HK1161261B

HK1161261B - 3-aminocyclopentanecarboxamides as chemokine receptor modulators

Info

Publication number: HK1161261B
Application number: HK12102079.6A
Authority: HK
Inventors: R‧V‧德弗拉耶; W‧黄; R‧O‧休斯; D‧J‧小罗吉尔; J‧I‧特鲁吉罗; S‧R‧特纳
Original assignee: 辉瑞大药厂
Priority date: 2008-11-26
Filing date: 2009-11-20
Publication date: 2015-05-15

Description

3-aminocyclopentanecarboxamides as chemokine receptor modulators

This application claims the benefit of U.S. provisional application No. 61/118,053 filed on 26.11.2008.

Technical Field

The present invention relates to compounds that modulate the activity of chemokine receptors, such as CCR2 and CCR 5. The compounds may be used, for example, in the treatment of diseases associated with chemokine receptor expression or activity.

Background

The migration and transport of leukocytes from blood vessels to diseased tissues is involved in the initiation of the normal inflammatory response against the disease. This process (also known as leukocyte recruitment) is also involved in the onset and progression of inflammatory and autoimmune diseases. The pathology caused by these diseases results from the body's immune system defenses against attacks on normal tissues. Thus, preventing and blocking leukocyte recruitment to target tissues in inflammatory, autoimmune diseases and cancer is an effective approach to therapeutic intervention.

Infiltration of monocytes/macrophages into sites of inflammation is associated with proteins such as monocyte chemoattractant protein-1 (MCP-1, CCL 2). Macrophages produce chemokines, such as macrophage inflammatory protein-1-beta (MIP-1 beta, CCL 4). Such proteins interact with chemokine receptors such as CCR2 and CCR 5. Modulation (such as antagonism or inhibition) of CCR2 or CCR5 is useful in the treatment of a variety of diseases.

The identification of compounds that modulate chemokine receptor activity represents an ideal drug design for the development of pharmacological agents for the treatment of diseases associated with chemokine receptor activity. The compounds of the present invention help fulfill these and other needs.

Disclosure of Invention

In one embodiment of the invention, there is provided a compound of formula i (a) or i (b):

or a pharmaceutically acceptable salt thereof, wherein:

a is O or CF₂；

W is CR¹³R¹⁴、C(O)、CHOR¹⁵、CHF、CF₂O or S

R¹Is H or C optionally substituted with 1-3 substituents_1-6An alkyl group, the substituents selected from: halogen, OH, CO₂H、CO₂-(C_1-6Alkyl) or C_1-3An alkoxy group;

R²and R³Each independently is H, (C)₁-C₆) Alkyl, (C)₁-C₆) Haloalkyl, halogen, (C)₃-C₆) Cycloalkyl, CN, OH, CO₂R、OCOR¹²(ii) a Wherein said (C)₁-C₆) Alkyl is optionally substituted with one or more substituents selected from: F. (C)₁-C₃) Alkoxy, OH, CN or CO₂R¹²；

R⁸And R⁹Each independently is H, (C)₁-C₆) Alkyl, (C)₁-C₆) Haloalkyl, (C)₃-C₆) Cycloalkyl group, (C)₃-C₆) Cycloalkoxy (cycloakyloxy), CN, OH, CO₂R、OCOR¹²(ii) a Wherein said (C)₁-C₆) Alkyl is optionally substituted with one or more substituents selected from: F. (C)₁-C₃) Alkoxy, OH, CN or CO₂R¹²；

R²And R⁹Together may form a 5-8 membered ring;

R⁴and R⁷Together may form a 5-8 membered ring;

R⁴and R⁵Each independently H, CN, (C)₁-C₆) Alkyl, halogen, (C)₁-C₃) Alkoxy group, (C)₁-C₃) Haloalkoxy, (C)₃-C₆) Cycloalkyl, OH, CO₂R¹²、OCOR¹²Wherein said (C)₁-C₆) Alkyl is optionally substituted by one or moreSubstituted with a substituent selected from: F. (C)₁-C₃) Alkoxy, OH or CO₂R¹²；

R⁶And R⁷Each independently H, CN, (C)₁-C₆) Alkyl, halogen, (C)₁-C₃) Alkoxy group, (C)₁-C₃) Haloalkoxy, (C)₃-C₆) Cycloalkyl, OH, CO₂R¹²、OCOR¹²Wherein said (C)₁-C₆) Alkyl is optionally substituted with one or more substituents selected from: F. (C)₁-C₃) Alkoxy, OH or CO₂R¹²；

Or R²And R³Together with the carbon atom to which they are attached form a 3-7 membered spirocyclic group;

or R⁴And R⁵Together with the carbon atom to which they are attached form a 4-7 membered spirocyclic group;

or R³And R⁴Together with the C atom to which they are attached form a fused 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl group;

R¹⁰is (C)₁-C₆) Alkyl, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Hydroxyalkyl group, (C)₁-C₆) Alkoxy group, (C)₃-C₆) Cycloalkyl, hydroxy (C)₃-C₆) Cycloalkyl group, (C)₁-C₆) Alkoxycycloalkyl, OH, (C)₁-C₅) Heterocyclyl, amino, aryl or CN,

R¹¹is aryl or heteroaryl, said R¹¹Optionally independently substituted with one or more of the following substituents: (C)₁-C₆) Alkyl, halogen, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Alkoxy, OH, amino, C (O) NH₂、NH₂SO₂、SF₅Or CN;

R¹²is H, (C)₁-C₄) Alkyl or (C)₃-C₆) A cycloalkyl group;

R¹³is H, halogen, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy or OH;

R¹⁴is H, halogen, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy or OH; and is

R¹⁵Is H, (C)₁-C₆) Alkyl or (C)₃-C₆) A cycloalkyl group.

Detailed description of the preferred embodiments

These inventions are not limited to the embodiments described in the present specification and may be modified.

A. Definition of

For the following defined terms, these definitions shall apply, unless a different definition is given in the claims or elsewhere in this specification.

The term aryl is intended to include aromatic carbocyclic groups such as phenyl, biphenyl, indenyl, naphthyl, as well as aromatic carbocyclic rings fused to a heterocycle such as benzothienyl, benzofuranyl, indolyl, quinolinyl, benzothiazolylOxazoles, benzimidazoles, isoquinolines, isoindolyl, benzotriazoles, indazoles, and acridinyl groups.

The term heteroaryl includes mono-and polycyclic aromatic rings containing from 3 to 20, or from 4 to 10 ring atoms, at least one of which is a heteroatom such as oxygen, sulfur, phosphorus or nitrogen. Examples of such groups include furyl, thienyl, pyrrolyl, imidazolyl, triazolyl, thiazolyl, tetrazolyl, triazolyl,Azolyl radical, isoAzolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolinyl, isoquinolinyl, quinoxalinyl, benzothiazolyl, benzolAzolyl, benzothienyl, or benzofuranyl.

The term "cycloalkyl" denotes cyclized hydrocarbons (both monocyclic and polycyclic), such as cyclized alkyl, alkenyl or alkynyl groups. In some embodiments, cycloalkyl is C_3-14、C_3-10、C_3-8、C_3-7、C_3-6Or C_3-5. In some embodiments, the cycloalkyl moieties each have 3 to 14, 3 to 10, or 3 to 6 ring-forming carbon atoms. In some embodiments, the cycloalkyl group has 0, 1, or 2 double or triple bonds. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl and the like. In this application, cycloalkyl is also intended to include bridged cyclic hydrocarbons such as adamantyl and the like.

Heterocycles are carbocycles (monocyclic or polycyclic) that include one or more heteroatoms, such as nitrogen, oxygen, or sulfur, in the ring. In some embodiments, the heterocyclic ring contains 3-8 ring members. In some embodiments, the heterocyclic ring contains 3-6 ring members. In some embodiments, the heterocyclic ring contains 1, 2, or 3 heteroatoms. The heterocyclic ring may be saturated or unsaturated. In some embodiments, the heterocyclic ring contains 0, 1 or 2 double or triple bonds. The ring-forming carbon atoms and heteroatoms may also carry oxo or sulphide substituents (e.g. CO, CS, SO)₂NO, etc.). Examples of heterocycles include tetrahydrofuranyl, tetrahydrothienyl, morpholino, thiomorpholino, azetidinyl, pyrrolidinyl, piperazinyl, piperidinyl, pyrane, diazacycloAlkyl anda thiazolidinyl group.

Monosubstituted aryl refers to an aryl group having one substituent. The polysubstituted aryl group means an aryl group having two or more substituents (for example, 2 to 4 substituents). Monosubstituted heteroaryl refers to heteroaryl having one substituent. Polysubstituted heteroaryl means heteroaryl having two or more substituents (e.g., 2 to 4 substituents). Monosubstituted cycloalkyl (or carbocycle) refers to a cycloalkyl group having one substituent. Polysubstituted cycloalkyl (or carbocycle) means cycloalkyl having two or more substituents, for example 2 to 4 substituents. Monosubstituted heterocyclic refers to a heterocyclic ring having one substituent. Polysubstituted heterocycle means a heterocycle having two or more substituents (e.g., 2 to 4 substituents).

The term halogen by itself or as part of another substituent means fluorine, chlorine, bromine or iodine unless otherwise stated. Similarly, terms such as haloalkyl are meant to include monohaloalkyl and polyhaloalkyl. For example, the term haloalkyl, such as halo (C)₁-C₄) Alkyl, is meant to include trifluoromethyl, 2,2, 2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

The term alkyl, used alone or as a suffix, includes both straight-chain and branched (branched) structures, such as primary, secondary and tertiary alkyl groups. These groups may contain up to 15, or up to 8, or up to 4 carbon atoms. In some embodiments, alkyl is C_1-10、C_1-8、C_1-6、C_1-5、C_1-4Or C_1-3. Examples of the alkyl radical include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl and sec-butyl. Similarly, the terms alkenyl and alkynyl refer to unsaturated straight or branched chain structures containing, for example, 2 to 12, or 2 to 6 carbon atoms. In some embodiments, alkenyl or alkynyl is C_2-10、C_2-8、C_2-6、C_2-5、C_2-4Or C_2-3. Examples of alkenyl and alkynyl groups include ethenyl, 2-propenyl, crotyl, 2-isopentenyl, 2- (butadienyl),2, 4-pentadienyl, 3- (1, 4-pentadienyl), ethynyl, 1-and 3-propynyl, 3-butynyl and the higher homologs and isomers.

The term "carrier" describes an ingredient other than a cation exchanger. The carrier may be a pharmaceutically acceptable substance or vehicle. Examples include liquid or solid fillers, diluents, excipients, solvents or encapsulating materials.

The phrase "contacting a chemokine receptor" refers to contacting a chemokine receptor in vivo, ex vivo or in vitro, and includes administering a compound or salt of the invention to a subject having a chemokine receptor, and, for example, introducing a compound or salt of the invention into a sample containing an unpurified or purified preparation of cells comprising a chemokine receptor. For example, contacting includes an interaction, such as binding, between the compound and the receptor.

The term "subject" means any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, primates, or humans.

The term "treatment" (and corresponding terms "treat" and "treatment") includes palliative (palliative), restorative, or prophylactic ("prophylactic") treatment of a subject. The term "palliative treatment" refers to a treatment that reduces or diminishes the effect or intensity of a disorder in a subject without curing the disorder. The term "prophylactic treatment" (and the corresponding term "prophylactic treatment") refers to a treatment that prevents the occurrence of a disorder in a subject. The term "restorative therapy" ("cured") refers to a treatment that stops the progression of a disorder in a subject, reduces the pathological manifestations of the disorder, or completely eliminates the disorder. Treatment may be effected as follows: using a therapeutically effective amount of a compound, salt or composition that elicits a biological or medical response in a tissue, system or subject that is being sought by an individual, such as a researcher, physician, veterinarian, or clinician.

B. Compound (I)

In one embodiment of the invention, there is provided a compound of i (a) or i (b):

or a pharmaceutically acceptable salt thereof, wherein:

a is O or CF₂；

W is CR¹³R¹⁴、C(O)、CHOR¹⁵、CHF、CF₂O or S

R⁸And R⁹Each independently is H, (C)₁-C₆) Alkyl, (C)₁-C₆) Haloalkyl, (C)₃-C₆) Cycloalkyl, CN, OH, CO₂R、OCOR¹²(ii) a Wherein said (C)₁-C₆) Alkyl is optionally substituted with one or more substituents selected from: F. (C)₁-C₃) Alkoxy, OH, CN or CO₂R¹²；

R²And R⁹Together may form a 5-8 membered ring;

R⁴and R⁷Together may form a 5-8 membered ring;

R⁴and R⁵Each independently H, CN, (C)₁-C₆) Alkyl, halogen, (C)₁-C₃) Alkoxy group, (C)₁-C₃) Haloalkoxy, (C)₃-C₆) Cycloalkyl, OH, CO₂R¹²、OCOR¹²Wherein said (C)₁-C₆) Alkyl is optionally substituted with one or more substituents selected from: F. c_1-3Alkoxy, OH or CO₂R¹²；

or R⁴And R⁵Together with the carbon atom to which they are attached form a 3-7 membered spirocyclic group;

R¹⁰is (C)₁-C₆) Alkyl, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Hydroxyalkyl group, (C)₁-C₆) Alkoxy group, (C)₃-C₆) Cycloalkyl, hydroxy (C)₃-C₆) Cycloalkyl, alkoxycycloalkyl, OH, (C)₁-C₅) Heterocyclic radicalAn amino group, an aryl group or CN,

R¹¹is aryl or heteroaryl, said R¹¹Optionally independently substituted with one or more of the following substituents: (C)₁-C₆) Alkyl, halogen, (C)₁C₆) Haloalkyl (C)₁-C₆) Alkoxy, OH, amino, C (O) NH₂、NH₂SO₂、SF₅Or CN;

R¹²is H, (C)₁-C₄) Alkyl or (C)₃-C₆) A cycloalkyl group;

R¹³is H, halogen, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy or OH;

R¹⁴is H, halogen, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy or OH; and is

R¹⁵Is H, (C)₁-C₆) Alkyl or (C)₃-C₆) A cycloalkyl group.

In another embodiment of the present invention, there is provided a compound of formula II:

or a pharmaceutically acceptable salt thereof, wherein:

R¹is H, (C)₁-C₆) Alkyl or cyclopropyl group, (C)₁-C₆) Alkyl is optionally substituted with halogen, CN, C (O) OH or OH;

R²is (C)₁-C₆) Alkyl, (C)₁-C₆) Haloalkyl or (C)₃-C₆) A cycloalkyl group;

R³ R⁴、R⁵、R⁶、R⁷、R⁸and R⁹Independently H, (C)₁-C₄) Alkyl, CN, halogen or amino;

R¹⁰is (C)₁-C₆) Alkyl, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Hydroxyalkyl group, (C)₁-C₆) Alkoxy group, (C)₃-C₆) Cycloalkyl, hydroxy (C)₃-C₆) Cycloalkyl, alkoxy (C)₃-C₆) Cycloalkyl, OH, (C)₁-C₅) Heterocyclyl, amino, aryl or CN;

R¹¹is aryl or heteroaryl, said R¹¹Optionally independently substituted with one or more of the following substituents: (C)₁-C₆) Alkyl, halogen, (C)₁-C₆) Haloalkyl (C)₁-C₆) Alkoxy, OH, amino, C (O) NH₂、NH₂SO₂、SF₅Or CN;

w is CR¹³R¹⁴、C(O)、CHOR¹⁵、CHF、CF₂O or S;

R¹³and R¹⁴Independently H, halogen, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy or OH; and is

R¹⁵Is H, (C)₁-C₆) Alkyl or (C)₃-C₆) A cycloalkyl group.

In another embodiment, there is provided a compound of formula II, or a pharmaceutically acceptable salt thereof, wherein:

R¹is H or (C)₁-C₆) Alkyl radical

R²Is (C)₁-C₆) Alkyl or (C)₁-C₆) Haloalkyl group

R³、R⁴、R⁵、R⁶、R⁷、R⁸And R⁹Each is H;

R¹¹is that

Or

Wherein X, Y, Z, Q and D are independently N or CR¹⁶And wherein 0, 1, 2 or 3 of X, Y, Z, Q and D are N; and is

Wherein T, U and V are independently selected from CH, N, S, or O, provided that T and U are not both O or S;

each R¹⁶Independently H, halogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Alkoxy or CN;

R¹⁷is H, (C)₁-C₆) Alkyl, (C)₁-C₆) Haloalkyl or (C)₁-C₆) An alkoxy group; and is

W is CR¹³R¹⁴、C(O)、CHOR¹⁵CHF or CF₂。

In some embodiments of the compound of formula II or a pharmaceutically acceptable salt thereof, R²Is methyl.

In some embodiments of the compound of formula II or a pharmaceutically acceptable salt thereof,

R²is methyl;

R³ R⁴、R⁵、R⁶、R⁷、R⁸and R⁹Independently is H, C₁-C₄Alkyl, CN, halogen or amino;

w is CR¹³R¹⁴、C(O)、CHOR¹⁵、CHF、CF₂O or S;

R¹⁵Is H, (C)₁-C₆) Alkyl or (C)₃-C₆) A cycloalkyl group.

In some embodiments of the compound of formula II or a pharmaceutically acceptable salt thereof, R¹⁰Is that

Wherein R is¹⁸Is H or (C)₁-C₆) An alkyl group.

R²is methyl;

R¹⁰is that

w is CR¹³R¹⁴、C(O)、CHOR¹⁵、CHF、CF₂O or S;

R¹³and R¹⁴Independently is H halogen, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy or OH;

R¹⁵is H, (C)₁-C₆) Alkyl or(C₃-C₆) A cycloalkyl group; and is

R¹⁸Is H or (C)₁-C₆) An alkyl group.

In some embodiments of the present invention, there are provided compounds of formula II or pharmaceutically acceptable salts thereof, wherein R¹¹Is that

OrWherein R is¹⁸Is H or (C)₁-C₆) An alkyl group.

In some embodiments of the present invention, there is provided a compound of formula II or a pharmaceutically acceptable salt thereof, wherein

R²is methyl;

R³R⁴、R⁵、R⁶、R⁷、R⁸and R⁹Independently is H, C₁-C₄Alkyl, CN, halogen or amino;

R¹⁰is that

R¹¹Is that

OrWherein R is¹⁸Is H or (C)₁-C₆) An alkyl group;

w is CR¹³R¹⁴、C(O)、CHOR¹⁵、CHF、CF₂O or S;

R¹⁵Is H, (C)₁-C₆) Alkyl or (C)₃-C₆) A cycloalkyl group.

In some embodiments, there is provided a compound of formula II or a pharmaceutically acceptable salt thereof, wherein

R¹⁰Is that

OrAnd is

R¹¹Is thatOr

R¹Is H;

R²is methyl;

R³ R⁴、R⁵、R⁶、R⁷、R⁸and R⁹Each is H;

R¹⁰is that

Or

R¹¹Is thatOrAnd is

W is CH₂。

In another embodiment, there is provided a compound selected from the group consisting of:

1, 5-anhydro (anhydro) -2, 3-dideoxy-3- { [ (1R,3S) -3-ethyl-3- ({ (1S,4S) -5- [4- (trifluoromethyl) pyridin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro (erythro) -pentitol (pentitol);

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3-ethyl-3- ({ (1S,4S) -5- [4- (trifluoromethyl) pyrimidin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol;

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3-ethyl-3- ({ (1S,4S) -5- [6- (trifluoromethyl) pyrimidin-4-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol;

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3-ethyl-3- ({ (1S,4S) -5- [6- (trifluoromethyl) pyrazin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol;

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3-ethyl-3- ({ (1S,4S) -5- [2- (trifluoromethyl) pyrimidin-4-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol;

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3-ethyl-3- ({ (1S,4S) -5- [6- (trifluoromethyl) pyridin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol;

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3-ethyl-3- ({ (1S,4S) -5- [2- (trifluoromethyl) pyridin-4-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol;

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3-ethyl-3- ({ (1S,4S) -5- [ 3-fluoro-4- (trifluoromethyl) pyridin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol;

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3-methyl-3- ({ (1S,4S) -5- [4- (trifluoromethyl) pyridin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol;

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3-methyl-3- ({ (1S,4S) -5- [6- (trifluoromethyl) pyrazin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol;

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3-isopropyl-3- ({ (1S,4S) -5- [4- (trifluoromethyl) pyridin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol;

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3-isopropyl-3- ({ (1S,4S) -5- [4- (trifluoromethyl) pyrimidin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol;

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3-isopropyl-3- ({ (1S,4S) -5- [6- (trifluoromethyl) pyrimidin-4-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol;

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3-isopropyl-3- ({ (1S,4S) -5- [6- (trifluoromethyl) pyrazin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol;

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3-isopropyl-3- ({ (1S,4S) -5- [2- (trifluoromethyl) pyrimidin-4-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol;

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3-isopropyl-3- ({ (1S,4S) -5- [6- (trifluoromethyl) pyridin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol;

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3-isopropyl-3- ({ (1S,4S) -5- [2- (trifluoromethyl) pyridin-4-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol;

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3-isopropyl-3- ({ (1S,4S) -5- [5- (trifluoromethyl) pyridazin-3-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol;

1, 5-anhydro-3- { [ (1R,3S) -3-isopropyl-3- ({ (1S,4S) -5- [2, 6-bis (trifluoromethyl) pyridin-4-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) -3-isopropylcyclopentyl ] amino } -2, 3-dideoxy-4-O-methyl-D-erythro-pentitol;

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3- ({ (1S,4S) -5- [ 3-fluoro-4- (trifluoromethyl) pyridin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) -3-isopropylcyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol;

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3-isopropyl-3- ({ (1S,4S) -5- [ 6-methyl-4- (trifluoromethyl) pyridin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol;

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3-isopropyl-3- ({ (1S,4S) -5- [3- (trifluoromethyl) phenyl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol;

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3- ({ (1S,4S) -5- [ 3-fluoro-5- (trifluoromethyl) phenyl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) -3-isopropylcyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol;

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3- (2, 2-difluoroethyl) -3- ({ (1S,4S) -5- [6- (trifluoromethyl) pyrimidin-4-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol;

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3- (2, 2-difluoroethyl) -3- ({ (1S,4S) -5- [4- (trifluoromethyl) pyridin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol;

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3- (2, 2-difluoroethyl) -3- ({ (1S,4S) -5- [2- (trifluoromethyl) pyridin-4-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol;

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3- (2, 2-difluoroethyl) -3- ({ (1S,4S) -5- [4- (trifluoromethyl) pyrimidin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3- (2, 2-difluoroethyl) -3- ({ (1S,4S) -5- [6- (trifluoromethyl) pyridin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol;

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3- (2, 2-difluoroethyl) -3- ({ (1S,4S) -5- [6- (trifluoromethyl) pyrazin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol;

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3- (2, 2-difluoroethyl) -3- ({ (1S,4S) -5- [2- (trifluoromethyl) pyrimidin-4-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol;

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3- (2, 2-difluoroethyl) -3- ({ (1S,4S) -5- [5- (trifluoromethyl) pyridazin-3-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol;

1, 5-anhydro-2, 3-dideoxy-4-O-methyl-3- { [ (1R,3S) -3- (2,2, 2-trifluoroethyl) -3- ({ (1S,4S) -5- [6- (trifluoromethyl) pyrimidin-4-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -D-erythro-pentitol;

1, 5-anhydro-2, 3-dideoxy-4-O-methyl-3- { [ (1R,3S) -3- (2,2, 2-trifluoroethyl) -3- ({ (1S,4S) -5- [4- (trifluoromethyl) pyridin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -D-erythro-pentitol (pentit);

1, 5-anhydro-2, 3-dideoxy-4-O-methyl-3- { [ (1R,3S) -3- (2,2, 2-trifluoroethyl) -3- ({ (1S,4S) -5- [2- (trifluoromethyl) pyridin-4-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -D-erythro-pentitol;

1, 5-anhydro-2, 3-dideoxy-4-O-methyl-3- { [ (1R,3S) -3- (2,2, 2-trifluoroethyl) -3- ({ (1S,4S) -5- [4- (trifluoromethyl) pyrimidin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -D-erythro-pentitol;

1, 5-anhydro-2, 3-dideoxy-4-O-methyl-3- { [ (1R,3S) -3- (2,2, 2-trifluoroethyl) -3- ({ (1S,4S) -5- [6- (trifluoromethyl) pyridin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -D-erythro-pentitol;

1, 5-anhydro-2, 3-dideoxy-4-O-methyl-3- { [ (1R,3S) -3- (2,2, 2-trifluoroethyl) -3- ({ (1S,4S) -5- [6- (trifluoromethyl) pyrazin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -D-erythro-pentitol;

1, 5-anhydro-2, 3-dideoxy-4-O-methyl-3- { [ (1R,3S) -3- (2,2, 2-trifluoroethyl) -3- ({ (1S,4S) -5- [2- (trifluoromethyl) pyrimidin-4-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -D-erythro-pentitol

1, 5-anhydro-2, 3-dideoxy-4-O-methyl-3- { [ (1R,3S) -3- (2,2, 2-trifluoroethyl) -3- ({ (1S,4S) -5- [5- (trifluoromethyl) pyridazin-3-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -D-erythro-pentitol;

1, 5-anhydro-2, 3-dideoxy-3- { [ (1S,4S) -4-isopropyl (isopropylll) -4- ({ (1S,4S) -5- [4- (trifluoromethyl) pyridin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopent-2-en-1-yl ] amino } -4-O-methyl-D-erythro-pentitol;

1, 5-anhydro-2, 3-dideoxy-3- { [ (1S,4S) -4-isopropyl-4- ({ (1S,4S) -5- [4- (trifluoromethyl) pyrimidin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopent-2-en-1-yl ] amino } -4-O-methyl-D-erythro-pentitol;

1, 5-anhydro-2, 3-dideoxy-3- { [ (1S,4S) -4-isopropyl-4- ({ (1S,4S) -5- [6- (trifluoromethyl) pyridin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopent-2-en-1-yl ] amino } -4-O-methyl-D-erythro-pentitol;

1, 5-anhydro-2, 3-dideoxy-3- { [ (1S,4S) -4-isopropyl-4- ({ (1S,4S) -5- [6- (trifluoromethyl) pyrazin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopent-2-en-1-yl ] amino } -4-O-methyl-D-erythro-pentitol;

1, 5-anhydro-3- { [ (1R,3S) -3- { [ (1S,4S) -5- (tert-butoxycarbonyl) -2, 5-diazabicyclo [2.2.1] hept-2-yl ] carbonyl } -3-ethylcyclopentyl ] amino } -2, 3-dideoxy-4-O-methyl-D-erythro-pentitol;

1, 5-anhydro-3- { [ (1R,3S) -3- { [ (1S,4S) -5- (tert-butoxycarbonyl) -2, 5-diazabicyclo [2.2.1] hept-2-yl ] carbonyl } -3- (2,2, 2-trifluoroethyl) cyclopentyl ] amino } -2, 3-dideoxy-4-O-methyl-D-erythro-pentitol;

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3- (1-hydroxycyclobutyl) -3- ({ (1S,4S) -5- [6- (trifluoromethyl) pyridin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol;

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3- (1-hydroxycyclobutyl) -3- ({ (1S,4S) -5- [4- (trifluoromethyl) pyridin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol;

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3- (1-hydroxycyclobutyl) -3- ({ (1S,4S) -5- [4- (trifluoromethyl) pyrimidin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol;

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3- (1-hydroxycyclobutyl) -3- ({ (1S,4S) -5- [2- (trifluoromethyl) pyrimidin-4-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3- (1-hydroxycyclobutyl) -3- ({ (1S,4S) -5- [6- (trifluoromethyl) pyrimidin-4-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol;

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3- (1-hydroxycyclobutyl) -3- ({ (1S,4S) -5- [6- (trifluoromethyl) pyrazin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol;

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3- (1-hydroxycyclobutyl) -3- ({ (1S,4S) -5- [2- (trifluoromethyl) pyridin-4-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol;

1, 5-anhydro-2, 3-dideoxy-3- { [3- (1-hydroxy-1-methylethyl) -3- ({5- [4- (trifluoromethyl) pyridin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methylpentanol;

1, 5-anhydro-2, 3-dideoxy-3- { [3- (1-hydroxy-1-methylethyl) -3- ({5- [6- (trifluoromethyl) pyrimidin-4-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methylpentanol;

1, 5-anhydro-2, 3-dideoxy-3- { [3- (1-hydroxy-1-methylethyl) -3- ({5- [4- (trifluoromethyl) pyrimidin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methylpentanol;

1, 5-anhydro-2, 3-dideoxy-3- { [3- (1-hydroxy-1-methylethyl) -3- ({5- [5- (trifluoromethyl) pyridazin-3-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methylpentanol;

1, 5-anhydro-2, 3-dideoxy-3- { [3- (1-hydroxy-1-methylethyl) -3- ({5- [2- (trifluoromethyl) pyrimidin-4-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methylpentanol;

1, 5-anhydro-2, 3-dideoxy-3- { [3- (1-hydroxy-1-methylethyl) -3- ({5- [6- (trifluoromethyl) pyridin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methylpentanol;

1, 5-anhydro-2, 3-dideoxy-3- { [3- (1-hydroxy-1-methylethyl) -3- ({5- [2- (trifluoromethyl) pyridin-4-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methylpentanol; and

1, 5-anhydro-2, 3-dideoxy-3- { [3- (1-hydroxy-1-methylethyl) -3- ({5- [6- (trifluoromethyl) pyrazin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methylpentanol.

In another embodiment, compounds of the formula:

or a pharmaceutically acceptable salt thereof.

In another embodiment, there are provided compounds of the formulaOr a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention, a composition is provided comprising a compound of formula I or II, or a pharmaceutically acceptable salt thereof, and a carrier.

In another embodiment, there is provided a method of treating a disease associated with expression or activity of a chemokine receptor in a patient, comprising administering to said patient a compound of formula I or II, or a pharmaceutically acceptable salt thereof.

In one embodiment of the method, the chemokine receptor is CCR2 or CCR 5.

In another embodiment of the method, the disease is rheumatoid arthritis, atherosclerosis, lupus, multiple sclerosis, pain, transplant rejection, diabetes, diabetic nephropathy, diabetic conditions, liver fibrosis, viral diseases, cancer, asthma, seasonal and perennial allergic rhinitis, sinusitis, conjunctivitis, age-related macular degeneration, food allergy, mackerel poisoning, psoriasis, undifferentiated spondyloarthropathy (undifferentiated facet pain), gout, urticaria, pruritis, eczema, inflammatory bowel disease, thrombotic diseases, otitis media, fibrosis, cirrhosis, cardiac disease, alzheimer's disease, sepsis, restenosis, crohn's disease, ulcerative colitis, irritable bowel syndrome, hypersensitivity lung disease, drug-induced pulmonary fibrosis, chronic obstructive pulmonary disease, arthritis, nephritis, atopic dermatitis, Stroke, acute nerve injury, sarcoidosis, hepatitis, endometriosis, neuropathic pain, hypersensitivity pneumonitis, eosinophilic pneumonia (eosinophilic pneumoconias), delayed-type hypersensitivity reactions, interstitial lung disease, ocular disorders, or obesity.

In another embodiment of the invention, there is provided the use of a compound of formula I or II, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of rheumatoid arthritis, atherosclerosis, lupus, multiple sclerosis, pain, transplant rejection, diabetes, diabetic nephropathy, a diabetic condition, liver fibrosis, viral diseases, cancer, asthma, seasonal and perennial allergic rhinitis, sinusitis, conjunctivitis, age-related macular degeneration, food allergy, mackerel poisoning, psoriasis, undifferentiated spondyloarthropathies, gout, urticaria, pruritis, eczema, inflammatory bowel disease, thrombotic disorders, otitis media, fibrosis, liver cirrhosis, cardiac disorders, alzheimer's disease, sepsis, restenosis, crohn's disease, ulcerative colitis, irritable bowel syndrome, hypersensitivity lung diseases, drug-induced pulmonary fibrosis, Chronic obstructive pulmonary disease, arthritis, nephritis, atopic dermatitis, stroke, acute nerve injury, sarcoidosis, hepatitis, endometriosis, neuropathic pain, hypersensitivity pneumonitis, eosinophilic pneumonia, delayed-type hypersensitivity reactions, interstitial lung disease, an ocular disorder, or obesity.

In another embodiment, the invention relates to a combination comprising a compound of formula I or II as defined above, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents for the treatment of a CCR2 or CCR2/CCR5 mediated disease, disorder or condition.

In another embodiment, the invention relates to a compound of formula I or II as defined above or a pharmaceutically acceptable salt thereof as defined above for use as a medicament.

In another embodiment, the invention relates to a method of treating a CCR2 or CCR2/CCR5 mediated disease, disorder or condition in a subject in need of such treatment, comprising administering to said subject a therapeutically effective amount of a compound of formula I or II as defined above or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, the invention relates to a compound of formula I or II as defined above or a pharmaceutically acceptable salt thereof for use in the treatment of a CCR2 or CCR2/CCR5 mediated disease, disorder or condition.

In another embodiment, the invention relates to the use of a compound of formula I or II as defined above or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of a CCR2 or CCR2/CCR5 mediated disease, disorder or condition.

Salts of the compounds of the present invention may include acid addition salts or base addition salts (including disalts) thereof. The salt may be pharmaceutically acceptable.

Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include acetate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorsulfonate, citrate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, oxybenzoylphthalate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthenate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/biphosphate, saccharate, stearate, succinate, bicarbonate, salicylate, and salicylate, Tartrate, tosylate and trifluoroacetate salts.

Suitable base salts are formed from bases which form non-toxic salts. Examples include aluminum salts, arginine salts, benzathine salts (benzathine), calcium salts, choline salts, diethylamine salts, diethanolamine salts, glycine salts, lysine salts, magnesium salts, meglumine salts, ethanolamine salts, potassium salts, sodium salts, tromethamine salts, and zinc salts.

Hemisalts of acids and bases, such as hemisulfate and hemicalcium salts, may also be formed.

For a review of suitable Salts, see Stahl and Wermuth, "Handbook of pharmaceutical Salts: properties, Selection, and Use "(Wiley-VCH, Weinheim, Germany, 2002).

Salts can be readily prepared by mixing together a solution of a compound of the invention and the desired acid or base, as desired. The salt may be precipitated from the solution and collected by filtration, or may be recovered by evaporation of the solvent. The degree of ionization of the salt can vary from fully ionized to almost unionized.

The compounds of the present invention may be administered as prodrugs. Thus, certain derivatives which themselves have little or no pharmacological activity are converted to the compounds of the invention which have the desired activity when administered in vivo or in the body, for example by hydrolytic cleavage. Such derivatives are referred to as "prodrugs". For further information on prodrug use, see ' Pro-drugs as Novel Delivery Systems, Vol.14, ACS Symposium Series (T Higuchi and W Stella) and ' Bioreversible Carriers in drug Design ', Pergamon Press, 1987(E B Roche eds., American pharmaceutical Association).

Prodrugs can be produced, for example, by replacing suitable functional groups (functionalities) present in the compounds of the invention with certain moieties known to those skilled in the art as 'precursor-moieties', as described, for example, in "Design of precursors" of h.

Some examples of such prodrugs include:

(i) in the case where the compound contains an alcohol function (-OH), an ether thereof, for example, with (C)₁-C₆) An alkanoyloxymethyl group for hydrogen; and

(ii) in the case where the compound contains secondary amino functions, amides thereof, e.g. with (C)₁-C₁₀) Alkanoyl in place of hydrogen.

All isomers of the compounds or salts, such as stereoisomers, geometric (cis/trans or Z/E) isomers and tautomeric forms are included within the scope of the invention, including compounds or salts having more than one type of isomerism, and mixtures of one or more thereof.

Also included are acid addition or base salts in which the counterion is optically active (e.g., D-lactate or L-lysine) or racemic (e.g., DL-tartrate or DL-arginine).

Isomers may be separated by conventional techniques well known to those skilled in the art.

The invention includes isotopically-labeled compounds of the present invention, wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.

Isotopically-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying examples and preparations using a suitable isotopically-labeled reagent in place of the unlabeled reagent previously employed.

For the treatment of the conditions mentioned below, the compounds of the invention may be administered. Salts of the compounds of the present invention may also be used.

C. Composition comprising a metal oxide and a metal oxide

The compounds or salts of the present invention may be part of a composition. The compositions may also include one or more compounds or salts of the present invention. The compositions may also include an enantiomeric excess of one or more compounds of the invention. Other pharmacologically active agents and carriers may be included in the compositions.

One embodiment is a composition comprising a compound of formula I or II or a salt thereof. Another embodiment is a composition comprising a compound of formula I or II or a salt thereof and a carrier.

For example, the carrier may be an excipient. The choice of excipient will depend in large part on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

The compositions may be solid, liquid or both and may be formulated with the compound as a unit-dose composition, for example, a tablet, which may contain from 0.05% to 95% by weight of the active compound. The compounds or salts of the present invention may be coupled to suitable polymers as targetable drug carriers.

D. Method of producing a composite material

In some embodiments, the compounds of the present invention may be used in methods of modulating the activity of one or more chemokine receptors. Accordingly, the present invention includes a method comprising contacting a chemokine receptor with a compound of formula I or II, or a salt thereof. In some embodiments, the chemokine receptor is CCR 2. In other embodiments, the chemokine receptor is CCR 5. In other embodiments, the invention encompasses methods of modulating a chemokine receptor, wherein the receptor is contacted with any one or more of the compounds or compositions described herein. In some embodiments, the compounds of the present invention may act as inhibitors or antagonists of chemokine receptors. In other embodiments, the compounds of the invention may be used to modulate the activity of a chemokine receptor in a subject in need of such modulation, by administering a modulating amount of a compound of formula I or II, or a salt thereof.

Chemokine receptors to which the compounds of the invention bind and/or modulate include any chemokine receptor. In some embodiments, the chemokine receptor belongs to the CC family of chemokine receptors, including, for example, CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, and CCR 10. In some embodiments, the chemokine receptor is CCR2 or CCR 5. In some embodiments, the chemokine receptor is CCR 2. In some embodiments, the chemokine receptor is CCR 5. In some embodiments, the chemokine receptor binds and/or modulates CCR2 and CCR 5.

The compounds of the invention may be selective, that is, bind to or inhibit a chemokine receptor with greater affinity or potency (potency), respectively, than to at least one other chemokine receptor.

The compounds of the invention may be dual-effect inhibitors or binders of CCR2 and CCR5, that is, they may bind or inhibit CCR2 and CCR5 with greater affinity or potency, respectively, than for other chemokine receptors such as CCR1, CCR3, CCR4, CCR6, CCR7, CCR8 and CCR 10. In some embodiments, the compounds of the invention have binding or inhibitory selectivity for CCR2 and CCR5 over any other chemokine receptor. Binding affinity and inhibitor potency can be measured according to routine methods in the art, such as according to the assays provided herein.

The invention further provides methods of treating a chemokine receptor-associated disease or disorder in an individual (e.g., patient) by administering to the individual in need of such treatment a therapeutically effective amount or dose of a compound of the invention or a pharmaceutical composition thereof. In other embodiments, the invention includes a method of treating a disorder mediated by chemokine receptor activity in a subject comprising administering to the subject a compound of formula I or II, or a pharmaceutically acceptable salt thereof.

Chemokine receptor-associated diseases or conditions can include any disease, disorder or condition that is directly or indirectly linked to the expression or activity of a chemokine receptor. Chemokine receptor-associated diseases or conditions can also include any disease, disorder or condition that can be prevented, ameliorated or cured by modulation of chemokine receptor activity. Chemokine receptor-associated diseases can further include any disease, disorder or condition characterized by the binding of an infectious agent, such as a virus or viral protein, to a chemokine receptor. In some embodiments, the chemokine receptor-associated disease is a CCR 5-associated disease, such as HIV infection.

Examples of conditions mediated by chemokine receptors include: inflammation, inflammatory disease, immune disorder, pain, cancer or viral infection.

Examples of inflammatory diseases include diseases believed to have an inflammatory component, such as asthma, seasonal and perennial allergic rhinitis, sinusitis, conjunctivitis, age-related macular degeneration, food allergy, mackerel poisoning, psoriasis, undifferentiated spondyloarthropathies, juvenile-onset spondyloarthritis, gout, urticaria, pruritis, eczema, inflammatory bowel disease, thrombotic diseases, otitis media, fibrosis, liver fibrosis, cirrhosis, heart disease, alzheimer's disease, sepsis, restenosis, atherosclerosis, multiple sclerosis, crohn's disease, ulcerative colitis, irritable bowel syndrome, inflammatory bowel disease, hypersensitivity lung disease, drug-induced pulmonary fibrosis, Chronic Obstructive Pulmonary Disease (COPD), arthritis, nephritis, ulcerative colitis, atopic colitis, stroke, acute nerve injury, sarcoidosis, hepatitis, inflammatory bowel disease, Chronic Obstructive Pulmonary Disease (COPD), arthritis, nephritis, ulcerative colitis, endometriosis, neuropathic pain, hypersensitivity pneumonitis, eosinophilic pneumonia, delayed hypersensitivity reactions, Interstitial Lung Disease (ILD) (e.g., idiopathic pulmonary fibrosis or ILD associated with rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, systemic sclerosis, sjogren's syndrome, polymyositis or dermatomyositis), ocular disorders (e.g., retinal neurodegeneration, choroidal neovascularization, etc.), and the like.

Examples of immune disorders include rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, myasthenia gravis, juvenile onset diabetes; glomerulonephritis, autoimmune thyroiditis (thyroiditis), organ transplant rejection including allograft rejection and graft versus host disease.

Examples of pain include nociceptive and neuropathic pain. The pain may be acute or chronic. Pain includes skin pain, somatic pain, visceral pain and phantom limb pain. Pain also includes fibromyalgia, rheumatoid arthritis pain, osteoarthritis pain, and pain associated with other diseases and conditions detailed herein.

Examples of cancers include breast cancer, ovarian cancer, multiple myeloma, and the like, which are characterized by infiltration of macrophages (e.g., tumor-associated macrophages, TAMs) into a tumor or diseased tissue.

Examples of viral infections include influenza, avian influenza, herpes infection, HIV infection, or AIDS.

Other inflammatory or immune diseases treatable by administration of the compounds of the invention include, for example, autoimmune nephritis, lupus nephritis, goodpasture's syndrome nephritis and wegener's granulomatosis nephritis, lupus erythematosus, goodpasture's syndrome, and wegener's granulomatosis.

Examples of diabetic conditions include diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis, tissue ischemia, diabetic cardiomyopathy, diabetic microangiopathy, diabetic macroangiopathy, and foot ulcers. Treatment of diabetes includes the prevention or alleviation of long-term conditions such as neuropathy, nephropathy, retinopathy or cataracts.

In some embodiments, the disorder to be treated is rheumatoid arthritis, atherosclerosis, lupus, multiple sclerosis, neuropathic pain, transplant rejection, diabetes, diabetic nephropathy, a diabetic disorder, or obesity.

In some embodiments, the disorder is rheumatoid arthritis.

In some embodiments, the disorder is diabetes.

In some embodiments, the disorder is diabetic nephropathy.

In some embodiments, the disorder is liver fibrosis.

In some embodiments, the disorder is osteoarthritis pain.

In some embodiments, the disorder is breast cancer, ovarian cancer, or multiple myeloma.

In some embodiments, the disorder is HIV infection.

E. Dosage and administration

Pharmaceutical formulations and dosage forms

When used as a medicament, the compounds of formula I or II may be administered in the form of a pharmaceutical composition. These compositions may be prepared in a manner well known in the pharmaceutical art and may be used by a variety of routes depending on whether local or systemic treatment is desired, and the area to be treated. Administration can be topical (including ophthalmic and mucosal, including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal), oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or injection or infusion; or intracranial, e.g., intrathecal or intraventricular administration. Parenteral administration may be in the form of rapid bolus dose, or may be, for example, by continuous infusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable. Coated condoms, gloves and the like may also be useful.

The invention also includes pharmaceutical compositions comprising, as an active ingredient, one or more compounds of formula I or II as described above in combination with one or more pharmaceutically acceptable carriers. In preparing the compositions of the present invention, the active ingredient is typically mixed with an excipient, diluted with an excipient, or enclosed within a carrier in a form such as a capsule, sachet, paper or other container. When the excipient serves as a diluent, it may be a solid, semi-solid, or liquid material that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the composition may be in the form of: tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.

In preparing the formulation, the active compound may be milled to provide the appropriate particle size prior to mixing with the other ingredients. If the active compound is substantially insoluble, it may be milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size may be adjusted by milling to provide a substantially uniform distribution in the formulation, for example about 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulation may additionally include: lubricants such as talc, magnesium stearate and mineral oil; a wetting agent; emulsifying and suspending agents; preservatives such as methyl-and propylhydroxy-benzoate; a sweetener; and a flavoring agent. The compositions of the present invention may be formulated to provide rapid, sustained or delayed release of the active ingredient after administration to a patient by employing procedures known in the art.

The compositions may be formulated in unit dose forms (unit dosage form) containing from about 5 to about 1000mg (1g), more usually from about 100 to about 500mg, of active ingredient per dose. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.

In some embodiments, the compounds or compositions of the present invention contain from about 5 to about 50mg of active ingredient. One of ordinary skill in the art will appreciate that this will result in a compound or composition containing from about 5 to about 10, from about 10 to about 15, from about 15 to about 20, from about 20 to about 25, from about 25 to about 30, from about 30 to about 35, from about 35 to about 40, from about 40 to about 45, or from about 45 to about 50mg of active ingredient. In another embodiment, the dose may be 35-45 mg.

In some embodiments, the compounds or compositions of the present invention contain from about 50 to about 500mg of active ingredient. One of ordinary skill in the art will appreciate that this will result in a compound or composition containing from about 50 to about 75, from about 75 to about 100, from about 100 to about 125, from about 125 to about 150, from about 150 to about 175, from about 175 to about 200, from about 200 to about 225, from about 225 to about 250, from about 250 to about 275, from about 275 to about 300, from about 300 to about 325, from about 325 to about 350, from about 350 to about 375, from about 375 to about 400, from about 400 to about 425, from about 425 to about 450, from about 450 to about 475, or from about 475 to about 500mg of active ingredient.

In some embodiments, the compounds or compositions of the present invention contain from about 500 to about 1000mg of active ingredient. One of ordinary skill in the art will appreciate that this will result in a compound or composition containing from about 500 to about 550, from about 550 to about 600, from about 600 to about 650, from about 650 to about 700, from about 700 to about 750, from about 750 to about 800, from about 800 to about 850, from about 850 to about 900, from about 900 to about 950, or from about 950 to about 1000mg of active ingredient.

The active compounds may be effective over a wide dosage range and are generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

To prepare solid compositions such as tablets, the principal active ingredient is mixed with pharmaceutically acceptable excipients to form a solid preformulation composition comprising a homogeneous mixture of a compound of the present invention. When referring to these preformulation compositions as homogeneous, the active ingredient is generally dispersed uniformly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. The solid preformulation composition is then subdivided into unit dosage forms of the type described above containing, for example, from 0.1 to about 1000mg of the active ingredient of the invention.

The tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, a tablet or pill may include an inner dose and an outer dose component, the latter being in the form of an outer membrane on the former. The two components may be separated by an enteric layer which serves to resist disintegration in the stomach and allows the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials may be used for such enteric layers or coatings, including a variety of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol and cellulose acetate.

Liquid forms in which the compounds and compositions of the present invention for oral or by injection administration may be incorporated include: aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions and suspensions and powders in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof. The liquid or solid composition may comprise suitable pharmaceutically acceptable excipients as described above. In some embodiments, the composition may be administered via the oral or nasal respiratory route to exert a local or systemic effect. By using an inert gas, the composition can be atomized. The nebulized solution may be breathed directly from the nebulizing device, or the nebulizing device may be attached to a mask tent (face masks tent) or intermittent positive pressure ventilator. The solution, suspension or powder composition may be administered orally or nasally from a device that delivers the formulation in a suitable manner.

The amount of the compound or composition administered to a patient varies depending on the substance to be administered, the purpose of administration (such as prevention or treatment), the state of the patient, the mode of administration, and the like. In therapeutic use, the composition may be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. The effective dosage will depend on the disease state being treated and the judgment of the attending clinician based on: such as the severity of the disease, the age, weight and general condition of the patient, etc.

The composition administered to the patient may be in the form of a pharmaceutical composition as described above. These compositions may be sterilized by conventional sterilization techniques, or may be sterile filtered. The aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized formulation being combined with a sterile aqueous carrier prior to administration. The pH of the compound formulation is typically 3-11, or 5-9, or 7-8. It will be appreciated that the use of certain of the aforementioned excipients, carriers or stabilizers will result in the formation of pharmaceutically acceptable salts.

The therapeutic dosage of the compounds of the invention may vary, for example, with the particular use being treated, the mode of administration of the compound, the health and condition of the patient, and the judgment of the attending physician. The proportion or concentration of a compound of the invention in a pharmaceutical composition may vary depending on a number of factors, including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration. For example, the compounds of the present invention may be provided in a physiologically buffered aqueous solution for parenteral administration, the solution containing from about 0.1 to about 10% w/v of the compound. Some typical dosage ranges are from about 1. mu.g/kg to about 1g/kg body weight/day. In some embodiments, the dosage range is from about 0.01mg/kg to about 100mg/kg body weight/day. The dosage may depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological potency of the compound selected, the composition of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model experimental systems.

The compounds of the present invention may also be formulated in combination with one or more other active ingredients, which may include any agent, such as antibodies, immunosuppressive agents, anti-inflammatory agents, chemotherapeutic agents, lipid lowering agents, HDL raising agents, insulin secretagogues or sensitizers, drugs for the treatment of rheumatoid arthritis, and the like.

Rheumatoid Arthritis (RA) treatment regimen

Rheumatoid Arthritis (RA) patients treated aggressively with a disease modifying agent (methotrexate, antimalarial, gold, penicillamine, sulfasalazine, dapsone, leflunomide, or biologic) can achieve varying degrees of disease control, including complete regression. These clinical responses are associated with an increase in standardized disease activity scores, specifically ACR criteria, which include: pain, function, number of tender joints, number of swollen joints, patient population assessment, physician population assessment, laboratory measurements of inflammation (CRP and ESR), and radiological assessment of joint structural damage. Current disease modifying drugs (DMARDs) require continuous administration to maintain optimal benefit. Long-term administration of these drugs is associated with significant toxicity and impaired host defense. In addition, patients often become refractory to (reflexory) specific therapies, requiring alternative regimens. For these reasons, new, effective therapies that allow withdrawal of standard DMARDs would be a clinically significant advance.

Patients who have achieved clinical regression of disease, who have had a significant response to anti-TNF therapy (infliximab, etanercept, adalimumab), anti-IL-1 therapy (kinaret), or other disease modifying anti-rheumatic drugs (DMARDs), including but not limited to methotrexate, cyclosporine, gold salts, antimalarials, penicillamine, or leflunomide, may be treated with substances that inhibit CCR2 expression and/or activity, such as nucleic acids (e.g., antisense or siRNA molecules), proteins (e.g., anti-CCR 2 antibodies), small molecule inhibitors (e.g., the compounds disclosed herein and other chemokine receptor inhibitors known in the art).

In some embodiments, the agent that inhibits CCR2 expression and/or activity is a small molecule CCR2 inhibitor (or antagonist). The CCR2 antagonist may be administered orally (q.d.) or twice a day (b.i.d.) at a dose of no more than about 500 mg/day. Patients may be withdrawn or dose reduced from current therapy and adhere to treatment with a CCR2 antagonist. Treatment of patients with a combination of a CCR2 antagonist and current therapy can be performed, for example, for about one to about two days, followed by discontinuation or dose reduction of the DMARD and continued CCR2 antagonist treatment.

The advantages of replacing traditional DMARDs with CCR2 antagonists are numerous. Traditional DMARDs have severe cumulative dose-limiting side effects, most commonly liver damage and immunosuppressive effects. CCR2 antagonism is expected to have improved long-term safety and will not have similar immunosuppressive tendencies associated with traditional DMARDs. In addition, the half-life of biologies is typically days or weeks, which is a problem when dealing with adverse reactions. The half-life of orally bioavailable CCR2 antagonists is expected to be on the order of hours, and thus the risk of sustained exposure to the drug following an adverse event is very minimal compared to biological agents. Moreover, current biological agents (infliximab, etanercept, adalimumab, kinaret) are typically administered intravenously or subcutaneously, requiring either physician administration or self-injection by the patient. This gives rise to the possibility of infusion reactions or injection site reactions. These problems can be avoided by using an orally administered CCR2 antagonist.

Diabetes and insulin resistance treatment regimens

Type 2 diabetes is one of the leading causes of morbidity and mortality in western society. In most patients, the disease is characterized by pancreatic β -cell dysfunction, with insulin resistance in the liver and in the surrounding tissues. Based on the primary mechanisms associated with the disease, 2 general categories of oral treatment are available for the treatment of type 2 diabetes: insulin secretagogues (sulfonylureas such as glibenclamide) and insulin sensitizers (metformin and thiazolidinediones such as rosiglitazone). Combination therapy to achieve both mechanisms has been shown to control the metabolic deficiencies of the disease and in many cases may be shown to improve the need for exogenous insulin administration. However, insulin resistance often progresses over time, resulting in a need for further insulin supplementation. In addition, it has been demonstrated that pre-diabetes (known as metabolic syndrome) is characterized by impaired glucose tolerance, especially in connection with obesity. Most patients developing type 2 diabetes begin with the development of insulin resistance and hyperglycemia occurs when these patients can no longer experience the degree of hyperinsulinemia necessary to prevent loss of glucose homeostasis. The onset of the insulin resistance component is a high precursor to the onset of the disease and is associated with an increased risk of developing type 2 diabetes, hypertension and coronary heart disease.

One of the strongest associations of impaired glucose tolerance and progression from the insulin resistant state to type 2 diabetes is the presence of central obesity. Most patients with type 2 diabetes are obese, and obesity is itself associated with insulin resistance. It is clear that central obesity is an important risk factor for the development of insulin resistance leading to type 2 diabetes, suggesting that signals from visceral fat contribute to the development of insulin resistance and progression to the disease. In addition to secreted protein factors, obesity induces a cellular inflammatory response in which bone marrow-derived macrophages accumulate in the fat depot (adipose depot) and become adipose tissue macrophages. Adipose tissue macrophages accumulate in adipose tissue in proportion to a measure of obesity. Macrophages infiltrating the tissue are a source of many inflammatory cytokines that have been shown to induce insulin resistance in adipocytes.

Adipose tissue produces MCP-1 in proportion to obesity, suggesting that its signaling activity through CCR2 may also play an important role in the accumulation of macrophages in adipose tissue. It is unclear whether the MCP-1/CCR2 interaction directly causes monocyte recruitment to adipose tissue, whether reduced macrophage recruitment in human adipose tissue directly results in reduced pro-inflammatory molecule production, and whether pro-inflammatory molecule production is directly correlated with insulin resistance.

Patients exhibiting insulin resistance, whether pre-diabetic (euglycemic) or diabetic (hyperglycemic), can be treated with agents that inhibit the expression and/or activity of CCR2, including, for example, nucleic acids (e.g., antisense or siRNA molecules), proteins (e.g., anti-CCR 2 antibodies), small molecule inhibitors (e.g., the compounds disclosed herein and other chemokine receptor inhibitors known in the art). In some embodiments, the agent that inhibits expression and/or activity of CCR2 is a small molecule CCR2 inhibitor (or antagonist). CCR2 antagonists may be administered orally (q.d.) or twice a day (b.i.d.). Patients may be withdrawn or dose-reduced from their current therapy and remain treated with CCR2 antagonists. Alternatively, CCR2 antagonist treatments can be used to supplement their current therapy to enhance its effectiveness or prevent further insulin-dependent progression.

The advantages of replacing or supplementing conventional agents with CCR2 antagonists are numerous. Such agents may be used, for example, to prevent progression from a prediabetic, insulin resistant state to a diabetic state. Such agents may reduce or replace the need for the use of insulin sensitizers, which are associated with toxicity. Such agents may also reduce the need for exogenous insulin supplementation, or extend the period until exogenous insulin supplementation is needed.

Atherosclerosis treatment regimen

Atherosclerosis is a condition characterized by the deposition of lipids in the arterial wall. Plaque includes this deposit of fatty matter, cholesterol, cellular waste, calcium, and other matter that makes up the inner lining of the artery. The plaque may grow large enough to significantly reduce blood flow through the artery. However, as the plaque becomes unstable and ruptures, more significant damage occurs. The ruptured plaque causes a blood clot to form that can block or disrupt blood flow and migrate to other parts of the body. A heart attack can result if the clot blocks a blood vessel that supplies blood to the heart. If it blocks the blood vessels supplying the brain, a stroke can result. Atherosclerosis is a slow, complex disease that usually begins in childhood and often progresses as people age.

High levels of cholesterol in the blood are an important risk factor for coronary heart disease. The development of plaque formation can be controlled by reducing circulating cholesterol or by raising High Density Lipoprotein (HDL) carrying cholesterol, based on cholesterol being the major component of plaque. Circulating cholesterol may also be reduced, for example, by inhibiting its synthesis for use in the liver, or by reducing refreshment from food. Such agents that act through these mechanisms may include agents for reducing high cholesterol levels: cholesterol absorbents, lipoprotein synthesis inhibitors, cholesterol synthesis inhibitors, and phenoxy acid (fibric acid) derivatives. In addition, circulating HDL can be elevated by using, for example, probucol (probucol) or high doses of nicotinic acid. Therapies that achieve multiple mechanisms have been shown to slow disease progression and progression to plaque rupture.

Atherosclerosis is often accompanied by a cellular inflammatory response in which bone marrow-derived macrophages accumulate along the vessel wall in fatty streaks, becoming foam cells. Foam cells are a source of many inflammatory cytokines (which have been shown to induce plaque progression) and enzymes that can promote plaque destabilization. The atherosclerotic tissue also produces MCP-1, suggesting that its signaling activity through CCR2 may also play an important role in the accumulation of macrophages (as foam cells in the plaque). CCR 2-/-mice have been shown to have significantly reduced macrophages in fatty streaks produced as a result of high fat diet or genetic alterations in lipid metabolism.

Patients exhibiting high circulating cholesterol, low HDL or elevated circulating CRP or exhibiting plaque or any other evidence of the presence of atherosclerosis by imaging the vessel wall can be treated with agents that inhibit the expression and/or activity of CCR2, including, for example, nucleic acids (e.g., antisense or siRNA molecules), proteins (e.g., anti-CCR 2 antibodies), small molecule inhibitors (e.g., the compounds disclosed herein and other chemokine receptor inhibitors known in the art). In some embodiments, the agent that inhibits expression and/or activity of CCR2 is a small molecule CCR2 inhibitor (or antagonist), such as a compound of the present invention. The CCR2 antagonist may be administered orally (q.d.) or twice a day (b.i.d.) at a dose of no more than about 500mg per day. Patients may be withdrawn or reduced in dose from their current therapy and adhere to treatment with CCR2 antagonists. Alternatively, CCR2 antagonist treatments can be used to supplement their current therapy to enhance its effectiveness in: for example, preventing plaque progression, stabilizing plaque that has already formed, or inducing plaque regression.

The advantages of replacing or supplementing conventional agents with CCR2 antagonists are numerous. Such agents may be used, for example, to prevent plaque progression to unstable stages with the risk of plaque rupture. Such agents may reduce or replace the need for the use of cholesterol modulating drugs or HDL raising drugs, which are associated with toxicity, including, but not limited to, flushing, liver damage, and muscle damage, such as myopathy. Such agents may also reduce the need for surgery, or extend the period until surgery is required to open the vessel wall, or until anticoagulant medication is required to limit the damage caused by potential plaque rupture.

Labeled compounds and assay methods

Another aspect of the invention relates to fluorochrome, rotation label, heavy metal or radiolabelled compounds of formula I, which are useful not only for imaging, but also in vitro and in vivo assays for locating and quantifying chemokine receptors in tissue samples, including humans, and for identifying chemokine receptor ligands by inhibiting the binding of labeled compounds. Accordingly, the invention includes chemokine receptor assays comprising such labeled compounds.

The invention further includes isotopically-labeled compounds of formula I. An "isotopically" or "radiolabeled" compound is a compound of the invention wherein one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (i.e., naturally occurring). Suitable radionuclides that may be incorporated in the compounds of the present invention include, but are not limited to²H、³H (also written as T or tritium),¹¹C、¹³C、¹⁴C、¹³N、¹⁵N、¹⁵O、¹⁷O、¹⁸O、¹⁸F、³⁵S、³⁶Cl、⁸²Br、⁷⁵Br、⁷⁶Br、⁷⁷Br、¹²³I、¹²⁴I、¹²⁵I and¹³¹I. the radionuclide that is incorporated into the radiolabeled compounds of the invention will depend on the particular application for which the radiolabeled compound is used. For example, for in vitro chemokine receptor labeling and competition assays, incorporation³H、¹⁴C、⁸²Br、¹²⁵I、¹³¹I or³⁵Compounds of S are generally most useful. In the case of a radiological imaging application,¹¹C、¹⁸F、¹²⁵I、¹²³I、¹²⁴I、¹³¹I、⁷⁵Br、⁷⁶br or⁷⁷Br is generally most useful.

It will be understood that "radiolabeled" or "labeled"The compound of (a) is a compound incorporating at least one radionuclide. In some embodiments, the radionuclide is selected from:³H、¹⁴C、¹²⁵I、³⁵s and⁸²Br。

synthetic methods for incorporating radioisotopes into organic compounds are useful for the compounds of the present invention and are well known in the art. The radiolabeled compounds of the invention may be used in screening assays to identify/evaluate compounds. In a general sense, a newly synthesized or identified compound (i.e., test compound) can be evaluated for its ability to reduce binding of a radiolabeled compound of the invention to a chemokine receptor. Thus, the ability of a test compound to compete with a radiolabeled compound for binding to a chemokine receptor is directly related to its binding affinity.

Reagent kit

The invention also includes pharmaceutical kits, e.g., useful for treating or preventing chemokine-associated diseases, which kits include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I. Such kits may further include, if desired, one or more of various conventional pharmaceutical kit components, e.g., containers containing one or more pharmaceutically acceptable carriers, additional containers, etc., as will be apparent to those skilled in the art. Instructions may also be included in the kit, as inserts (inserts) or as labels indicating the amounts of the components to be administered, directions for administration and/or directions for mixing the components.

Combination of

The compounds or salts of the present invention or mixtures thereof may be administered in combination with one or more other therapeutic agents, such as drugs. The compounds of the invention or salts thereof may be administered with one or more other therapeutic agents, either simultaneously or non-simultaneously.

For example, "combination" includes: administering a combination of a compound or salt of the invention and a therapeutic agent to a subject simultaneously (when such components are formulated together in a single dosage form that releases the components to the subject substantially simultaneously); administering a combination of a compound or salt of the invention and a therapeutic agent to a subject in need of treatment substantially simultaneously (when such components are formulated separately from each other in separate dosage forms, the separate dosage forms are ingested by the subject substantially simultaneously, whereupon the components are released to the subject substantially simultaneously); administering a combination of a compound or salt of the invention and a therapeutic agent to a subject sequentially (when such components are formulated separately from one another in separate dosage forms, the separate dosage forms are ingested sequentially by the subject, separated by a significant period of time between each administration, whereupon the components are released to the subject at substantially different times); such combinations of a compound or salt of the invention and a therapeutic agent are administered to a subject sequentially (when such components are formulated together in a single dosage form that releases the components in a controlled manner, so that they are taken up by the subject simultaneously, consecutively and/or overlappingly, simultaneously and/or not, wherein each portion may be administered by the same or different routes).

One or more additional agents (e.g., antibodies, anti-inflammatory agents, immunosuppressive agents, chemotherapeutic agents) can be used in combination with the compounds of the present invention for treating chemokine receptor-associated diseases, disorders, or conditions.

One or more additional pharmaceutical agents (e.g., antiviral agents, antibodies, anti-inflammatory agents, insulin secretagogues and sensitizers, serum lipids and lipid-carrier modulators, and/or immunosuppressive agents) can be used in combination with the compounds of the present invention for the treatment of chemokine receptor-associated diseases, disorders, or conditions. These agents may be combined with the compounds of the present invention in a single or continuous dosage form, or the agents may be administered simultaneously or sequentially as separate dosage forms.

It is envisioned that antiviral agents suitable for use in combination with the compounds of the present invention may comprise nucleoside and Nucleotide Reverse Transcriptase Inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors and other antiviral agents.

It is envisioned that antiviral agents suitable for use in combination with the compounds of the present invention may comprise nucleoside and Nucleotide Reverse Transcriptase Inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors, entry inhibitors (entry inhibitors), fusion inhibitors, maturation inhibitors (maturatin inhibitors), and other antiviral agents.

Examples of suitable NRTIs include zidovudine (AZT), didanosine (ddl), zalcitabine (ddC), stavudine (D4T), lamivudine (3TC), abacavir (1592U89), adefovir dipivoxil [ bis (POM) -PMEA ], lobecavir (BMS-180194), BCH-10652, emtricitabine [ (-) -FTC ], β -L-FD4 (also known as β -L-D4C and named β -L-2 ', 3' -dideoxy-5-fluoro-cyidene), DAPD ((-) - β -D-2, 6, -diamino-purine dioxolane), and lodenosine (FddA).

Typical suitable NNRTIs include nevirapine (BI-RG-587), delaviradine (BHAP, U-90152), efavirenz (DMP-266), PNU-142721, AG-1549, MKC-442(1- (ethoxy-methyl) -5- (1-methylethyl) -6- (phenylmethyl) - (2, 4(1H, 3H) -pyrimidinedione), and (+) -calanolide A (NSC-675451) and B.

Typical suitable protease inhibitors include saquinavir (Ro 31-8959), ritonavir (ABT-538), indinavir (MK-639), nelfnavir (AG-1343), amprenavir (141W94), lacinavir (BMS-234475), DMP-450, BMS-2322623, ABT-378, and AG-1549.

Other antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12, pentafuside, enfuvirdine, C-34, cyclotriazabicylamide CADA, PA-457 and YIssum project No. 11607.

In some embodiments, anti-inflammatory or analgesic agents contemplated for use in combination with the compounds of the present invention may comprise, for example, opioid agonists, lipoxygenase inhibitors (e.g., 5-lipoxygenase inhibitors), cyclooxygenase inhibitors (e.g., cyclooxygenase-2 inhibitors), interleukin inhibitors (e.g., interleukin-1 inhibitors), TNF inhibitors (such as infliximab, etanercept, or adalimumab), NNMA antagonists, nitric oxide inhibitors or inhibitors of nitric oxide synthesis, non-steroidal anti-inflammatory agents, or cytokine-inhibitory anti-inflammatory agents, such as acetaminophen, aspirin, codeine, fentanyl, ibuprofen, indomethacin, ketorolac (ketorolac), morphine, naproxen, phenacetin, piroxicam, steroidal analgesics, sufentanyl, sulindac, tenidap, and the like. Similarly, the compounds of the present invention may be administered with: a pain relieving agent; fortifiers, such as caffeine; h2-antagonists, such as simethicone, aluminum or magnesium hydroxide; decongestants such as phenylephrine, phenylpropanolamine, pseudoephedrine, oxymetazoline, ephinephrine, naphazoline, xylometazoline, propylhexedrine, or levo-desoxyephedrine; antifitutive, such as codeine, hydrocodone, caramiphene, pentoxyverine or dextromethorphan (dextramethorphan); a diuretic; and sedating or non-sedating antihistamines.

In some embodiments, agents contemplated for use in combination with the compounds of the present invention may include, but are not limited to: (a) VLA-4 antagonists, such as those described in US5,510,332, WO95/15973, WO96/01644, WO96/06108, WO96/20216, WO96/229661, WO96/31206, WO96/4078, WO97/030941, WO97/022897, WO98/426567, WO98/53814, WO98/53817, WO98/538185, WO98/54207 and WO 98/58902; (b) steroids such as beclomethasone, methylprednisolone, betamethasone, prednisone, dexamethasone, and hydrocortisone; (c) immunosuppressants such as cyclosporin, tacrolimus, rapamycin, and other FK506 type immunosuppressants; (d) antihistamines (H1-histamine antagonists) such as brompheniramine, chlorpheniramine, dexchlorpheniramine, triprolidine, clemastine, diphenhydramine, diphenyllene, tripelennamine, hydroxyzine, methdilazine, promethamine, almazine, azatadine, cyproheptadine, antazoline, pheniramine, mepyramine (pyrilamine), asimilazole, terfenadine, loratadine, cetirizine, fexofenadine (fexofenadine), descarboethoxyloratadine (descarboethoxyloratadine), and the like; (e) non-steroidal anti-asthmatics, e.g. terbutaline, metaproterenol, fenoterol, isoetharine, salbutamol, bitolterol, pirbuterol, theophyllineBase, cromolyn sodium, atropine, ipratropium bromide, leukotriene antagonists (e.g., zafirlukast, montelukast, pranlukast, iralukast, pobilukast, SKB-106,203), leukotriene biosynthesis inhibitors (e.g., zileuton, BAY-1005); (f) non-steroidal anti-inflammatory agents (NSAIDs), e.g. propionic acid derivatives (e.g. alminoprofen, benzene)Loxfen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic acid, and thioprofenLoxacin), acetic acid derivatives (e.g. indomethacin, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, fentiazac, furofenac, ibufenac, isoxepac, oxyphenbutac (oxpinac), sulindac, thiofenac, tolmetin, zidometacin and zomepirac), fenamic acid derivatives (flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid and tolfenamic acid), biphenyl carboxylic acid derivatives (diflunisal and flufenisal), oxicams (isoxicam, piroxicam, sudoxicam and tenoxicam), salicylic acids (acetylsalicylic acid, sulfasalazine) and pyrazolones (azapropazone, bezoperylon, feprazone, mofebuzubuzole, oxyphenbutazone, phenylbutazone); (g) cyclooxygenase-2 (COX-2) inhibitors; (h) phosphodiesterase type IV (PDE-IV) inhibitors; (i) antagonists of other chemokine receptors, especially CXCR-4, CCR1, CCR2, CCR3 and CCR 5; (j) cholesterol lowering agents, such as HMG-CoA reductase inhibitors (lovastatin, simvastatin and pravastatin, fluvastatin, atorvastatin and other statins), sequestrants (cholestyramine and colestipol), nicotinic acid, fenofibric acid derivatives (gemfibrozil, clofibrate, fenofibrate and bezafibrate) and probucol; (k) anti-inflammatory agents such as anti-TNF therapy, anti-IL-1 receptor, CTLA-4Ig, anti-CD 20 and anti-VLA 4 antibodies; (l) Antidiabetic agents, e.g. insulin, sulphonylureasBiguanides (metformin), U-glucosidase inhibitors (acarbose) and glitazones (troglitazone and pioglitazone); (m) interferon beta preparations (interferon beta-lo, interferon beta-1P); (n) other compounds, such as aminosalicylic acid, antimetabolites, such as azathioprine and 6-mercaptopurine, and cytotoxic cancer chemotherapeutic agents. The weight ratio of the compound of the invention to the second active ingredient may vary and will vary with the effective dosage of each ingredient.

For example, CCR2 and/or CCR5 antagonists may be used in combination with anti-inflammatory agents for the treatment of inflammation, metabolic diseases, autoimmune diseases, pain, cancer, or viral infection, increasing the therapeutic response compared to that of the therapeutic agent alone, without exacerbating its toxic effects. Additive or synergistic effects are desirable results of combining a CCR2 and/or CCR5 antagonist of the present invention with other agents. In addition, resistance of cancer cells to agents such as dexamethasone can be reversible following treatment with the CCR2 and/or CCR5 antagonists of the invention.

F. Use in the preparation of a composition or medicament

In one embodiment, the invention includes a method of making a composition or medicament comprising a compound or salt of the invention for treating a chemokine receptor mediated disorder.

In another embodiment, the invention includes the use of one or more compounds or salts of the invention in the preparation of a composition or medicament for the treatment of inflammation, inflammatory disease, immune disorder, pain, cancer or viral infection.

The invention also includes the use of one or more compounds or salts of the invention for the preparation of a composition or medicament for the treatment of one or more of the conditions detailed in the methods section.

G. Scheme(s)

The compounds of the invention can be prepared using methods exemplified in the general synthetic schemes and experimental methods detailed below. The reactions of the synthetic methods herein are carried out in a suitable solvent, which can be readily selected by one skilled in the art of organic synthesis, and which is generally any solvent that: which is substantially unreactive with the starting materials (reactants), intermediates, or products at the temperature at which the reaction is carried out. A given reaction may be carried out in one solvent or in a mixture of more than one solvent. Depending on the particular reaction step, a solvent may be selected that is suitable for the particular reaction step.

The preparation of the compounds of the invention may involve the protection and deprotection of various chemical groups. The need for protection and deprotection and the choice of an appropriate protecting group can be readily determined by those skilled in the art. The chemistry of protecting groups can be found, for example, in t.w.greene and p.g.m.wuts, Protective group in Organic Synthesis, 3 rd edition, Wiley & Sons, inc., New York (1999), which are all incorporated herein by reference.

The reaction may be monitored according to any suitable method known in the art. For example, the production of the product can be monitored by spectroscopy, such as nuclear magnetic resonance spectroscopy (e.g., nuclear magnetic resonance spectroscopy)¹H or¹³C) Infrared spectroscopy, spectrophotometry (e.g. UV-visible) or mass spectrometry, or chromatography, such as High Performance Liquid Chromatography (HPLC) or thin layer chromatography.

The starting materials used herein are commercially available or can be prepared by conventional synthetic methods.

For purposes of illustration, a general synthetic scheme is provided and is not intended to be limiting.

Scheme 1 preparation of examples 1-23

Scheme 1

Example 1

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3-ethyl-3- ({ (1S,4S) -5- [4- (trifluoromethyl) pyridin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol

Step 1: preparation of methyl (1R, 4S) -4- (2, 5-dimethyl-1H-pyrrol-1-yl) -1-ethylcyclopent-2-ene-1-carboxylate

A-40 ℃ solution of 2M (in THF/ethylbenzene/heptane) LDA (68ml, 138mmol) in tetrahydrofuran (120ml) was treated with methyl (1R, 4S) -4- (2, 5-dimethyl-1H-pyrrol-1-yl) cyclopent-2-ene-1-carboxylate (14.02g, 63.9mmol) while maintaining the temperature below-33 ℃. The cooled reaction (reaction) was stirred for 40 minutes, then a solution of ethyl iodide (13.63g, 87.4mmol) in tetrahydrofuran (5ml) was added slowly while maintaining the temperature below-33 ℃. The reaction was stirred for 4 hours in situ (in place) in a cold water bath and allowed to warm slowly. The reaction was poured into NH4Cl solution (300ml) and then extracted with ethyl acetate (2 × 200ml), washed with brine, over MgSO₄Dried and concentrated under reduced pressure. The resulting brown oil was passed through a silica gel column using 10% ethyl acetate/hexane to give methyl (1R, 4S) -4- (2, 5-dimethyl-1H-pyrrol-1-yl) -1-ethylcyclopent-2-ene-1-carboxylate as a brown oil (12.96g, 82%).¹H NMR(400MHz，CDCl₃)δppm 5.98-5.96(1H)，5.93-5.91(1H)，5.73(2H)，5.30-5.24(1H)，3.71(3H)，2.45-2.34(2H)，2.19(6H)，1.79-1.73(2H)，0.91-0.87(3H)。

Step 2: preparation of (1R, 4S) -4- (2, 5-dimethyl-1H-pyrrol-1-yl) -1-ethylcyclopent-2-ene-1-carboxylic acid

A solution of methyl (1R, 4S) -4- (2, 5-dimethyl-1H-pyrrol-1-yl) -1-ethylcyclopent-2-ene-1-carboxylate (12.94g, 52.3mmol) in methanol (100ml) was treated with 2.5N NaOH (30ml, 75.0mmol) and stirred at room temperature. After 15h, more 2.5N NaOH (10ml, 25.0mmol) was added and the reaction was stirred for an additional 4 days. The methanol was removed under reduced pressure and the residue was partitioned between diethyl ether and water. The layers were separated and the aqueous layer was acidified with 4N HCl, extracted 2 times with ethyl acetate, washed with brine, and over MgSO₄Dried and concentrated under reduced pressure to give (1R, 4S) -4- (2, 5-dimethyl-1H-pyrrol-1-yl) -1-ethylcyclopent-2-ene-1-carboxylic acid as a brown oil (11.83g, 97%).¹H NMR(400MHz，CDCl₃)δppm 5.98-5.96(2H)，5.73(2H)，5.30-5.26(1H)，2.47-2.35(2H)，2.20(6H)，1.82-1.77(2H)，0.96-0.92(3H)。

And step 3: preparation of tert-butyl (1S,4S) -5- { [ (1R, 4S) -4- (2, 5-dimethyl-1H-pyrrol-1-yl) -1-ethylcyclopent-2-en-1-yl ] carbonyl } -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylate

BOP ═ benzotriazole-1-yloxytris (dimethylamino) phosphineHexafluorophosphate (phosphoniumhexafluorophosphate)

A solution of (1R, 4S) -4- (2, 5-dimethyl-1H-pyrrol-1-yl) -1-ethylcyclopent-2-ene-1-carboxylic acid (6.59g, 28.2mmol) in DMF (40ml) was treated with N, N-diisopropylethylamine (14.7ml, 84.4mmol) and BOP (14.51g, 32.8mmol) and stirred at room temperature under nitrogen for 20 minutes. Adding (1S,4S) -2-BOC-2, 5-diazepineBicyclo [2.2.1]A solution of heptane (5.66g, 28.5mmol) in DMF (5ml) was added and the reaction stirred for 24 h. The reaction was diluted with ethyl acetate (100ml) and 60% saturated NaHCO₃(125ml) washing. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine and MgSO₄Dried and concentrated under reduced pressure to give a brown oil (21.25 g). The oil was passed through a silica gel column using 50% ethyl acetate/hexane to give (1S,4S) -5- { [ (1R, 4S) -4- (2, 5-dimethyl-1H-pyrrol-1-yl) -1-ethylcyclopent-2-en-1-yl]Carbonyl } -2, 5-diazabicyclo [2.2.1]Tert-butyl heptane-2-carboxylate as a white foam (8.14g, 70%).¹H NMR(400MHz，CDCl₃)δppm6.24-6.17(1H)，5.90-5.86(1H)，5.73-5.68(2H)，5.34-5.22(1H)，5.02-4.41(2H)，3.71-3.24(4H)，2.61-2.39(1H)，2.27-2.16(7H)，1.89-1.59(4H)，1.49-1.32(9H)，0.95-0.85(3H)。

And 4, step 4: preparation of tert-butyl (1S,4S) -5- { [ (1R, 4S) -4-amino-1-ethylcyclopent-2-en-1-yl ] carbonyl } -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylate

(1S,4S) -5- { [ (1R, 4S) -4- (2, 5-dimethyl-1H-pyrrol-1-yl) -1-ethylcyclopent-2-en-1-yl) -1-yl is treated with hydroxylamine hydrochloride (2.73g, 39.1mmol) and a 50% by weight hydroxylamine solution (2.4ml, 39.2mmol)]Carbonyl } -2, 5-diazabicyclo [2.2.1]A solution of tert-butyl heptane-2-carboxylate (2.61g, 6.3mmol) in methanol (40ml) and water (10 ml). The reaction was stirred under nitrogen and heated to 68 ℃ for 38.5 hours. The reaction was cooled to room temperature, diluted with water, and basified by addition of 2.5n naoh (pH 11). The reaction mixture was extracted with ethyl acetate (3 × 100ml), washed with brine, over MgSO₄Drying and concentration under reduced pressure gave (1S,4S) -5- { [ (1R, 4S) -4-amino-1-ethylcyclopent-2-en-1-yl]Carbonyl } -2, 5-diazabicyclo [2.2.1]Crude mixture of tert-butyl heptane-2-carboxylate as yellow oil (2.68g, theoretical yield 2.12g), which was purified without further purificationUsed in the next step.

And 5: preparation of tert-butyl (1S,4S) -5- { [ (1S, 3R) -3-amino-1-ethylcyclopentyl ] carbonyl } -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylate

A mixture of tert-butyl (1S,4S) -5- { [ (1R, 4S) -4-amino-1-ethylcyclopent-2-en-1-yl ] carbonyl } -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylate (2.12g, 6.32mmol) and 5% palladium on charcoal in methanol (35ml) was stirred at room temperature under 48psi of hydrogen for 21 hours. The reaction was filtered through celite and the filter cake was washed with methanol. The filtrate and washings were concentrated under reduced pressure to give tert-butyl (1S,4S) -5- { [ (1S, 3R) -3-amino-1-ethylcyclopentyl ] carbonyl } -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylate as a brown oil/foam (2.46g, theoretical yield 2.13g), which was used in the next step without further purification.

Step 6: preparation of (1S,4S) -tert-butyl 5- ((1S, 3R) -1-ethyl-3- ((3S, 4R) -3-methoxy-tetrahydro-2H-pyran-4-ylamino) cyclopentanecarbonyl) -2, 5-diaza-bicyclo [2.2.1] heptane-2-carboxylate

Treatment of (1S,4S) -5- { [ (1S, 3R) -3-amino-1-ethylcyclopentyl ] with sodium triacetoxyborohydride (2.36g, 11.1mmol) and 3R) -3-methoxytetrahydro-4H-pyran-4-one (0.76g, 7.6mmol)]Carbonyl } -2, 5-diazabicyclo [2.2.1]A solution of tert-butyl heptane-2-carboxylate (1.58g, 4.7mmol) in dichloromethane (25ml) at 0 ℃. The reaction was stirred at 0 ℃ under nitrogen for 30 minutes, then warmed to room temperature and stirred for 15 hours. The reaction was treated with 2.5N NaOH (10mL) and stirred for 10 min. The reaction was diluted with water and the layers were separated. The aqueous layer was extracted 2 times with ethyl acetate. Under reduced pressureThe dichloromethane layer was concentrated and partitioned between ethyl acetate and water. The combined organic layers were washed with brine and MgSO₄Drying, concentration under reduced pressure, and purification with Biotage (0-100% methanol/ethyl acetate, 15 column volumes) afforded the desired product, 1, 5-anhydro-3- { [ (1R,3S) -3- { [ (1S,4S) -5- (tert-butoxycarbonyl) -2, 5-diazabicyclo [2.2.1]]Hept-2-yl]Carbonyl } -3-ethylcyclopentyl]Amino } -2, 3-dideoxy-4-O-methyl-D-erythro-pentitol. LC/MS (M + H) 452.3124 expected, 452.3135 measured;¹H NMR(400MHz，CDCl₃)δppm 4.94-4.41(2H)，4.11-4.04(1H)，3.97-3.91(1H)，3.53-3.18(11H)，2.83-2.75(1H)，2.60-2.30(1H)，2.03-1.55(10H)，1.48-1.37(11H)，0.85-0.78(3H)

and 7: preparation of (1S,4S) -2, 5-diaza-bicyclo [2.2.1] heptan-2-yl ((1S, 3R) -1-ethyl-3- ((3S, 4R) -3-methoxy-tetrahydro-2H-pyran-4-ylamino) cyclopentyl) methanone

To (1S,4S) -tert-butyl 5- ((1S, 3R) -1-ethyl-3- ((3S, 4R) -3-methoxy-tetrahydro-2H-pyran-4-ylamino) cyclopentanecarbonyl) -2, 5-diaza-bicyclo [2.2.1]Heptane-2-carboxylate (1.22g, 2.89mmol) in 1, 4-bisTo a solution in an alkane (15ml) was added 4N HCl/1, 4-bisAlkane (15 ml). The reaction was stirred at room temperature for 18 hours. The liquid was decanted to leave a gummy solid, which was dissolved in methanol and concentrated under reduced pressure. The residue was dissolved in dichloromethane and concentrated to give the product HCl salt as a brown foam (1.23g, theoretical yield 1.03g), which was used in the next step without further purification.

And 8: preparation of 1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3-ethyl-3- ({ (1S,4S) -5- [4- (trifluoromethyl) pyridin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol

To (1S,4S) -2, 5-diaza-bicyclo [2.2.1]To a solution of the HCl salt of hept-2-yl ((1S, 3R) -1-ethyl-3- ((3S, 4R) -3-methoxy-tetrahydro-2H-pyran-4-ylamino) cyclopentyl) methanone (118mg, 0.33mmol) in DMSO (2ml) were added triethylamine (0.15ml, 1.08mmol) and 2-chloro-4- (trifluoromethyl) pyridine (183mg, 1.01 mmol). The reaction was heated to 120 ℃ for 15 hours. The reaction was cooled to room temperature and added to stirred ice water. The mixture was extracted with ethyl acetate (3 ×). The combined organic phases were washed with brine, MgSO₄Dry, concentrate under reduced pressure and purify with Biotage (0-100% methanol/ethyl acetate, 15 column volumes) to give the product as a brown foam (40mg 26%). LC/MS (M + H) 497.2739 expected, 497.2884 measured;¹H NMR(400MHz，CDCl₃)δppm 8.25-8.24(1H)，6.75-6.74(1H)，6.51-6.45(1H)，5.13-4.76(2H)，4.10-4.03(1H)，3.95-3.90(1H)，3.72-3.16(11H)，2.82-2.67(1H)，2.58-2.36(1H)，2.06-1.36(12H)，0.86-0.67(3H)

example 2

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3-ethyl-3- ({ (1S,4S) -5- [4- (trifluoromethyl) pyrimidin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol

It was prepared as described in example 1, substituting 2-chloro-4- (trifluoromethyl) pyridine with 2-chloro-4- (trifluoromethyl) pyrimidine and modifying step 8 as follows.

The HCl salt of the amine (91mg, 0.25mmol) was charged with 1, 4-bisAlkane (3ml) in a flask. Triethylamine (0.12ml, 0.86mmol) and 2-chloro-4- (trifluoromethyl) pyrimidine (148mg, 0.81mmol) were added. DMSO (0.3ml) was added for dissolution and the reaction was heated to 100 ℃ for 20 hours. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic phases were washed with brine, MgSO₄Dry, concentrate under reduced pressure and purify with Biotage (0-100% methanol/ethyl acetate, 15 column volumes) to give the product as a brown foam (43mg, 58%). LC/MS (M + H) 498.2692 expected, 498.2799 measured;¹H NMR(400MHz，CDCl₃)δppm 8.48-8.47(1H)，6.80-6.78(1H)，5.16-4.71(2H)，4.09-4.00(1H)，3.93-3.86(1H)，3.70-3.51(3H)，3.45-3.13(8H)，2.85-2.66(1H)，2.60-2.33(1H)，2.06-1.35(12H)，0.87-0.66(3H)

example 3

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3-ethyl-3- ({ (1S,4S) -5- [6- (trifluoromethyl) pyrimidin-4-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol

It was prepared as described in example 1, substituting 4-chloro-6- (trifluoromethyl) pyrimidine for 2-chloro-4- (trifluoromethyl) pyridine and modifying step 8 as follows. The HCl salt of the amine (227mg, 0.63mmol) was charged with 1, 4-bisAlkane (3ml) in a flask. To which is stirredAdding the mixture into the solution, dissolving in 1, 4-bisXantphos (26mg, 0.045mmol), Pd in alkane (1ml)₂(dba)₃(39mg，0.042mmol)、Cs₂CO₃(258mg, 0.79mmol) and 4-chloro-6- (trifluoromethyl) pyrimidine (261mg, 1.43 mmol). DMSO (0.3ml) was added for dissolution and the reaction was heated to 100 ℃ for 15 hours. The reaction was cooled to room temperature and filtered through celite. The filtrate was concentrated under reduced pressure and purified by Biotage (0-100% methanol/ethyl acetate, 15 column volumes) to give the product as a brown foam (93mg, 37%). LC/MS (M + H) 498.2692 expected, 498.2853 measured;¹HNMR(400 MHz，CDCl₃)δ ppm 8.63(1H)，6.76-6.42(1H)，5.31-4.54(2H)，4.12-4.03(1H)，3.96-3.85(1H)，3.72-3.15(11H)，2.80-2.66(1H)，2.57-2.35(1H)，2.09-1.33(12H)，0.88-0.64(3H)

example 4

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3-ethyl-3- ({ (1S,4S) -5- [6- (trifluoromethyl) pyrazin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol

Its preparation is as described in example 3, wherein 2-iodo-6- (trifluoromethyl) pyrazine is used in place of 4-chloro-6- (trifluoromethyl) pyrimidine in step 8. LC/MS (M + H) 498.2692 expected, 498.2867 measured;¹H NMR(400 MHz，CDCl₃)δ ppm 8.16(1H)，8.05-7.97(1H)，5.18-4.78(2H)，4.12-4.02(1H)，3.99-3.88(1H)，3.74-3.14(11H)，2.82-2.66(1H)，2.61-2.36(1H)，2.07-1.36(12H)，0.86-0.68(3H)

example 5

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3-ethyl-3- ({ (1S,4S) -5- [2- (trifluoromethyl) pyrimidin-4-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol

Its preparation is as described in example 3, wherein 4-chloro-6- (trifluoromethyl) pyrimidine in step 8 is replaced by 4-chloro-2- (trifluoromethyl) pyrimidine. LC/MS (M + H) 498.2692 expected, 498.2839 measured;¹H NMR(400MHz，CDCl₃)δppm 8.24-8.22(1H)，6.54-6.19(1H)，5.31-4.50(2H)，4.09-4.00(1H)，3.90-3.85(1H)，3.72-3.17(11H)，2.78-2.62(1H)，2.55-2.35(1H)，2.04-1.32(12H)，0.85-0.63(3H)

example 6

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3-ethyl-3- ({ (1S,4S) -5- [6- (trifluoromethyl) pyridin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol

It was prepared as described in example 1, substituting 2-chloro-6- (trifluoromethyl) pyridine for 4-chloro-6- (trifluoromethyl) pyrimidine in step 8. LC/MS (M + H) 497.2739 expected, 497.2641 measured;¹H NMR(400MHz，CDCl₃)δppm 7.56-7.52(1H)，6.92-6.90(1H)，6.52-6.41(1H)，5.11-4.73(2H)，4.08-4.03(1H)，3.95-3.89(1H)，3.73-3.13(11H)，2.82-2.64(1H)，2.58-2.35(1H)，2.05-1.35(12H)，0.85-0.66(3H)

example 7

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3-ethyl-3- ({ (1S,4S) -5- [2- (trifluoromethyl) pyridin-4-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol

Its preparation is as described in example 3, wherein 4-chloro-6- (trifluoromethyl) pyrimidine in step 8 is replaced with 4-iodo-2- (trifluoromethyl) pyridine. LC/MS (M + H) 497.2739 expected, 497.2878 measured;¹H NMR(400MHz，CDCl₃)δppm 8.30-8.28(1H)，6.76-6.69(1H)，6.52-6.44(1H)，5.16-4.79(1H)，4.54(1H)，4.07-4.04(1H)，3.93-3.90(1H)，3.68-3.14(11H)，2.81-2.64(1H)，2.59-2.31(1H)，2.08-1.35(12H)，0.87-0.65(3H)

example 8

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3-ethyl-3- ({ (1S,4S) -5- [ 3-fluoro-4- (trifluoromethyl) pyridin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol

Its preparation is as described in example 3, wherein 2-chloro-3-fluoro-4- (trifluoromethyl) pyridine is used instead of 4-chloro-6- (trifluoromethyl) pyrimidine in step 8. LC/MS (M + H) 515.2645 expected, 515.2772 measured;¹H NMR(400MHz，CDCl₃)δppm 8.00-7.99(1H)，6.75-6.73(1H)，5.09-4.69(2H)，4.09-4.04(1H)，3.96-3.90(1H)，3.86-3.78(1H)，3.69-3.53(3H)，3.42-3.17(7H)，2.81-2.68(1H)，2.57-2.38(1H)，2.04-1.36(12H)，0.88-0.69(3H)

example 9

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3-methyl-3- ({ (1S,4S) -5- [4- (trifluoromethyl) pyridin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol

Its preparation is as described in example 1, where methyl iodide is used in place of ethyl iodide in step 1. LC/MS (M + H) 483.2583 expected, 483.2543 measured;¹H NMR(400MHz，CDCl₃) Delta ppm of 8.25-8.24(1H), 6.75-6.74(1H), 6.51-6.45(1H), 5.09-4.76(2H), 4.09-4.03(1H), 3.96-3.90(1H), 3.70-3.23(11H), 2.81-2.65(1H), 2.53-2.27(1H), 2.07-1.02 (13H); HRMS M/z 483.2543 (calculate M + H, 483.2583).

Example 10

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3-methyl-3- ({ (1S,4S) -5- [6- (trifluoromethyl) pyrazin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol

It was prepared as described in example 3, substituting methyl iodide for ethyl iodide in step 1 and 2-iodo-6- (trifluoromethyl) pyrazine for 4-chloro-6- (trifluoromethyl) pyrimidine in step 8. LC/MS (M + H) 483.2583 expected, 483.2543 measured;¹H NMR(400MHz，CDCl₃)δppm 8.25-8.24(1H)，6.75-6.74(1H)，6.51-6.45(1H)，5.09-4.76(2H)，4.09-4.03(1H)，3.96-3.90(1H)，3.70-3.23(11H)，2.81-2.65(1H)，2.53-2.27(1H)，2.07-1.02(13H)

example 11

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3-isopropyl-3- ({ (1S,4S) -5- [4- (trifluoromethyl) pyridin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol

It was prepared as described in example 1, starting from (1S,4S) -4- (2, 5-dimethyl-1H-pyrrol-1-yl) -1-isopropylcyclopent-2-ene-1-carboxylic acid and skipping steps 1 and 2. LC/MS (M + H) 511.2896 expected, 511.3218 measured;¹H NMR(400MHz，CDCl₃)δppm 8.23-8.22(1H)，6.73-6.72(1H)，6.49-6.44(1H)，5.11-4.73(2H)，4.06-4.03(1H)，3.92-3.89(1H)，3.67-3.52(2H)，3.44-3.22(8H)，3.12-3.03(1H)，2.80-2.61(1H)，2.51-2.40(1H)，2.09-1.72(6H)，1.68-1.42(4H)，1.35-1.25(1H)，0.92-0.75(6H)

example 12

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3-isopropyl-3- ({ (1S,4S) -5- [4- (trifluoromethyl) pyrimidin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol

It was prepared as described in example 2, starting from (1S,4S) -4- (2, 5-dimethyl-1H-pyrrol-1-yl) -1-isopropylcyclopent-2-ene-1-carboxylic acid and skipping steps 1 and 2. LC/MS (M + H) 512.2849 expected, 512.2827 measured;¹H NMR(400MHz，CDCl₃)δppm 8.45-8.44(1H)，6.77-6.76(1H)，5.09-4.71(2H)，4.07-4.01(1H)，3.92-3.87(1H)，3.67-3.51(3H)，3.42-3.23(7H)，3.15-3.08(1H)，2.83-2.76(1H)，2.58-2.33(2H)，2.11-1.56(8H)，1.51-1.42(1H)，1.38-1.30(1H)，0.91-0.74(6H)

example 13

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3-isopropyl-3- ({ (1S,4S) -5- [6- (trifluoromethyl) pyrimidin-4-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol

It was prepared as described in example 3, starting from (1S,4S) -4- (2, 5-dimethyl-1H-pyrrol-1-yl) -1-isopropylcyclopent-2-ene-1-carboxylic acid and skipping steps 1 and 2. LC/MS (M + H) 512.2849 expected, 512.3227 measured;¹H NMR(400MHz，CDCl₃)δppm 8.61(1H)，6.73-6.44(1H)，5.25-4.52(2H)，4.05-4.01(1H)，3.91-3.86(1H)，3.68-3.46(2H)，3.38-3.17(8H)，3.10-3.03(1H)，2.76-2.63(1H)，2.48-2.37(1H)，2.07-1.39(10H)，1.34-1.23(1H)，0.90-0.74(6H)

example 14

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3-isopropyl-3- ({ (1S,4S) -5- [6- (trifluoromethyl) pyrazin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol

It was prepared as described in example 3, starting from (1S,4S) -4- (2, 5-dimethyl-1H-pyrrol-1-yl) -1-isopropylcyclopent-2-ene-1-carboxylic acid and skipping steps 1 and 2 and replacing 4-chloro-6- (trifluoromethyl) pyrimidine in step 8 with 2-iodo-6- (trifluoromethyl) pyrazine. LC/MS (M + H) 512.2849 expected, 512.3221 measured;¹H NMR(400MHz，CDCl₃)δppm 8.12(1H)，8.01-7.97(1H)，5.14-4.75(2H)，4.05-4.01(1H)，3.90-3.87(1H)，3.67-3.56(2H)，3.44-3.20(8H)，3.11-3.02(1H)，2.78-2.60(1H)，2.48-2.39(1H)，2.10-1.86(4H)，1.82-1.71(2H)，1.68-1.53(2H)，1.50-1.38(2H)，1.33-1.24(1H)，0.91-0.74(6H)

example 15

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3-isopropyl-3- ({ (1S,4S) -5- [2- (trifluoromethyl) pyrimidin-4-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol

It was prepared as described in example 3, starting from (1S,4S) -4- (2, 5-dimethyl-1H-pyrrol-1-yl) -1-isopropylcyclopent-2-ene-1-carboxylic acid and skipping steps 1 and 2 and replacing 4-chloro-6- (trifluoromethyl) pyrimidine in step 8 with 4-chloro-2- (trifluoromethyl) pyrimidine. LC/MS (M + H) 512.2849 expected, 512.2891 measured;¹H NMR(400MHz，CDCl₃)δppm 8.25-8.24(1H)，6.52-6.23(1H)，5.30-4.47(2H)，4.05-4.02(1H)，3.91-3.88(1H)，3.70-3.54(2H)，3.52-3.18(8H)，3.12-3.03(1H)，2.78-2.61(1H)，2.49-2.39(1H)，2.08-1.85(5H)，1.82-1.72(1H)，1.68-1.41(4H)，1.35-1.24(1H)，0.93-0.75(6H)

example 16

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3-isopropyl-3- ({ (1S,4S) -5- [6- (trifluoromethyl) pyridin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol

It was prepared as described in example 1, starting from (1S,4S) -4- (2, 5-dimethyl-1H-pyrrol-1-yl) -1-isopropylcyclopent-2-ene-1-carboxylic acid and skipping steps 1 and 2 and replacing 2-chloro-4- (trifluoromethyl) pyridine in step 8 with 2-chloro-6- (trifluoromethyl) pyridine. LC/MS (M + H) 511.2896 expected,511.2856 measured value;¹H NMR(400MHz，CDCl₃)δppm 7.54-7.50(1H)，6.90-6.88(1H)，6.50-6.41(1H)，5.08-4.70(2H)，4.08-3.99(1H)，3.94-3.87(1H)，3.73-3.46(2H)，3.46-3.13(8H)，3.13-2.97(1H)，2.81-2.58(1H)，2.52-2.38(1H)，2.10-1.70(5H)，1.70-1.40(5H)，1.36-1.25(1H)，0.94-0.73(6H)

0.75(6H)

example 17

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3-isopropyl-3- ({ (1S,4S) -5- [2- (trifluoromethyl) pyridin-4-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol

It was prepared as described in example 3, starting from (1S,4S) -4- (2, 5-dimethyl-1H-pyrrol-1-yl) -1-isopropylcyclopent-2-ene-1-carboxylic acid and skipping steps 1 and 2 and replacing 2-chloro-4- (trifluoromethyl) pyridine in step 8 with 4-iodo-2- (trifluoromethyl) pyridine. LC/MS (M + H) 511.2896 expected, 511.2958 measured;¹H NMR(400MHz，CDCl₃)δppm 8.27-8.26(1H)，6.72-6.69(1H)，6.49-6.44(1H)，5.09-4.75(1H)，4.52(1H)，4.05-4.02(1H)，3.91-3.88(1H)，3.65-3.50(3H)，3.41-3.03(8H)，2.78-2.55(1H)，2.49-2.35(1H)，2.08-1.87(4H)，1.84-1.72(2H)，1.68-1.53(2H)，1.51-1.38(2H)，1.34-1.26(1H)，0.92-0.75(6H)

example 18

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3-isopropyl-3- ({ (1S,4S) -5- [5- (trifluoromethyl) pyridazin-3-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol

It was prepared as described in example 2, starting from (1S,4S) -4- (2, 5-dimethyl-1H-pyrrol-1-yl) -1-isopropylcyclopent-2-ene-1-carboxylic acid and skipping steps 1 and 2 and replacing 2-chloro-4- (trifluoromethyl) pyrimidine in step 8 with 3-chloro-5- (trifluoromethyl) pyridazine. LC/MS (M + H) 512.2849 expected, 512.2864 measured;¹H NMR(400MHz，CDCl₃)δppm 8.73(1H)，6.75-6.68(1H)，5.32-4.79(2H)，4.07-4.04(1H)，3.93-3.89(1H)，3.80-3.55(2H)，3.52-3.16(8H)，3.13-3.03(1H)，2.82-2.63(1H)，2.51-2.38(1H)，2.09-1.42(10H)，1.36-1.24(1H)，0.93-0.75(6H)

example 19

1, 5-anhydro-3- { [ (1R,3S) -3-isopropyl-3- ({ (1S,4S) -5- [2, 6-bis (trifluoromethyl) pyridin-4-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) -3-isopropylcyclopentyl ] amino } -2, 3-dideoxy-4-O-methyl-D-erythro-pentitol

It was prepared as described in example 3, starting from (1S,4S) -4- (2, 5-dimethyl-1H-pyrrol-1-yl) -1-isopropylcyclopent-2-ene-1-carboxylic acid and skipping steps 1 and 2 and replacing 4-chloro-6- (trifluoromethyl) pyrimidine in step 8 with 4-chloro-2, 6-bis (trifluoromethyl) pyridine. LC/MS (M + H) 579.2770 expected, 579.2667 measured;¹H NMR(400MHz，CDCl₃)δppm 6.94-6.67(2H)，5.17-4.78(1H)，4.60(1H)，4.06-4.04(1H)，3.92-3.89(1H)，3.68-3.57(2H)，3.42-3.16(8H)，3.13-3.05(1H)，2.79-2.62(1H)，2.48-2.37(1H)，2.08-1.86(3H)，1.83-1.54(6H)，1.52-1.42(1H)，1.37-1.24(1H)，0.92-0.76(6H)

example 20

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3- ({ (1S,4S) -5- [ 3-fluoro-4- (trifluoromethyl) pyridin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) -3-isopropylcyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol

It was prepared as described in example 3, starting from (1S,4S) -4- (2, 5-dimethyl-1H-pyrrol-1-yl) -1-isopropylcyclopent-2-ene-1-carboxylic acid and skipping steps 1 and 2 and replacing 4-chloro-6- (trifluoromethyl) pyrimidine in step 8 with 2-chloro-3-fluoro-4- (trifluoromethyl) pyridine. LC/MS (M + H) 529.2802 expected, 529.3431 measured;¹H NMR(400MHz，CDCl₃)δppm7.98-7.97(1H)，6.73-6.71(1H)，5.07-4.67(2H)，4.08-4.02(1H)，3.94-3.88(1H)，3.84-3.78(1H)，3.64-3.47(3H)，3.40-3.21(6H)，3.13-3.04(1H)，2.80-2.69(1H)，2.49-2.39(1H)，2.10-1.56(9H)，1.54-1.42(1H)，1.37-1.28(1H)，0.92-0.75(6H)

example 21

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3-isopropyl-3- ({ (1S,4S) -5- [ 6-methyl-4- (trifluoromethyl) pyridin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol

It was prepared as described in example 3, starting from (1S,4S) -4- (2, 5-dimethyl-1H-pyrrol-1-yl) -1-isopropylcyclopent-2-ene-1-carboxylic acid and skipping steps 1 and 2 and replacing 4-chloro-6- (trifluoromethyl) pyrimidine in step 8 with 2-chloro-6-methyl-4- (trifluoromethyl) pyridine. LC/MS (M + H) 525.3052 expected, 525.3242 measured;¹H NMR(400MHz，CDCl₃)δppm6.61(1H)，6.29-6.24(1H)，5.14-4.71(2H)，4.17-4.04(2H)，3.98-3.90(1H)，3.70-3.49(3H)，3.48-3.13(7H)，2.91-2.72(1H)，2.50-2.32(4H)，2.11-1.39(11H)，0.94-0.71(6H)

example 22

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3-isopropyl-3- ({ (1S,4S) -5- [3- (trifluoromethyl) phenyl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol

It was prepared as described in example 3, starting from (1S,4S) -4- (2, 5-dimethyl-1H-pyrrol-1-yl) -1-isopropylcyclopent-2-ene-1-carboxylic acid and skipping steps 1 and 2 and replacing 4-chloro-6- (trifluoromethyl) pyrimidine in step 8 with 3-iodo-trifluorotoluene. LC/MS (M + H) 510.2943 expected, 510.2976 measured;¹H NMR(400MHz，CDCl₃)δppm 7.30-7.25(1H)，6.92-6.90(1H)，6.72-6.65(2H)，5.06-4.68(1H)，4.44(1H)，4.07-3.99(1H)，3.94-3.86(1H)，3.71-3.51(2H)，3.48-3.19(7H)，3.14-3.01(1H)，2.81-2.69(1H)，2.61-2.35(1H)，2.09-1.54(9H)，1.51-1.40(1H)，1.35-1.27(1H)，0.94-0.72(6H)

example 23

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3- ({ (1S,4S) -5- [ 3-fluoro-5- (trifluoromethyl) phenyl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) -3-isopropylcyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol

It was prepared as described in example 3, starting from (1S,4S) -4- (2, 5-dimethyl-1H-pyrrol-1-yl) -1-isopropylcyclopent-2-ene-1-carboxylic acid and skipping steps 1 and 2 and replacing 4-chloro-6- (trifluoromethyl) benzotrifluoride in step 8 with 3-bromo-5-fluorotrifluorotoluene) A pyrimidine. LC/MS (M + H) 528.2849 expected, 528.2996 measured;¹H NMR(400MHz，CDCl₃)δppm 6.61-6.58(1H)，6.48(1H)，6.35-6.33(1H)，5.06-4.69(1H)，4.39(1H)，4.06-4.00(1H)，3.94-3.86(1H)，3.65-3.50(2H)，3.46-3.15(7H)，3.12-3.00(1H)，2.80-2.70(1H)，2.49-2.32(1H)，2.06-1.73(6H)，1.69-1.40(4H)，1.36-1.27(1H)，0.94-0.72(6H)

scheme 2 preparation of examples 24-44

Example 24

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3- (2, 2-difluoroethyl) -3- ({ (1S,4S) -5- [6- (trifluoromethyl) pyrimidin-4-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol

Step 1: preparation of 2, 2-difluoroethyl trifluoromethanesulfonate

Trifluoromethanesulfonic anhydride (27.9g, 99.1mmol) was placed in a flask and cooled with an ice bath. 2, 2-Difluoroethanol (8.1g, 99.1mmol) was added and the reaction heated to 84 ℃ for 1 hour. The reaction was cooled in an ice bath and 100ml of cold 5% NaHCO was poured in₃In solution. The mixture was extracted with diethyl ether over MgSO₄Dried and concentrated under reduced pressure to remove ether. The residue was distilled under vacuum to give 2, 2-difluoroethyl trifluoromethanesulfonate as a clear liquid(13.6g, 64%, b.p.. degree.55 ℃ C.).¹H NMR(400MHz，CDCl₃)δppm 6.17-5.88(1H)，4.61-4.13(2H)

Step 2: preparation of methyl (1S,4S) -1- (2, 2-difluoroethyl) -4- (2, 5-dimethyl-1H-pyrrol-1-yl) cyclopent-2-ene-1-carboxylate

A-40 ℃ solution of 2M (in ethylbenzene/THF/heptane) LDA (36ml, 72mmol) in THF (80ml) was placed in a flask containing THF (80ml) and treated with a solution of methyl (1R, 4S) -4- (2, 5-dimethyl-1H-pyrrol-1-yl) cyclopent-2-ene-1-carboxylate (7.9g, 36.3mmol) in THF (17ml) while maintaining the temperature below-32 ℃. The reaction was stirred for 30min, then 2, 2-difluoroethyl triflate was added slowly, maintaining the temperature < -28 ℃. The reaction was stirred for 4 hours under an in situ cold water bath and allowed to warm slowly. After 4 hours, the reaction was poured into NH₄Cl solution and extracted 2 times with ethyl acetate. The combined organic phases were washed with brine, MgSO₄Dried and concentrated to give a brown oil. The oil was passed through a silica gel column using 10% ethyl acetate/hexane to give methyl (1S,4S) -1- (2, 2-difluoroethyl) -4- (2, 5-dimethyl-1H-pyrrol-1-yl) cyclopent-2-ene-1-carboxylate as a brown oil. (7.5g, 73%).¹H NMR(400MHz，CDCl₃)δppm 6.07-6.04(1H)，6.02-6.00(0.25H)5.98-5.96(1H)，5.88-5.86(0.5H)，5.75-5.72(2.25H)，5.36-5.30(1H)，3.74(3H)，2.53-2.41(2H)，2.39-2.22(2H)，2.19(6H)

And step 3: preparation of (1S,4S) -1- (2, 2-difluoroethyl) -4- (2, 5-dimethyl-1H-pyrrol-1-yl) cyclopent-2-ene-1-carboxylic acid

A solution of methyl (1S,4S) -1- (2, 2-difluoroethyl) -4- (2, 5-dimethyl-1H-pyrrol-1-yl) cyclopent-2-ene-1-carboxylate (7.54g, 26.6mmol) in methanol (60ml) was treated with 2.5N NaOH (15ml, 37.5mmol) and stirred at room temperature for 22H. The methanol was removed under reduced pressure and the residue was partitioned between diethyl ether and water. The layers were separated and the aqueous layer was acidified with 4N HCl, extracted with ethyl acetate, washed with brine, and over MgSO₄Dried and concentrated under reduced pressure to give (1S,4S) -1- (2, 2-difluoroethyl) -4- (2, 5-dimethyl-1H-pyrrol-1-yl) cyclopent-2-ene-1-carboxylic acid as a brown oil (6.59g, 92%).¹H NMR(400MHz，CDCl₃)δppm 6.12-6.09(1H)，6.07-6.05(0.25H)，5.99-5.96(1H)，5.93-5.91(0.5H)，5.79-5.76(0.25H)，5.74(2H)，5.38-5.32(1H)，2.54-2.46(2H)，2.43-2.25(2H)，2.20(6H)。

And 4, step 4: preparation of tert-butyl (1S,4S) -5- { [ (1S,4S) -1- (2, 2-difluoroethyl) -4- (2, 5-dimethyl-1H-pyrrol-1-yl) cyclopent-2-en-1-yl ] carbonyl } -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylate

BOP ═ benzotriazole-1-yloxytris (dimethylamino) phosphineHexafluorophosphate esters

A solution of (1S,4S) -1- (2, 2-difluoroethyl) -4- (2, 5-dimethyl-1H-pyrrol-1-yl) cyclopent-2-ene-1-carboxylic acid (6.12g, 22.6mmol) in DMF (45ml) was treated with N, N-diisopropylethylamine (11.7ml, 67.2mmol) and BOP (11.93g, 27.0mmol) and stirred at room temperature for 40 minutes under nitrogen. Adding (1S,4S) -2-BOC-2, 5-diazabicyclo [2.2.1]Heptane (4.46g, 22.5mmol) and the reaction was stirred for 18 hours. The reaction was diluted with ethyl acetate (100ml) and 60% saturated NaHCO₃(125ml) washing. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, and dried over sodium sulfateMgSO₄Dried and concentrated under reduced pressure to give a brown oil (16.8 g). The oil was passed through a silica gel column using 50% ethyl acetate/hexane to give (1S,4S) -5- { [ (1S,4S) -1- (2, 2-difluoroethyl) -4- (2, 5-dimethyl-1H-pyrrol-1-yl) cyclopent-2-en-1-yl]Carbonyl } -2, 5-diazabicyclo [2.2.1]Tert-butyl heptane-2-carboxylate as a brown foam (7.86g, 78%).¹H NMR(400MHz，CDCl₃)δppm6.25-6.19(1H)，6.04-5.96(1.25H)，5.85-5.81(0.5H)，5.74-5.68(2.25H)，5.37-5.25(1H)，4.98-4.43(2H)，3.73-3.29(4H)，2.77-2.29(2H)，2.26-2.09(8H)，1.93-1.67(2H)，1.46-1.34(9H)。

And 5: preparation of tert-butyl (1S,4S) -5- { [ (1S,4S) -4-amino-1- (2, 2-difluoroethyl) cyclopent-2-en-1-yl ] carbonyl } -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylate

Treatment of (1S,4S) -5- { [ (1S,4S) -1- (2, 2-difluoroethyl) -4- (2, 5-dimethyl-1H-pyrrol-1-yl) cyclopent-2-en-1-yl) with hydroxylamine hydrochloride (6.35g, 91.0mmol) and a 50 wt% hydroxylamine solution (5.0ml, 81.6mmol)]Carbonyl } -2, 5-diazabicyclo [2.2.1]A solution of tert-butyl heptane-2-carboxylate (7.86g, 17.5mmol) in methanol (100ml) and water (30 ml). The reaction was stirred under nitrogen and heated to 66 ℃ for 39 hours. The reaction was cooled to room temperature, diluted with water, and basified by addition of 2.5n naoh (pH 11). The reaction mixture was extracted with ethyl acetate (3 × 150ml), washed with brine, over MgSO₄Drying and concentration under reduced pressure gave (1S,4S) -5- { [ (1S,4S) -4-amino-1- (2, 2-difluoroethyl) cyclopent-2-en-1-yl]Carbonyl } -2, 5-diazabicyclo [2.2.1]The crude mixture of tert-butyl heptane-2-carboxylate, as a brown oil (9.12g, theoretical yield 6.50g), was used in the next step without further purification.

Step 6: preparation of tert-butyl (1S,4S) -5- { [ (1S, 3R) -3-amino-1- (2, 2-difluoroethyl) cyclopentyl ] carbonyl } -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylate

A mixture of tert-butyl (1S,4S) -5- { [ (1S,4S) -4-amino-1- (2, 2-difluoroethyl) cyclopent-2-en-1-yl ] carbonyl } -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylate (6.50g, 17.5mmol) and 5% palladium on charcoal in methanol (100ml) was stirred at room temperature under 46psi of hydrogen for 21 hours. The reaction was filtered through celite and the filter cake was washed with methanol. The filtrate and washings were concentrated under reduced pressure to give tert-butyl (1S,4S) -5- { [ (1S, 3R) -3-amino-1- (2, 2-difluoroethyl) cyclopentyl ] carbonyl } -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylate as a brown oil (6.67g, theoretical yield 6.54g), which was used in the next step without further purification.

And 7: preparation of 1, 5-anhydro-3- { [ (1R,3S) -3- { [ (1S,4S) -5- (tert-butoxycarbonyl) -2, 5-diazabicyclo [2.2.1] hept-2-yl ] carbonyl } -3- (2, 2-difluoroethyl) cyclopentyl ] amino } -2, 3-dideoxy-4-O-methyl-D-erythro-pentitol

Treatment of (1S,4S) -5- { [ (1S, 3R) -3-amino-1- (2, 2-difluoroethyl) cyclopentyl ] with sodium triacetoxyborohydride (5.34g, 25.2mmol) and (3R) -3-methoxytetrahydro-4H-pyran-4-one (2.31g, 17.8mmol)]Carbonyl } -2, 5-diazabicyclo [2.2.1]A solution of tert-butyl heptane-2-carboxylate (3.45g, 9.2mmol) in dichloromethane (50ml) at 0 ℃. The reaction was stirred at 0 ℃ under nitrogen for 30 minutes, then warmed to room temperature and stirred for 47 hours. The reaction was treated with 2.5N NaOH (35mL) and stirred for 10 min. The reaction was diluted with water and the layers were separated. The aqueous layer was extracted 2 times with ethyl acetate. The dichloromethane layer was concentrated under reduced pressure and partitioned between ethyl acetate and water. The organic layers were combined, washed with brine, and dried over sodium sulfateMgSO₄Dried, concentrated under reduced pressure and purified by Biotage (0-100% methanol/ethyl acetate, 15 column volumes) to give 1, 5-anhydro-3- { [ (1R,3S) -3- { [ (1S,4S) -5- (tert-butoxycarbonyl) -2, 5-diazabicyclo [2.2.1]Hept-2-yl]Carbonyl } -3- (2, 2-difluoroethyl) cyclopentyl]Amino } -2, 3-dideoxy-4-O-methyl-D-erythro-pentitol (2.13g, 47%) which was used in the next step without further purification.

And 8: preparation of 1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3- { [ (1S,4S) -2, 5-diazabicyclo [2.2.1] hept-2-yl ] carbonyl } -3- (2, 2-difluoroethyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol (HCl salt)

To 1, 5-anhydro-3- { [ (1R,3S) -3- { [ (1S,4S) -5- (tert-butoxycarbonyl) -2, 5-diazabicyclo [2.2.1]]Hept-2-yl]Carbonyl } -3- (2, 2-difluoroethyl) cyclopentyl]Amino } -2, 3-dideoxy-4-O-methyl-D-erythro-pentitol (2.13g, 4.4mmol) in 1, 4-dideTo a solution in an alkane (20ml) was added 4N HCl/1, 4-bisAlkane (20 ml). The reaction was stirred at room temperature for 16 hours. The liquid was decanted to leave a gummy solid, which was dissolved in methanol and concentrated under reduced pressure. The residue was dissolved in methanol/dichloromethane and concentrated to give 1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3- { [ (1S,4S) -2, 5-diazabicyclo [2.2.1]Hept-2-yl]Carbonyl } -3- (2, 2-difluoroethyl) cyclopentyl]HCl salt of amino } -4-O-methyl-D-erythro-pentitol as brown foam (2.23g, theoretical yield 1.85g), which was used in the next step without further purification.

And step 9: preparation of 1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3- (2, 2-difluoroethyl) -3- ({ (1S,4S) -5- [6- (trifluoromethyl) pyrimidin-4-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3- { [ (1S,4S) -2, 5-diazabicyclo [2.2.1]Hept-2-yl]Carbonyl } -3- (2, 2-difluoroethyl) cyclopentyl]HCl salt of amino } -4-O-methyl-D-erythro-pentitol (177mg, 0.42mmol) was charged with 1, 4-diAlkane (3ml) in a flask. Adding the solution dissolved in 1, 4-bisXantphos (36mg, 0.062mmol), Pd in alkane (1ml)₂(dba)₃(22mg，0.024mmol)、Cs₂CO₃(350mg, 1.07mmol) and 4-chloro-6- (trifluoromethyl) pyrimidine (195mg, 1.07 mmol). DMSO (0.5ml) was added for dissolution and the reaction was heated to 100 ℃ for 21.5 hours. The reaction was cooled to room temperature and filtered through celite. The filtrate was concentrated under reduced pressure and purified by Biotage (0-100% methanol/ethyl acetate, 15 column volumes) to give 1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3- (2, 2-difluoroethyl) -3- ({ (1S,4S) -5- [6- (trifluoromethyl) pyrimidin-4-yl]-2, 5-diazabicyclo [2.2.1]Hept-2-yl } carbonyl) cyclopentyl]Amino } -4-O-methyl-D-erythro-pentitol as a white foam (43mg, 20%). LC/MS (M + H) 534.2504 expected, 534.2597 measured;¹H NMR(400MHz，CDCl₃)δppm 8.62(1H)，6.74-6.46(1H)，5.93-5.62(1H)，5.29-4.50(2H)，4.08-4.03(1H)，3.93-3.88(1H)，3.77-3.55(2H)，3.52-3.32(6H)，3.30-3.21(3H)，2.76-2.65(1H)，2.51-2.33(1H)，2.21-1.84(7H)，1.70-1.40(5H)

example 25

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3- (2, 2-difluoroethyl) -3- ({ (1S,4S) -5- [4- (trifluoromethyl) pyridin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol

It is prepared as described in example 24, substituting 2-chloro-4- (trifluoromethyl) pyridine for 4-chloro-6- (trifluoromethyl) pyrimidine in step 9. LC/MS (M + H) 533.2551 expected, 533.2651 measured;¹H NMR(400MHz，CDCl₃)δppm 8.24-8.20(1H)，6.74-6.73(1H)，6.49-6.44(1H)，5.95-5.57(1H)，5.07-4.73(2H)，4.06-4.01(1H)，3.93-3.87(1H)，3.70-3.49(2H)，3.45-3.30(6H)，3.28-3.20(3H)，2.77-2.64(1H)，2.53-2.36(1H)，2.23-1.81(7H)，1.73-1.41(5H)

example 26

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3- (2, 2-difluoroethyl) -3- ({ (1S,4S) -5- [2- (trifluoromethyl) pyridin-4-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol

Its preparation is as described in example 24, where 4-chloro-6- (trifluoromethyl) pyrimidine in step 9 is replaced with 4-iodo-2- (trifluoromethyl) pyridine. LC/MS (M + H) 533.2551 expected, 533.2598 measured;¹H NMR(400MHz，CDCl₃)δppm 8.29-8.27(1H)，6.74-6.70(1H)，6.50-6.43(1H)，5.93-5.59(1H)，5.09-4.74(1H)，4.54(1H)，4.07-4.02(1H)，3.93-3.88(1H)，3.68-3.48(2H)，3.39-3.20(7H)，2.74-2.62(1H)，2.51-2.37(1H)，2.19-1.77(7H)，1.70-1.40(5H)

example 27

It was prepared as described in example 24, substituting 2-chloro-4- (trifluoromethyl) pyrimidine for 4-chloro-6- (trifluoromethyl) pyrimidine and modifying step 9 as follows. 1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3- { [ (1S,4S) -2, 5-diazabicyclo [2.2.1]Hept-2-yl]Carbonyl } -3- (2, 2-difluoroethyl) cyclopentyl]HCl salt of amino } -4-O-methyl-D-erythro-pentitol (175mg, 0.41mmol) was charged with 1, 4-diAlkane (3ml) in a flask. Triethylamine (0.2ml, 1.43mmol) and 2-chloro-4- (trifluoromethyl) pyrimidine (237mg, 1.30mmol) were added. DMSO (0.3ml) was added for dissolution and the reaction was heated to 100 ℃ for 14.5 hours. The reaction was cooled to room temperature and partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic phases were washed with brine, MgSO₄Dried, concentrated under reduced pressure and purified by Biotage (0-100% methanol/ethyl acetate, 15 column volumes) to give 1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3- (2, 2-difluoroethyl) -3- ({ (1S,4S) -5- [4- (trifluoromethyl) pyrimidin-2-yl]-2, 5-diazabicyclo [2.2.1]Hept-2-yl } carbonyl) cyclopentyl]Amino } -4-O-methyl-D-erythro-pentitol as a brown foam (126mg, 58%). LC/MS (M + H) 534.2504 expected, 534.2452 measured;¹H NMR(400MHz，CDCl₃)δppm 8.48-8.45(1H)，6.79-6.78(1H)，5.96-5.58(1H)，5.10-4.71(2H)，4.07-4.01(1H)，3.93-3.87(1H)，3.69-3.55(4H)，3.39-3.32(4H)，3.30-3.21(3H)，2.77-2.66(1H)，2.52-2.40(1H)，2.23-1.82(7H)，1.70-1.39(5H)

example 28

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3- (2, 2-difluoroethyl) -3- ({ (1S,4S) -5- [6- (trifluoromethyl) pyridin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol

It was prepared as described in example 24, substituting 2-chloro-6- (trifluoromethyl) pyridine for 4-chloro-6- (trifluoromethyl) pyrimidine and modifying step 9 as follows. To 1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3- { [ (1S,4S) -2, 5-diazabicyclo [2.2.1]]Hept-2-yl]Carbonyl } -3- (2, 2-difluoroethyl) cyclopentyl]To a solution of HCl salt of amino } -4-O-methyl-D-erythro-pentitol (183mg, 0.43mmol) in DMSO (2ml) were added triethylamine (0.2ml, 1.43mmol) and 2-chloro-6- (trifluoromethyl) pyridine (179mg, 1.05 mmol). The reaction was heated to 120 ℃ for 14.5 hours. The reaction was cooled to room temperature and added to stirred ice water. The mixture was extracted with ethyl acetate (3 ×). The combined organic phases were washed with brine, MgSO₄Dried, concentrated under reduced pressure and purified by Biotage (0-100% methanol/ethyl acetate, 15 column volumes) to give 1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3- (2, 2-difluoroethyl) -3- ({ (1S,4S) -5- [6- (trifluoromethyl) pyridin-2-yl]-2, 5-diazabicyclo [2.2.1]Hept-2-yl } carbonyl) cyclopentyl]Amino } -4-O-methyl-D-erythro-pentitol as a brown foam (58mg 28%). LC/MS (M + H) 533.2551 expected, 533.2546 measured;¹H NMR(400MHz，CDCl₃)δppm 7.54-7.51(1H)，6.91-6.89(1H)，6.51-6.38(1H)，5.94-5.54(1H)，5.11-4.70(2H)，4.06-4.01(1H)，3.93-3.87(1H)，3.70-3.53(2H)，3.51-3.31(6H)，3.27-3.20(3H)，2.78-2.61(1H)，2.53-2.36(1H)，2.20-1.80(7H)，1.68-1.38(5H)

example 29

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3- (2, 2-difluoroethyl) -3- ({ (1S,4S) -5- [6- (trifluoromethyl) pyrazin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol

Its preparation is as described in example 24, where 2-iodo-6- (trifluoromethyl) pyrazine is used instead of 4-chloro-6- (trifluoromethyl) pyrimidine in step 9. LC/MS (M + H) 534.2504 expected, 534.2548 measured;¹H NMR(400MHz，CDCl₃)δppm 8.13(1H)，8.01-7.93(1H)，5.92-5.57(1H)，5.09-4.75(2H)，4.06-4.01(1H)，3.92-3.87(1H)，3.68-3.48(4H)，3.38-3.30(4H)，3.28-3.20(3H)，2.74-2.63(1H)，2.51-2.32(1H)，2.21-1.83(7H)，1.75-1.42(5H)

example 30

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3- (2, 2-difluoroethyl) -3- ({ (1S,4S) -5- [2- (trifluoromethyl) pyrimidin-4-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol

Its preparation is as described in example 24, wherein 4-chloro-6- (trifluoromethyl) pyrimidine in step 9 is replaced by 4-chloro-2- (trifluoromethyl) pyrimidine. LC/MS (M + H) 534.2504 expected, 534.2521 measured;¹H NMR(400MHz，CDCl₃)δppm 8.28-8.26(1H)，6.52-6.24(1H)，5.93-5.62(1H)，5.33-4.38(2H)，4.08-4.03(1H)，3.94-3.89(1H)，3.71-3.57(2H)，3.49-3.33(6H)，3.29-3.21(3H)，2.75-2.66(1H)，2.50-2.36(1H)，2.22-1.86(7H)，1.69-1.41(5H)

example 31

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3- (2, 2-difluoroethyl) -3- ({ (1S,4S) -5- [5- (trifluoromethyl) pyridazin-3-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol

It was prepared as described in example 27, using 3-chloro-5- (trifluoromethyl) pyridazine in place of 2-chloro-4- (trifluoromethyl) pyrimidine in step 9. LC/MS (M + H) 534.2504 expected, 534.2531 measured;¹H NMR(400MHz，CDCl₃)δppm 8.76(1H)，6.74-6.68(1H)，5.96-5.90(1H)，5.37-4.84(2H)，4.10-4.04(1H)，3.96-3.90(1H)，3.81-3.54(3H)，3.47-3.34(4H)，3.32-3.22(4H)，2.77-2.67(1H)，2.51-2.37(1H)，2.22-1.86(7H)，1.72-1.46(5H)

example 32

1, 5-anhydro-2, 3-dideoxy-4-O-methyl-3- { [ (1R,3S) -3- (2,2, 2-trifluoroethyl) -3- ({ (1S,4S) -5- [6- (trifluoromethyl) pyrimidin-4-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -D-erythro-pentitol

It was prepared as described in example 24, substituting 3, 3, 3-trifluoroethanol for 2, 2-difluoroethanol in step 1. LC/MS (M + H) 552.2409 expected, 552.2432 measured;¹HNMR(400MHz，CDCl₃)δppm 8.61(1H)，6.70-6.45(1H)，5.26-5.21(1H)，5.08-4.96(1H)，4.08-4.03(1H)，3.92-3.87(1H)，3.68-3.61(2H)，3.53-3.44(1H)，3.42-3.20(8H)，2.72-2.65(1H)，2.56-2.27(3H)，2.08-1.88(5H)，1.80-1.47(5H)

example 33

1, 5-anhydro-2, 3-dideoxy-4-O-methyl-3- { [ (1R,3S) -3- (2,2, 2-trifluoroethyl) -3- ({ (1S,4S) -5- [4- (trifluoromethyl) pyridin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -D-erythro-pentitol

It is prepared as described in example 24, substituting 3, 3, 3-trifluoroethanol for 2, 2-difluoroethanol in step 1 and 2-chloro-4- (trifluoromethyl) pyridine for 2-chloro-6- (trifluoromethyl) pyridine in step 9. LC/MS (M + H) 551.2457 expected, 551.2703 measured;¹H NMR(400MHz，CDCl₃)δppm 8.22-8.21(1H)，6.74-6.73(1H)，6.47-6.43(1H)，5.06-4.71(2H)，4.06-4.01(1H)，3.92-3.87(1H)，3.65-3.50(3H)，3.40-3.20(8H)，2.72-2.63(1H)，2.53-2.27(3H)，2.08-1.82(5H)，1.78-1.45(5H)

example 34

1, 5-anhydro-2, 3-dideoxy-4-O-methyl-3- { [ (1R,3S) -3- (2,2, 2-trifluoroethyl) -3- ({ (1S,4S) -5- [2- (trifluoromethyl) pyridin-4-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -D-erythro-pentitol

It was prepared as described in example 24, substituting 3, 3, 3-trifluoroethanol for 2, 2-difluoroethanol in step 1 and 4-iodo-2- (trifluoromethyl) pyridine for 2-chloro-4- (trifluoromethyl) pyrimidine in step 9. LC/MS (M + H) 551.2457 expected, 551.2610 measured;¹H NMR(400MHz，CDCl₃)δppm 8.26-8.25(1H)，6.71-6.68(1H)，6.46-6.42(1H)，5.09-4.83(1H)，4.55-4.52(1H)，4.05-4.01(1H)，3.90-3.85(1H)，3.66-3.48(3H)，3.36-3.18(8H)，2.70-2.62(1H)，2.51-2.27(3H)，2.06-1.87(5H)，1.80-1.45(5H)

example 35

1, 5-anhydro-2, 3-dideoxy-4-O-methyl-3- { [ (1R,3S) -3- (2,2, 2-trifluoroethyl) -3- ({ (1S,4S) -5- [4- (trifluoromethyl) pyrimidin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -D-erythro-pentitol

It was prepared as described in example 27, substituting 3, 3, 3-trifluoroethanol for 2, 2-difluoroethanol in step 1. LC/MS (M + H) 552.2409 expected, 551.2426 measured;¹HNMR(400MHz，CDCl₃)δppm 8.50-8.46(1H)，6.81-6.80(1H)，5.11-4.74(2H)，4.13-4.06(1H)，3.97-3.92(1H)，3.67-3.59(4H)，3.41-3.25(7H)，2.90-2.75(1H)，2.54-2.33(3H)，2.07-1.88(5H)，1.79-1.58(5H)

example 36

1, 5-anhydro-2, 3-dideoxy-4-O-methyl-3- { [ (1R,3S) -3- (2,2, 2-trifluoroethyl) -3- ({ (1S,4S) -5- [6- (trifluoromethyl) pyridin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -D-erythro-pentitol

It was prepared as described in example 27, substituting 3, 3, 3-trifluoroethanol for 2, 2-difluoroethanol in step 1 and 2-chloro-6- (trifluoromethyl) pyridine for 2-chloro-4- (trifluoromethyl) pyrimidine in step 9. LC/MS (M + H) 551.2457 expected, 551.2581 measured;¹H NMR(400MHz，CDCl₃)δppm 7.55-7.51(1H)，6.92-6.90(1H)，6.47-6.40(1H)，5.12-4.70(2H)，4.07-4.03(1H)，3.93-3.88(1H)，3.72-3.47(3H)，3.40-3.31(5H)，3.28-3.20(3H)，2.73-2.64(1H)，2.53-2.25(3H)，2.10-1.80(5H)，1.77-1.44(5H)

example 37

1, 5-anhydro-2, 3-dideoxy-4-O-methyl-3- { [ (1R,3S) -3- (2,2, 2-trifluoroethyl) -3- ({ (1S,4S) -5- [6- (trifluoromethyl) pyrazin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -D-erythro-pentitol

It was prepared as described in example 24, substituting 3, 3, 3-trifluoroethanol for 2, 2-difluoroethanol in step 1 and 1-iodo-6- (trifluoromethyl) pyrazine for 4-chloro-6- (trifluoromethyl) pyrimidine in step 9. LC/MS (M + H) 552.2409 expected, 552.2443 measured;¹H NMR(400MHz，CDCl₃)δppm 8.16(1H)，8.01-7.96(1H)，5.09-4.96(2H)，4.09-4.04(1H)，3.94-3.89(1H)，3.68-3.57(3H)，3.53-3.49(1H)，3.39-3.23(7H)，2.74-2.67(1H)，2.54-2.29(3H)，2.09-1.90(5H)，1.81-1.49(5H)

example 38

Prepared as described in example 24, using 3, 3, 3-trifluoroethanol instead of 2, 2-difluoroethanol in step 1 and 4-chloro-2- (trifluoromethyl) pyrimidine replaces 4-chloro-6- (trifluoromethyl) pyrimidine in step 9. LC/MS (M + H) 552.2409 expected, 552.3073 measured;¹H NMR(400MHz，CDCl₃)δppm 8.23-8.21(1H)，6.49-6.22(1H)，5.25-4.93(2H)，4.04-3.99(1H)，3.89-3.83(1H)，3.65-3.57(2H)，3.46-3.17(9H)，2.68-2.62(1H)，2.52-2.26(3H)，2.05-1.85(5H)，1.76-1.43(5H)

example 39

1, 5-anhydro-2, 3-dideoxy-4-O-methyl-3- { [ (1R,3S) -3- (2,2, 2-trifluoroethyl) -3- ({ (1S,4S) -5- [5- (trifluoromethyl) pyridazin-3-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -D-erythro-pentitol

It was prepared as described in example 27, using 3, 3, 3-trifluoroethanol instead of 2, 2-difluoroethanol in step 1 and 3-chloro-5- (trifluoromethyl) pyridazine instead of 2-chloro-4- (trifluoromethyl) pyrimidine in step 9. LC/MS (M + H) 552.2409 expected, 552.2344 measured;¹H NMR(400MHz，CDCl₃)δppm 8.72(1H)，6.72-6.64(1H)，5.32-4.82(2H)，4.06-4.01(1H)，3.91-3.86(1H)，3.78-3.53(3H)，3.42-3.18(8H)，2.69-2.64(1H)，2.52-2.24(3H)，2.07-1.84(5H)，1.76-1.44(5H)

example 40

1, 5-anhydro-2, 3-dideoxy-3- { [ (1S,4S) -4-isopropyl-4- ({ (1S,4S) -5- [4- (trifluoromethyl) pyridin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopent-2-en-1-yl ] amino } -4-O-methyl-D-erythro-pentitol

Preparation thereofStarting from (1S,4S) -4- (2, 5-dimethyl-1H-pyrrol-1-yl) -1-isopropylcyclopent-2-ene-1-carboxylic acid and skipping steps 1, 2 and 5 as described in example 1. LC/MS (M + H) 509.2739 expected, 509.2724 measured;¹H NMR(400MHz，CDCl₃)δppm 8.19(1H)，6.72-6.68(1H)，6.46-6.38(1H)，5.90-5.75(2H)，5.09-4.82(2H)，4.02-3.12(13H)，2.86-2.67(1H)，2.46-2.16(1H)，2.08-1.47(7H)，0.84-0.64(6H)

EXAMPLE 41

1, 5-anhydro-2, 3-dideoxy-3- { [ (1S,4S) -4-isopropyl-4- ({ (1S,4S) -5- [4- (trifluoromethyl) pyrimidin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopent-2-en-1-yl ] amino } -4-O-methyl-D-erythro-pentitol

It was prepared as described in example 2, starting from (1S,4S) -4- (2, 5-dimethyl-1H-pyrrol-1-yl) -1-isopropylcyclopent-2-ene-1-carboxylic acid and skipping steps 1, 2 and 5. LC/MS (M + H) 510.2692 expected, 510.2926 measured;¹H NMR(400MHz，CDCl₃)δppm 8.43-8.42(1H)，6.75-6.74(1H)，5.90-5.77(2H)，5.09-4.80(2H)，4.01-3.16(13H)，2.86-2.69(1H)，2.45-2.17(1H)，2.08-1.30(7H)，0.82-0.66(6H)

example 42

1, 5-anhydro-2, 3-dideoxy-3- { [ (1S,4S) -4-isopropyl-4- ({ (1S,4S) -5- [6- (trifluoromethyl) pyridin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopent-2-en-1-yl ] amino } -4-O-methyl-D-erythro-pentitol

Prepared as described in example 1, from (1S,4S) -4- (2, 5-dimethyl-1H-pyrrol-1-yl) -1-isopropylcyclopent-2-ene-1-carboxylic acid and steps 1, 2 and 5 are skipped. LC/MS (M + H) 509.2739 expected, 509.2680 measured;¹H NMR(400MHz，CDCl₃)δppm 7.55-7.52(1H)，6.94-6.89(1H)，6.52-6.40(1H)，5.96-5.78(2H)，5.12-4.84(2H)，4.07-3.16(13H)，2.90-2.69(1H)，2.49-2.21(1H)，2.12-1.42(7H)，0.87-0.68(3H)

example 43

1, 5-anhydro-2, 3-dideoxy-3- { [ (1S,4S) -4-isopropyl-4- ({ (1S,4S) -5- [6- (trifluoromethyl) pyrazin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopent-2-en-1-yl ] amino } -4-O-methyl-D-erythro-pentitol

Its preparation is as described in example 3, starting from (1S,4S) -4- (2, 5-dimethyl-1H-pyrrol-1-yl) -1-isopropylcyclopent-2-ene-1-carboxylic acid and skipping steps 1 and 2, skipping step 5, using (3R) -3-methoxytetrahydro-4H-pyran-4-one in step 6 and 2-chloro-6- (trifluoromethyl) pyrazine instead of 4-chloro-6- (trifluoromethyl) pyrimidine in step 8. LC/MS (M + H) 510.2692 expected, 510.2699 measured;¹H NMR(400MHz，CDCl₃)δppm 8.15(1H)，8.04-7.95(1H)，5.93-5.82(2H)，5.17-4.91(2H)，4.16-3.18(13H)，2.91-2.69(1H)，2.48-2.21(1H)，2.10-1.52(7H)，0.85-0.67(6H)

example 44

1, 5-anhydro-3- { [ (1R,3S) -3- { [ (1S,4S) -5- (tert-butoxycarbonyl) -2, 5-diazabicyclo [2.2.1] hept-2-yl ] carbonyl } -3- (2,2, 2-trifluoroethyl) cyclopentyl ] amino } -2, 3-dideoxy-4-O-methyl-D-erythro-pentitol

It was prepared as described in example 24, substituting 2,2, 2-trifluoroethanol for 2, 2-difluoroethanol in step 1, and skipping steps 8 and 9. LC/MS (M + H) 506.2842 expected, 506.3033 measured;¹H NMR(400MHz，CDCl₃)δppm 4.86-4.65(1H)，4.52-4.38(1H)，4.09-4.03(1H)，3.93-3.87(1H)，3.68-3.23(11H)，2.73-2.68(1H)，2.55-2.24(3H)，2.10-2.03(1H)，1.96-1.89(1H)，1.85-1.59(7H)，1.54-1.47(1H)，1.44-1.39(9H)

scheme 3 preparation of examples 45-59

a)NaOH，MeOH，H₂O；b)BnOH，EDC，DMAP；c)LDA，R₁COR₂；d)NH₂OH＊HCl，NH₂OH＊H₂O, MeOH; e) MeO-pyrone, Na (OAc)₃BH; f) TFAA; g) AcCl, pyridine; h) h₂，Pt/C；i)(COCl)₂(ii) a j) An aryl piperazine; k) k₂CO₃，MeOH；l)NaBH₄(ii) a m) HCl/bisAn alkane; n) Ar-Cl, heating or Pd catalyst

Example 45

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3- (1-hydroxycyclobutyl) -3- ({ (1S,4S) -5- [6- (trifluoromethyl) pyridin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol

Step 1.(4S) -4- (2, 5-dimethyl-1H-pyrrol-1-yl) cyclopent-2-ene-1-carboxylic acid benzyl ester

A solution of 11.04g (50.4mmol) methyl (1R, 4S) -4- (2, 5-dimethyl-1H-pyrrol-1-yl) cyclopent-2-ene-1-carboxylate and 40ml 2.5M sodium hydroxide in 100ml MeOH is stirred at ambient temperature for 45 minutes and then concentrated under reduced pressure to remove the methanol. The residual aqueous solution was added to a stirred mixture of 20g citric acid, 100ml water and 100ml dichloromethane. The phases were separated and the aqueous phase was extracted with 2 additional portions of dichloromethane. Drying (Na)₂SO₄) The organic phase was concentrated under reduced pressure to give the corresponding acid as a brown gum (10.98 g).

To a stirred solution of the acid, 10mL (96mmol) of benzyl alcohol and 1.74g (14mmol) of DMAP in 50mL of dichloromethane, 13g (69mmol) of EDC divided into 5 equal parts are added over the course of 30 min. After 18h, the solution was concentrated under reduced pressure and the residual slurry was partitioned between ether and water. The organic phase was washed with water and brine, and the aqueous phase was back-extracted once with ether (back-extraction). Drying (MgSO)₄) The organic phases were combined and concentrated under reduced pressure. Flash chromatography of the crude material on silica gel using 10% ethyl acetate in heptane gave 13.75g (93%) of the title compound as colorless oil. 1H NMR (400MHz, chloroform-d) confirmed a 60: 40 mixture of epimers: δ ppm 2.09-2.32(m, 1H)2.20(s, 6H)2.67-2.85(m, 1H)3.62-3.70(m, 0.6H)3.85-3.92(m, 0.4H)5.16(2s, 2H)5.26-5.34(m, 0.6H)5.49-5.56(m, 0.4H)5.74(br.s., 2H)5.93-6.04(m, 2H)7.30-7.42(m, 5H). TLC Rf 0.32 and 0.25 (10% ethyl acetate in hexane). LC-MS ES + 296.2.

Step 2 benzyl (1R, 4S) -4- (2, 5-dimethyl-1H-pyrrol-1-yl) -1- (1-hydroxycyclobutyl) cyclopent-2-ene-1-carboxylate

To a stirred solution of 6.17g (20.9mmol) of benzyl (4S) -4- (2, 5-dimethyl-1H-pyrrol-1-yl) cyclopent-2-ene-1-carboxylate (preparation SRT-0233) in 40ml of anhydrous THF under Ar (-78 deg.C) was slowly added 23.3ml of a commercial 1.8M LDA solution. The resulting solution was warmed to 0 deg.C, stirred at that temperature for 10min, then cooled again to-78 deg.C and 2.3mL (31mmol) of cyclobutanone was added. The solution was stirred at-78 ℃ for 1h and then quenched at-78 ℃ by slowly adding a solution of 4.0ml of 12N HCl in 10ml of THF. Ethyl acetate and excess 1M citric acid were added and the mixture was allowed to warm to room temperature. After the post-extraction procedure, flash chromatography on silica using 25% ethyl acetate in heptane yielded 5.55g (73%) of the title compound as a thick amber oil.¹H NMR (400MHz, chloroform-d) δ ppm 1.44-1.56(m, 1H)1.88-2.31(m, 6H)2.12(s, 6H)2.27(dd, J ═ 14.7, 7.5Hz, 1H)2.76(dd, J ═ 14.5, 9.0Hz, 1H)5.18(s, 2H)5.26-5.32(m, 1H)5.71(s, 2H)6.06(dd, 1H)6.10(dd, 1H)7.30-7.39(m, 5H). TLC Rf0.36 (30% ethyl acetate in hexane). LC-MS ES + 366.2.

Step 3 benzyl (1R, 4S) -4-amino-1- (1-hydroxycyclobutyl) cyclopent-2-ene-1-carboxylate

A mixture of 5.52g (15.1mmol) of benzyl (1R, 4S) -4- (2, 5-dimethyl-1H-pyrrol-1-yl) -1- (1-hydroxycyclobutyl) cyclopent-2-ene-1-carboxylate (preparation SRT-0229), 8.20g (120mmol) of hydroxylamine hydrochloride and 7.0ml of 50% aqueous hydroxylamine solution (100mmol) in 50ml of methanol was heated at 68 ℃ for 8H and then cooled. Sufficient water was added to dissolve the deposited crystals and the solution was concentrated under reduced pressure to remove methanol. The resulting mixture was adjusted to pH 10 with aqueous NaOH solution and then extracted with several portions of dichloromethane. The organic phase is passed through Na₂SO₄Drying and then concentration under reduced pressure gave 4.15g (96%) of the title amine as an almost colourless oil with sufficient purity for subsequent reactions.¹HNMR (400MHz, chloroform-d) δ ppm 1.42-1.53(m, 1H)1.85(dd, 1H)1.88-2.08(m, 4H)2.19-2.27(m, 1H)2.46(dd, J ═ 14.5, 8.3Hz, 1H)3.97-4.02(m, 1H)4.70(s, 1H)5.16(s, 2H)5.84(dd, J ═ 5.6, 1.6Hz, 1H)5.98(dd, J ═ 5.6, 2.1Hz, 1H)7.31-7.38(m, 5H). LC-MS ES + 288.2.

Step 4.1, 5-anhydro-3- { [ (1S, 4R) -4- [ (benzyloxy) carbonyl ] -4- (1-hydroxycyclobutyl) cyclopent-2-en-1-yl ] amino } -2, 3-dideoxy-4-O-methyl-D-erythro-pentitol

A solution of 3.83g (13.3mmol) of benzyl (1R, 4S) -4-amino-1- (1-hydroxycyclobutyl) cyclopent-2-ene-1-carboxylate (preparation SRT-0235) and 1.89g (14.5mmol) of (3R) -3-methoxytetrahydro-4H-pyran-4-one in 26ml of dichloromethane was stirred with activated 3A molecular sieve for 10min and then cooled to 0 ℃. Sodium triacetoxyborohydride (3.35g, 15.8mmol) was added in portions over 10min, and the mixture was stirred for 1.5 h. The cloudy mixture was added to dichloromethane and NaHCO₃+ aqueous NaOH (pH 14) and the aqueous phase extracted with several additional portions of dichloromethane. Drying (Na)₂SO₄) The organic phase was concentrated under reduced pressure. Flash chromatography of the residue on silica using 3-5% methanolic ammonia (7M) in dichloromethane afforded 3.94g (74%) of the title compound as a yellow oil.¹H NMR (400MHz, chloroform-d) δ ppm 1.41-1.52(m, 1H)1.55-1.64(m, 1H)1.64-1.79(m, 2H)1.86-2.09(m, 5H)2.19-2.29(m, 1H)2.41(dd, J ═ 14.2, 7.7Hz, 1H)2.84-2.91(m, 1H)3.17-3.44(m, 4H)3.34(s, 3H)3.88-3.96(m, 2H)4.00(dd, J ═ 12.3, 4.4Hz, 1H)5.10-5.20(m, 2H)5.88-5.93(m, 1H)6.00(dd, J ═ 5.6, 1.9, 1.7H) 7.39-39H). TLC Rf 0.41 (4% 7M methanolic ammonia in dichloromethane). LC-MS ES + 402.1.

Step 5.1, 5-anhydro-3- { [ (1S, 4R) -4- [ (benzyloxy) carbonyl ] -4- (1-hydroxycyclobutyl) cyclopent-2-en-1-yl ] (trifluoroacetyl) amino } -2, 3-dideoxy-4-O-methyl-D-erythro-pentitol

To a cooled (0 ℃ C.) stirred solution of 805mg (2.00mmol) of 1, 5-anhydro-3- { [ (1S, 4R) -4- [ (benzyloxy) carbonyl]-4- (1-hydroxycyclobutyl) cyclopent-2-en-1-yl]To a solution of amino } -2, 3-dideoxy-4-O-methyl-D-erythro-pentose alcohol and 0.87mL (5.0mmol) of diisopropylethylamine in 6mL of dichloromethane was added 0.61mL (4.4mmol) of trifluoroacetic anhydride dropwise. The solution was stirred for 2h and then with aqueous sodium citrate for 30 min. The organic phase was separated and dried (Na)₂SO₄) And concentrated under reduced pressure to 1.36g of a brown oil. It was dissolved in 5ml of methanol and treated with 2ml of 7M methanolic ammonia. After 1h, the solution was concentrated under reduced pressure and the residue was chromatographed on silica using 15-20% ethyl acetate in dichloromethane to give 1.11g (111%) of the title compound as an amber oil which still retained some solvent.¹H NMR (400MHz, chloroform-d) δ ppm 1.37-1.49(m, 1H)1.50-1.57(m, 1H)1.78-2.00(m, 3H)2.01-2.10(m, 1H)2.26-2.38(m, 3H)2.40-2.53(m, 1H)3.10(br.s., 0H)3.31(d, J ═ 13.0Hz, 1H)3.39-3.45(m, 1H)3.43(s, 3H)3.50(t, J ═ 11.4Hz, 1H)3.89(d, J ═ 11.6Hz, 1H)4.06-4.14(m, 1H)4.19(d, J ═ 13.0, 1H)5.00(t, 1H)4.5 (m, 1H)4.19(d, J ═ 13.0, 1H) 5.5H), 1H (1H) 5.5 (d, 7.8, 7H) 3.7, 7H) (1H, 7.8H, 7H)3.8 (1H, 7H)3.8 (m, 7H)3.8 (d, 7H)3.8, 7H). TLC Rf 0.34 (25% ethyl acetate in dichloromethane). LC-MSES + 498.2.

Step 6.3- [ { (1S, 4R) -4- [1- (acetyloxy) cyclobutyl ] -4- [ (benzyloxy) carbonyl ] cyclopent-2-en-1-yl } (trifluoroacetyl) amino ] -1, 5-anhydro-2, 3-dideoxy-4-O-methyl-D-erythro-pentitol

To a stirred solution of 3.58g (7.2mmol) of 1, 5-anhydro-3- { [ (1S, 4R) -4- [ (benzyloxy) carbonyl]-4- (1-hydroxycyclobutyl) cyclopent-2-en-1-yl]To a solution of (trifluoroacetyl) amino } -2, 3-dideoxy-4-O-methyl-D-erythro-pentitol, 1.6mL (9.2mmol) of diisopropylethylamine and 100mg (0.82mmol) of DMAP in 10mL of dichloromethane was added 5.1mL (72mmol) of acetyl chloride dropwise. The solution was stirred at ambient temperature for 18h, then cooled in ice and treated with NaHCO₃The aqueous solution was quenched. The aqueous phase was extracted with additional dichloromethane and dried (Na)₂SO₄) The combined organic phases were concentrated under reduced pressure. Flash chromatography of the residue on silica using 8-10% ethyl acetate in dichloromethane afforded 2.63g (68%) of the title compound as a viscous yellow oil.¹H NMR (400MHz, chloroform-d) δ ppm 1.35-1.48(m, 1H)1.54-1.61(m, 1H)1.82-1.94(m, 1H)1.88(s, 3H)2.17-2.26(m, 1H)2.34(dd, J-14.7, 9.9Hz, 1H)2.43-2.64(m, 5H)3.32(d, J-12.6 Hz, 1H)3.37-3.43(m, 1H)3.43(s, 3H)3.46-3.55(m, 1H)3.84-3.94(m, 1H)4.09-4.15(m, 1H)4.19(d, J-13.0 Hz, 1H)4.98-5.05(m, 1H) 4.08H, 1H)4.19(d, J-13.0 Hz, 1H)4.8 (d, 1H)3.7, 8H) 3.7, 1H (d, 8H)3.6 Hz, 1H)3.7, 1H)3.6 Hz, 1H, 8(m, 7H) 3.7H) 3.6 Hz, 1H). TLC Rf 0.39 (10% ethyl acetate-dichloromethane). LC-MS ES + 540.2.

Step 7.3- [ { (1R,3S) -3- [1- (acetyloxy) cyclobutyl ] -3-carboxycyclopentyl } (trifluoroacetyl) amino ] -1, 5-anhydro-2, 3-dideoxy-4-O-methyl-D-erythro-pentitol

2.62g (4.86mmol) of 3- [ { (1S, 4R) -4- [1- (acetyloxy) cyclobutyl ] butyl]-4- [ (benzyloxy) carbonyl]Cyclopentyl-2-En-1-yl } (trifluoroacetyl) amino]A mixture of-1, 5-anhydro-2, 3-dideoxy-4-O-methyl-D-erythro-pentose alcohol and 750mg each of 5% Pt/C and 5% Pd/C in 10ml acetic acid was stirred rapidly under 50psi of hydrogen for 18h and then filtered through celite to remove the catalyst. The filtrate was concentrated under reduced pressure and toluene was added to azeotropically remove acetic acid to give 2.25g (103%) of the title compound as a white foam.¹H NMR (400MHz, chloroform-d) δ ppm 1.50-1.71(m, 3H)1.74-1.84(m, 1H)2.02(s, 3H)2.04-2.17(m, 1H)2.34-2.55(m, 5H)2.60(dd, J ═ 14.3, 8.5Hz, 1H)2.66-2.81(m, 2H)3.30(d, J ═ 13.0Hz, 1H)3.35-3.39(m, 1H)3.42(s, 3H)3.47-3.56(m, 1H)3.83-3.91(m, 1H)4.13(dd, J ═ 11.6, 4.4Hz, 1H)4.16-4.23(m, 1H)4.26-4.38(m, 1H). LC-MS ES + 452.1.

Step 8.3- { [ (1R,3S) -3- [1- (acetyloxy) cyclobutyl ] -3- { [ (1S,4S) -5- (tert-butoxycarbonyl) -2, 5-diazabicyclo [2.2.1] hept-2-yl ] carbonyl } cyclopentyl ] (trifluoroacetyl) amino } -1, 5-anhydro-2, 3-dideoxy-4-O-methyl-D-erythro-pentitol

A stirred solution of 1.42g (3.15mmol) of 3- [ { (1R,3S) -3- [1- (acetyloxy) cyclobutyl ] -3-carboxycyclopentyl } (trifluoroacetyl) amino ] -1, 5-anhydro-2, 3-dideoxy-4-O-methyl-D-erythro-pentitol in 6ml of dichloromethane is treated with 6.5ml of a 2M solution of oxalyl chloride in dichloromethane and 2 drops of anhydrous DMF under argon. After 2h, the solution was dried under reduced pressure to give the acid chloride as a yellow foam.

This material was dissolved in 8ml dichloromethane. To 6ml of the stirred solution, 562mg (2.84mmol) of (1S,4S) - (-) -2-Boc-2, 5-diazabicyclo [2.2.1] were added]Heptane and 1.2mL (6.9mmol) of diisopropylethylamine. The reaction mixture was stirred at ambient temperature for 18h and then partitioned between dichloromethane and 1M aqueous citric acid. Drying (Na)₂SO₄) The organic phase was concentrated under reduced pressure. Is used inFlash chromatography of the residue on silica in 40-50% ethyl acetate in dichloromethane afforded 1.44g (97%) of the title compound as a white foam.¹H NMR (400MHz, chloroform-d) delta ppm 1.34-1.62(m, 12H)1.73-1.88(m, 2H)1.88-2.27(m, 7H)2.29-2.41(m, 1H)2.40-2.65(m, 4H)2.66-2.80(m, 1H)3.27-3.64(m, 9H)3.81-3.89(m, 1H)4.08-4.24(m, 2H)4.37-4.60(m, 2H)4.85-4.94(m, 1H). TLCRf0.36 (1: 1 ethyl acetate in dichloromethane). LC-MS ES + 632.3.

Step 9.1, 5-anhydro-3- { [ (1R,3S) -3- { [ (1S,4S) -5- (tert-butoxycarbonyl) -2, 5-diazabicyclo [2.2.1] hept-2-yl ] carbonyl } -3- (1-hydroxycyclobutyl) cyclopentyl ] (trifluoroacetyl) amino } -2, 3-dideoxy-4-O-methyl-D-erythro-pentitol

1.43g (2.26mmol) of 3- { [ (1R,3S) -3- [1- (acetyloxy) cyclobutyl ] -c]-3- { [ (1S,4S) -5- (tert-Butoxycarbonyl) -2, 5-diazabicyclo [2.2.1]Hept-2-yl]Carbonyl } cyclopentyl group]A mixture of (trifluoroacetyl) amino } -1, 5-anhydro-2, 3-dideoxy-4-O-methyl-D-erythro-pentose alcohol and 1.60g (11.6mmol) potassium carbonate powder in 8ml methanol was stirred at ambient temperature for 18h and then partitioned between dichloromethane and brine with sufficient water to dissolve the solids. Drying (Na)₂SO₄) The organic phase was concentrated under reduced pressure. Flash chromatography of the residue on silica using acetate gave 1.33g (100%) of the title compound as a white foam.¹H NMR (400MHz, chloroform-d)ppm 1.34-1.62(m，10H)1.66-2.93(m，15H)3.20-3.63(m，8H)3.66-4.03(m，3H)4.06-4.24(m，3H)4.25-4.65(m，2H)4.68-5.29(m，1H)。TLC Rf 0.33(EtOAc)。LC-MS ES+590.3。

Step 10.1, 5-anhydro-3- { [ (1R,3S) -3- { [ (1S,4S) -5- (tert-Butoxycarbonyl) -2, 5-diazabicyclo [2.2.1] hept-2-yl ] carbonyl } -3- (1-hydroxycyclobutyl) cyclopentyl ] amino } -2, 3-dideoxy-4-O-methyl-D-erythro-pentitol

1.31g (2.23mmol) of 1, 5-anhydro-3- { [ (1R,3S) -3- { [ (1S,4S) -5- (tert-butoxycarbonyl) -2, 5-diazabicyclo [2.2.1]Hept-2-yl]Carbonyl } -3- (1-hydroxycyclobutyl) cyclopentyl]A mixture of (trifluoroacetyl) amino } -2, 3-dideoxy-4-O-methyl-D-erythro-pentose alcohol and 860mg (23mmol) of sodium borohydride in 6.3ml of ethanol was stirred at ambient temperature for 18h and then partitioned between water and dichloromethane. The aqueous phase was extracted with additional dichloromethane and dried (Na)₂SO₄) The organic phases were combined and concentrated under reduced pressure. Flash chromatography on silica using 6-15% methanol in dichloromethane afforded 1.08g (98%) of the title compound as a white foam.¹H NMR (400MHz, chloroform-d) δ ppm 1.42-1.47(m, 9H)1.56-2.35(m, 14H)2.72(br.s., 1H)3.11-3.68(m, 10H)3.90-3.98(m, 1H)4.08(dd, J ═ 12.6, 2.7Hz, 1H)4.38-4.58(m, 1H)4.84-5.16(m, 1H). LC-MS ES + 494.3. C₂₆H₄₃N₃O₆HRMS calculated of (a): 494.3230, respectively; actually measuring: 494.3260.

step 11.1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3- [ (1S,4S) -2, 5-diazabicyclo [2.2.1] hept-2-ylcarbonyl ] -3- (1-hydroxycyclobutyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol dihydrochloride

To 902mg (1.827mmol) of 1, 5-anhydro-3- { [ (1R,3S) -3- { [ (1S,4S) -5- (tert-butoxycarbonyl) -2, 5-diazabicyclo [2.2.1]Hept-2-yl]Carbonyl } -3- (1-hydroxy ring)Butyl) cyclopentyl group]Amino } -2, 3-dideoxy-4-O-methyl-D-erythro-pentitol 10ml of di4M HCl in an alkane and a few drops of methanol sufficient to give a clear solution. The solution was stirred at ambient temperature for 45 minutes and then concentrated under reduced pressure to give 973mg of the intermediate salt as a foam.¹H NMR(400MHz，MeOD)δppm 1.57-1.70(m，1H)1.73-1.93(m，4H)1.93-2.10(m，4H)2.14-2.28(m，2H)2.29-2.44(m，3H)2.46-2.59(m，2H)3.35-3.77(m，12H)3.98(dd，J＝11.6，4.4Hz，1H)4.26(d，J＝13.3Hz，1H)4.45(s，1H)5.21(br.s.，1H)。LC-MS ES+394.2。

Example 45

93mg (0.20mmol) of 1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3- [ (1S,4S) -2, 5-diazabicyclo [2.2.1]Hept-2-ylcarbonyl]-3- (1-hydroxycyclobutyl) cyclopentyl]A solution of amino } -4-O-methyl-D-erythro-pentitol dihydrochloride, 91mg (0.49mmol) 2-chloro-6-trifluoromethylpyridine and 0.14mL (0.80mmol) diisopropylethylamine in 0.5mL DMSO, heated at 80 deg.C for 18h, then cooled, and partitioned between ethyl acetate and water. Drying (Na)₂SO₄) The organic phase was concentrated under reduced pressure. The crude material was purified by preparative RP-HPLC using acetonitrile-water containing 0.05% TFA as the mobile phase.¹H NMR (400MHz, chloroform-d) δ ppm 1.46-2.52(m, 16H)3.26-3.54(m, 8H)3.53-3.92(m, 4H)4.02(dd, J ═ 11.8, 4.3Hz, 1H)4.22(d, J ═ 13.0Hz, 1H)5.01(d, J ═ 14.3Hz, 2H)6.47(d, J ═ 8.5Hz, 1H)6.93(d, J ═ 7.5Hz, 1H)7.56(t,J＝8.0Hz，1H)。C₂₇H₃₇N₄O₄F₃HRMS calculated of (a): 539.2845, respectively; actually measuring: 539.2894.

example 46

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3- (1-hydroxycyclobutyl) -3- ({ (1S,4S) -5- [4- (trifluoromethyl) pyridin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol

The title compound was prepared in a similar manner to that described in preparation example 45.¹HNMR (400MHz, chloroform-d) δ ppm 1.57-2.31(m, 14H)2.33-2.47(m, 2H)2.49-2.62(m, 1H)3.28-3.54(m, 7H)3.57-3.91(m, 4H)4.02(dd, J ═ 11.8, 4.3Hz, 1H)4.22(d, J ═ 13.3Hz, 1H)5.07(br.s., 1H)5.25(s, 1H)6.88-6.96(m, 2H)8.14(d, J ═ 6.5Hz, 1H). C₂₇H₃₇N₄O₄F₃HRMS calculated of (a): 539.2845, respectively; actually measuring: 539.2894.

example 47

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3- (1-hydroxycyclobutyl) -3- ({ (1S,4S) -5- [4- (trifluoromethyl) pyrimidin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol

The title compound was prepared in a similar manner to that described in preparation example 45.¹HNMR (400MHz, chloroform-d) δ ppm 1.65-2.51(m, 15H)2.52-2.64(m, 1H)3.35(s, 3H)3.44(d, J ═ 13.7Hz, 1H)3.49-3.98(m, 7H)4.19(dd, J ═ 11.4, 4.6Hz, 1H)4.35(d，J＝14.0Hz，1H)5.07-5.48(m，2H)7.16(d，J＝6.5Hz，1H)8.49(d，J＝6.5Hz，1H)。C₂₆H₃₆N₅O₄F₃HRMS calculated of (a): 540.2797, respectively; actually measuring: 540.2812.

example 48

The title compound was prepared in a similar manner to that described in preparation example 45.¹HNMR (400MHz, chloroform-d) δ ppm 1.57-2.53(m, 16H)3.31(d, J ═ 13.3Hz, 1H)3.35-3.79(m, 10H)4.03(dd, J ═ 11.4, 4.3Hz, 1H)4.23(d, J ═ 12.6Hz, 1H)5.11(s, 1H)5.29(br.s., 1H)6.23-6.75(m, 2H)8.30(d, J ═ 6.1Hz, 1H). C₂₆H₃₆N₅O₄F₃HRMS calculated of (a): 540.2797, respectively; actually measuring: 540.2891.

example 49

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3- (1-hydroxycyclobutyl) -3- ({ (1S,4S) -5- [6- (trifluoromethyl) pyrimidin-4-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol

The title compound was prepared in a similar manner to that described in preparation example 45.¹HNMR (400MHz, chloroform-d) δ ppm 1.56-2.35(m, 14H)2.36-2.44(m, 1H)2.45-2.54(m, 1H)3.32(d, J ═ 13.3Hz, 1H)3.36-3.92(m，10H)4.04(dd，J＝12.3，4.1Hz，1H)4.24(d，J＝13.0Hz，1H)5.15(s，1H)5.23-5.30(m，1H)6.45-7.05(m，3H)8.67(s，1H)。C₂₆H₃₆N₅O₄F₃HRMS calculated of (a): 540.2797, respectively; actually measuring: 540.2830.

example 50

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3- (1-hydroxycyclobutyl) -3- ({ (1S,4S) -5- [6- (trifluoromethyl) pyrazin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol

93mg (0.20mmol) of 1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3- [ (1S,4S) -2, 5-diazabicyclo [2.2.1]Hept-2-ylcarbonyl]-3- (1-hydroxycyclobutyl) cyclopentyl]Amino } -4-O-methyl-D-erythro-pentitol dihydrochloride, 121mg (0.442mmol) of 2-iodo-6-trifluoromethylpyrazine, 326mg (1.0mmol) of cesium carbonate, 24mg (40. mu. mol) of XantPhos, and 16mg (28. mu. mol) of tris (dibenzylideneacetone) palladium (0) in 0.8ml of bis (benzylalkone)A solution of an alkane and 0.4ml DMSO was heated at 80 ℃ under argon for 18h, then cooled and partitioned between ethyl acetate and water. Drying (Na)₂SO₄) The organic phase was concentrated under reduced pressure. Flash chromatography of the residue on silica using 0-2-4% methanolic ammonia and 3% methanol in dichloromethane afforded 89mg (82%) of the title compound.¹HNMR (400MHz, chloroform-d) δ ppm 1.51-2.40(m, 16H)2.65-2.74(m, 1H)3.09-3.49(m, 10H)3.54(d, J ═ 9.6Hz, 1H)3.61-3.80(m, 2H)3.88-3.96(m, 1H)4.06(dd, J ═ 12.5, 2.9Hz, 1H)4.96(br.s., 1H)5.21(br.s., 1H)8.02(s, 1H)8.15(s, 1H). C₂₆H₃₆N₅O₄F₃HRMS calculated of (a): 540.2797, respectively; actually measuring: 540.2896.

example 51

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3- (1-hydroxycyclobutyl) -3- ({ (1S,4S) -5- [2- (trifluoromethyl) pyridin-4-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol

The title compound was prepared in a similar manner as described in example 45.¹H NMR (400MHz, chloroform-d) δ ppm 1.51-2.40(m, 18H)2.65-2.73(m, 1H)3.04-3.47(m, 8H)3.59(d, J ═ 8.5Hz, 1H)3.70(d, J ═ 9.9Hz, 1H)3.86-3.95(m, 1H)4.05(dd, J ═ 12.3, 2.4Hz, 1H)4.52(s, 1H)5.17(br.s., 1H)6.48(br.s., 1H)6.72(br.s., 1H)8.26(d, J ═ 5.8Hz, 1H). C₂₇H₃₇N₄O₄F₃HRMS calculated of (a): 539.2845, respectively; actually measuring: 539.2979.

example 52

1, 5-anhydro-2, 3-dideoxy-3- { [3- (1-hydroxy-1-methylethyl) -3- ({5- [4- (trifluoromethyl) pyridin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methylpentanol

Step 1.4- (2, 5-dimethyl-1H-pyrrol-1-yl) -1- (1-hydroxy-1-methylethyl) cyclopent-2-ene-1-carboxylic acid benzyl ester

To and inThe title compound was prepared in a similar manner as described in example 45, step 2, above.¹H NMR (400MHz, chloroform-d) δ ppm 1.18(s, 3H)1.22(s, 3H)2.11(s, 6H)2.22(dd, J ═ 14.7, 7.5Hz, 1H)2.88(dd, J ═ 14.7, 8.5Hz, 1H)3.43(s, 1H)5.15-5.23(m, 2H)5.24-5.31(m, 1H)5.71(s, 2H)5.99(dd, 1H)6.03(dd, 1H)7.30-7.40(m, 5H). TLC Rf 0.29 (30% ethyl acetate in hexane). LC-MS ES + 354.2.

Step 24-amino-1- (1-hydroxy-1-methylethyl) cyclopent-2-ene-1-carboxylic acid benzyl ester

The title compound was prepared in a similar manner as described above in example 45, step 3.¹H NMR (400MHz, chloroform-d) δ ppm 1.11(s, 3H)1.14(s, 3H)1.81(dd, J ═ 14.5, 4.9Hz, 1H)1.85-1.92(m, 1H)2.67(dd, J ═ 14.3, 8.2Hz, 1H)3.97-4.03(m, 1H)5.18(s, 2H)5.83(dd, 1H)5.89(dd, 1H)7.32-7.42(m, 5H). LC-MS ES + 276.2.

Step 31, 5-anhydro-3- ({4- [ (benzyloxy) carbonyl ] -4- (1-hydroxy-1-methylethyl) cyclopent-2-en-1-yl } amino) -2, 3-dideoxy-4-O-methylpentanol

The title compound was prepared in a similar manner as described above in example 45, step 4.¹H NMR (400MHz, chloroform-d) delta ppm 1.11(s, 3H)1.15(s, 3H)1.41-1.66(m, 2H)1.68-1.80(m, 1H)1.87-1.94(m, 1H)2.56-2.65(m, 1H)2.82-2.89(m, 1H)3.24-3.46(m, 7H)3.87-3.97(m, 2H)3.98-4.07(m, 1H)5.11-5.21(m, 2H)5.84-5.97(m, 2H)7.30-7.41(m, 5H). TLC Rf 0.34 (4% methanolic ammonia in dichloromethane). LC-MS ES + 390.2.

Step 4.1, 5-anhydro-3- [ {4- [ (benzyloxy) carbonyl ] -4- (1-hydroxy-1-methylethyl) cyclopent-2-en-1-yl } (trifluoroacetyl) amino ] -2, 3-dideoxy-4-O-methylpentanol

The title compound was prepared in a similar manner as described above in example 45, step 5.¹H NMR (400MHz, chloroform-d) δ ppm 1.35-1.75(m, 2H)1.78-2.08(m, 4H)2.24-2.54(m, 4H)3.31(d, J ═ 12.6Hz, 1H)3.38-3.45(m, 2H)3.43(s, 3H)3.45-3.55(m, 1H)3.84-3.94(m, 1H)4.07-4.14(m, 1H)4.19(d, J ═ 13.0Hz, 1H)4.95-5.05(m, 1H)5.14(d, J ═ 12.3Hz, 1H)5.31(d, 1H)5.78(dd, J ═ 5.6, 2.2, 1H)6.12(dd, J ═ 8, J ═ 7.7, 7.7H) 4.19(d, 1H). Rf-0.34 (25% ethyl acetate-dichloromethane). LC-MS ES + 498.2.

Step 5.3- [ {4- [1- (acetyloxy) -1-methylethyl ] -4- [ (benzyloxy) carbonyl ] cyclopent-2-en-1-yl } (trifluoroacetyl) amino ] -1, 5-anhydro-2, 3-dideoxy-4-O-methylpentanol

The title compound was prepared in a similar manner as described above in example 45, step 6.¹H NMR (400MHz, chloroform-d) δ ppm 1.49(s, 3H)1.53-1.61(m, 4H)1.82-1.86(m, 3H)2.38-2.57(m, 2H)3.32(d, J ═ 13.0Hz, 1H)3.37-3.44(m, 3H)3.45-3.56(m, 2H)3.84-3.95(m, 1H)4.05-4.23(m, 2H)4.93-5.04(m, 1H)5.08-5.15(m, 1H)5.26-5.36(m, 3H)6.11 (J ═ 5.8, 2.4Hz, 1H)7.28-7.42(m, 5H). TLC Rf 0.29 (40% ethyl acetate-hexane). LC-MS ES +550.2(M + Na).

Step 6.3- [ {3- [1- (acetyloxy) -1-methylethyl ] -3-carboxycyclopentyl } (trifluoroacetyl) amino ] -1, 5-anhydro-2, 3-dideoxy-4-O-methylpentanol

The title compound was prepared in a similar manner as described above in example 45, step 7.¹H NMR (400MHz, chloroform-d) δ ppm 0.86(none, 1H)1.51-1.91(m, 10H)2.02-2.04(m, 3H)2.24-2.54(m, 3H)3.31(d, J ═ 13.0Hz, 1H)3.37(br.s., 1H)3.41-3.46(m, 3H)3.46-3.56(m, 1H)3.82-3.91(m, 1H)4.08-4.16(m, 1H)4.16-4.23(m, 1H)4.25-4.39(m, 1H). LC-MS ES + 440.2.

Step 7.3- [ (3- [1- (acetyloxy) -1-methylethyl ] -3- { [5- (tert-butoxycarbonyl) -2, 5-diazabicyclo [2.2.1] hept-2-yl ] carbonyl } cyclopentyl) (trifluoroacetyl) amino ] -1, 5-anhydro-2, 3-dideoxy-4-O-methylpentanol

The title compound was prepared in a similar manner as described above in example 45, step 8.¹H NMR (400MHz, chloroform-d) delta ppm 1.35-1.51(m, 9H)1.54-1.66(m, 6H)1.72-1.87(m, 2H)1.97-2.33(m, 7H)2.36-2.65(m, 2H)3.25-3.68(m, 9H)3.80-3.90(m, 1H)4.06-4.25(m, 2H)4.34-4.64(m, 2H)4.88-4.99(m, 1H). TLC Rf 0.38.LC-MS ES +642.3(M + Na).

Step 8.1, 5-anhydro-3- { [3- { [5- (tert-butoxycarbonyl) -2, 5-diazabicyclo [2.2.1] hept-2-yl ] carbonyl } -3- (1-hydroxy-1-methylethyl) cyclopentyl ] (trifluoroacetyl) amino } -2, 3-dideoxy-4-O-methylpentanol

The title compound was prepared in a similar manner as described above in example 45, step 9.¹H NMR (400MHz, chloroform-d) delta ppm 1.08-1.28(m, 5H)1.36-2.77(m, 18H)3.25-3.57(m, 8H)3.68-3.91(m, 2H)4.06-4.24(m, 2H)4.37-4.73(m, 2H)4.82-5.00(m, 1H). TLC Rf 0.30 (2% MeOH in ethyl acetate). LC-MS ES + 578.3.

Step 9.1, 5-anhydro-3- { [3- { [5- (tert-butoxycarbonyl) -2, 5-diazabicyclo [2.2.1] hept-2-yl ] carbonyl } -3- (1-hydroxy-1-methylethyl) cyclopentyl ] amino } -2, 3-dideoxy-4-O-methylpentanol

The title compound was prepared in a similar manner as described above in example 45, step 10.¹H NMR (400MHz, chloroform-d) delta ppm 1.10-1.26(m, 6H)1.37-1.90(m, 16H)2.23-2.52(m, 2H)2.63-2.74(m, 1H)3.10-3.72(m, 10H)3.84-3.97(m, 1H)4.03-4.12(m, 1H)4.34-4.62(m, 1H)4.80-4.99(m, 1H). TLC rf0.19 (4% methanolic ammonia in dichloromethane). C₂₅H₄₃N₃O₆HRMS calculated of (a): 482.3230, respectively; actually measuring: 482.3276.

step 101, 5-anhydro-2, 3-dideoxy-3- { [3- (2, 5-diazabicyclo [2.2.1] hept-2-ylcarbonyl) -3- (1-hydroxy-1-methylethyl) cyclopentyl ] amino } -4-O-methylpentanol

The title compound was prepared in a similar manner as described above in example 45, step 11.¹H NMR(400MHz，CD3OD)δppm 1.16(s，3H)1.23-1.25(m，3H)1.62-2.34(m，7H)2.66(br.s.，2H)3.33-3.68(m，14H)3.98(dd，J＝11.8，4.6Hz，1H)4.26(d，J＝13.3Hz，1H)4.44(s，1H)。LC-MS ES+382.3。

Example 52

The title compound was prepared in a similar manner as described in example 45.¹H NMR(400MHz，DMSO-d₆)δppm 1.00-1.20(m，6H)1.48-1.60(m，1H)1.65-2.47(m，8H)3.13-3.22(m，1H)3.23-3.54(m，8H)3.55-3.64(m，1H)3.80-3.90(m，1H)4.08-4.16(m，1H)4.87-5.02(m，1H)5.15-5.26(m，1H)6.84(d，J＝5.1Hz，1H)8.28(d，J＝5.5Hz，1H)。C₂₆H₃₇N₄O₄F₃HRMS calculated of (a): 527.2845, respectively; actually measuring: 527.2939.

example 53

1, 5-anhydro-2, 3-dideoxy-3- { [3- (1-hydroxy-1-methylethyl) -3- ({5- [6- (trifluoromethyl) pyrimidin-4-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methylpentanol

The title compound was prepared in a similar manner as described in example 45.¹H NMR(400MHz，DMSO-d₆) Delta ppm 0.92-1.19(m, 6H)1.48-1.62(m, 1H)1.64-2.47(m, 8H)3.09-3.68(m, 10H)3.81-3.91(m, 1H)4.06-4.18(m, 1H)4.87-5.04(m, 1H)5.09-5.33(m, 1H)8.29-8.64(m, 2H). HRMS calculated value C of₂₅H₃₆N₅O₄F₃: 528.2797, respectively; actually measuring: 528.2812.

example 54

1, 5-anhydro-2, 3-dideoxy-3- { [3- (1-hydroxy-1-methylethyl) -3- ({5- [4- (trifluoromethyl) pyrimidin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methylpentanol

The title compound was prepared in a similar manner as described in example 45.¹H NMR(400MHz，DMSO-d₆)δppm 0.99-1.20(m，6H)1.45-1.64(m，1H)1.63-2.18(m，7H)2.25-2.47(m，2H)3.13-3.65(m，10H)3.78-3.91(m，1H)4.12(dd，1H)4.87-5.04(m，2H)5.20(br.s.，1H)8.67(d，J＝3.8Hz，1H)。C₂₅H₃₆N₅O₄F₃HRMS calculated of (a): 528.2797, respectively; actually measuring: 528.2856.

example 55

1, 5-anhydro-2, 3-dideoxy-3- { [3- (1-hydroxy-1-methylethyl) -3- ({5- [5- (trifluoromethyl) pyridazin-3-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methylpentanol

The title compound was prepared in a similar manner as described in example 45.¹H NMR(400MHz，DMSO-d₆)δppm 0.87-1.20(m，7H)1.49-2.46(m，10H)3.16-3.73(m，10H)3.79-3.89(m，1H)4.08-4.17(m，1H)5.20-5.31(m，1H)8.30-8.61(m，2H)8.84(s，1H)。C₂₅H₃₆N₅O₄F₃HRMS calculated of (a): 528.2797, respectively; actually measuring:528.2863。

example 56

1, 5-anhydro-2, 3-dideoxy-3- { [3- (1-hydroxy-1-methylethyl) -3- ({5- [2- (trifluoromethyl) pyrimidin-4-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methylpentanol

The title compound was prepared in a similar manner as described in example 45.¹H NMR(400MHz，DMSO-d₆)δppm 0.96-1.20(m，6H)1.45-2.48(m，9H)3.08-3.66(m，10H)3.80-3.89(m，1H)4.08-4.17(m，1H)4.85-5.11(m，1H)5.16-5.29(m，1H)8.27-8.34(m，1H)。C₂₅H₃₆N₅O₄F₃HRMS calculated of (a): 528.2797, respectively; actually measuring: 528.2927.

example 57

1, 5-anhydro-2, 3-dideoxy-3- { [3- (1-hydroxy-1-methylethyl) -3- ({5- [6- (trifluoromethyl) pyridin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methylpentanol

The title compound was prepared in a similar manner as described in example 45.¹H NMR (400MHz, chloroform-d) δ ppm 0.82-1.37(m, 6H)1.64-2.67(m, 10H)3.19-3.78(m, 11H)3.91-4.08(m, 1H)4.15-4.28(m, 1H)4.93-5.09(m, 1H)6.40-6.54(m, 1H)6.92(d, J ═ 7.2Hz, 1H)7.55(t, J ═ 8.0Hz, 1H). C₂₆H₃₇N₄O₄F₃HRMS calculated of (a): 527.2845, respectively; actually measuring: 527.2869.

example 58

1, 5-anhydro-2, 3-dideoxy-3- { [3- (1-hydroxy-1-methylethyl) -3- ({5- [2- (trifluoromethyl) pyridin-4-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methylpentanol

The title compound was prepared in a similar manner as described in example 45.¹H NMR(400MHz，DMSO-d₆)δppm 0.99-1.19(m，6H)1.47-1.62(m，1H)1.64-2.46(m，9H)3.08-3.68(m，11H)3.80-3.91(m，1H)4.07-4.18(m，1H)4.75-5.28(m，2H)8.24(d，J＝5.8Hz，1H)8.30-8.77(m，2H)。C₂₆H₃₇N₄O₄F₃HRMS calculated of (a): 527.2845, respectively; actually measuring: 527.2943.

example 59

1, 5-anhydro-2, 3-dideoxy-3- { [3- (1-hydroxy-1-methylethyl) -3- ({5- [6- (trifluoromethyl) pyrazin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methylpentanol

The title compound was prepared in a similar manner as described in example 50.¹H NMR(400MHz，DMSO-d₆)δppm 0.99-1.19(m，6H)1.45-2.48(m，10H)3.15-3.69(m，10H)3.80-3.90(m，1H)4.07-4.17(m，1H)4.88-5.31(m，2H)8.20(s，1H)8.28-8.63(m，3H)。C₂₅H₃₆N₅O₄F₃HRMS calculated of (a): 528.2797, respectively; actually measuring: 528.2905.

example 60/61

((1S, 3R) -3- ((3S, 4S) -3-methoxy-tetrahydro-2H-pyran-4-ylamino) -1- (tetrahydrofuran-3-yl) cyclopentyl) ((1S, 4S) -5- (4- (trifluoromethyl) pyridin-2-yl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl) methanone

¹HNMR(400MHz，CD₃OD)δ8.20(d，1H)，7.18(s，1H)，6.97(d，1H)，5.11(m，2H)，4.24(d，1H)，3.38-3.99(m，17H)，2.87(m，1H)，2.65(m，1H)，2.48(m，1H)，1.90-2.39(m，8H)，1.81(m，2H)，1.65(m，1H)。

Example 62/63

((1S, 3R) -3- ((3S, 4S) -3-methoxy-tetrahydro-2H-pyran-4-ylamino) -1- (2,2, 2-trifluoro-1-hydroxyethyl) cyclopentyl) ((1S, 4S) -5- (4- (trifluoromethyl) pyridin-2-yl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl) methanone

¹HNMR(400MHz，CD3OD)δ8.23(d，J＝8Hz，1H)，6.8(d，J＝8Hz，1H)，6.72(d，J＝8Hz，1H)，5.0(m，1H)，4.2，(m，1H)，3.85(m，2H)，3.6(m，1H)，3.52(m，1H)，3.30(s，3H)3.4(m，4H)，2.7(m，2H)，2.4(m，1H)，2.0(m，4H)，1.8(m，4H)，1.6(m，4H)

1HNMR(400MHz，CD3OD)δ8.23(d，J＝8Hz，1H)，6.8(d，J＝8Hz，1H)，6.72(d，J＝8Hz，1H)，5.0(m，1H)，4.2，(m，1H)，3.85(m，2H)，3.6(m，1H)，3.30(s，3H)，3.52(m，1H)，3.4(m，4H)，2.7(m，2H)，2.4(m，1H)，2.0(m，4H)，1.8(m，4H)，1.6(m，4H)

Example 64

((1S, 3R) -3- ((3S, 4S) -3-methoxy-tetrahydro-2H-pyran-4-ylamino) -1- (2,2, 2-trifluoro-1-hydroxyethyl) cyclopentyl) ((1S, 4S) -5- (2- (trifluoromethyl) pyrimidin-4-yl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl) methanone

¹HNMR(400MHz，CD3OD)δ8.23(m，1H)，6.6(m，1H)，4.25(m，1H)，4.0(m，2H)，3.85(m，1H)，3.7(m，1H)3.6(m，4H)，3.42(m，4H)，2.52(m，2H)，2.25(m，2H)，2.1(m，2H)2.0(m，4H)，1.6(m，2H)

Example 65

((1S, 3R) -3- ((3S, 4S) -3-methoxy-tetrahydro-2H-pyran-4-ylamino) cyclopentyl) ((1S, 4S) -5- (4- (trifluoromethyl) pyridin-2-yl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl) methanone

¹HNMR(400MHz，CD3OD)δ8.23(d，J＝8Hz，1H)，6.8(d，J＝8Hz，1H)，6.72(d，J＝16Hz，1H)，5.0(m，1H)，4.2，(m，1H)，3.9(m，1H)，3.85(m，1H)，3.8(m，4H)，3.4(m，4H)，3.30(m，3H)，3.2(m，4H)，2.0(m，4H)，1.8(m，4H)

Example 66

((1S, 4S) -5- (3-fluoro-5- (trifluoromethyl) phenyl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl) ((1S, 3R) -3- ((3S, 4S) -3-methoxy-tetrahydro-2H-pyran-4-ylamino) -1- (tetrahydrofuran-3-yl) cyclopentyl) methanone

1HNMR(400Mhz，CD3OD)，δ6.6(m，3H)，5.0(m，1H)，4.6(m，1H)，4.25(d，J＝4Hz，1H)，4.0(m，1H)，3.85(m，1H)，3.8(m，2H)，3.7(m，2H)，3.65(m，2H)3.5(m，2H)，3.4(3H)，3.2(d，J＝4Hz，2H)，2.8(m，1H)，2.6(m，1H)，2.5(m，1H)，2.35(m，1H)，2.2(m，1H)，2.1(m，2H)，2.05(m，2H)，2.0(m，2H)，1.8(m，2H)，1.6(m，2H)

Preparation examples 67 to 71

Preparation scheme of F-221

Step 1 preparation of (1R, 4S) -tert-butyl 7-hydroxy-5- (4- (trifluoromethyl) pyridin-2-yl) -2, 5-diaza-bicyclo [2.2.1] heptane-2-carboxylate

To a solution of alcohol (2.48g, 11.6mmol) in DMSO (30mL) was added 2-chloro-5- (trifluoromethyl) pyridine (2.0g, 11.0mmol) and TEA (3.4mL, 24.2 mmol). After heating the mixture at 95 ℃ overnight, the mixture was poured into H₂O and the aqueous mixture 2X is extracted with ether. Drying (Na)₂SO₄) Organic extracts, solvent was removed to give an oil which was purified by chromatography (silica, EtOAc: heptane) to yield the product (1.0 g). LC/MS (M + Na) ═ 382 expected, 382 measured.

Step 2 preparation of (1R, 4S) -tert-butyl 7-fluoro-5- (4- (trifluoromethyl) pyridin-2-yl) -2, 5-diaza-bicyclo [2.2.1] heptane-2-carboxylate

To a solution of alcohol in DCM at 0 deg.C, add dropwiseDAST. After the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred at room temperature overnight. The reaction mixture was poured into saturated NaHCO₃/DCM and the layers were separated. The organic layer was collected and dried (Na)₂SO₄) And the solvent was removed to give an oil which was purified by chromatography (silica, EtOAc: heptane) to yield the desired product (750 mg). LC/MS (M + H) 362.1491 expected, 362.1491 measured. 1H NMR (400MHz, DMSO-d)₆)δppm 8.31(1H，d，J＝5.5Hz)，6.85-6.96(2H，m)，5.35(1H，d，J＝55.6Hz)，4.90(1H，br.s.)，4.47(1H，d，J＝22.7Hz)，3.64(1H，dd，J＝10.2，1.8Hz)，3.47-3.57(1H，m)，3.39-3.46(1H，m)，3.26-3.32(1H，m)，1.39(9H，d，J＝12.4Hz)。

Step 3 preparation of (1S, 4R) -7-fluoro-2- (4- (trifluoromethyl) pyridin-2-yl) -2, 5-diaza-bicyclo [2.2.1] heptane

To (1R, 4S) -tert-butyl 7-fluoro-5- (4- (trifluoromethyl) pyridin-2-yl) -2, 5-diaza-bicyclo [2.2.1]Heptane-2-carboxylate (700mg, 1.9mmol) in bisTo a solution in alkane (2ml) was added 4N HCl/bisAlkane (5 mL). The reaction mixture was stirred at room temperature for 5 hours, then diluted with ether to give a precipitate, filtered and collected to give the product as HCl salt (506 mg). LC/MS (M + H) 262.0967 expected, 262.1308 measured; 1H NMR (400MHz, methanol-d)₄)ppm8.26(1H，d，J＝6.1Hz)，7.40(1H，s)，7.20(1H，dd，J＝6.3，1.0Hz)，5.65(1H，dd，J＝52.4，1.9Hz)，5.28(1H，s)，4.70(1H，s)，3.92-4.09(2H，m)，3.66-3.81(2H，m)，3.62(1H，s)

Step 4 preparation of (1S, 4R) -7-hydroxy-2- (4- (trifluoromethyl) pyridin-2-yl) -2, 5-diaza-bicyclo [2.2.1] heptane

To (1R, 4S) -tert-butyl 7-hydroxy-5- (4- (trifluoromethyl) pyridin-2-yl) -2, 5-diaza-bicyclo [2.2.1]Heptane-2-carboxylate (5g, 14mmol) in bisTo a solution in alkane (5ml) was added 4N HCl/bisAlkane (15 mL). The reaction mixture was stirred at room temperature for 6 hours, then diluted with ether to give a precipitate, filtered and collected to give the product as HCl salt (4.0 g). LC/MS (M + H) ═ 260.0 expected, 260.0 measured; 1H NMR (500MHz, DMSO-d)₆)δppm 3.42-3.50(m，1H)3.67-3.72(m，1H)3.75-3.82(m，1H)4.16(br.s.，1H)4.50(d，J＝1.81Hz，1H)4.72(br.s.，1H)6.95(d，J＝5.13Hz，2H)8.31(d，J＝5.43Hz，1H)9.34(br.s.，1H)9.75(br.s.，1H)

Scheme 5

Scheme 6

Example 67

((1R, 4R, 7S) -7-fluoro-5- (4- (trifluoromethyl) pyridin-2-yl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl) ((1S, 3R) -1-isopropyl-3- ((3S, 4S) -3-methoxy-tetrahydro-2H-pyran-4-ylamino) cyclopentyl) methanone

It is prepared in analogy to example 1, but using (1R, 4R, 7R) -7-fluoro-2- (4- (trifluoromethyl) pyridin-2-yl) -2, 5-diaza-bicyclo [2.2.1]Heptane as the coupling amine. LC/MS (M + H) 529 expected, 529 measured; 1H NMR (400MHz, DMSO-d)₆)δppm 8.31(1H，d，J＝5.1Hz)，6.92(2H，d，J＝5.1Hz)，5.39(1H，d，J＝55.6Hz)，4.81-4.98(2H，m)，3.78-3.88(1H，m)，3.66-3.75(2H，m)，3.57-3.65(1H，m)，3.37-3.43(1H，m)，3.23-3.31(2H，m)，3.15-3.22(4H，m)，3.06-3.10(1H，m)，2.95-3.03(1H，m)，2.68-2.77(1H，m)，2.22-2.32(1H，m)，1.93-2.09(2H，m)，1.61-1.72(2H，m)，1.35-1.53(3H，m)，1.21-1.29(1H，m)，1.08-1.20(1H，m)，0.82(2H，d，J＝6.2Hz)，0.64-0.77(4H，m)

Example 68

((1R, 4R, 7S) -7-hydroxy-5- (4- (trifluoromethyl) pyridin-2-yl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl) ((1S, 3R) -1-isopropyl-3- ((3S, 4S) -3-methoxy-tetrahydro-2H-pyran-4-ylamino) cyclopentyl) methanone

To (1S, 3R) -1-isopropyl-3- (2,2, 2-trifluoro-N- ((3S, 4S) -3-methoxy-tetrahydro-2H-pyran-4-yl) acetamido (acetamido)) cyclopentanecarbonyl chloride (185mg, 0.463mmol) in CH₂Cl₂Et was added to the solution (2mL)₃N (0.161ml, 1.16mmol) and (1R, 4R, 7R) -7-hydroxy-2- (4- (trifluoromethyl) pyridin-2-yl) -2, 5-diaza-bicyclo [2.2.1]Heptane (100mg, 0.386 mmol). The mixture was stirred at room temperature for 4 hours. Then with NaHCO₃(1X3ml) and brine (1X3ml) wash solution. Then over MgSO₄The organic layer was dried, filtered, and concentrated and chromatographed using (100% EtOAc-70% MeOH/EtOAc) to give TFA-protected product, which was then treated with 2N NaOH (0.5mL, 1mmol) in THF (2mL) at room temperature for 4h, thenChromatography purification using (100% EtOAc-100% MeOH) afforded 60mg (30%) of the desired product. LC/MS (M + H) 527.2845 expected, 527.2996 measured; 1H NMR (400MHz, DMSO-d)₆)δppm0.64-0.76(m，4H)0.77-0.88(m，3H)1.13(d，J＝1.83Hz，1H)1.34(br.s.，1H)1.36-1.48(m，3H)1.66(dt，J＝7.69，3.84Hz，1H)1.77-1.90(m，1H)1.99(dt，J＝13.55，6.77Hz，2H)2.29(dd，J＝12.08，8.05Hz，1H)2.73-2.79(m，1H)2.97-3.04(m，1H)3.07-3.14(m，2H)3.15-3.24(m，5H)3.59(br.s.，1H)3.61-3.72(m，2H)3.75-3.88(m，1H)4.26(d，J＝0.73Hz，1H)4.44-4.55(m，2H)5.72(d，J＝3.29Hz，1H)6.75-6.85(m，2H)8.27(d，J＝5.49Hz，1H)

Example 69

((1R, 4R) -7-fluoro-5- (4- (trifluoromethyl) pyridin-2-yl) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl) ((1S, 3R) -1-isopropyl-3- ((3S, 4S) -3-methoxy-tetrahydro-2H-pyran-4-ylamino) cyclopentyl) methanone

Will be in CH₂Cl₂2,2, 2-trifluoro-N- ((1R, 3S) -3- ((1R, 4R, 7S) -7-hydroxy-2- (4- (trifluoromethyl) pyridin-2-yl) -2, 5-diaza-bicyclo [2.2.1] in (2ml)]Heptane-5-carbonyl) -3-isopropylcyclopentyl) -N- ((3S, 4S) -3-methoxy-tetrahydro-2H-pyran-4-yl) acetamide (30mg, 0.057mmol) was cooled to 0 ℃ and DAST (0.025ml, 0.086mmol) was added to the solution. The reaction mixture was stirred overnight and purified by chromatography (10% EtOAc to 100% MeOH) to give the desired product (16mg, 32%). LC/MS (M + H) 529.2802 expected, 529.3112 measured; 1H NMR (400MHz, DMSO-d)₆)δppm 0.67-0.78(m，5H)0.82(d，J＝6.59Hz，3H)1.23(br.s.，1H)1.50(d，J＝3.66Hz，3H)1.75(d，J＝4.39Hz，2H)1.94-2.03(m，1H)2.24-2.32(m，1H)2.98(s，1H)3.12(br.s.，1H)3.18-3.23(m，4H)3.31-3.34(m，1H)3.40(d，J＝10.98Hz，1H)3.62(d，J＝12.08Hz，1H)3.72(d，J＝10.62Hz，3H)3.80-3.92(m，1H)4.87(br.s.，1H)4.90-4.96(m，1H)5.31(d，J＝1.83Hz，1H)5.40-5.46(m，1H)6.86-6.94(m，2H)8.31(d，J＝5.49Hz，1H)

Example 70

(1R, 4R, 7S) -tert-butyl 7-hydroxy-5- ((1S) -1-isopropyl-3- (3-methoxy-tetrahydro-2H-pyran-4-ylamino) cyclopentanecarbonyl) -2, 5-diaza-bicyclo [2.2.1] heptane-2-carboxylate

To be at N₂(1S, 3R) -1-isopropyl-3- (2,2, 2-trifluoro-N- ((3S, 4S) -3-methoxy-tetrahydro-2H-pyran-4-yl) acetamido) cyclopentanecarboxylic acid (0.95g, 2.5mmol) in CH at 0 deg.C₂Cl₂To a solution in (5mL) was added oxalyl chloride (623mg, 4.98mmol) and DMF (3 drops). The mixture was warmed to room temperature and stirred for 2 hours, then concentrated. The acid chloride was redissolved in DCM (10ml), cooled to 0 ℃ and quenched with (1R, 4R, 7S) -tert-butyl 7-hydroxy-2, 5-diaza-bicyclo [2.2.1]]Heptane-2-carboxylate (534mg, 0.249mmol), then Et3N (0.1mL, 0.75 mmol). The resulting mixture was warmed to room temperature and stirred for 2 hours. Then with NaHCO₃(1X5ml) and brine (1X5ml) wash solution. The organic layer was MgSO₄Drying, filtration, and concentration, purification by chromatography (100% EtOAc-60% MeOH/EtOAc) afforded the crude intermediate, which was dried and concentrated. It was then dissolved in EtOH (2ml) and treated with NaOH (3ml, 7.5mmol) overnight. The reaction mixture was then purified by chromatography (100% EtOAc-100% MeOH) to afford the desired product (300mg, 25%). LC/MS (M + H) 482.3230 expected, 482.3334 measured; 1H NMR (400MHz, DMSO-d)₆)δppm 0.67(dd，J＝6.95，3.66Hz，3H)0.80(dd，J＝6.59，2.93Hz，3H)1.22(br.s.，1H)1.35-1.41(m，12H)1.43-1.48(m，2H)1.55-1.68(m，2H)1.85-1.93(m，1H)1.95-2.04(m，1H)2.16-2.28(m，1H)2.66-2.80(m，1H)2.97-3.02(m，1H)3.03-3.10(m，2H)3.17-3.29(m，5H)3.37-3.47(m，1H)3.47-3.58(m，1H)3.61-3.74(m，1H)3.81-3.89(m，1H)3.94-4.04(m，2H)4.24(br.s.，1H)5.65-5.77(m，1H)

Example 71

7-fluoro-5- ((1S, 3R) -1-isopropyl-3- ((3S, 4S) -3-methoxy-tetrahydro-2H-pyran-4-ylamino) cyclopentanecarbonyl) -2, 5-diaza-bicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester

Will be in CH₂Cl₂7-hydroxy-5- ((1S) -1-isopropyl-3- (2,2, 2-trifluoro-N- (3-methoxy-tetrahydro-2H-pyran-4-yl) acetamido) cyclopentanecarbonyl) -2, 5-diaza-bicyclo [2.2.1] in (2ml)]Tert-butyl heptane-2-carboxylate (100mg, 0.173mmol) was cooled to 0 deg.C and DAST (0.036ml, 0.259mmol) was added to the solution. The reaction mixture was stirred overnight and purified by chromatography (10% EtOAc to 100% MeOH) to give TFA protected product, which was then treated with 2.5N NaOH (0.014ml, 0.5mmol) in THF (2ml) at rt for 4h and then purified by chromatography (100% EtOAc to 100% MeOH) to give 12mg of the target product (14%). LC/MS (M + H) 484.3187 expected, 484.3197 measured; 1H NMR (400MHz, DMSO-d)₆)δppm 0.63-0.72(m，3H)0.81(dd，J＝7.14，1.65Hz，3H)1.22(br.s.，1H)1.36-1.48(m，13H)1.56-1.68(m，2H)1.85-1.96(m，2H)2.16-2.28(m，1H)2.68-2.79(m，1H)2.95-3.05(m，1H)3.15(br.s.，1H)3.17-3.29(m，7H)3.52(d，J＝10.62Hz，2H)3.66-3.74(m，1H)3.82-3.90(m，1H)4.27-4.37(m，1H)4.69(br.s.，1H)5.08-5.35(m，1H)

Biological data

CCR2 in vitro assay

The ability of the novel compounds of the present invention to antagonize chemokine receptor (e.g., CCR2) function can be determined using a suitable screening method (e.g., a high throughput assay). For example, agents can be tested in extracellular acidification assays, calcium flux assays, ligand binding assays, or chemotaxis assays (see, e.g., Hesselgesser et al, J biol. chem.273 (25): 15687-15692 (1998); WO 00/05265 and WO 98/02151).

In a suitable assay, an isolated or recombinantly derived CCR2 protein is used that has at least one property, activity or functional characteristic of a mammalian CCR2 protein. Specific properties may be binding properties (binding e.g. ligand or inhibitor), signalling activity (e.g. activation of mammalian G-protein, cytosolic free calcium concentration [ Ca ]⁺⁺]induction of a rapid transient increase in i), cellular response functions (e.g., stimulation of chemotaxis or inflammatory mediator release by leukocytes), and the like.

In one example binding assay, a composition containing a CCR2 protein or variant thereof is maintained under conditions suitable for binding. The CCR2 receptor is contacted with the compound to be tested and binding is detected or measured.

In one example cell-based assay, cells stably or transiently transfected with a vector or expression cassette having a nucleic acid sequence encoding a CCR2 receptor are used. The cells are maintained under conditions suitable for expression of the receptor and contacted with the agent under conditions suitable for binding to occur. Binding can be detected using standard techniques. For example, the extent of binding can be determined relative to a suitable control. Also, a cell fraction containing the receptor (e.g., membrane fraction) may be used instead of the whole cells.

Binding or complex formation in the assay can be detected directly or indirectly. For example, the agent can be labeled with a suitable label (e.g., fluorescent label, tag, isotopic label, enzymatic label, etc.) and binding can be determined by detecting the label. Specific and/or competitive binding can be assessed by competition or displacement studies using unlabeled agent or ligand as a competitor.

The CCR2 antagonist activity of the compounds of the present invention can be reported as the concentration of inhibitor required to inhibit 50% of specific binding (IC) in the receptor binding assay₅₀Value), in said assay, use¹²⁵I-labeled MCP-1 serves as a ligand, and Peripheral Blood Mononuclear Cells (PBMC) prepared from normal human whole blood via density gradient centrifugation are used. Specific binding is defined as total binding (e.g., total cpm on filter) minus non-specific binding. Non-specific binding is defined as the amount of cpm still detected in the presence of excess unlabeled competitor (e.g., MCP-1).

CCR2 binding IC₅₀

Human PBMCs are used in binding assays to test compounds of the invention. For example, 200,000 to 500,000 cells can be contacted with 0.1 to 0.2nM¹²⁵I-labeled MCP-1 incubation with or without unlabeled competitor (10nM MCP-1) or varying concentrations of test compound.¹²⁵I-labeled MCP-1 may be prepared by a suitable method or purchased from a supplier (Perkin Elmer, Boston MA). The binding reaction was performed in 50 to 250 μ L binding buffer consisting of 1M HEPES pH 7.2 and 0.1% BSA (bovine serum albumin) for 30min at room temperature. The membranes were harvested by rapid filtration through a glass fiber filter (Perkin Elmer) pre-soaked in 0.3% polyethyleneimine or Phosphate Buffered Saline (PBS) to terminate the binding reaction. The filters were rinsed with approximately 600. mu.L of binding buffer containing 0.5M NaCl or PBS, then dried and the amount of bound radioactivity was determined by counting on a Gamma counter (Perkinelmer).

More specifically, the following assays can be used to determine the IC of the compounds of the invention₅₀The value is obtained.

hCR 2(125-I hMCP-1) small molecule binding assay

The following reagents and auxiliary materials have been used in the above assay:

MCP-1

Biosource # PHC1013

1mg

reconstitution with 2ml binding buffer (0.5mg/ml or 60uM)

¹²⁵I MCP-1

Perkin Elmer #NEX332

25uCi

Reconstitution with 0.2ml PBS

RPMI 1640 containing L-glutamine

MediaTech/Cellgro # 10-040-CM

BSA

Sigma # A2153

HEPES

1M solution

Media Tech/Cellgro # 25-060-CL

NaCl

Sigma # S7653

Auxiliary material

Muliscreen BV filter plate

Millipore # MABVN1250

Multiscreen Punch tip

Millipore #MADP19650

Multiscreen filtering system multi-head vacuum pumping device

Millipore # MAVM0960R

Normal human leukopheresis (leukoreduction) contents (available from Biological Specialty Corporation, Colmar, Pa.) were diluted 1: 1 with PBS, divided into 50ml conical tubes (preferably less than 40ml per tube), and layered underneath with 10ml Ficoll-Paque PLUS (GEHealthcare 17-1440-02). The tubes were centrifuged at 2800rpm in a clinical centrifuge at room temperature for 30 minutes without braking. The plasma layer was aspirated and the buffy coat was collected. The collected buffy coat was washed 2 times with 50ml PBS and centrifuged at 1400rpm, braked. The cells were counted. Then in combinationCells were diluted to 1 × 10 in buffer⁷Cells/ml.

The 96-well plates (e.g., Millipore MultiScreen96 plates) were pre-wetted with about 100. mu.l of binding buffer (RPMI + 0.1% BSA +20mM HEPES) and blotted just prior to addition of the compounds.

An automated system, such as TelCel (Hamilton Storage technologies, Inc., 103 South Street, Hopkinton, MA 01748 USA), can be advantageously used to store or process plates containing the compounds to be tested.

Mu.l of 50. mu.M of the test compound in 100% DMSO were spotted onto U-bottom polypropylene 96-well plates.

245 μ l of binding buffer per well was added to each well to give a 1 μ M concentration of compound in 2% DMSO.

50 μ l of 1 μ M compound was transferred to a prewetted Millipore plate.

50 μ l/well of 1 × 10E7 cells/ml freshly prepared human PBMC were added.

The samples were preincubated at room temperature for 30 minutes or 1 hour.

Mu.l 450pM 125-I-hMCP-1(Perkin-Elmer/NEN Cat No. NEX332025UC) was added to give a final concentration of 150pM 125-I-hMCP-1/well.

The final test compound concentration in all wells was 0.333. mu.M in a total volume of 150. mu.l containing 0.67% DMSO. The control for this assay consisted of 0% inhibition and 100% inhibition with 1. mu.M hMCP-1 (saturation conditions). All wells were run in duplicate. The control may be an 8-fold parallel assay.

The samples were incubated at room temperature for 30 minutes.

Buffer was aspirated through Millipore plates. The plates were washed 3 times with wash buffer (PRMI + 0.1% BSA +20mM HEPES +0.4M NaC).

And taking out the flat underdrain. The flat filter was dried. The filter was then ejected into a plastic test tube.

Finally, the samples were counted on a Gamma counter.

Repeat all IC50 plates, n 2.

The following table summarizes the ICs identified by the assays₅₀The value is obtained.

TABLE 1 biological data

Diabetic nephropathy rat model

The renal protective effect of pharmacological inhibition of CCR2 was determined using a rat model of diabetic nephropathy. Streptozotocin (STZ) -induced diabetic rat models have been widely used to study the progression of diabetic nephropathy. STZ injection causes immediate destruction of pancreatic β -cells, resulting in hyperglycemia and similar renal disease progression as observed in human diabetes. Diabetes was induced in male Wistar rats by a single dose of STZ (45mg/kg, i.v.). Fasting blood glucose levels were assessed 3 days after induction of diabetes. Animals with fasting blood glucose levels above 200mg/dL were included in the study. All treatments were then started. 1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3-isopropyl-3- ({ (1S,4S) -5- [6- (trifluoromethyl) pyrimidin-4-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol was administered at doses of 0.03, 0.3, 1, and 10mg/kg (mpk) (in food) for 11 weeks. At 1, 4, 8, and 11 weeks post-treatment, 24-hour urine collections were obtained for assessment of 24-hour Urinary Albumin Excretion (UAE). As expected, UAE continued to increase during the 11 weeks of the study after induction of diabetes. Doses at 0.3mpk (1.73. + -. 0.69mg/24h), 1mpk (1.09. + -. 0.20mg/24h) and 10mpk (0.71. + -. 0.22mg/24h) at week 8, and at all doses (at 0.03, 0.3, 1 and 10mpk, respectively, 2.17. + -. 1.31, 1.96. + -. 0.85, 1.66. + -. 0.65 and 1.02. + -. 0.32mg/24 h) at week 11, relative to 6.36. + -. 2.08mg/24h in untreated STZ rats, 1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3-isopropyl-3- ({ (1S,4S) -5- [6- (trifluoromethyl) pyrimidin-4-yl ] -2, 5-diaza-bicyclo [2.2 ] cyclopentyl } amino-2-1H-oxo-2-cyclopentyl } cyclopentyl-methyl-2-oxo-2-D-amino-2-n-methyl-O-n-ethyl } -2, 2-n-ethyl-methyl-O-n-ethyl-2-ethyl-n-ethyl-methyl-O-n- Erythro-pentitol treatment significantly reduced UAE. These data demonstrate that pharmacological inhibition of CCR2 will provide renal protection during the development and progression of diabetic nephropathy and support CCR2 antagonism as a new therapeutic strategy for the treatment of diabetic nephropathy.

Claims

1. A compound of formula I (a) or I (b):

or a pharmaceutically acceptable salt thereof, wherein:

a is O;

w is CR¹³R¹⁴；

R¹Is H;

R²is methyl；

R³Is H;

R⁸and R⁹Is H;

R⁴and R⁵Is H;

R⁶and R⁷Is H;

R¹⁰is (C)₁-C₆) Alkyl, (C)₁-C₆) Haloalkyl, (C)₁-C₆) A hydroxyalkyl group;

R¹¹is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or phenyl, said R¹¹Optionally independently substituted with one or more of the following substituents: trifluoromethyl, fluoro or methyl;

R¹³is H, halogen or OH;

R¹⁴is H, halogen or OH.

2. The compound of claim 1, wherein the compound is represented by formula II:

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2, wherein R¹⁰Is that

Or

4. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R¹¹Is thatOr

5. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein R¹¹Is thatOr

6. The compound of claim 5, wherein R¹⁰Is that

OrAnd is

R¹¹Is thatOr

7. A compound selected from the group consisting of:

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3-ethyl-3- ({ (1S,4S) -5- [4- (trifluoromethyl) pyridin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol;

1, 5-anhydro-2, 3-dideoxy-3- { [ (1R,3S) -3- (2, 2-difluoroethyl) -3- ({ (1S,4S) -5- [4- (trifluoromethyl) pyrimidin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -4-O-methyl-D-erythro-pentitol;

1, 5-anhydro-2, 3-dideoxy-4-O-methyl-3- { [ (1R,3S) -3- (2,2, 2-trifluoroethyl) -3- ({ (1S,4S) -5- [4- (trifluoromethyl) pyridin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -D-erythro-pentitol;

1, 5-anhydro-2, 3-dideoxy-4-O-methyl-3- { [ (1R,3S) -3- (2,2, 2-trifluoroethyl) -3- ({ (1S,4S) -5- [2- (trifluoromethyl) pyrimidin-4-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopentyl ] amino } -D-erythro-pentitol;

1, 5-anhydro-2, 3-dideoxy-3- { [ (1S,4S) -4-isopropyl-4- ({ (1S,4S) -5- [4- (trifluoromethyl) pyridin-2-yl ] -2, 5-diazabicyclo [2.2.1] hept-2-yl } carbonyl) cyclopent-2-en-1-yl ] amino } -4-O-methyl-D-erythro-pentitol;

8. A compound of the formula:

or a pharmaceutically acceptable salt thereof.

9. A compound of the formula

Or a pharmaceutically acceptable salt thereof.

10. A composition comprising the compound of claim 2, or a pharmaceutically acceptable salt thereof, and a carrier.

11. The use of a compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of atherosclerosis, lupus, multiple sclerosis, pain, transplant rejection, diabetes, viral diseases, cancer, asthma, seasonal and perennial allergic rhinitis, sinusitis, conjunctivitis, age-related macular degeneration, food allergy, mackerel poisoning, psoriasis, undifferentiated spondyloarthropathy, gout, urticaria, pruritus, eczema, inflammatory bowel disease, thrombotic disease, otitis media, fibrosis, liver cirrhosis, cardiac disease, alzheimer's disease, sepsis, restenosis, crohn's disease, ulcerative colitis, irritable bowel syndrome, hypersensitivity lung disease, chronic obstructive pulmonary disease, arthritis, nephritis, atopic dermatitis, stroke, acute nerve injury, or a combination thereof, Sarcoidosis, hepatitis, endometriosis, hypersensitivity pneumonitis, eosinophilic pneumonia, delayed-type hypersensitivity reactions, interstitial lung disease, ocular disorders or obesity.

12. The use of a compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of rheumatoid arthritis, liver fibrosis, drug induced pulmonary fibrosis, neuropathic pain and diabetic nephropathy.