolysis of dipeptide and tripeptide substrates as well as the colorimetric 7-amino-4-methylcoumarin (AMC) derivatives of amino acids. AMC derivatives of arginine (Arg-AMC) as an alternative to the subject matter and is capable of LTA4H by monitoring the fluorescence intensity after the release of AMC is to measure the activity of the compound and the IC ₅₀ value.

For compound testing, the compounds were delivered in a media tube in 10 mM stock solution in 90% DMSO (10% water). Thus, a 1:5 dilution series was prepared in which the initial concentration of 10 mM was gradually reduced to 0.64 μM. For enzyme analysis, 0.5 μL of the compound solution was transferred to each well and 24.5 μL of assay buffer (50 mM Tris buffer, pH 7.5, 150 mM NaCl, 10 mM CaCl ₂ ) was added to the well, followed by addition of 25 μL of enzyme solution (36 nM human) LTA4H, in assay buffer). The enzyme compound mixture was incubated for 15 minutes at room temperature, after which 50 μL of the substrate solution was added. The final substrate concentration of 600 μM (which is approximately K _M value of Arg-AMC) was selected at a final enzyme concentration of 9 nM. Immediately after the addition of the substrate, the plate was placed in a fluorescence reader and the filter was used to set λ _excitation = 380 nm and λ _emission = 460 nm, and the fluorescence was measured every 10 minutes for 60 minutes. AMC at different concentrations (0.00128-100 μM) in the assay buffer was used as a standard curve. The raw data was converted to velocity (m/min) using an AMC calibration curve calculated from the AMC standard. In GraphPad Prism (GraphPad Software, Inc.), using nonlinear regression analysis to determine the data value ₅₀ of the IC LTA4H inhibitor.

Due to the analytical setup, the maximum detectable efficacy of the compound is approximately 2-3 nM. Therefore, a compound having an effect of theoretically producing an IC ₅₀ value of less than 2 nM is given by 2 nM (= the lower limit of the analysis). The efficacy of the tested compounds is shown in Table 1 (providing an average of at least 3 measurements).

b) Human whole blood analysis:

Compounds were tested in human whole blood assays (hWB) to test their ability to inhibit LTB4 biosynthesis in human cell systems. To this end, fresh blood was collected in a heparinized vacuum vessel by venipuncture from a volunteer. Blood was diluted 1:3 with RPMI (Roswell Park Memorial Institute) medium and 200 μL aliquots were transferred to 96-well round bottom cell culture plates. For compound testing, compounds were delivered in a media tube in 10 mM stock in 90% DMSO. Thus, a 1:4 series dilution was prepared in which the initial concentration of 250 μM was gradually reduced to 2.45 μM. 4 μL of the compound dilution or vehicle was added to 200 μL of blood and incubated at 37 ° C for 15 minutes in a humidification incubator. Then, the blood was stimulated with 10 μg/ml calcium ionophore A23187 (Sigma) or an equal volume of DMSO (control) and incubated for an additional 15 minutes at 37 ° C in a humidified incubator. The incubation was terminated by centrifugation at 300 g for 10 minutes at 22 °C. Plasma supernatants were removed and transferred to 96-well plates to determine eicosanoids by ELISA (Assay designs) after dilution at 1:20 in assay buffer according to the manufacturer's protocol. Using nonlinear regression in GraphPad Prism (GraphPad Software, Inc.) to determine the analytical data values ₅₀ of the IC LTA4H inhibitor. The efficacy of the test compounds is shown in Table 1.

c) Murine PD analysis:

The LTA4H inhibitor compound or vehicle control (30% PEG200 (70%), 5% dextrose) was applied orally ( po .) to female C57BL/6 mice (Charles River France) at a dose of 0.3 mg/kg. Three hours after the application of the compound, the mice were stopped from bleeding and blood was collected in a heparinized tube. The collected blood was diluted 1 :3 in RPMI medium, added to a 96-well round-bottomed cell culture plate, and placed in a humidified incubator at 37 ° C with 10 μg/ml calcium ionophore A23187 (Sigma) or an equal volume of DMSO ( Control) was incubated for 15 minutes. The incubation was terminated by centrifugation at 300 g for 10 minutes at 22 °C. Plasma supernatants were removed, diluted 1:10 in assay buffer and transferred to 96-well plates to determine eicosanoids by ELISA (Assay designs) according to the manufacturer's protocol. % inhibition of LTB4 release compared to vehicle control was calculated and is shown in Table 2 for test compounds. (For clarity: the larger the value in Table 2, the stronger the suppression)

application

The compounds of the invention are especially inhibitors of LTA4H-activity and are therefore useful in the treatment of diseases and conditions which are generally ameliorated by inhibition of LTA4H. Such diseases and conditions may include inflammatory conditions and autoimmune disorders as well as inflammation of the lungs and respiratory tract.

Thus, the compounds are useful in the treatment of acute or chronic inflammation, allergic reactions, allergic reactions, atopic dermatitis, psoriasis, acute respiratory distress syndrome, immune complex-mediated lung injury, and chronic obstructive pulmonary disease, Inflammatory bowel disease (including ulcerative colitis, Crohn's disease and post-operative trauma), gastrointestinal ulcers, neutrophilic skin disease (including but not limited to gangrenous pyoderma, Sweet Sweet's syndrome, severe acne and neutrophil urticaria, immune complex-mediated glomerulonephritis, autoimmune disease (including insulin-dependent diabetes, multiple sclerosis, class Rheumatoid arthritis, osteoarthritis and systemic lupus erythematosus), vasculitis (including but not limited to) cutaneous vasculitis, Behcets disease, and Henoch Schönlein Purpura )), cardiovascular disorders (including but not limited to hypertension, atherosclerosis, aneurysms, severe limb ischemia, peripheral arterial obstructive disease, pulmonary hypertension, and Raynaud's syndrome (Reynaud's) Syndrome)), sepsis, inflammatory and neuropathic pain (including arthritis pain), periodontal disease (including gingivitis), ear infection, migraine, benign prostatic hyperplasia, Sjogren-Larsson Syndrome And cancer (including but not limited to leukemia and lymphoma, prostate cancer, breast cancer, lung cancer, malignant melanoma, kidney cancer, head and neck cancer, and colorectal cancer).

The compounds of the invention are especially useful for the treatment of acute or chronic inflammation, especially autologous inflammatory conditions such as sterile neutrophil inflammatory conditions, inflammatory bowel diseases (including ulcerative colitis and Crohn's disease), neutrophils Spherical skin diseases (including gangrenous pyoderma and severe acne), vasculitis, rheumatoid arthritis, gout and cardiovascular disease.

combination

The compounds of the invention may be administered simultaneously with or before one or more other therapeutic agents Cast. The compounds of the invention may be administered separately by the same or different routes of administration, or together with other agents in the same pharmaceutical composition.

The compounds of the invention may be administered as the sole active ingredient or in combination with other drugs (e.g., as adjuvants), such as immunosuppressive or immunomodulatory agents or other anti-inflammatory agents, for example, for treatment or prevention. Allogeneic or xenograft acute or chronic rejection or an inflammatory or autoimmune disorder; or a chemotherapeutic agent (eg, a malignant antiproliferative agent).

For example, the compounds of the invention may be used in combination with: COX inhibitors, cysteamine-leukotriene receptor antagonists (including Montelukast, Pranlukast, Zaluzetast) (Zafirlukast)), leukotriene C4 synthase (LTC4S) inhibitor, statin, sulfasalazine, mesalamine, calcineurin inhibitor (eg cyclosporine) A (cyclosporin A) or FK 506); mTOR inhibitors, such as rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, belimolix-7 (biolimus- 7) or Bayerolimus-9; ascomycin with immunosuppressive properties, such as ABT-281, ASM981; corticosteroids; cyclophosphamide; azathioprene; (methotrexate); leflunomide; mizoribine; mycophenolic acid or salt; mycophenolate mofetil; IL-1β inhibitor.

The term "co-administration or combined administration" or the like as used herein is intended to encompass the administration of a selected therapeutic agent to a single patient, and is intended to include that such agents need not be administered by the same route of administration or at the same time. The treatment plan.

The term "pharmaceutical combination" as used herein means a product that results from the mixing or combination of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that the active ingredient (eg, a compound of formula (I)) and an adjuvant are both as a single entity or agent. The form of the dose is administered to the patient at the same time. The term "non-fixed combination" means that the active ingredient (eg, a compound of formula (I)) and an adjuvant are administered to a patient simultaneously, in parallel, or sequentially as separate entities without a specific time limit, wherein the administration is provided in the patient Two compounds that treat effective levels. The latter also applies to cocktail therapy, for example to three or more active ingredients.

In one embodiment, the invention provides a product comprising a compound of formula (I) and at least one additional therapeutic agent as a combined preparation for simultaneous, separate or sequential use in a therapy. In one embodiment, the therapy treats a disease or condition mediated by LTA4H. The product provided as a combined preparation comprises a composition comprising a compound of formula (I) and other therapeutic agents together in the same pharmaceutical composition, or a compound of formula (I) and other therapeutic agents in a separate form (for example in a kit).

In one embodiment, the invention provides a pharmaceutical composition comprising a compound of formula (I) and another therapeutic agent. Optionally, the pharmaceutical composition may comprise a pharmaceutically acceptable excipient, as set forth above.

In one embodiment, the invention provides a kit comprising two or more separate pharmaceutical compositions, wherein at least one pharmaceutical composition comprises a compound of formula (I). In one embodiment, the kit includes components that retain the compositions separately, such as a container, a split bottle, or a separate foil package. Examples of such a set are such as packaged tablets, capsules, and the like, which are commonly used in blister packs.

The kits of the invention can be used to administer different dosage forms (e.g., oral and parenteral) for administration of separate compositions at different dosage intervals, or for titration analysis of individual compositions. To aid compliance, the kits of the present invention typically contain instructions for administration.

Claims (20)

a compound of formula (I) or a pharmaceutically acceptable salt thereof, Wherein R1 is OH or NH ₂ ; Y is O, S or CH ₂ ; X ₁ , X ₂ , X ₃ and X ₄ are N; or X ₁ , X ₂ , X ₃ and X ₄ are selected from N, NH. , C, CH and O, provided that at least two of X ₁ , X ₂ , X ₃ or X ₄ are N or NH; R 2 is optionally substituted by phenyl C ₁ -C ₆ alkyl; C ₃ -C ₆ cycloalkyl; phenyl substituted as follows: halogen, cyano, C ₁ -C ₆ alkyl optionally substituted by halogen, C ₁ -C ₆ alkoxy or containing 1 to 3 a 5 to 6 membered heteroaryl ring of a hetero atom of N, O and S; or a 5 to 10 membered monocyclic or bicyclic heteroaryl group having 1 to 4 hetero atoms selected from N, O and S, The heteroaryl group is optionally substituted with a C ₁ -C ₆ alkyl group, a cyano group or a halogen which is optionally substituted by halogen; wherein the Y group is attached to the para or meta position of the phenyl moiety. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is OH or NH ₂ ; Y is O; X ₁ , X ₂ , X ₃ and X ₄ are selected from the group consisting of N, NH, C, CH and O. with the proviso lines X _1, X _2, X ₃ or X _{4 is} at least two lines of N or NH; and R2 substituents of the following substituted with phenyl visual system: halo, cyano, optionally halogen-substituted C ₁ of a C ₆ alkyl group, a C ₁ -C ₆ alkoxy group or a 5- to 6-membered heteroaryl ring containing 1 to 3 hetero atoms selected from N, O and S; or an R 2 system containing 1 to 4 a 5 to 10 membered monocyclic or bicyclic heteroaryl group of a hetero atom of N, O and S, which is optionally substituted by a halogen-substituted C ₁ -C ₆ alkyl group, a cyano group or a halogen . The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is OH or NH ₂ ; Y is CH ₂ ; X ₁ , X ₂ , X ₃ and X ₄ are N; and R 2 is optionally phenyl. Substituted C ₁ -C ₆ alkyl; or C ₃ -C ₆ cycloalkyl. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is a compound of formula (II), Wherein the variables R1, R2 and Y have the meanings as defined in claim 1. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is a compound of formula (III), Wherein the variables R1, R2 and Y have the meanings as defined in claim 1. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is a compound of formula (IV), Wherein the variables R1, R2 and Y have the meanings as defined in claim 1. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is a compound of formula (V); Wherein the variables R1, R2 and Y have the meanings as defined in claim 1. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein R1 is OH; Y is O; and R2 is phenyl substituted as follows: halogen, C ₁ -C ₆ alkyl, C ₁ -C _{a 6} alkoxy group; or a 5 to 10 membered monocyclic or bicyclic heteroaryl group having 1 to 4 hetero atoms selected from N, O and S, which heteroaryl group is optionally substituted by halogen substitution as appropriate C ₁ -C ₆ alkyl, cyano or halogen. A compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein R1 is OH; Y is O; and R2 is a pyridyl ring optionally substituted by a cyano group or a halogen. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: ( R )-3-amino-4-(5-(4-(benzo[ d ]thiazol-2-yl) oxy) phenyl) -2 H - tetrazol-2-yl) butanoic acid; (R) -3- amino-4- (5- (4 - ((5-chloro-pyridin-2-yl) oxy ) phenyl) -2 H - tetrazol-2-yl) butanoic acid; (R & lt) -3- amino-4- (5- (4 - ((5-chloro-3-fluoropyridin-2-yl) oxy) phenyl) -2 H - tetrazol-2-yl) butanoic acid; (R) -3- amino-4- (5- (4- (4- (oxazol-2-yl) - benzene oxy) phenyl) -2 H - tetrazol-2-yl) - butanoic acid; (R) -3- amino-4- (5- (3- (4-chlorophenoxy) phenyl) - 2 H -tetrazol-2-yl)butyric acid; ( R )-3-amino-4-(5-(4-(4-chlorophenoxy)-phenyl)-2 H -tetrazole-2 - yl) butanoic acid; (R) -3- amino-4- (5- (4- (4-fluorophenoxy) - phenyl) -2 H - tetrazol-2-yl) butanoic acid; ( R) -3- amino-4- (5- (4- (3-chloro-4-fluorophenoxy) phenyl) -2 H - tetrazol-2-yl) butanoic acid; (R) -3 - amino-4- (5- (4- (p-tolyloxy) phenyl) -2 H - tetrazol-2-yl) butanoic acid; (S) -3- amino-4- (5- (3-phenoxyphenyl) -2 H - tetrazol-2-yl) butanoic acid; (S) -3- amino-4- (5- (4- (benzo [d] thiazol-2 yloxy) phenyl) -2 H - tetrazol-2-yl) butanoic acid; (S) -3- amino-4- (5- ( 4- (4-chlorophenoxy) - phenyl) -2 H - tetrazol-2-yl) butanoic acid; (R) -3- amino-4- (5- (3-phenethyloxy-phenyl yl) -2 H - tetrazol-2-yl) butanoic acid; (R) -3- amino-4- (5- (4-phenethyloxy-phenyl) -2 H - tetrazol-2-yl ) butanoic acid; (R) -3- amino-4- (5- (4- (benzyloxy) phenyl) -2 H - tetrazol-2-yl) butanoic acid; (R) -3- amino-4- (5- (3- (benzyloxy) phenyl) -2 H - tetrazol-2-yl) butanoic acid; (R) -3- amino-4- (5- (4 - butoxyphenyl) -2 H - tetrazol-2-yl) butanoic acid; (R) -3- amino-4- (5- (4- (pentyloxy) phenyl) -2 H -tetrazol-2-yl)butyric acid; ( R )-3-amino-4-(5-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl) -2 H -tetrazol-2-yl)butyric acid; ( R )-3-amino-4-(5-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)) phenyl) -2 H - tetrazol-2-yl) butanoic acid; (R) -3- amino-4- (5- (3- (benzo [d] thiazol-2-yloxy) phenyl ) -2 H - tetrazol-2-yl) butanoic acid; (R) -3- amino-4- (5- (3- (3,5-difluorophenoxy) phenyl) -2 H - Tetrazol-2-yl)butyric acid; ( S )-3-amino-4-(5-(4-(p-tolyloxy)phenyl)-2 H -tetrazol-2-yl)butyric acid ( R )-3-amino-4-(5-(4-(4-fluorophenoxy)phenyl)-1,3,4-oxadiazol-2-yl)butyric acid; ( R ) -3 -amino-4-(5-(4-(4-chlorophenoxy)phenyl)-1,3,4-oxadiazol-2-yl)butyric acid; ( R )-3-amino- 4-(3-(4-(4-chlorophenoxy)phenyl)-1,2,4-oxadiazol-5-yl)butyric acid; ( R )-3-amino-4-(3) -(4-(4-chlorophenoxy)phenyl)-1,2,4-oxadiazol-5-yl)butanamine; ( S )-3-amino-4-(4-(4) -(4-chlorophenoxy)phenyl)-1 H -pyrazol-1-yl)butyric acid; and ( S )-3-amino-4-(5-(4-((5-chloro-)- 3-fluoro-2-yl) oxy) phenyl) -2 H - tetrazol-2-yl) butanoic acid. The compound of claim 10, wherein the compound is ( S )-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)), or a pharmaceutically acceptable salt thereof Oxy)phenyl)-2 H -tetrazol-2-yl)butanoic acid. The request entry acceptable compound or a pharmaceutically salt of 10, wherein the compound is (R) -3- amino-4- (5- (4-phenethyloxy-phenyl) -2 H - tetrazole - 2-based) butyric acid. The compound of claim 10, wherein the compound is ( R )-3-amino-4-(5-(4-(4-chlorophenoxy)-phenyl)-2, or a pharmaceutically acceptable salt thereof H -tetrazol-2-yl)butyric acid. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers Agent. A combination comprising a therapeutically effective amount of a compound of any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof and one or more therapeutic active agents. A use of a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament, wherein the medicament is for regulating LTA4H activity in an individual. A use of a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament, wherein the medicament is for treating a disease or condition which is ameliorated by inhibiting LTA4H activity in an individual, wherein The disease and condition are selected from the following: acute or chronic inflammation, allergic reaction, atopic dermatitis, psoriasis, acute respiratory distress syndrome, immune complex-mediated lung injury and chronic obstructive pulmonary disease, inflammatory bowel disease, gastrointestinal Ulcer, neutrophilic dermatosis, immune complex-mediated glomerulonephritis, autoimmune disease, vasculitis, cardiovascular disease, sepsis, inflammatory and neuropathic pain including arthritic pain, periodontal disease Disease, ear infections, migraine, benign prostatic hyperplasia, Sjogren-Larsson Syndrome and cancer. The use of claim 17, wherein the disease and condition to be treated is a cardiovascular disease selected from the group consisting of atherosclerosis, myocardial infarction, and stroke. The use of claim 17, wherein the disease and condition to be treated is a neutrophil selected from the group consisting of gangrenous pyoderma, Sweet's syndrome, severe acne, and neutrophil urticaria. skin disease. The use of claim 17, wherein the disease and condition to be treated is an inflammatory bowel disease selected from the group consisting of ulcerative colitis and Crohn's disease.