CZ348999A3 - Nicotinamide derivatives and pharmaceutical preparation containing thereof - Google Patents

Abstract

Compounds of formula I are described wherein m, n, o, p, q, r, A, B, D, E, R 1, R 2, R 3, R 4, R 5, R 6, R 7 and R 8 have specific meanings, these compounds being useful for treatment respiratory, allergic and rheumatic disorders, disorders weight control, inflammatory disorders and disorders central nervous system, such as asthma, chronic obstructive pulmonary disease, syndromrespiratory adult disease, shock, fibrosis, pulmonary hypersensitivity allergic rhinitis, atopic dermatitis, psoriasis, control weight, rheumatoid arthritis, cachemia, Crohn's diseases, ulcerative colitis, arthritic conditions and others inflammatory diseases, depression, multi-infarct dementia a AIDS.

Description

Nicotinamide derivatives and pharmaceutical compositions containing them

Technical field

The invention relates to nicotinamide derivatives which are selective inhibitors of phosphodiesterase type 4 (PDE4) and tumor necrosis factor (TNF) production and as such are useful for the treatment of respiratory, allergic and rheumatic disorders, weight control disorders, inflammatory disorders and central nervous system disorders such as asthma, chronic obstructive pulmonary disease, adult respiratory disease syndrome, shock, fibrosis, pulmonary hypersensitivity, runny nose, atopic dermatitis, psoriasis, rheumatoid arthritis control, cachexia, Crohn's disease, ulcerative colitis, arthritic conditions, and other inflammatory conditions , multi-infarct dementia and AIDS.

The invention also relates to a method of using these compounds in the treatment of the aforementioned diseases in mammals, particularly humans, and to pharmaceutical compositions comprising the compounds.

allergic weight,

Recently, they have been therapeutic

Since recognizing that cyclic adenosine triphosphate (cAMP) is an intracellular secondary information carrier, inhibition of phosphodiesterases is a target for modulation and thus intervention in a variety of disease processes, various classes of PDEs have been identified and their selective inhibition has led to improved therapeutics. In particular, it has been found that inhibition of PDE4 may lead to inhibition of the release of inflammatory mediators and relaxation of respiratory smooth muscles. Thus, compounds that inhibit PDE4 but have little activity against •

Other PDE types inhibited the release of inflammatory mediators and relaxation of the smooth respiratory muscles without causing cardiovascular effects or antiplateletal effects.

Recent molecular cloning has revealed the complexity and diversity of PDE4 enzymes. It is known that there are four distinct PDE4 isozymes (A, B, C and D), each of which is encoded into a separate gene. Kinetic studies with human recombinant materials suggest that these four isozymes may differ in their Km and Vmax in the hydrolysis of cAMP. Analyzes of tissue distributions of PDE4 mRNA suggest that each isozyme can be localized in a cell-specific arrangement. For example, different human skeletal muscle peripheral blood leukocytes do not express PDE4 information and guinea pig eosinophils express predominant PDE4 information. The structural and distribution diversity of PDE4 isozymes offers the possibility of discovering a selective isozyme inhibitor that blocks only inflammatory cell function. Using selective PDE4D isozyme inhibitors, we have shown that PDE4D isozyme plays a key role in regulating activation and degranulation of human eosinophils. In a primate asthma model, PDE4D isozyme selective compounds inhibit antigen-induced pulmonary eosinophilia. Therefore, by selective blocking of D isozyme, PDE4D inhibitors exhibit reduced side effects and maintain anti-asthmatic (anti-inflammatory) effects.

SUMMARY OF THE INVENTION

The present invention provides a compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein the dotted line represents an optional double bond, m is 0 or 1, n is 0 or 1, o is 0, 1, 2, 3 or 4, p is 0 or 1, q is 0, 1, 2 or 3 , r is 0, 1, 2, 3 or 4, t is 0 or 1,

A is an oxygen atom,> NH or a sulfur atom,

B is O or NH,

D is oxygen or NR ⁹ wherein R ⁹ is hydrogen or C 1 -C 6 alkyl,

E is CH ₂ , O, NH or S (O) _a , wherein a is 0, 1 or 2,

R ¹ is hydrogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkenyl, C 6 -C 10 aryl, C 7 -C 9 bridged bicycloalkyl or a saturated or unsaturated, cyclic or bicyclic heterocyclic group having from 3 to 7 carbon atoms, wherein said saturated or unsaturated, cyclic or bicyclic heterocyclic group having from 3 to 7 carbon atoms contains from one to four heteroatoms independently selected from

Oxygen, sulfur, nitrogen and NR ⁹ groups wherein R ⁹ is as defined above, wherein said R ¹ group as cycloalkyl, cycloalkenyl, cycloalkanone, aryl, bicycloalkyl and heterocyclic groups are optionally substituted with one to three substituents independently selected from the group consisting of halogen, cyano, carboxy, amino, nitro, hydroxy, (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy, (C 3 -C 7) cycloalkyl, (C 1 -C 6) hydroxyalkyl, (C 1 -C 6) hydroxyalkylamino, (C 1 -C 6) alkoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C 1 -C 6) acyl, (C 1 -C 6) acylamino, acyloxy having 1 to 6 carbon atoms, alkylamino having 1 to 6 carbon atoms C1-C6-dialkylamino in each alkyl moiety, alkyl-NH- (C = O) -, wherein the alkyl moiety has 1 to 6 carbon atoms, (alkyl) ₂ -N- (C = O) - wherein each alkyl moiety has 1 to 6 carbon atoms, an aminosulfonyl group, an alkylaminosulfonyl group having 1 to 6 carbon atoms, or a saturated or unsaturated, cyclic or bicyclic heterocyclic group having 3 to 7 carbon atoms, wherein said saturated or unsaturated, cyclic or bicyclic heterocyclic group substituents of 3 to 7 carbon atoms on said R ¹ group as cycloalkyl, cycloalkenyl, aryl, bicycloalkyl and heterocyclic group contain from one to four heteroatoms independently selected from oxygen, sulfur, nitrogen and NR ⁹ , wherein R is ⁹ is as defined above, and wherein these heterocyclic groups are optionally substituted with one to three substituents independently selected from a halogen atom, a cyano group, a carboxy group,

-5amino, nitro, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, acyl C 1 -C 6 aryl, C 1 -C 6 aryl, C 1 -C 6 acylamino, C 1 -C 6 acyloxy, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino an alkyl moiety, an alkylsulfonyl group having 1 to 6 carbon atoms, an aminosulfonyl group, an alkylaminosulfonyl group having 1 to 6 carbon atoms, a dialkylaminosulfonyl group having 1 to 6 carbon atoms in each alkyl portion, or a heteroaryl group having 2 to 9 carbon atoms, wherein said alkyl, alkoxy or cycloalkyl substituents on said R ¹ group as cycloalkyl, cycloalkenyl an aryl, a bicycloalkyl, or a heterocyclic group are optionally further independently substituted with one to three substituents independently selected from halogen, cyano, carboxy, amino, nitro, hydroxy, C 1 -C 6 alkyl, C 1 hydroxyalkyl C 1 -C 6 alkoxy, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, C 1 -C 6 acyl, C 1 -C 10 aryl, C 1 acylamino C 1 -C 6 acyloxy, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino in each alkyl moiety, C 1 -C 6 alkylsulfonyl, aminosulfonyl, C 1 -C 6 alkylaminosulfonyl C 6 dialkylaminosulfonyl a group having from 1 to 6

The carbon atoms in each alkyl moiety or a C 2 -C 9 heteroaryl group, or said R ¹ group as a cycloalkyl group, a cycloalkenyl group, an aryl group, a bicycloalkyl group and a heterocyclic group are further optionally optionally substituted with one to three substituents formulas

wherein R ¹⁰ is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkenyl, C 6 -C 10 arylamino, aryl of 6 to 10 carbon atoms, bridged bicycloalkyl group having 7 to 9 carbon atoms or a saturated or unsaturated, cyclic or bicyclic heterocyclic group with 3-7 carbon atoms, wherein said group R ¹⁰ as a saturated or unsaturated, cyclic or bicyclic heterocyclic group C 3-7 carbon atoms contain one to four heteroatoms independently selected from oxygen, sulfur, nitrogen and NR ⁹ , wherein R ⁹ is as defined above, wherein said R ¹⁰ as alkyl, alkoxy, cycloalkyl, cycloalkenyl , aryl, bicycloalkyl and heterocyclic is optionally substituted with one to three substituents independently selected from the group consisting of halogen, cyano, carboxy, amino, nitro, hydroxy, C 1 -C 6 alkylalkoxy and C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, hydroxyalkyl (C 1 -C 6) group, (C 1 -C 6) hydroxyalkylamino, alkoxy

C 1 -C 6, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, C 1 -C 6 acyl, C 1 -C 6 acylamino, C 1 -C 6 acyloxy, C 1 -C 6 alkylamino, dialkylamino C 1 -C 6 alkyl, aminosulfonyl, C 1 -C 6 alkylaminosulfonyl, or a saturated or unsaturated cyclic or bicyclic heterocyclic group of 3 to 7 carbon atoms, wherein said saturated or unsaturated, cyclic or bicyclic heterocycle of 3 up to 7 carbon atoms contain from one to four heteroatoms independently selected from oxygen, sulfur, nitrogen and NR ⁹ , wherein R ⁹ is as defined above, and wherein said heterocyclic group is optionally substituted with one to three substituents independently selected from the group consisting of halogen, cyano, carboxy amino, nitro, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C 1 -C 6) acyl, (C 6 -C 10) aryl, (C 1 -C 6) acylamino, (C 1 -C 6) acyloxy, (C 1 -C 6) alkylamino (C 1 -C 6) dialkylamino each alkyl moiety, (C 1 -C 6) alkylsulfonyl, aminosulfonyl, (C 1 -C 6) alkylaminosulfonyl, (C 1 -C 6) dialkylaminosulfonyl (C 2 -C 9) heteroaryl, alkoxy or cycloalkyl substituents on said R ¹⁰ groups as alkyl, alkoxy, cycloalkyl, a cycloalkenyl group, an aryl group, a bicycloalkyl group, or a heterocyclic group

-8 are optionally substituted with one to three substituents independently selected from the group consisting of halogen, cyano, carboxy, amino, nitro, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy C 1 -C 6 alkylthio, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, C 1 -C 6 acyl, C 1 -C 6 aryl, C 1 -C 6 acylamino, C 1 -C 6 acyloxy C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino in each alkyl moiety, C 1 -C 6 alkylsulfonyl, aminosulfonyl, C 1 -C 6 alkylaminosulfonyl, C 1 -C 6 dialkylaminosulfonyl carbon in each alkyl moiety or heteroaryl group having 2 to 9 atoms y is carbon, or R ¹ is a group of the formula

where u is 0 or 1, and

G, J, K and L are independently O, S, N, NR ⁹ , where R ⁹ is as defined above, carbonyl or CHR ¹⁶ , wherein the dotted lines indicate optional double bonds and where it is understood that when the double a bond exists between G and J, J and K or K and L that R ⁹ is absent,> CHR ¹⁶ is> CR ¹⁶ and G, J, K or L cannot be a carbonyl group where R ¹⁶ is hydrogen, halogen , cyano, carboxy, amino, nitro, hydroxy, C 1 -C 6 alkylalkoxy and C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, C 1 -C 6 hydroxyalkyl carbon atoms, C 1 -C 6 hydroxyalkylamino, C 1 -C 6 alkoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, C 1 -C 6 acyl, C 1 -C 6 acylamino, acyloxy C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino in each alkyl moiety, aminosulfonyl, C 1 -C 6 alkylaminosulfonyl or a saturated or unsaturated, cyclic or bicyclic 3 to 6 heterocyclic group 7 carbon atoms containing one to four heteroatoms independently selected from oxygen, sulfur, nitrogen and NR ⁹ , wherein R ⁹ is as defined above, wherein the heterocyclic group is optionally substituted with one to three substituents independently selected from halogen; cyano, carboxy, amino, nitro, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, acyl with 1 a 6 to 6 carbon atoms, 6 to 10 carbon aryl groups, 1 to 6 carbon acylamino, 1 to 6 carbon acyloxy, 1 to 6 carbon alkylamino, 1 to 6 carbon dialkylamino in each alkyl moiety, (C 1 -C 6) alkylsulfonyl, aminosulfonyl, (C 1 -C 6) alkylaminosulfonyl, (C 1 -C 6) dialkylaminosulfonyl (C 1 -C 6) alkyl or C 2 -C 9 heteroaryl, wherein R ¹⁶ as alkyl the alkoxy or cycloalkyl substituents are optionally substituted with one to three substituents independently selected from the group consisting of halogen, cyano, carboxy,

- amino, nitro, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, (C 1 -C 6) alkylthio, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C 1 -C 6) acyl, (C 1 -C 6) aryl, (C 1 -C 6) acylamino, (C 1 -C 6) acyloxy, (C 1 -C 6) alkylamino, (C 1 -C 6) dialkylamino, (C 1 -C 6) alkylsulfonyl, (C 1 -C 6) alkylamino, (C 1 -C 6) alkylaminosulfonyl, (C 1 -C 6) dialkylaminosulfonyl each alkyl moiety or heteroaryl group having 2 to 9 carbon atoms, wherein R ² , R ³ and R ⁴ are each independently hydrogen, hydroxy, halogen, cyano, carboxy, nitro, amino, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino in each alkyl moiety, hydroxyamino, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl or formula

O

wherein R ¹⁰ is as defined above, or R ² and R ³ together with the carbon atom to which they are attached form a carbonyl group or R ² and R ³ together with the carbon atom to which they are attached form a cycloalkyl ring of 3 to 7 or when m is 1, n is 1, o is 1 and p is 0, A and R ² together form a group of the formula

9 · 9 9 9 • 999

wherein the dotted lines denote optional double bonds and q, A, B, R ¹ , R ³ and R ⁴ are as defined above, and when the double bond comprises the carbon atom to which R ^{3 is} attached, then R ³ is absent, or n is 1, A is R ² together, and R ³ and - [R ⁴ ] _q -R ¹ together form a group of the formula

R ⁵ is a saturated or unsaturated, cyclic or bicyclic heterocyclic group of 3 to 7 carbon atoms containing one to four heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and NR ⁹ , wherein R ⁹ is as defined above, wherein the heterocyclic group is optionally substituted with one to three substituents independently selected from the group consisting of halogen, cyano, carboxy, amino, nitro, hydroxy, C 1 -C 6 alkylalkoxy and C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl carbon atoms, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, C 1 -C 6 acyl, C 1 -C 6 acylamino, C 1 -C 6 acyloxy carbon atoms, »v

-12t to C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino in each alkyl moiety, C 1 -C 6 alkyl-NH- (C = O) - carbon in the alkyl moiety, (alkyl) ₂ -N- (C = O) - having 1 to 6 carbon atoms in each alkyl moiety, an aminosulfonyl group, an alkylaminosulfonyl group having 1 to 6 carbon atoms, or a saturated or unsaturated, cyclic or bicyclic heterocyclic group having 3 to 7 carbon atoms containing one to four heteroatoms independently selected from oxygen, sulfur, nitrogen and NR ⁹ , wherein R ⁹ is as defined above, wherein the heterocyclic substituent on R ⁵ as a saturated or unsaturated, cyclic or bicyclic heterocyclic C 3 -C 7 is optionally substituted with one to three substituents independently selected from halogen, cyano, carboxy, amino, nitro, hydroxy n, alkyl of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, acyl of 1 to 6 carbon atoms, (C 1 -C 6) aryl group, (C 1 -C 6) acylamino, (C 1 -C 6) acyloxy, (C 1 -C 6) alkylamino, (C 1 -C 6) dialkylamino, alkylsulfonyl group (C 1 -C 6), aminosulfonyl, (C 1 -C 6) alkylaminosulfonyl, (C 1 -C 6) dialkylaminosulfonyl (C 1 -C 6) alkyl or C 2 -C 9 heteroaryl group, wherein alkyl, alkoxy or cycloalkyl substituents on the group R ⁵ as a saturated or unsaturated, cyclic or bicyclic heterocyclic group with 3-7 carbon Uhl are optionally substituted with one to three substituents independently selected from the group consisting of a halogen atom, or a halogen atom; * «« ·

- -X · »<<<

Cyano, carboxy, amino, nitro, hydroxy, alkyl of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, alkoxy of (C 1 -C 6) alkyl, (C 1 -C 6) alkylthio, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C 1 -C 6) acyl, (C 6 -C 10) aryl, (C 1 -C 6) acylamino, acyloxy (C 1 -C 6) C 1 -C 6 alkylamino, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino, C 1 -C 6 alkylsulfonyl, aminosulfonyl, C 1 -C 6 alkylaminosulfonyl, C 1 -C 6 alkylaminosulfonyl C 1 -C 6 alkyl or C 2 -C 9 heteroaryl, or R ⁵ as saturated or unsaturated, cyclic or bicyclic The C 3-7 heterocyclic group is optionally further substituted with a radical of formula

wherein R ¹⁰ is as defined above, or R ⁵ is a group of the formula

wherein R ¹¹ , R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ are independently selected from the group consisting of hydrogen, halogen, cyano, carboxy, amino, nitro, hydroxy,

-14ft-C 1 -C 6 alkyl-C 1 -C 6 alkylalkoxy, C 3 -C 7 -cycloalkyl, hydroxyalkyl (C 1 -C 6) alkoxy, (C 1 -C 6) alkoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C 1 -C 6) acyl, (C 1 -C 6) acylamino, alkyl- (C = O) -NH- (C = O) - having 1 to 6 carbon atoms in the alkyl moiety, aryl- (C = O) -NH- (C = O) - having 6 to 10 carbon atoms in the aryl moiety, acyloxy having 1 to 6 carbon atoms, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino in each alkyl moiety, alkyl-NH- (C = O) - C 1 -C 6 -alkyl, (alkyl) ₂ -N- (C = O) - having 1 to 6 carbon atoms in each alkyl moiety, an aminosulfonyl group, an alkylaminosulfonyl group having 1 to 6 carbon atoms, a dialkylaminosulfonyl group (C 1 -C 6) alkyl or saturated or unsaturated, cyclic or bicyclic (C 3 -C 7) heterocyclic group containing one to four heteroatoms independently selected from oxygen, sulfur, nitrogen and NR ⁹ , wherein R ⁹ is as defined above, and wherein the heterocyclic group is optionally substituted with one to three substituents independently selected from the group consisting of halogen, cyano, carboxy, amino, nitro, hydroxy, alkyl of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 atoms C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, C 1 -C 6 acyl, C 1 -C 6 aryl, C 1 -C 6 acylamino C1 -C6 acyloxy, C1 -C6 alkylamino; C 1 -C 6 dialkylamino, C 1 -C 6 dialkylamino, C 1 -C 6 alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl

A C 1 -C 6 group, a C 1 -C 6 dialkylaminosulfonyl group in each alkyl moiety, or a heteroaryl group C 2 -C 9, or R ¹¹ , R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ are optionally independently

R ¹⁰ wherein R ¹⁰ is as defined above, wherein the alkyl, alkoxy or cycloalkyl groups of R ¹¹ , R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ are optionally substituted with one to three substituents independently selected from the group consisting of halogen, cyano, carboxy, amino, nitro, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C 1 -C 6) acyl, (C 6 -C 10) aryl, (C 1 -C 6) acylamino, (C 1 -C 6) acyloxy, (C 1 -C 6) alkylamino (C 1 -C 6) dialkylamino each alkyl moiety, C 1 -C 6 alkylsulfonyl, aminosulfonyl, C 1 -C 6 alkylaminosulfonyl C 6 -C 6, C 1 -C 6 dialkylaminosulfonyl or C 2 -C 9 heteroaryl, or R ¹² and R ¹³ together with the carbon atoms to which they are attached form a radical of formula: · · ·

- 2.6 ~ ········ · · ··

where u, G, J, K and L are as defined above,

R ⁶ , R ⁷ and R ⁸ are independently hydrogen, halogen, cyano, carboxy, amino, nitro, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy C 6 -C 6 alkylthio, C 1 -C 6 alkylthio, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, C 1 -C 6 acyl, C 6 -C 10 aryl, C 1 -C 6 acylamino, C 1 -C 6 acyloxy C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino in each alkyl moiety, C 1 -C 6 alkylsulfonyl, aminosulfonyl, C 1 -C 6 alkylaminosulfonyl, C 1 -C 6 dialkylaminosulfonyl 6 carbon atoms in each alkyl moiety or a heteroaryl group having 2 to 9 carbon atoms, or R ⁷ and R ⁸ together with the carbon atoms to which they are attached form a fused bicyclic ring of formula II

(II) •

-1 / - ································································ kde where the dotted lines indicate optional double bonds, and Μ, P, Q and T are independently O, N or CR ¹ ' R ¹⁷ is hydrogen or C 1 -C 6 alkyl, with the proviso that when m is 1, n is 1, o is 1, p is 0, q is 0, r is 0, A is oxygen, B is NH, R ² and R ^J are hydrogen, R ^J is phenyl substituted with methyl, methoxy, chlorine or fluorine, E is oxygen and R ⁵ is phenyl optionally substituted with one or two fluorine or chlorine atoms, then R ¹ must be at least disubstituted with substituents other than methyl, methoxy or halogen, with the proviso that when t is one, the compound of formula I is a zwitterionic N-oxide, provided that adjacent positions are delimited by G, J, K and L they cannot both be oxygen, and with the proviso that when the dashed line in formula 1 represents a double bond, p is 0 and R ³ is absent.

As used herein, the term alkyl refers to a saturated monovalent hydrocarbon moiety having straight, branched, or cyclic moieties, or combinations thereof, unless otherwise indicated.

As used herein, alkoxy refers to O-alkyl groups wherein alkyl is as defined above.

As used herein, the term aryl means, unless otherwise indicated, an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen atom, such as phenyl or naphthyl, optionally substituted with 1 to 3 substituents selected from the group consisting of fluorine, chlorine, trifluoromethyl, C 6 -C 10 aryloxy, trifluoromethoxy, difluoromethoxy and C 1 -C 6 alkyl.

The term saturated or unsaturated, cyclic or bicyclic heterocyclic group of 3 to 7 carbon atoms containing one or four oxygen, sulfur, nitrogen and NR ⁹ atoms as heteroatom, wherein R ⁹ is as defined above,

18 unless otherwise specified and without limitation, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, oxiranyl, methylenedioxyl, chromenyl, isoxazolidinyl, 1,3-oxazalidin-3-yl, isothiazolidinyl,

1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl, piperidinyl, thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl,

1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl, 1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, tetrahydroazepinyl, piperazinyl, chromanyl, furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, imidazolyl,

1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl,

1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,

1,3,5-oxa1,3,5-thiapyridyl, pyrrolyl, diazolyl, diazolyl, pyrimidyl, indolizinyl, quinoxalinyl, phthalazinyl, Preferred thiazolyl, pyridyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl,

1,2,3-triazinyl, 1,3,5-triazinyl, pyrazolo [3,4-b] pyridinyl, cinnolinyl, pteridinyl, purinyl, 6,7-dihydro-5H- [1] pyrindinyl, benzo [b] thiophenyl 5,6,7,8-tetrahydroquinolin-3-yl, benzoxazyl, benzothiazolyl, benzothiadiazole, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl, isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl, indazolyl, isoquinolyl, quinololyl, quinololyl, quinololyl, quinololyl, quinololyl, quinololyl, quinololyl, quinololyl, quinololyl, quinololyl, quinolinyl;

heterocyclic groups are furyl, thienyl, oxazolyl, isoxazolyl, 1,2,3-thiadiazolyl, benzoxazolyl or indolyl.

As used herein, the term acyl means, unless otherwise indicated, a radical of formula RCO wherein R is alkyl, alkoxy, aryl, arylalkyl or arylalkoxy, and alkyl or aryl are as defined above.

As used herein, acyloxy refers to O-acyl groups wherein acyl is as defined above.

The compound of formula (I) may have chiral centers and therefore exists in various enantiomeric forms. The invention is

It relates to all optical isomers and stereoisomers of the compounds of formula I and mixtures thereof.

Preferred compounds of formula I are compounds wherein mjel, njel, fucked, p is zero, qjeO, r is zero, A is oxygen or nitrogen, B is NH, R ² is hydrogen or an alkyl group having 1 to 6 carbon atoms, R ³ is hydrogen, R ¹ is a C 6 -C 10 aryl group, a C 3 -C 7 cycloalkyl group or a saturated or unsaturated, C 3 -C 7 cyclic or bicyclic heterocyclic group containing from one to four oxygen, sulfur, nitrogen or NR ⁹ , wherein R ⁹ is hydrogen or C 1 -C 6 alkyl, wherein the aryl, cycloalkyl and heterocyclic group are optionally substituted with a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, dialkylamino of 1 to 6 carbon atoms in each alkyl moiety or hyd roxyalkyl amino group having 1 to 6 carbon atoms, E is oxygen and ^R5 is a group of the formula

or R ⁵ is a saturated or unsaturated, cyclic or bicyclic heterocyclic group of 3 to 7 carbon atoms containing one to four oxygen, sulfur, nitrogen or NR ⁹ atoms as a heteroatom, wherein R ⁹ is a hydrogen atom or an alkyl group of 1 to 6 carbon atoms .

Even more preferred are compounds of formula I wherein R ¹ is an optionally substituted C 6 -C 10 aryl group.

-20 carbon, wherein the substituents are hydroxyalkyl of 1 to 6 carbon atoms or wherein at least one of R ¹¹ , R ¹² , R ¹³ , R ¹⁴ or R ¹⁵ is halogen, or wherein R ¹² and R ¹³ together form a fused bicyclic a ring wherein u is zero, G and L is an oxygen atom, and J is CH ₂ .

Other preferred compounds of formula I are those wherein m is 0, n is 0, o is 3, p is 0, q is 0, r is 0, R ² and R ³ are hydrogen, R ¹ is a C 6 -C 10 aryl group optionally substituted with halogen, alkyl (C 1 -C 6), (C 1 -C 6) alkoxy, (C 1 -C 6) hydroxyalkyl, amino, (C 1 -C 6) alkylamino, (C 1 -C 6) dialkylamino, or hydroxy (C 1 -C 6) alkyl to 6 carbon atoms, E is oxygen and ^R5 is a group of the formula

or R ⁵ is a saturated or unsaturated, cyclic or bicyclic heterocyclic group of 3 to 7 carbon atoms containing one to four oxygen, sulfur, nitrogen or NR ⁹ atoms as a heteroatom, wherein R ⁹ is a hydrogen atom or an alkyl group of 1 to 6 carbon atoms .

Other preferred compounds of formula I are those wherein m is 1, n is 0, o is 2, p is 0, q is 0, r is 0, A is oxygen, R ² and R ³ are hydrogen, R ¹ is a (C 1 -C 10) aryl group optionally substituted by a halogen atom, (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy, (C 1 -C 6) hydroxyalkyl, amino; ·

(C 1 -C 6) alkylamino, (C 1 -C 6) dialkylamino in each alkyl moiety or (C 1 -C 6) hydroxyalkylamino, E is O and R ⁵ is of the formula

or R ⁵ is a saturated or unsaturated, cyclic or bicyclic heterocyclic group of 3 to 7 carbon atoms containing one to four oxygen, sulfur, nitrogen or NR ⁹ atoms as a heteroatom, wherein R ⁹ is a hydrogen atom or an alkyl group of 1 to 6 carbon atoms .

Other preferred compounds of formula I are those wherein m is 0, n is 0, o is 1, p is 1, q is 1, r is

O, R ² and R ³ are hydrogen, D is oxygen, R ⁴ is hydrogen, R ¹ is aryl of 6 to 10 carbon atoms, optionally substituted with halogen, C 1 -C 6 alkyl, alkoxy C 1 -C 6, C 1 -C 6 hydroxyalkyl, amino, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino in each alkyl moiety or C 1 -C 6 hydroxyalkylamino, E is oxygen and R ⁵ is a radical of formula

or R ⁵ is a saturated or unsaturated, cyclic or bicyclic heterocyclic group of 3 to 7 carbon atoms containing from one to four oxygen, sulfur, nitrogen or NR ⁹ atoms as a heteroatom, wherein R ⁹ is a hydrogen atom or an alkyl group of 1 to 6 carbon atoms.

Further preferred compounds of formula I are those wherein m is 0, ⁿ is 0, o is 3, p is 0, q is 0, r is 0, R ² is hydrogen or hydroxy, R ³ is hydrogen, R ¹ is C 6 -C 10 aryl, optionally substituted with halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 hydroxyalkyl, amino, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino in each alkyl or C 1 -C 6 hydroxyalkylamino, E is O and R ⁵ is of the formula

or R ⁵ is a saturated or unsaturated, cyclic or bicyclic heterocyclic group of 3 to 7 carbon atoms containing one to four oxygen, sulfur, nitrogen or NR ⁹ atoms as a heteroatom, wherein R ⁹ is a hydrogen atom or an alkyl group of 1 to 6 carbon atoms .

Other preferred compounds of formula I are those wherein m, n is 0, ojel, pjel, q is 0, r is 0, A is O, R ² and R ³ are hydrogen, D is oxygen, R ¹ is an aryl group having from 6 to 6 carbon atoms. 10 carbon atoms, · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ···· ···· _Λ _ ········ ·· ·· ·· ·> ·

-23 optionally substituted with halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 hydroxyalkyl, amino, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino each alkyl moiety or a (C 1 -C 6) hydroxyalkylamino group, E is oxygen and R ⁵ is of the formula

or R ⁵ is a saturated or unsaturated, cyclic or bicyclic heterocyclic group of 3 to 7 carbon atoms containing one to four oxygen, sulfur, nitrogen or NR ⁹ atoms as a heteroatom, wherein R ⁹ is a hydrogen atom or an alkyl group of 1 to 6 carbon atoms .

Other preferred compounds of formula I are those wherein m is 1, n is 1, o is 1, p is 0, q is 0, r is 0, A is oxygen, B is oxygen, R ² and R ³ are hydrogen, R ¹ is aryl of 6 to 10 carbon atoms, optionally substituted with halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, amino, alkylamino of C 1 -C 6, C 1 -C 6 dialkylamino, or C 1 -C 6 hydroxyalkylamino, E is O and R ⁵ is of the formula

• · · · · · · · · · · · · · · · · ·

-24or R ⁵ is a saturated or unsaturated, cyclic or bicyclic heterocyclic group of 3 to 7 carbon atoms containing one to four oxygen, sulfur, nitrogen or NR ⁹ atoms as heteroatom, wherein R ⁹ is hydrogen or (1-6C) alkyl carbon.

Other preferred compounds of formula I are those wherein m, m, n is, o is 0, p is, q is 0, r is 0, A is O, B is NH, D is NR ⁸ , wherein R ⁸ is hydrogen or alkyl of 1 to 6 R ¹ is an aryl group having 6 to 10 carbon atoms, optionally substituted with a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a hydroxyalkyl group having 1 to 6 carbon atoms, an amino group, an alkylamino group having 1 to 6 C 1 -C 6, C 1 -C 6 dialkylamino, or C 1 -C 6 hydroxyalkylamino, E is O and R ⁵ is of the formula

or R ⁵ is a saturated or unsaturated, cyclic or bicyclic heterocyclic group of 3 to 7 carbon atoms containing one to four oxygen, sulfur, nitrogen or NR ⁹ atoms as a heteroatom, wherein R ⁹ is a hydrogen atom or an alkyl group of 1 to 6 carbon atoms .

Other preferred compounds of formula I are those wherein m is 0, n is 1, o is 1, p is 0, q is 1, r is 0, B is NH, R ² and R ³ together form a carbonyl group, R ⁴ is hydrogen, R ¹ is an aryl group having 6 to 10 carbon atoms optionally substituted by halogen, C 2 _ • · 5- ········ ·· · · · · · ¹ group having from 1 to 6 carbon atoms, C 1 -C 6 alkoxy, C 1 -C 6 hydroxyalkyl, amino, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino or C 1 -C 6 hydroxyalkylamino, E is oxygen and ^R5 is a group of the formula

or R ⁵ is a saturated or unsaturated, cyclic or bicyclic heterocyclic group of 3 to 7 carbon atoms containing one to four oxygen, sulfur, nitrogen or NR ⁹ atoms as a heteroatom, wherein R ⁹ is a hydrogen atom or an alkyl group of 1 to 6 carbon atoms .

Other preferred compounds of formula I are those wherein m is 1, n is 1, o is 1, p is 0, q is 0, r is 0, A and R ² taken together form a group of the formula

wherein A is N, B is NH, R ¹ is C 1 -C 6 alkyl or C 6 -C 10 aryl, the aryl being optionally substituted with carbon atoms of up to 6 to 6 carbon atoms, hydroxyalkyl up to 6 carbon atoms, amino, halogen, alkoxy alkyl having 1 to 6 alkylamino, dialkylamino, 26s 1 to 6 6 carbon atoms in each alkyl moiety or a (C 1 -C 6) hydroxyalkylamino group, E is an oxygen atom and R ⁵ is a group of the general formula

or R ⁵ is a saturated or unsaturated, cyclic or bicyclic heterocyclic group of 3 to 7 carbon atoms containing one to four oxygen, sulfur, nitrogen or NR ⁹ atoms as heteroatom, where R ⁹ is hydrogen or (1-6C) alkyl carbon.

Other preferred compounds of formula I are those wherein m is 0, ⁿ is 0, ojel, p is 0, q is 2, r is 0, R ² is hydrogen or hydroxy, R ³ is hydrogen, R ⁴ is independently hydrogen or hydroxy, R ¹ C 1 -C 6 aryl optionally substituted by halogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino the carbon atoms in each alkyl moiety or a (C 1 -C 6) hydroxyalkylamino group, E is an oxygen atom and R ⁵ is a carbon atom, a hydroxyalkylamino group,

Or R ⁵ is a saturated or unsaturated, cyclic or bicyclic heterocyclic group of 3 to 7 carbon atoms containing from 1 to 4 heteroatoms as a heteroatom oxygen, sulfur, nitrogen or NR ⁹ , wherein R ⁹ is hydrogen or C 1 -C 6 alkyl.

Other preferred compounds of formula I are those wherein m is 1, n is 1, o is 1, 2, 3 or 4, p is 0, q is 1, 2 or 3, r is 0, A is oxygen, B R is O, R ² , R ³ , R ⁴ and R ¹ are hydrogen, E is oxygen and R ⁵ is a group of the formula

or R ⁵ is a saturated or unsaturated, cyclic or bicyclic heterocyclic group of 3 to 7 carbon atoms containing one to four oxygen, sulfur, nitrogen or NR ⁹ atoms as heteroatom, where R ⁹ is hydrogen or (1-6C) alkyl carbon.

Other preferred compounds of formula I are compounds wherein mjel, njel, fucked, p is zero, qjeO, r is 0, A and R ² together form a group of the formula

wherein A is a nitrogen atom, B is an oxygen atom, R ¹ is an alkyl group having 1 to 6 carbon atoms or an aryl group having 6 to 10 carbon atoms, wherein the aryl group is optionally substituted ··· ··· *

-28- • ♦ ti ti ti ti ti ti ti ti ti ti # # halogen atom, alkyl group s 1 to 6 carbon atoms, alkoxy with 1 to 6 atoms carbon, hydroxya1ky1ovou group with 1 to 6 atoms carbon, amino,

(C 1 -C 6) alkylamino, (C 1 -C 6) dialkylamino in each alkyl moiety or (C 1 -C 6) hydroxyalkylamino, E is O and R ⁵ is of the formula

or R ⁵ is a saturated or unsaturated, cyclic or bicyclic heterocyclic group of 3 to 7 carbon atoms containing one to four oxygen, sulfur, nitrogen or NR ⁹ atoms as heteroatom, where R ⁹ is hydrogen or (1-6C) alkyl carbon.

Other preferred compounds of formula I are those wherein m is 1, n is 1, o is 1, p is 0, q is 0, r is 0, A and R ² taken together form a group of the formula

wherein A is an oxygen atom, B is an oxygen atom, R ¹ is an alkyl group having 1 to 6 carbon atoms or an aryl group having 6 to 10 carbon atoms, the aryl group being optionally substituted with a halogen atom, an alkyl group having 1 to 6 carbon atoms, (C 1 -C 6) alkoxy

9t

C 1 -C 6 hydroxyalkyl, amino, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino in each alkyl moiety or C 1 -C 6 hydroxyalkylamino; carbon atoms, E is oxygen and ^R5 is a group of the formula

or R ⁵ is a saturated or unsaturated, cyclic or bicyclic heterocyclic group of 3 to 7 carbon atoms containing one to four oxygen, sulfur, nitrogen or NR ⁹ atoms as heteroatom, wherein R ⁹ is hydrogen or (1-6C) alkyl carbon.

Other preferred compounds of formula I are those wherein m, n is 0, o is 0, p is 0, q is 0, r is 0, A is O, R ¹ is C 6 -C 10 aryl, or a saturated or unsaturated, cyclic or bicyclic heterocyclic group C 3 -C 7 heteroatoms having one to four oxygen, sulfur, nitrogen and NR ⁹ atoms, wherein R ⁹ is hydrogen or C 1 -C 6 alkyl, wherein the aryl or heterocyclic group is optionally substituted with a halogen atom, an alkyl group (C1-C6) alkoxy, (C1-C6) -alkoxy, (C1-C6) -alkoxy, (C1-C6), amino, C1-C6alkylamino (C1-C6) alkylamino, or (C1-C6) hydroxyalkylamino; 6 carbon atoms, E is oxygen and ^R5 is a group of the formula

-30 • w ·· e «* * • * 30 · · · · ·

or R ⁵ is a saturated or unsaturated, cyclic or bicyclic heterocyclic group of 3 to 7 carbon atoms containing one to four oxygen, sulfur, nitrogen or NR ⁹ atoms as heteroatom, where R ⁹ is hydrogen or (1-6C) alkyl carbon.

Other preferred compounds of formula (I) are those wherein m is 1, n is 1, o is 0, p is 0, q is 1, r is 0, A is oxygen, B is NH, R ⁴ is hydroxyalkyl having 1; R ¹ is an alkyl group having 1 to 6 carbon atoms, E is an oxygen atom, and R ⁵ is a radical of formula

or R ⁵ is a saturated or unsaturated, cyclic or bicyclic heterocyclic group of 3 to 7 carbon atoms containing one to four oxygen, sulfur, nitrogen or NR ⁹ atoms as a heteroatom, wherein R ⁹ is a hydrogen atom or an alkyl group of 1 to 6 carbon atoms .

Specific compounds of formula I are the following:

N- (4- (1-hydroxy-1-methyl-ethyl) -benzyl) -2- (3-methyl-benzo (d) -isoxazol-7-yloxy) -nicotinamide,

N- (4- (1-hydroxy-1-methyl-ethyl) -benzyl) -2- (3-oxo-indan-5-yloxy) -nicotinamide, · ···· · · «· · fr fr fr fr fr 2 2 2 2 2 2 2 2 2 2 fr 1 ·· 9 ·

2- (3- (1-hydroxyimino-ethyl) -phenoxy) -N- (4- (1-hydroxy-1-methyl-ethyl) -benzyl) -nicotinamide,

N- (4- (1-hydroxy-1-methyl-ethyl) -benzyl) -2- (4-oxo-chroman-6-yloxy) -nicotinamide, (+) - 2- (3-acetyl-phenoxy) - N- (1-hydroxy-indan-5-ylmethyl) -nicotinamide

- (2,3-dihydro-benzo (1,4) dioxin-6-yloxy) -N- (4- (1-hydroxy-1-methyl-ethyl) -benzyl) -nicotinamide,

N- (4- (1-hydroxy-1-methyl-ethyl) -benzyl) -2- (3- (1-methoxyimino-ethyl) -phenoxy) -nicotinamide,

N- (2-chloro-benzyl) -2- (4-fluoro-phenoxy) -nicotinamide,

N- (5-chloro-thiophen-2-ylmethyl) - (2-pyridin-3-yloxy) -nicotinamide,

2- (4-fluoro-phenoxy) -N- [4- (3-hydroxy-azetidin-1-yl) -benzyl] -nicotinamide,

N- [4- (1-hydroxy-1-methyl-ethyl) -benzyl] -2- (3-nitro-phenoxy) -nicotinamide,

2- (4-fluoro-phenoxy) -N- (2-oxo-2,3-dihydro-4-indol-5-ylmethyl) -nicotinamide,

N- [2- (3-acetyl-phenoxy) -pyridin-3-yl] -2- [4- (1-hydroxy-1-methyl-ethyl) -phenyl] -acetamide, methyl 3- {3- [4] - (1-hydroxy-1-methyl-ethyl) -benzylcarbamoyl] -pyridin-2-yloxy} -benzoic acid,

2- (4-fluoro-phenoxy) -N- [4- (1-hydroxy-1-methyl-ethyl) -benzyl] -nicotinamide,

2- (4-fluoro-phenoxy) -N- (1-thiophen-2-yl-ethyl) -nicotinamide,

N- [2-chloro-4- (1-hydroxy-1-methyl-ethyl) -benzyl] -2- (3-cyanophenoxy) -nicotinamide,

2- (3-cyano-4-fluoro-phenoxy) -N- [4- (1-hydroxy-1-methylethyl) -benzyl] -nicotinamide,

N- [2-chloro-4- (1-hydroxy-1-methyl-ethyl) -benzyl] -2- (3,4-difluoro-phenoxy) -nicotinamide, (+) - 2- (benzo [1,3] ] dioxol-5-yloxy) -N- [4- (1-hydroxy-ethyl) -cyclohexylmethyl] -nicotinamide, - (-) (-) ) -2- (3-cyano-4-fluoro-phenoxy) -N- [4- (1-hydroxy-ethyl) -cyclohexylmethyl] -nicotinamide, (+) - 2- (3-cyano-4-fluoro-phenoxy) ) -N- [4- (1-hydroxy-ethyl) -cyclohexylmethyl] -nicotinamide, (+) - 2- (2,3-dihydro-benzo [1,4] dioxin-6-yloxy) -N- [4] - (1-hydroxy-ethyl) -cyclohexylmethyl] -nicotinamide, (-) -2- (2,3-dihydro-benzo [1,4] dioxin-6-yloxy) -N- [4- (1-hydroxy- ethyl) -cyclohexylmethyl] -nicotinamide,

2- (benzo [1,3] dioxol-5-yloxy) -N- [4- (1-hydroxy-1-methyl-ethyl) -benzyl] -nicotinamide,

2- (benzo [1,3] dioxol-5-yloxy) -N- [4- (1-hydroxy-1-methyl-ethyl) -cyclohexylmethyl] -nicotinamide,

2- (3-acetyl-phenoxy) -N- [4- (1-hydroxy-ethyl) -cyclohexylmethyl] -nicotinamide, and

2- (3-cyano-4-fluoro-phenoxy) -N- [2-fluoro-4- (1-hydroxy-1-methyl-ethyl) -benzyl] -nicotinamide,

N- [2-chloro-4- (1-hydroxy-1-methyl-ethyl) -benzyl] -2- (3-cyano-4-fluoro-phenoxy) -nicotinamide,

2- (3-acetyl-phenoxy) -N- [2-chloro-4- (1-hydroxy-1-methyl-ethyl) -benzyl] -nicotinamide,

2- (3-acetyl-phenoxy) -N- [4- (1-hydroxy-1-methyl-ethyl) -cyclohexylmethyl] -nicotinamide,

2- (3-acetyl-phenoxy) -N- [4- (1-hydroxy-1-methyl-ethyl) -benzyl] -nicotinamide,

2- (3,4-difluoro-phenoxy) -N- [4- (1-hydroxy-1-methyl-ethyl) -benzyl] -nicotinamide,

2- (4-fluoro-phenoxy) -N- [4- (1-hydroxy-1-methyl-ethyl) -cyclohexylmethyl] -nicotinamide,

2- (3-cyanophenoxy) -N- [4- (1-hydroxy-1-methyl-ethyl) -cyclohexylmethyl] -nicotinamide,

N- [4- (1-hydroxy-1-methyl-ethyl) -benzyl] -2- (3-methoxy-phenoxy) -nicotinamide,

2- (3-cyanophenoxy) -N- [4- (1-hydroxy-1-methyl-ethyl) -benzyl] -nicotinamide, • · · · ·········

N- [4- (1-hydroxy-1-methyl-ethyl) -benzyl] -2- (pyridin-3-yloxy) -nicotinamide and

2- (3-acetyl-phenoxy) -N- [4- (1-hydroxy-1-methyl-ethyl) -benzyl] -nicotinamide.

The present invention also relates to a pharmaceutical composition for the treatment of respiratory, allergic and rheumatic diseases, weight control disorders, inflammatory diseases and central nervous system diseases such as asthma, chronic obstructive pulmonary disease, adult respiratory disease syndrome, shock, fibrosis, pulmonary hypersensitivity, allergic rhinitis, atopic dermatitis, psoriasis, weight control, rheumatoid arthritis, cachexia, Crohn's disease, ulcerative colitis, arthritic conditions and other inflammatory diseases, depression, multi-infarct dementia and AIDS, in mammals, including humans, comprising the compound of claim 1 or a compound thereof a pharmaceutically acceptable salt in an amount effective to prevent or treat, and a pharmaceutically acceptable carrier.

The present invention also relates to a method of treating respiratory, allergic and rheumatic diseases, weight control disorders, inflammatory diseases and central nervous system diseases such as asthma, chronic obstructive pulmonary disease, adult respiratory disease syndrome, shock, fibrosis, pulmonary hypersensitivity, allergic rhinitis , atopic dermatitis, psoriasis, weight control, rheumatoid arthritis, cachexia, Crohn's disease, ulcerative colitis, arthritic conditions and other inflammatory diseases, depression, multi-infarct dementia and AIDS, in mammals, including humans, comprising administering the compound of claim 1 or a compound thereof pharmaceutically acceptable salts in an amount effective for such treatment.

The present invention also relates to a pharmaceutical composition for selectively inhibiting PDE4 D isozymes that regulate activation and degranulation of human eosinophils.

-34 allergic weights, useful in the treatment of respiratory, allergic and rheumatic diseases, weight control disorders, inflammatory diseases and central nervous system disorders such as asthma, chronic obstructive pulmonary disease, adult respiratory disease syndrome, shock, fibrosis, pulmonary hypersensitivity, allergic rhinitis , atopic dermatitis, psoriasis, weight control, rheumatoid arthritis, cachexia, Crohn's disease, ulcerative colitis, arthritic conditions and other inflammatory diseases, depression, multi-infarct dementia and AIDS, in mammals, including humans, which contain a PDE4 D isozyme inhibiting compound or a pharmaceutically acceptable salt thereof an acceptable salt in an amount effective for such treatment, and a pharmaceutically acceptable carrier.

The present invention also relates to a method of selectively inhibiting PDE4 D isozymes that regulate activation and degranulation of human eosinophils, which is useful for the treatment of respiratory, allergic and rheumatic diseases, weight control disorders, inflammatory diseases and central nervous system diseases such as asthma, chronic obstructive pulmonary disease, adult respiratory disease syndrome, shock, fibrosis, pulmonary hypersensitivity, runny nose, atopic dermatitis, psoriasis, rheumatoid arthritis control, cachexia, Crohn's disease, ulcerative colitis, arthritic conditions and other inflammatory diseases, AIDS, depression, multiinf, mammals, including humans, comprising administering a compound inhibiting the PDE4 D isozyme or a pharmaceutically acceptable salt thereof in an amount effective for such treatment.

The following reaction schemes illustrate in more detail the preparation of the compounds of the present invention.

• • •

R8

O (CH ₂ ) _r R 5

-36Schema 2

IV

VI

III

-37Schema 3

VII • ·

-38Schema 4

III

XI • ·

-39Schema 5

III

XIII • ·

-40Schema 6

XVI

XV

-41Schema 7

XVII

XVI · · · · · · · · · · · · · · · · · · · · · · · · ·

Scheme 8

XIX

XVIII • ·

-43Schema 9

XXI

XX

-44Schema 10 · ema · ema ema ema ema ema ema ema ·· ·· ·· ·· ··

XXIII

XXII

-45Schema 11

O

XXV

-46Schema 12 9 9

XXVII

9 • 999

-Achema 13 ··· * · «· Λ

XXX

XXIX

-48Schema 14 · ema «ema ema ema ema ema ema ema

o \\ .0 hT ^ CH

XXXII

-49Schema 15

XXXV

XXXIV • • · __ __ __ __ __ IV __ IV IV IV IV IV IV

-50Scheme 16

XXXVI

XXXIX

XXXVIII

XLI

XL

-53 «· · · * 4 4 4 4 4 4 4 4 4 4 4 4 4 4

s-ch ₃

XLIII

XLII

• · · ·

-54Schema 20

XLVII

XLIV

k «· · · 4

-55Scheme 21

• 9 9 9 9 9 9 9 9 9 9 9 9

9 9 9

XLVIII • ·

-56Schema 22

CO ₂ Bu

N, E (CH ₂ ) _r R 5

R ¹

LIV

E (CH ₂ ) _r R 5

R ¹

Lil • ·

-57Schema 23

LV • · · ·

-58Schema 24 · · · · · · · · · · · · · · · · ·

LVII · II II II II II II II II II II II II II II II II II II

-59- ............

Scheme 25

^R8 ^ ^x N ^<> \ _E (CH _{2) r} R 5

LX

LIX • ·

-60Schema 26

XLVIII • ·

-61Schema 27

LXVI

LXVII • ·

-62Schema 28

LXVI

R ⁴

• · · · ·

-63 ···· ····

In Reaction 1 of Scheme 1, a 2-chloropyridine compound of formula IV is converted to the corresponding compound of formula III by reacting a compound of formula IV with a compound of formula R ⁵ (CH ₂ ) _r -OH, in the presence of sodium hydride and a polar aprotic solvent such as dimethylformamide. The reaction is carried out at room temperature for about 3 hours to about 20 hours, preferably for about 4 hours.

In Reaction 1 of Scheme 2, the 3-carboxylic compound of formula IV is converted to the corresponding ethyl ester of the pyridine compound of formula VI by reacting the compound of formula IV with ethanol in the presence of thienyl chloride. The reaction mixture is heated to reflux for about 1 hour to about 3 hours, preferably for about 1.5 hours.

In Reaction 2 of Scheme 2, a 2-chloropyridine compound of formula VI is converted to the corresponding compound of formula V by reacting a compound of formula IV with a compound of formula R ⁵ (CH ₂ ) _r -OH in the presence of cesium carbonate and a polar aprotic solvent such as dimethylformamide. The reaction is carried out at a temperature of about 65 ° C to about 90 ° C, preferably at about 65 ° C, for about 10 hours to about 18 hours, preferably about 10 hours.

In reaction 3 of Scheme 2, compounds of formula V

3-carboxylic acid of formula III by reaction of a compound of formula V with ethanol in the presence of sodium hydroxide. The reaction mixture is heated to reflux for about 3 hours to about 5 hours, preferably for about 4 hours.

In reaction 1 of Scheme 3, the 3-carboxylic acid of formula IV is converted to the corresponding benzyl ester of the pyridine compound of formula X by reacting the compound of formula IV with benzyl bromide in the presence of potassium carbonate and a polar aprotic solvent such as dimethylformamide. The reaction is carried out at room temperature after the pyridine ethyl ester is converted to the corresponding salt.

A period of from about 1 hour to about 24 hours, preferably about 10 hours.

In Reaction 2 of Scheme 3, a 2-chloropyridine compound of formula X is converted to the corresponding compound of formula IX by reacting a compound of formula X with 3-iodophenol in the presence of cesium carbonate and a polar aprotic solvent such as dimethylformamide. The reaction is carried out at a temperature of about 70 ° C to about 80 ° C, preferably at about 75 ° C, for about 1 hour to about 6 hours, preferably for about 2 hours.

In reaction 3 of Scheme 3, a compound of formula IX is converted to the corresponding compound of formula VIII by reacting a compound of formula IX with (3-iodophenoxy) pyridine

IX with carbon monoxide and methanol in the presence of palladium acetate, 1,1-bis (diphenylphosphino) ferrocene, triethylamide and a polar aprotic solvent such as dimethylformamide. The reaction mixture is heated to a temperature between about 50 ° C and about 70 ° C, preferably at about 60 ° C, for about 2 hours to about 4 hours, preferably for about 4 hours.

In reaction 4 of Scheme 3, the benzyl ester of the pyridine compound of formula VIII is converted to the corresponding compound of formula VIII by hydrogenation of the compound of formula VIII in the presence of palladium on carbon, methanol and ethyl acetate. The reaction is carried out at room temperature for about 1 hour to about 2 hours, preferably for about 2 hours.

In Reaction 1 of Scheme 4, the pyridinecarboxylic acid of formula III is converted to the corresponding compound of formula XI by reacting a compound of formula III with a compound of formula XII.

one of four different methods of synthesis.

In a first procedure, a compound of formula III is reacted with a compound of formula XII in the presence of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, 1-hydroxybenzotriazole hydrate and a polar aprotic solvent such as dimethylformamide. The reaction is carried out at room temperature for about 1 hour to about 24 hours, preferably for about 10 hours.

In a second process, a compound of formula III is reacted with a chloroformate such as isobutyl chloroformate in the presence of N-methylmorpholine and a polar aprotic solvent such as methylene chloride at a temperature of about 0 ° C to about -20 ° C, preferably at about -10 ° C. 15 ° C to about 1 hour, preferably about 30 minutes. The reaction mixture is warmed to room temperature and the compound of formula XII is added. The resulting reaction mixture is stirred for about 1 hour to about 24 hours, preferably for about 10 hours.

In a third process, the compound of formula III is heated to reflux in the presence of thionyl chloride for about 1 hour to about 24 hours, preferably about 1 hour. The resulting acid chloride is then reacted with a compound of formula XII in the presence of pyridine and a polar aprotic solvent such as tetrahydrofuran. The reaction is carried out at a temperature of about 0 ° C to about room temperature, preferably at about 0 ° C.

• · · ·

In a fourth procedure, a compound of formula II is reacted with a compound of formula XII in the presence of BOP, diisopropylethylamine and a polar aprotic solvent such as dimethylformamide. The reaction is carried out at room temperature for about 3 hours to about 4 hours, preferably for about 4 hours.

In Reaction 1 of Scheme 5, a 3-carboxypyridine compound of formula III is converted to the corresponding compound of formula XIII by reacting a compound of formula III with a compound of formula XIV

in the presence of 4-dimethylaminopyridine, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, pyridine and diethyl ether. The reaction is carried out at room temperature for about 1 hour to about 3 hours, preferably for about 1 hour.

In Reaction 1 of Scheme 6, a compound of Formula XVI is converted to the corresponding compound of Formula XV by reacting a compound of Formula XVI with acetonitrile in the presence of formaldehyde and sodium cyanoborohydride. The reaction is carried out at room temperature for about 14 hours to about 16 hours, preferably for about 16 hours.

In Reaction 1 of Scheme 7, a compound of Formula XVII is converted to the corresponding compound of Formula XVI by first reacting a compound of Formula XVII with phosphorous oxychloride in an aprotic solvent such as toluene and then reacting the resulting compound with sodium hydroxide in a polar protic solvent such as methanol. . The reaction is carried out at a temperature of about 0 to room temperature, with

Preferably, at about 22 ° C, for a time period between about 1 hour to about 24 hours, preferably about 12 hours.

In Reaction 1 of Scheme 8, a compound of Formula XIX is converted to the corresponding compound of Formula XVIII as described in Reaction 1 of Scheme 7.

In Reaction 1 of Scheme 9, a 3-aminopyridine compound of formula XXI is converted to the corresponding compound of formula XX by reacting a compound of formula XXI with a compound of formula XIV

in the presence of 1-hydroxybenzotriazole hydrate and a polar aprotic solvent such as dimethylformamide. The reaction is carried out at room temperature for about 1 hour to about 24 hours, preferably for about 16 hours.

In Reaction 1 of Scheme 10, a compound of formula XXIII is converted to the corresponding compound of formula XXII by reacting a compound of formula XXIII with a compound of formula XXIV

(XXIV) in the presence of p-toluenesulfonic acid and an aprotic solvent such as toluene. The reaction mixture is heated to reflux for about 1 hour to about 48 hours, preferably for about 24 hours.

♦ t · 1 · · »

-68 · · 68 68 68 68 68 68 68 68 68 68

In Reaction 1 of Scheme 11, a compound of formula XXVI is converted to the corresponding compound of formula XXV by reacting a compound of formula XXVI with methyllithium in an aprotic solvent such as tetrahydrofuran. The reaction is carried out at a temperature of about -75 ° C to about -85 ° C, preferably about -78 ° C, for about 1 hour to about 6 hours, preferably for about 2 hours.

In Reaction 1 of Scheme 12, a compound of Formula XXVII is prepared by reacting a compound of Formula XXVIII with boron tribromide in a polar aprotic solvent such as methylene chloride. The reaction is carried out at a temperature of about -78 ° C to room temperature, preferably about 0 ° C, for about 1 hour to about 24 hours, preferably for 16 hours.

In reaction 1 of Scheme 13, a compound of formula XXX is converted to the corresponding compound of formula XXIX by reacting a compound of formula XXX with a compound of formula XXXI

O

in the presence of triethylamine and a polar aprotic solvent such as methylene chloride. The reaction is carried out at a temperature of about 0 ° C to room temperature, preferably about 0 ° C, for about 30 minutes to about 2 hours, preferably for about 1 hour.

In Reaction 1 of Scheme 14, a compound of Formula XXX is converted to the corresponding compound of Formula XXXII by reacting a compound of Formula XXX with methanesulfonic anhydride in the presence of triethylamine. The reaction is carried out at room temperature for about 30 minutes to about 24 hours, preferably for about 12 hours.

In Reaction 1 of Scheme 15, a compound of Formula XXXV is converted to the corresponding compound of Formula XXXIV by the compound of Formula XXXIV. »« · · »E- i _rn * * ·· * · * -.

By reacting a compound of formula XXXV with sodium hydroxide in a polar aprotic solvent such as ethanol. The reaction mixture is heated to reflux for about 1 hour to about 24 hours, preferably for about 9 hours.

In Reaction 1 of Scheme 16, a compound of Formula XXXVII is converted to the corresponding compound of Formula XXXVI by oxidizing the compound of Formula XXXVII with tetrapropylammonium perruthenate and 4-methylmorpholine N-oxide in a polar aprotic solvent such as methylene chloride. The reaction is carried out at room temperature for about 2 hours to about 6 hours, preferably for about 4 hours.

In Reaction 1 of Scheme 17, a 2-aminopyridine compound of formula XXXIX is converted to the corresponding compound of formula XXXVIII by reacting a compound of formula XXXIX with a compound of formula R ⁵ -N = C = O. The reaction mixture is heated to reflux for about 1 hour to about 24 hours, preferably for about 16 hours.

In Reaction 1 of Scheme 18, the 2-nitropyridine compound of formula XLI is converted to the corresponding 2-aminopyridine compound of formula XL by reducing the compound of formula XLI using 10% platinum oxide on carbon, methanol, and tetrahydrofuran. The reaction is carried out at room temperature for about 1 hour to about 3 hours, preferably about 2 hours.

In Reaction 1 of Scheme 19, a compound of Formula XLIII is converted to the corresponding compound of Formula XLII by reacting a compound of Formula XLIII with MCPBA in a polar aprotic solvent such as methylene chloride. The reaction is carried out at room temperature for about 1 hour to about 4 hours, preferably for about 1 hour.

In Reaction 1 of Scheme 20, a 2-chloropyridine compound of formula XLV is converted to the corresponding compound of formula XLVI by reacting a compound of formula XLV with a compound of formula R ⁵ (CH ₂ ) _r OH in the presence of a carbonate. ··· · «· · ····································

70% and polar aprotic solvents such as dimethylformamide. The reaction is carried out at a temperature of about 65 ° C to about 90 ° C, preferably at about 80 ° C for about 10 hours to about 18 hours, preferably for about 16 hours.

In Reaction 2 of Scheme 20, a 3-cyanopyridine compound of formula XLVI is converted to the corresponding compound of formula XLVII by reacting a compound of formula XLVI with hydrogen peroxide in the presence of potassium hydroxide and a polar protic solvent such as ethanol. The reaction is carried out at room temperature for about 1 hour to about 24 hours, preferably for about 12 hours.

In reaction 3 of Scheme 20, a compound of formula XLVII is converted to the corresponding compound of formula XLIV by reacting a compound of formula XLVII with a compound of formula XLVIII

wherein X is a chlorine, bromine or iodine atom, in the presence of potassium hydroxide and a polar aprotic solvent such as dimethylsulfoxide. The reaction is carried out at room temperature for about 1 hour to about 24 hours, preferably for about 1 hour.

In Reaction 1 of Scheme 21, a compound of formula XLIX is converted to the corresponding compound of formula L by reacting a compound of formula XLIX with a compound of formula

in a polar aprotic solvent such as tetrahydrofuran. The reaction is carried out at a temperature of about -85 ° C to about -75 ° C, preferably at about -78 ° C, for about 0.5 hours to about 16 hours, preferably for about 2 hours.

In Reaction 2 of Scheme 21, a compound of Formula L is converted to the corresponding compound of Formula XLVIII by reacting a compound of Formula L with chromic acid, sulfuric acid, and water in a polar aprotic solvent such as acetone. The reaction is carried out at a temperature of about 0 ° C to about 25 ° C, preferably at about 0 ° C, for about 0.5 hours to about 16 hours, preferably for about 2 hours.

In reaction 1 of Scheme 22, a compound of formula Lili is converted to the corresponding compound of formula LIV by reacting a compound of formula Lili with a compound of formula XLVIII

in the presence of sodium hydride and a polar aprotic solvent such as tetrahydrofuran. The reaction is carried out at a temperature of about 0 ° C to about 60 ° C, preferably at about 0 ° C, for about 1 hour to about 16 hours, preferably for about 4 hours.

In Reaction 2 of Scheme 22, a compound of formula LIV is converted to the corresponding compound of formula LII. ···· · · · ·

By reacting the compound of formula LIV with undiluted trifluoroacetic acid for about 1 hour to about 16 hours, preferably about 4 hours.

In Reaction 1 of Scheme 23, a compound of formula LVI is converted to the corresponding compound of formula LV by reacting a compound of formula LVI with a compound of formula R 1 OH in the presence of lithium diisopropylamide and a polar aprotic solvent such as tetrahydrofuran. The reaction is carried out at a temperature of about -75 ° C to about -85 ° C, preferably at about -78 ° C, for about 1 hour to about 6 hours, preferably for about 1 hour.

In Reaction 1 of Scheme 24, a compound of formula LVIII is converted to the corresponding compound of formula LVU by reacting a compound of formula LVIII with sodium borohydride in the presence of a polar protic solvent such as methanol. The reaction is carried out at a temperature of about -10 ° C to about 10 ° C, preferably about 0 ° C, for about 0.5 hours to about 16 hours, preferably for about 1 hour.

In reaction 1 of Scheme 25, a compound of formula LX is converted to the corresponding compound of formula LIX by reacting a compound of formula LX with a compound of formula

FU

wherein X is a chlorine, bromine or iodine atom, in the presence of sodium hydride and a polar aprotic solvent such as dimethylformamide.

In Reaction 1 of Scheme 26, a 2-fluoropyridine compound of formula LXII is converted to the corresponding compound of formula LXIII by reacting a compound of formula LXII with a compound of formula

in the presence of lithium diisopropylamide and a polar aprotic solvent such as tetrahydrofuran.

In Reaction 2 of Scheme 26, a compound of formula LXIII is converted to the corresponding compound of formula XLVIII by reacting a compound of formula LXIII with a compound of formula HE- (CH ₂ ) _r -R ⁵ in the presence of sodium hydride and a polar aprotic solvent such as dimethylformamide.

In Reaction 1 of Scheme 27, a compound of formula LXV is converted to the corresponding compound of formula LXVI by reacting a compound of formula LXV with a Burgess reagent, CH ₃ OOCNSO ₂ NCH ₂ CH ₃ , in the presence of benzene.

In Reaction 2 of Scheme 27, a compound of formula LXVI is converted to the corresponding compound of formula LXIV by reacting a compound of formula LXVI with osmium tetroxide in the presence of tert-butanol, NMO, and acetone.

In Reaction 1 of Scheme 28, a compound of formula LXVI is converted to the corresponding compound of formula LXVII by hydrogenation of a compound of formula LXVI in the presence of palladium on carbon and ethanol.

The compounds of formula I which are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. While these salts for administration to humans or animals must be pharmaceutically acceptable, it is often desirable in practice to first isolate a compound of Formula I from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert it.

Back to the free base compound by treatment with an alkaline reagent, and then converting the free base to a pharmaceutically acceptable acid salt. Salts of the basic compounds of the invention with acids are readily prepared by reacting the basic compound with a substantially equivalent amount of the selected mineral or organic acid in an aqueous medium or in a suitable organic solvent such as methanol or ethanol. The desired solid salt is readily obtained by evaporation of the solvent. The desired acid salt may also be precipitated from a solution of the free base in an organic solvent by adding the appropriate mineral or organic acid to the solution. Pharmaceutically acceptable amino salts are hydrochloride (preferably), hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate). The cationic salts of the compounds of formula (I) are prepared similarly by reaction of a carboxy group, for example when R ⁶ is a carboxy group with an appropriate cationic reagent such as sodium, potassium, calcium, magnesium, ammonium, N, N'-dibenzylethylenediamine, N-methylglucamine ( meglumine), ethanolamine, tromethamine or diethanolamine.

For administration to humans in the therapeutic or prophylactic treatment of inflammatory diseases, oral doses of a compound of Formula I or a pharmaceutically acceptable salt (active compound) thereof are usually in the range of 0.1 to 1000 mg per day, in single or divided doses for the average adult patient ( 70 kg). The active compounds may be administered in a single dose or in divided doses. Individual tablets or capsules should generally contain from 0.1 to 100 mg of the active compound in a suitable pharmaceutically acceptable diluent or carrier. Dosages for intravenous administration are typically in the range of 0.1 to 10 mg per single dose as desired. For intranasal or inhalation administration, the dose is generally

-75 formulated as a 0.1 to 1% (w / v) solution. In practice, the physician will determine the actual dose that is most appropriate for an individual patient and this dose will depend on the age, weight and response of the individual patient. The above dosages are given as examples for average cases, but of course higher or lower dosages may be used in individual cases and all such dosages are within the scope of the present invention.

For use in humans, the active compounds of the present invention may be administered alone, but are usually administered in admixture with a pharmaceutical diluent or carrier selected according to the intended mode of administration and standard pharmaceutical practice. For example, they may be administered orally in the form of tablets containing an excipient such as starch or lactose, or in capsules containing the compound alone or in admixture with excipients, or in the form of infusions or suspensions containing flavoring and coloring agents. These can be injected parenterally, for example intravenously, intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other substances, for example enough salts or glucose, to render the solution isotonic.

In addition, the active compounds may be administered topically in the treatment of inflammatory conditions of the skin in the form of creams, jellies, gels, pastes and ointments according to standard pharmaceutical practice.

The therapeutic compounds can also be administered to mammals other than humans. The dose to be administered to the mammal depends on the species of animal and the disease or disorder to be treated. The therapeutic compounds may be administered to the animals in the form of capsules, large pills, tablets or liquid enemas. The therapeutic compounds can also be administered to animals by injection or as an implant. These preparations are prepared in a conventional manner according to standard veterinary practice. Alternatively, the therapeutic compounds may be administered with an animal feed, and for this purpose, a concentrated feed additive or premix may be prepared for mixing with the normal animal feed.

The ability of compounds of formula I or their pharmaceutically acceptable salts to inhibit PDE ₄ can be determined by the following assay.

Inhibition of eosinophil degranulation and activation in whole human blood

Degranulation of human blood eosinophils and activation measurements

Blood collection and compound incubation

100 ml of blood is obtained from normal volunteer donors in a Vacutainer # 6480 tube (14.3 USP units of sodium heparin per ml of blood). The heparinized blood was pooled into 50 ml conical centrifuge tubes at 22 ° C. Place 1 ml of blood in a 12 x 75 mm siliconized glass tube containing μΐ DMSO or 1 μΐ of the test compound in triplicate. After mixing, the tubes were placed in a water bath shaker at 37 ° C for 15 minutes. Add 1 μΐ PGE1 in DMSO to all tubes to give a final concentration of 1 μΜ. After mixing, add 100 μΐ PBS (negative control) or Sephadex G-15 particles in PBS (8.25 to 16.5 mg / ml final concentration) to the tubes. After mixing, all tubes are incubated in a water-shaker at 37 ° C for 1 to 2 hours.

Preparation of plasma samples

At the end of incubation, add 20 μΐ 15% EDTA in PBS to each test tube. After mixing, the samples are centrifuged at 2000 rpm (Sorvall 6000B centrifuge) at 22 ° C for 5 minutes.

Measurement of EDN (or EPX) and LTE4 and effect of compounds

All plasma samples are tested for EDN (neurotoxin-derived eosinophile) and LTE4 (leukotriene E4) levels. Extensive studies suggest that Sephadex particles trigger eosinophils-mediated release of EDN and LTE4 in whole human blood. EDN and LTE4 levels were determined using RIA (Kabi Pharmacia Diagnostics) and EIA (Cayman Chemical). Layers 77

EDN and LTE4 are calculated by comparing a standard curve using Microsoft Excel or other appropriate software. The percentage of control released by EDN or LTE4 is calculated according to the equations:

% of EDN control = [EDN (compounds) - EDN (blank)] / [EDN (whole) - EDN (blank)]% of control LTE4 = [LTE4 (compounds) - LTE4 (blank)] / [LTE4 (whole) - LTE4 (blank)] wherein blank is the EDN or LTE4 level in the absence of Sephadex particles and the whole is the EDN or LTE4 level in the presence of Sephadex particles. The IC ₃₀ or IC _S0 is defined as the concentration of compound that inhibits specific EDN or LTE4 release of 30% or 50%.

Inhibition of PDE4 isozyme and activation of eosinophil (+) and (-) enantiomers

To pharmacologically determine which of the PDE4 isozymes is responsible for eosinophil activation, the enantiomers of PDE4 inhibitors were prepared and compared the inhibitory effect of these enantiomers on PDE activity and eosinophil activation. PDE4 activity is determined by measuring the hydrolysis of 1 μΜ cAMP of individual human recombinant PDE4 isozymes (PDE4A, 4B, 4C or 4D). Activation of eosinophils is determined by measuring particles of Sephadex-induced release of neurotoxin-derived eosinophils (EDN) and leukotriene E4 in whole human blood. Table 1 provides a comparison of one example of the (-) and (+) enantiomers for the activity of individual PDE4 isozymes and for the release of EDN and LTE4. The (+) enantiomer ((S) - (-) -2- (4-fluorophenoxy) -N- [1- (4-methoxyphenyl) -ethyl] -nicotinamide) is 22 times more potent in inhibiting PDE4D than the (-) enantiomer (( R 2 -2- (4-fluorophenoxy) -N- [1- (4-methoxyphenyl) -ethyl] -nicotinamide), but both are approximately equally effective in inhibiting the other three isozymes, i.e. PDE4A, 4B and 4C. Importantly, the (+) enantiomer is 20 to 37 times more potent on the EDN and LTE4 responses. These results show that the different effect of the (+) and (-) enantiomers on PDE4D isozyme inhibition is identical to their effects on EDN / LTE4 release, demonstrating that

The PDE4D isozyme plays a key role in the regulation of eosinophils.

-78 Responses (+) versus

Table 1 of the (-) enantiomers for PDE4 isozymes and eosinophils

isozyme - IC ₅₀ , μΜ HWB eosinophil IC ₃₀ or IC ₅₀ , μΜ AND (B) C 4 D EDN LTE4 ( ⁺ ) Enantiomer • 6 (2) 6 (3) • 8 (2) 0 .009 (2) 0. 05 (2) 0.0 08 (2) (-) Enantiomer • 6 (2) • 3 (3) • 4 (3) 0 • 2 (2) 1. 0 (2) 0.3 ( 2) (+) vs. (-) .with. , 5X 0.5X 2 2X 2 OX 37 X

Including the above enantiomers, a total of 8 pairs of (+) and (-) enantiomers were prepared. As can be seen in Table 2, the enantioselective effect of these compounds on PDE4 isozyme inhibition significantly correlates with the response to EDN and LTE4.

Table 2

Correlation of enantioselective effects on PDE activity and EDN / LTE4 response by eight compounds, each having the (+) and (-) enantiomers

correlation of various effects of (+) and (-) enantiomers on: vs. EDN response vs. LTE4 response PDE4A no correlation no correlation PDE4B no correlation no correlation PDE4C no correlation no correlation PDE4D positive correlation (p <0,02) positive correlation (p <0.005)

Inhibition of pulmonary eosinophilia

A well characterized model of monkey asthma (Turner et al.) Was used to evaluate these compounds for pulmonary activity.

-Ί9TNF and diseases

Am. J. Respir. Crit. Care Med. 149, 1153-1159, 1994).

Maca fascicularis atopic monkeys are exposed to the antigen causing a significant sudden influx of inflammatory cells in the bronchoalveolar fluid (BAL) of these monkeys 4 to 24 hours after exposure to the antigen. In this model, subcutaneously administered compounds selectively affecting the PDE4D isozyme significantly inhibit pulmonary eosinophilic infiltration by 59-76% 24 hours after antigen administration. However, these compounds have no effect on neutrophil or lymphocyte infiltration, demonstrating selective inhibition of the eosinophilic response by these compounds.

Inhibition of TNF production in isolated human monocytes

The ability of the compounds of Formula I or their pharmaceutically acceptable salts to inhibit the production of the following demonstration of their effect for treatment caused by TNF production has been demonstrated in the following in vitro assay:

Peripheral blood (100 ml) of human volunteer donors is collected in ethylenediaminetetraacetic acid (EDTA). Mononuclear cells were isolated using FICOLL / Hypaque and washed three times in incomplete HBSS. Cells are resuspended to a final concentration of 1 x 10 ⁶ cells per ml in pre-warmed RPMI (containing 5% FCS, glutamine, pen / step and nystatin). Monocytes are plated at 1 x 10 ⁶ cells in 1.0 ml 24-well plates. The cells were incubated at 37 ° C (5% carbon dioxide) and allowed to adhere to the plates for 2 hours, after which the non-adherent cells were removed by careful washing. Test compounds (10 ml) are then added to the cells at 3-4 concentrations each and incubated for 1 hour. LPS (10 ml) was added to the appropriate wells. Plates are incubated overnight (18 hours) at 37 ° C. Towards the end of the incubation period, TNF is analyzed by a sandwich ELISA (R&D Quantikine Kit). IC ₅₀ determinations for each compound were performed by linear regression analysis.

«· · · · ·

The present invention is further illustrated by the following preparations and examples. Mass spectra were determined by GC-MS, AMPI, APCI, or thermospray method. All ³ Η NMR was measured on a 400 MHz device.

DETAILED DESCRIPTION OF THE INVENTION

Preparation 1

2- (4-Fluorophenoxy) -nicotinic acid

To a stirred solution of 4-fluorophenol (5.0 g, 44.6 mmol) in dimethylformamide (40 mL) was added portionwise at room temperature 60% sodium hydride (3.6 g, 89.0 mmol) and stirred for 30 minutes. 2-Chloronicotinic acid (7.1 g, 45.0 mmol) was added portionwise and the mixture was heated to reflux for 3 hours. The solution was poured into 300 ml of water and washed with diethyl ether. The aqueous phase is poured into 400 ml of ice and water and acidified to pH 3 with acetic acid. The resulting precipitate was collected by filtration to give an off-white solid (5.2 g). Melting point 180-182 ° C, MW 233.21, MS (m / e) 234 (M ⁺ +1).

Following the procedure of Preparation 1, the compounds of Preparations 2-5 were prepared, substituting 4-fluorophenol with the corresponding alcohol. The duration of the reaction is between 1 and 24 hours.

Preparation 2

2- (3-fluorophenoxy) -nicotinic acid Molecular Weight 233.21, MS (m / e) 233 (M ⁺ ).

Preparation 3

2- (2,4-Difluorophenoxy) -nicotinic acid Molecular Weight 251.19, MS (m / e) 252 (M ⁺ +1).

Preparation 4

2- (3-chlorophenoxy) -nicotinic acid

Molecular -81- • «· · • • · • · • · · · weight 249,65, MS (m / h) 250 (M @ ⁺ +1). Preparation 5 2- (3-methoxyphenoxy) nicotinic acid Molecular weight 245,23, MS (m / h) 261 (M @ ⁺ +18).

Preparation 6

2- (pyridin-3-yloxy) -nicotinic acid

A solution of 2- (pyridin-3-yloxy) -nicotinic acid ethyl ester (0.419 g, 1.71 mmol) in ethanol (10 mL) and 1 N sodium hydroxide (4 mL) was heated at reflux for 4 hours. The mixture was poured into 100 mL of water, acidified to pH 4 with 1 N hydrochloric acid and concentrated to dryness to give a solid (0.643 g). Molecular Weight 216.21, MS (m / e) 217 (M ⁺ +1).

Preparation 6 was prepared according to Preparation 7-22, substituting 2- (pyridin-3-yloxy) nicotinic acid ethyl ester for the corresponding ester. The duration of the reaction is between 1 and 24 hours.

Preparation 7

2- (5-chloropyridin-3-yloxy) -nicotinic acid Molecular Weight 250.65, MS (m / e) 251 (M ⁺ +1).

Preparation 8

2- (3-nitrophenoxy) -nicotinic acid, m.p. 172-174 ° C, molecular weight 260, MS (m / e) 261 (M ⁺ +1). Anal _. Calcd for C ₁₂ H ₈ N ₂ O ₅ : C 55.39, H 3.10, N

Found: C, 54.71; H, 3.15; N, 10.65.

Preparation 9

2- (3-cyanophenoxy) -nicotinic acid, m.p. 220-222 ° C, molecular weight 240.22, MS (m / e) 240 (M ⁺ ).

»

-82Preparation 10

2- (3-dimethylaminophenoxy) -nicotinic acid

Molecular Weight 258,27, MS (m / e) 259 (M ⁺ +1).

Preparation 11

2- (3-acetylaminophenoxy) -nicotinic acid, m.p. 273-275 ° C, molecular weight 272.26, MS (m / e) 273 (M ⁺ +1).

Preparation 12

2- (1H-indol-4-yloxy) -nicotinic acid Molecular weight 254, MS (m / e) 255 (M ⁺ +1).

Preparation 13

2- (3-trifluoromethylphenoxy) -nicotinic acid, m.p. 148-150 ° C, molecular weight 283.05. Anal _. Calcd for C ₁₃ H ₈ NO ₃ F ₃ : C 55.10, H 2.85, N 4.95. Found: C 54.71, H 2.51, N 4.83.

Preparation 14

2- (3-Tetrazol-1-yl-phenoxy) -nicotinic acid, m.p. 185-188 ° C, MW 283.2, MS (m / e) 282 (M ⁺ -1).

Preparation 15

2- (3-Methylsulfanyl-phenoxy) -nicotinic acid Molecular weight 261,302, MS (m / e) 262 (M ⁺ +1).

Preparation 16

2- (3-acetylphenoxy) -nicotinic acid Molecular Weight 257,248, MS (m / e) 256 (M ⁺ -1).

Preparation 17

2- (3-Trifluoromethoxyphenoxy) -nicotinic acid Molecular Weight 299,208, MS (m / e) 300 (M ⁺ +1).

· Ř k k k k k k k k k k k k k k k k 9 9 9 9 9 9 9

Preparation 18

2- (3,4-difluorophenoxy) -nicotinic acid

Molecular Weight 251.20, MS (m / e) 251 (M ⁺ ).

Preparation 19

2- (3,5-difluorophenoxy) -nicotinic acid Molecular Weight 251.20, MS (m / e) 252 (M ⁺ +1).

Preparation 20

2- (3-Fluorophenoxy) -nicotinic acid, m.p. 135-137 ° C. Analysis for C ₁₂ H ₈ F ₃ NO: Calculated: C 61.79, H 3.46, N 6.01 Found: C 61.51, H 3.69, N 5.78.

Preparation 21

2- (benzo [1,3] dioxol-5-yloxy) -nicotinic acid, m.p. 162-164 ° C, 1 H NMR (DMSO-d ⁶ ) d 6.0 (2H, s),

6.5-8.3 (6 H, m).

Preparation 22

2- (3-Dimethylcarbamoyl-phenoxy) -N- [4- (1-hydroxy-1-methylethyl) -benzyl] -nicotinic acid

NMR (DMSO-d ⁶ ) d 2.88 (3H, s), 2.93 (3H, s), 7.08 (4H, m),

7.42 (1 H, m), 8.22 (2 H, m).

Preparation 23

2- (Pyridin-3-yloxy) -nicotinic acid ethyl ester

A solution of 2-chloronicotinic acid ethyl ester (0.53 g, 2.85 mmol), cesium carbonate (2.326 g, 6.73 mmol) and pyridin-3-ol (0.271 g, 2.85 mmol) in dimethylformamide (20 mL) Heat at 65 ° C for 10 hours. The mixture was diluted with 300 mL of water and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over Na ₂ SO ₄ , filtered, and concentrated to an oil (0.55 g). Molecular Weight 244.25, MS (m / e) 244 (M ⁺ ).

• · · · · ·

-84 · * t t t * 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 ·· * · v *

Following the procedure of Preparation 23, but substituting pyridine-3-ol for the corresponding alcohol, the compounds of Preparations 24 to 43 were prepared. The reaction time was between 1 and 24 hours.

Preparation 24

2- (5-Chloro-pyridin-3-yloxy) -nicotinic acid ethyl ester

A solution of 2-chloronicotinic acid ethyl ester (2.07 g, 11.2 mmol), cesium carbonate (7.27 g, 22.3 mmol) and

Of 5-chloro-3-pyridinol (1.45 g, 11.2 mmol) in anhydrous dimethyl formamide (40 mL) was stirred at 90 ° C overnight. The suspension was cooled to room temperature, poured into water and extracted with diethyl ether. The combined organic phases were washed with water and brine, dried over MgSO ₄ and concentrated to a light brown solid. Recrystallization from hexane gave a yellow solid (1.0 g). Melting point 65-69 ° C. Analysis calculated for C ₁₃ H ₁₁ ClN ₂ O ₃ : C 56.03, H 3.98, N 10.05. Found: C 56.14, H 4.04, N 10.16. Molecular Weight 278.72, MS (m / e) 279 (M ⁺ +1).

Preparation 25

2- (3-Nitrophenoxy) -nicotinic acid ethyl ester M.p. 70-72 ° C, MW 288.26, MS (m / e) 289 (M ⁺ +1).

Preparation 26

Ethyl 2- (3-cyano-phenoxy) -nicotinic acid ethyl ester MW 268, ³ Η NMR _CDCl3) d 1.4 (3H, t), 4.39 (2H,

q), 7.12-8.4 (7H, m).

Preparation 27

2- (3-Dimethylaminophenoxy) -nicotinic acid ethyl ester Molecular Weight 286.33, MS (m / e) 287 (M ⁺ +1).

Preparation 28 • ·

-35- ········ ·· ·· ·· ··

2- (4-Cyanophenoxy) -nicotinic acid ethyl ester

MW 268; MS (m / e) 268 (M ^& lt ^{; +} & gt ^; ).

Preparation 29

2- (3-Acetylaminophenoxy) -nicotinic acid ethyl ester Molecular Weight 300.32, MS (m / e) 301 (M ⁺ +1).

Preparation 30

2- (3-Chloro-phenoxy) -nicotinic acid ethyl ester Molecular Weight 277.71, MS (m / e) 278 (M ⁺ +1).

Preparation 31

Ethyl 2- (1H-indol-4-yloxy) -nicotinic acid ethyl ester MW 282; NMR (DMSO-d ⁶⁾ d 5.9 (1H, s)

6.4-8.4 (7H, m), 11.20 (1H, broad s).

Preparation 32

2- (3-Trifluoromethyl-phenoxy) -nicotinic acid ethyl ester M.p. 46-48 ° C, MW 311, MS (m / e)

312 (M @ ⁺ +1).

Preparation 33

2- (3-Tetrazol-1-yl-phenoxy) -nicotinic acid ethyl ester M.p. 100-102 ° C, MW 311.27, MS (m / e) 312 (M ⁺ +1).

Preparation 34

2- (3-Methylsulfanyl-phenoxy) -nicotinic acid ethyl ester Molecular Weight 289,356, MS (m / e) 290 (M ⁺ +1).

Preparation 35

2- (3-Acetyl-phenoxy) -nicotinic acid ethyl ester

Molecular Weight 285,302, MS (m / e) 286 (M ⁺ +1).

• • •

-86Preparation 36

2- (3-Trifluoromethoxyphenoxy) -nicotinic acid ethyl ester

Molecular Weight 327,262, MS (m / e) 328 (M ⁺ +1).

Preparation 37

2- (3,4-Difluorophenoxy) -nicotinic acid ethyl ester Molecular Weight 279.26, MS (m / e) 279 (M ⁺ ).

Preparation 38

2- (3,5-Difluorophenoxy) -nicotinic acid ethyl ester Molecular Weight 279,26, MS (m / e) 279 (M ⁺ ).

Preparation 39

2- (3-Fluorophenoxy) -nicotinic acid ethyl ester Molecular weight 261.26, MS (m / e) 262 (M ⁺ ).

Preparation 40

2- (3-Cyano-4-fluorophenoxy) -nicotinic acid ethyl ester Molecular Weight 286.28, MS (m / e) 286 (M ⁺ ).

Preparation 41

2- (Benzo [1,3] dioxol-5-yloxy) -nicotinic acid ethyl ester

Molecular Weight 287, ³ H NMR (DMSO-d ⁶ ) d 1.2 (3H, t), 4.30 (2H, q), 6.0 (2H, s), 6.5-8.4 (6H) , m).

Preparation 42

2- (3-Dimethylcarbamoyl-phenoxy) -nicotinic acid ethyl ester

1 H NMR (CDCl ₃ ) d 1.36 (3H, t), 3.00 (3H, s), 4.38 (2H, q), 7.06 (1H, m), 7.19 (1H, m) 7.24 (2H, m), 7.42 (1H, m), 8.24 (2H, dd).

-87 ··········

Preparation 43

2- (3-Formyl-phenoxy) -nicotinic acid ethyl ester

Molecular Weight 271.29, MS (m / e) 271 (M ⁺ ).

Preparation 44

2-Chloronicotinic acid ethyl ester

To a solution of 2-chloronicotinic acid (12.5 g) in ethanol (250 mL) was added dropwise thionyl chloride (5.77 mL) and heated to reflux for 1.5 hours. The mixture was concentrated to remove ethanol and diluted with 300 mL of water. Solid sodium bicarbonate was added to adjust the pH of the solution to 8.0. The solution was extracted with ethyl acetate, washed with water, saturated sodium bicarbonate solution, water and brine, dried over Na ₂ SO ₄ , filtered and concentrated to a yellow liquid (10.0 g). MW 185.61; MS (m / e) 185 (M ^& lt ^{; +} & gt ^; ).

Preparation 45

2- (4-cyanophenoxy) -nicotinic acid

A solution of 2- (4-cyanophenoxy) -nicotinic acid methyl ester (0.200 g, 0.787 mmol) in tetrahydrofuran (3 mL) and 1 M LiOH.H ₂ O (1.97 mL) was stirred overnight. The mixture was diluted with 25 mL of water, acidified to pH 1 with 2N hydrochloric acid and filtered to give a white solid (0.144 g). MW 240; NMR (DMSO-d ⁶⁾ d 7.2 (3H, m), 7.90 (2H, m), 8.35 (2H, m)

13.5 (1H, broad s).

The compound of Preparation 46 was prepared according to the method of preparation, but the 2- (4-cyanophenoxy) -nicotinic acid methyl ester was replaced with the corresponding ester. The duration of the reaction is between 1 and 24 hours.

Preparation 46

2- (3-Cyano-4-fluorophenoxy) -nicotinic acid

Molecular Weight 258,22, MS (m / e) (M ⁺ ).

• ·

-88Preparation 47

2- (4-Aminomethylphenyl) -propan-2-ol

To a stirred solution of 4- (1-hydroxy-1-methylethyl) -benzonitrile (20.9 g, 0.13 mol) in anhydrous tetrahydrofuran (300 mL) at 0 ° C was slowly added dropwise 1.0 M lithium aluminum hydride in water. tetrahydrofuran (388 mL, 0.39 mol). The mixture was heated to reflux for 30 minutes, then cooled to 0 ° C and quenched by the slow dropwise addition of methanol (50 mL). The mixture was concentrated under reduced pressure to half volume and diluted with chloroform (1200 mL) and then washed with water (300 mL). The resulting suspension was filtered through Celite and the filtrate layers were separated. The organic extract was dried (MgSO ₄ ) and concentrated to give 16.2 g of a pale yellow solid, mp 64-66 ° C. NMR (CDCl ₃ ): 7.45 (d, 2H), 7.26 (d, 2H), 3.83 (s, 2H), 1.57 (s, 6H). GC-MS (m / e,%): 164 (M ^& lt ^{; +} & gt ^; , 15), 150 (80), 132 (75), 106 (100).

Preparation 48

2- (4-Cyanophenoxy) -nicotinic acid methyl ester

A solution of 2- (4-cyanophenoxy) -nicotinic acid ethyl ester (0.90 g, 2.44 mmol) in methanol (10 mL) and potassium carbonate (1.01 g, 7.33 mmol) was heated to reflux. for 20 minutes. The mixture was diluted with 100 mL of water, acidified to pH 1 and filtered to give a solid (0.200 g). MW 254; MS (m / e) 254 (M ^T).

Preparation 49

2- (3-chlorophenoxy) nicotinamide

A solution of 2- (3-chlorophenoxy) nicotinenitrile (7.81 g, 33.9 mmol), 3% hydrogen peroxide (190 mL, 169 mmol) and 50% potassium hydroxide (380 mL, 3.39 mmol) in ethanol ( 100 mL) was stirred at 70 ° C overnight. The mixture was concentrated to 250 mL and cooled to 0 ° C. The solid is collected by filtration, dissolved •

-89- in ethyl acetate, dried over magnesium sulfate and concentrated to give a white solid (6.51 g). Mp 225-228 ° C, MW 248.67, MS (m / e) 250 (M ⁺ +1).

Preparation 50

2- (3-chlorophenoxy) nicotinonitrile

A solution of 2-chloronicotinenitrile (5.0 g, 36.1 mmol), cesium carbonate (23.5 g, 72.2 mmol) and 3-chlorophenol (4.65 g, 36.1 mmol) in dimethylformamide (100 mL) Heat at 80 ° C overnight. The mixture was cooled and poured into 500 ml of water and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgSO ₄ , filtered and concentrated to give a white solid (8.21 g). Mp 88-90 ° C. Analysis for C ₁₂ H ₇ N ₂ OCl Calcd

H, 3.06; N, 12.15. Found: C, 62.43; H, 3.00; N, 12.13.

Preparation 51

2- (4-Fluorophenoxy) -pyridin-3-ylamine

To a solution of 2- (4-fluorophenoxy) -3-nitropyridine (3.00 g, 12.81 mmol) in ethyl acetate (100 mL) was added 10% palladium on carbon (0.600 g). The mixture is shaken under 50 psi of hydrogen for 1 hour. The catalyst was removed by filtration and the solution was concentrated to give a white solid (2.49 g). Mp 92-94 ° C, molecular weight 204.20, MS (m / e) 204 (M ⁺ ).

The compound of Preparation 10a was prepared according to the procedure of Preparation 10, but the 2- (4-fluorophenoxy) -3-nitropyridine was replaced by the corresponding nitro compound. The duration of the reaction is between 1 and 24 hours.

Preparation 52

2- (pyridin-3-yloxy) -pyridin-3-ylamine Molecular Weight 187, MS (m / e) 188 (M ⁺ +1).

Preparation 53

2- (4-Fluorophenoxy) -3-nitropyridine

A solution of 2-chloro-3-nitropyridine (5.0 g, 31.54 mmol), cesium carbonate (25.7 g, 78.85 mmol) and 4-fluorophenol (3.6 g, 34.69 mmol) in dimethyl of formamide (85 mL) was stirred at room temperature for 2 hours. The mixture was diluted with 250 mL of water and extracted with ethyl acetate. The combined extracts were washed with 1 N NaOH, water and brine, dried over Na ₂ SO ₄ , filtered and concentrated to give a yellow solid (7.16 g). M.p. 87-89 ° C, MW 234.1, MS (m / e) 234 (M ⁺ ).

Following the procedure of Preparation 53, the compound of Preparation 54 was prepared but the 4-fluorophenol was replaced with the corresponding alcohol. The duration of the reaction is between 1 and 24 hours.

Preparation 54

2- (pyridin-3-yloxy) -3-nitropyridine Molecular Weight 217,186, MS (m / e) 218 (M ⁺ +1).

Preparation 55

2- (3-chlorophenoxy) pyridine-3-carbaldehyde

To a solution of methyl sulfoxide (0.23 mL, 3.3 mmol) and methylene chloride (10 mL) was added oxalyl chloride (0.20 mL, 2.3 mmol) dropwise over 5 min at -70 ° C, and the mixture was stirred for for 1 hour. To the stirred mixture was added dropwise a solution of [2- (3-chlorophenoxy) -pyridin-3-yl] -methanol (0.39 g, 1.7 mmol) in methylene chloride (10 mL), and the mixture was stirred at -70. ° C for 1 hour. The mixture was then warmed to -35 ° C for 15 minutes and recooled to -70 ° C while triethylamine (1.15 mL, 8.3 mmol) was added and the mixture warmed to 0 ° C. The mixture was diluted with 20 mL of methylene chloride and washed with saturated sodium bicarbonate and sodium chloride, dried over Na ₂ SO ₄ , filtered and concentrated to give an orange oil which was purified by silica gel chromatography eluting with ethyl acetate / hexane 1/3 , which • • * ·

-91 Obtained a yellow oil (0.180 g). Molecular Weight 233.65, MS (m / e) 234 (M ⁺ +1).

Following the procedure of Preparation 55, the compound of Preparation 56 was prepared, but [2- (3-chlorophenoxy) -pyridin-3-yl] -methanol was replaced with the corresponding alcohol. The duration of the reaction is between 1 and 24 hours.

Preparation 56

2- (pyridin-3-yloxy) -pyridine-3-carbaldehyde

Molecular Weight 200.20, MS (m / e) (M ⁺ +1).

Preparation 57 [2- (3-Chloro-phenoxy) -pyridin-3-yl] -methanol

To a solution of 2- (3-chlorophenoxy) -nicotinic acid ethyl ester (0.5 g) and tetrahydrofuran (10 mL) was added lithium aluminum hydride (0.4 g) at 0 ° C in two portions and the mixture was stirred for 30 minutes . The solution was allowed to warm to room temperature and stirred overnight. Add 1 N sodium hydroxide (0.5 mL) and dilute with water. The mixture was filtered through Celite, then washed with ethyl acetate to extract the product. The combined extracts were washed with water and brine, dried over MgSO ₄ , filtered, and concentrated to an oil (0.39 g). Molecular Weight 235.67, MS (m / e) 236 (M ⁺ +1).

Following the procedure of Preparation 57, the compound of Preparation 58 was prepared but the 2- (3-chlorophenoxy) -nicotinic acid ethyl ester was replaced with the corresponding ester. The duration of the reaction is between 1 and 24 hours.

Preparation 58 [2- (Pyridin-3-yloxy) -pyridin-3-yl] -methanol MW 202.21, MS (m / e) 203 (M ⁺ +1).

Preparation 59

3-Tetrazol-1-ylphenol

To a solution of 1- (3-benzyloxyphenyl) -4-tetrazole (0.640 g, 2.54 mmol) in ethanol (150 mL) was added 10% palladium on carbon (-0.100 g). The mixture was stirred under a hydrogen atmosphere in a round flask overnight. The catalyst was removed by filtration and the solution was concentrated to give a white solid (0.364 g). Melting point 171-172 ° C, molecular weight 162.12, MS (m / e) 163 (M ⁺ +1).

Preparation 60

1- (3-Benzyloxyphenyl) -1H-tetrazole

To a solution of 3-benzyloxyphenylamine (1.50 g, 7.53 mmol) and acetic acid (15 mL) at 70 ° C was added a solution of ethyl orthoformate (1.116 g, 7.53 mmol) in acetic acid (4 mL) and a mixture of is stirred for 4 hours. Sodium azide (1.488 g, 22.6 mmol) was added in two portions and the mixture was stirred at 70 ° C for 20 hours. The mixture was extracted with ethyl acetate. The combined extracts were washed with saturated sodium bicarbonate solution and brine, dried over Na ₂ SO ₄ , filtered and concentrated. The product was purified by flash chromatography on silica gel eluting with hexane / ethyl acetate 3/1 to give white crystals (0.650 g). 85-86 ° C, molecular weight 252.25, MS (m / e) 252.8 (M ⁺ ).

Preparation 61

3-Methylsulfanylphenol

The acetic acid solution (200 mL) was cooled to -50 ° C and bubbled in HBr gas (20 g). M-Methoxyphenylmethylsulfide (20 g, 130 mmol) and 48% aqueous HBr (10 mL) were added and the mixture was refluxed for 3 hours. The acetic acid was removed and the oil was poured into 150 ml of ice water and extracted with diethyl ether. The combined extracts were washed with 15% KOH and the aqueous phase was acidified with concentrated hydrochloric acid and extracted with diethyl ether.

The combined extracts were dried over Na ₂ SO ₄ , filtered, and concentrated to an oil (11.5 g). Molecular Weight 140,205, MS (m / e) 141 (M ⁺ +1).

Preparation 62

1-Methoxy-3-methylsulfanylbenzene

To a suspension of magnesium (7.2 g, 296 mmol) and iodine (100 mL) in diethyl ether (250 mL) was slowly added m-bromoanisole (47.0 g, 250 mmol) with spontaneous boiling. Methyl disulfide (16.0 g, 160 mmol) was added and the mixture was stirred for 1 hour. Once the mixture was cooled, a solution of water (100 mL) and concentrated hydrochloric acid (30 mL) was added. The layers were separated and the aqueous layer was extracted with diethyl ether. The combined extracts were dried over MgSO ₄ , filtered, and concentrated to an oil which was purified by distillation (2.7 kPa) at 130-135 ° C (23.5 g).

Preparation 63

2- (Pyridin-3-ylmethoxy) -nicotinic acid ethyl ester

To a solution of pyridin-3-ylmethanol (0.59 g, 5.4 mmol) in dimethylformamide (20 mL) was added sodium hydride (0.259 g, 6.5 mmol) and the mixture was stirred for 30 minutes. Add chloronicotinic acid ethyl ester (1.0 g, 5.4 mmol) via syringe and stir at room temperature overnight. The mixture was diluted with water (150 mL) and extracted with diethyl ether and ethyl acetate. The combined extracts were washed with 1 N NaOH, water and brine, dried over Na ₂ SO ₄ , filtered and concentrated to an oil (1.3 g). Molecular Weight 258,28, MS (m / e) 259 (M ⁺ +1).

Preparation 64

2- (3-methoxycarbonylphenoxy) -nicotinic acid

To a solution of 2- (3-methoxycarbonylphenoxy) -nicotinic acid benzyl ester (1.1 g) in methanol (15 mL) and ethyl acetate (15 mL) was added 10% palladium on carbon (0.2 g). Shake the mixture •

-94- ........ ** Pressure of 206.85 kPa of hydrogen for 2 hours. The catalyst was removed by filtration and the solution was concentrated to give a solid which was triturated in methylene chloride / hexane to give a white solid (0.630 g). Molecular Weight 273.26, MS (m / e) 274 (M ⁺ +1).

Preparation 65

2- (3-Methoxycarbonylphenoxy) -nicotinic acid benzyl ester

A solution of 2- (3-iodophenoxy) -nicotinic acid benzyl ester (1.7 g, 3.94 mmol), dppf (0.131 g, 0.24 mmol), Pd (OAc) ₂ (0.027 g, 0.12 mmol) and triethylamine (0.797 g, 7.9 mmol) in methanol (10 mL) was bubbled with carbon monoxide gas for 5 minutes. The mixture was heated at 60 ° C for 4 hours, poured into 200 mL of water and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgSO ₄ , filtered, and concentrated to an oil which was purified by flash chromatography on silica gel using 25% ethyl acetate in hexane as eluent (1.2 g). Molecular Weight 363.39, MS (m / e) 364 (M ⁺ +1).

Preparation 66

2- (3-Iodophenoxy) -nicotinic acid benzyl ester A solution of 2-chloronicotinic acid benzyl ester (1.7 g, 6.86 mmol), cesium carbonate (4.5 g, 13.7 mmol) and 3-iodophenol (1.7 g (7.54 mmol) in dimethylformamide (20 ml) was stirred at 70-80 ° C for 2 hours. The mixture was poured into 150 ml of water and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgSO ₄ , filtered, and concentrated to an oil which was purified on silica gel eluting with 30% (2.32 g).

flash chromatography of ethyl acetate in hexane

Molecular Weight 431.24, MS (m / e) 432 (M ⁺ +1).

• ·

-95 ···· ····

Preparation 67

2-Chloro-nicotinic acid benzyl ester

A solution of 2-chloronicotinic acid (3.0 g, 19.0 mmol), potassium carbonate (6.5 g, 48.0 mmol) and benzyl bromide (2.8 mL, 24.0 mmol) in dimethylformamide (20 mL) was stirred at room temperature overnight. The mixture was poured into 200 ml of water and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgSO ₄ , filtered and concentrated to an oil which was purified by flash chromatography on silica gel eluting with 10% ethyl acetate in hexane (2.8 g). MW 247.69, MS (m / e) 247 (M ^& lt ^{; +} & gt ^; ).

Preparation 68

C- (5-chlorofuran-2-yl) -methylamine

To a solution of 5-chlorofuran-2-carbaldehyde oxime (1.38 g, 9.5 mmol) in tetrahydrofuran (30 mL) was added dropwise 1.0 M lithium aluminum hydride (21 mL, 21 mmol) and the mixture was heated to reflux. condenser for 30 minutes. The mixture was cooled to 0 ° C and 5 mL of methanol and 5 mL of saturated NH ₄ Cl were added. The mixture was poured into 150 ml of water and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgSO ₄ , filtered, and concentrated to an oil (0.403 g). Molecular Weight 131.57, MS (m / e) 130/131 (M ⁺ ).

Following the procedure of Preparation 68, the compounds of Preparations 69-71 were prepared, but the 5-chlorofuran-2-carbaldehyde oxime was replaced with the corresponding oxime. The duration of the reaction is between 30 minutes and 24 hours.

Preparation 69

C- (5-methylfuran-2-yl) -methylamine Molecular Weight 111.16, MS (m / e) 111 (M ⁺ ).

Preparation 70 • · ··· »» ··········

• · · · · φ · φ · φ · φ · φ · φ

- 9 6 ^- ♦ ······ * · ·· · * ··

C- (4-chlorothiophen-2-yl) -methylamine Molecular Weight 147.64.

Preparation 71

C-thiazol-2-yl-methylamine MW 114.19.

Preparation 72

5-chlorofuran-2-carbaldehyde oxime

To a solution of 5-chlorofuran-2-carbaldehyde (1.3 g, 9.96 mmol) and NaOAc (1.8 g, 21.9 mmol) in methylene chloride (30 mL) and water (30 mL) was added NH ₂ OH HCl (0.761 g, 10.96 mmol) and stirred at room temperature overnight. The mixture was poured into 150 ml of water and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgSO ₄ , filtered and concentrated to give a solid (1.38 g). MW 145.55, MS (m / e) 145/147 (M ^& lt ^{; +} & gt ^; ).

Preparation 72 was prepared to prepare compounds 73-75, but 5-chlorofuran-2-carbaldehyde was replaced with the corresponding aldehyde. The duration of the reaction is between 1 and 24 hours.

Preparation 73

5-methylfuran-2-carbaldehyde oxime

Mixture of E / Z isomers, MW 125.11, NMR (CDC1 ₃₎ d 2.32 (3H, s), 6.03 (1H, d), 6.12 (1H, d), 6.0 (2H s, 6.48 (1H, d), 7.22 (1H, d), 7.42 (1H, s), 7.91 (1H, s).

Preparation 74

4-chlorothiophene-2-carbaldehyde oxime MW 161.62.

Preparation 75

Thiazole-2-carbaldehyde oxime • ·

Molecular Weight 128,17.

Preparation 76

5-chlorofuran-2-carbaldehyde

A solution of 5-nitrofuran-2-carbaldehyde (14.1 g) in concentrated hydrochloric acid (60 ml) was distilled with water vapor until -150 ml of liquid was obtained. The mixture was poured into 150 ml of water and extracted with diethyl ether. The combined extracts were washed with saturated NaHCO ₃ solution, water and brine, dried over MgSO ₄ , filtered and concentrated to an oil which was purified by flash chromatography on silica gel using 20% ethyl acetate in hexane as eluent to afford white solid (1.3 g). Molecular Weight 130.53, MS (m / e) 129/131 (M ⁺ +1).

Preparation 77

2,4,6-Trifluorobenzylamine

A solution of 2-bromomethyl-1,3,5-trifluorobenzene (2.0 g, 8.9 mmol) and HMTA (3.1 g, 22.2 mmol) in chloroform (35 mL) was heated at reflux for 1 h. for 18 hours. The resulting precipitate was collected by filtration and taken up in methanol (10 mL), water (5 mL), and concentrated hydrochloric acid (5 mL) and heated at reflux for 4 hours. The mixture was poured into 200 ml of water and washed with diethyl ether. The aqueous phase was made alkaline with 5 N sodium hydroxide and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgSO ₄ , filtered, and concentrated to an oil which solidified on standing (1.32 g). MW 161.14, MS (m / e) 145 (M ⁺ -NH ₂ ).

The compound of Preparation 78-79 was prepared according to Preparation 77, but the 2-bromomethyl-1,3,5-trifluorobenzene was replaced with the corresponding halide. The duration of the reaction is between 1 and 24 hours.

• w • »» • 9

-98- · »·· ·· ··

Preparation 78

C- (5-chlorothiophen-2-yl) -methylamine Molecular Weight 147.64, MS (m / e) 147 (M ⁺ ).

Preparation

C- (3,5-dichlorothiophen-2-yl) -methylamine Molecular Weight 182.08, MS (m / e) 181-186 (M ⁺ ).

Preparation 80

C- (3,4-Dichlorothiophen-2-yl) -methylamine

To a solution of 3,4-dichlorothiophene-2-carboxylic acid amide (0.640 g, 3.3 mmol) in tetrahydrofuran (20 mL) was added dropwise 1.0 M lithium aluminum hydride (7 mL, 7 mmol) and the mixture is stirred at room temperature for 30 minutes. The mixture was cooled to 0 ° C and 3 mL of methanol and 5 mL of saturated NH ₄ Cl were added dropwise. The mixture was poured into 100 ml of water and extracted with diethyl ether. The mixture was then filtered through Celite. The combined extracts were washed with water and brine, dried over MgSO ₄ , filtered, and concentrated to an oil which was purified by flash chromatography on silica gel using 5% methanol in methylene chloride as eluent to give an oil (0.335 g) . MW 182.08; ^L 1 HNMR (CDCl ₃₎ d 4.01 (2H, s), 7.09 (1H, s).

Following the procedure of Preparation 80, the compounds of Preparations 81-88 were prepared, but the 3,4-dichlorothiophene-2-carboxylic acid amide was replaced with the corresponding amide. The duration of the reaction is between 30 minutes and 24 hours.

Preparation 81

C- (3-chloro-thiophen-2-yl) -methylamine MW 147.64; NMR (CDC1 ₃₎ d 3.99 (2H, s), 6.86 (1H, d), 7.16 (1H, d ).

Preparation 82 Ir Ir Ir Ir Ir Ir Ir Ir Ir Ir Ir W W Ir W W W W W W W W Ir Ir

-99 ^- ···· · ··· · »

C-benzo [b] thiophen-2-ylmethylamine Molecular Weight 163.26, MS (m / e) 163 (M ⁺ ).

Preparation 83

C- (5-trifluoromethylthiophen-2-yl) -methylamine Molecular Weight 181.20, MS (m / e) 181 (M ⁺ ).

Preparation 84

2- (5-Aminomethylthiophen-2-yl) -propan-2-ol Molecular Weight 171.29.

Preparation 85

2- (5-Aminomethyl-3-chloro-thiophen-2-yl) -propan-2-ol Molecular Weight 205.73, ³ H NMR (CDCl ₃ ) d 1.69 (6H, s), 3.92 (2H, s), 6.69 (1H, s).

Preparation 86

2- (5-Aminomethyl-furan-2-yl) -propan-2-ol

MW 155.22, ^X 1 HNMR (CDCl ₃₎ d 1.56 (6H, s), 3.77 (2H, s), 6.02 (1H, d), 6.06 (1H, d).

Preparation 87

3- (5-Aminomethyl-thiophen-2-yl) -pentan-3-ol

Molecular Weight 199,35, 1 H NMR (CDCl ₃ ) d 0.85 (6H, t), 1.82 (4H, q), 3.97 (2H, s), 6.67 (1H, d), 6 73 (1 H, d).

Preparation 88

2- (5-aminomethyl-4-chloro-thiophen-2-yl) -propan-2-ol MW 205.73, ^X 1 HNMR (CDCl ₃₎ d 1.60 (6H, s), 3.92 (2H, s), 6.71 (1 H, s).

Preparation 89

3,4-Dichloro-thiophene-2-carboxylic acid amide · «· · ♦... ♦ 3,4 3,4 3,4 3,4

-100- ........ ... · .. ..

To a stirred suspension of 3,4-dichlorothiophene-2-carboxylic acid (1.0 g, 5.08 mmol) in methylene chloride (20 mL) and dimethylformamide (0.2 mL) was added thionyl chloride (1.9 mL,

25.3 mmol) and the mixture was heated to reflux for 3 hours. The mixture was concentrated to give an oil. This was taken up in methylene chloride (15 mL), cooled to 0 ° C and NH ₃ gas was bubbled through for 5 minutes and then stirred for 20 minutes. The mixture was diluted with methylene chloride (150 mL), washed with water and brine, dried over MgSO ₄ , filtered and concentrated to give a solid which was purified by flash chromatography on silica gel using 2.5% methanol in methanol. methylene chloride as eluent to give a solid which was triturated in methylene chloride to give a white solid (0.475 g). Molecular Weight 196,06,

MS (m / e) 195/197 (M ^& lt ^{; +} & gt ^; ).

The compound of Preparation 90-92 was prepared according to Preparation 89, but the 3,4-dichlorothiophene-2-carboxylic acid was replaced with the corresponding acid. The duration of the reaction is between 1 and 24 hours.

Preparation 90

3-Chlorothiophene-2-carboxylic acid amide MW 161, MS (m / e) 161/163 (M ⁺ ).

Preparation 91

5-Trifluoromethylthiophene-2-carboxylic acid amide Molecular Weight 195.18, MS (m / e) 196 (M ⁺ +1).

Preparation 92

5- (1-Hydroxy-1-methylethyl) -furan-2-carboxylic acid amide

Molecular Weight 169,18, 1 H NMR (DMSO-d ⁶ ) d 1.40 (6H, s),

5.20 (1H, d), 6.26 (1H, d), 6.93 (1H, d), 7.24 (1H, broad s),

7.58 (1H, broad s).

• ·

-101 • · · · · ··········

Preparation 93

- (2,2,2-trifluoroethoxy) -benzylamine

To a solution of 4- (2,2,2-trifluoroethoxy) -benzonitrile (0.5 g, 2.48 mmol) in tetrahydrofuran (10 mL) was added 1.0 M lithium aluminum hydride (6.2 mL, 6.2 mmol). ) and the mixture was heated to reflux for 40 minutes. The mixture was cooled to 0 ° C and 5 mL of methanol was added dropwise and diluted with saturated NH ₄ Cl (50 mL). The mixture was extracted with diethyl ether. The combined extracts were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to an oil which was purified by flash chromatography on silica gel using 5% methanol in methylene chloride as eluent to give an oil (0.230 g) . Molecular Weight 205.18, MS (m / e) 206 (M ⁺ +1).

The compound of Preparation 94-106 was prepared according to the procedure of Preparation 93 but replaced with the corresponding nitrile 4- (2,2,2-trifluoroethoxy) -benzonitrile. The duration of the reaction is between 30 minutes and 24 hours.

Preparation 94

4-difluoromethoxybenzylamine

MW 173.18, ¹ H NMR (CDCl ₃ ) d 3.85 (2H, s), 6.48 (1H, t), 7.09 (2H, m), 7.30 (2H, m).

Preparation

C- (1H-indol-5-yl) -methylamine Molecular Weight 146.21, MS (m / e) 146 (M ⁺ ).

Preparation 96

5-Fluorothiophene-2- (2-methylamine)

1 H NMR (CDCl ₃ ) d 6.47 (m, 1H), 6.26 (m, 1H), 3.91 (m, 2H, GC-MS (m / e,%)) 131 (M ⁺ , 100) .

Preparation 97 • • • · · ·

-102- ........ ·· .. ·.

4-Aminomethyl-2,6-di-tert-butylphenol Molecular Weight 235, MS (m / e) 235 (M ⁺ ).

Preparation 98

2,3-difluorobenzylamine Molecular Weight 143,14.

Preparation 99

2- (4-Aminomethyl-2-chloro-phenyl) -propan-2-ol Molecular Weight 199.70, MS (m / e) 199/201 (M ⁺ ).

Preparation 100

2- (4-Aminomethyl-3-chlorophenyl) -propan-2-ol Molecular Weight 199.70, MS (m / e) 198/200 (M ⁺ +1). ¹ H NMR (CDCl ₃ ) d 1.54 (6H, s), 3.89 (2H, s), 7.31 (2H, m), 7.48 (1H,

d).

Preparation 101

1- (4-Aminomethylphenyl) -cyclobutanol MW 177.27, MS (m / e,%) 177 (M ⁺ , 3), 160 (45),

148 (100).

Preparation

1- (4-aminomethylphenyl) -prop-2-yn-1-ol Molecular Weight 161.22, MS (m / e,%) 160 (M ^& lt ^{; +} & gt ^; , 15), 115 (20), 106 (100).

Preparation 103

- (2-methyl- [1,3] dioxolan-2-yl) -benzylamine Molecular Weight 193,248, MS (m / e) 178 (M ⁺ -NH ₃ ).

Preparation 104

C- (1-dioxaspiro [4.5] dec-8-yl) -methylamine Molecular Weight 171,241, MS (m / e) 172 (M ⁺ +1).

• · · ·

-10 3 “········ ·· ·· ··

Preparation 105

1- (4-Aminomethylphenyl) -ethanol

Molecular Weight 151,21, MS (m / e) 152 (M ⁺ +1).

Preparation

2- (4-aminomethyl-3-fluorophenyl) -propan-2-ol ^{: 1} H NMR (CDCl ₃ ) d 1.54 (6H, s), 3.89 (2H, s), 7.30 (2H, m) 7.48 (1H, s).

Preparation 107

4- (1-hydroxy-1-methylethyl) -benzonitrile

To a stirred solution of 4-cyanacetophenone (49.5 g, 0.34 mol) in anhydrous tetrahydrofuran (400 mL) at -78 ° C was added dropwise 3.0 M methylmagnasium chloride (150 mL, 0.45 mol). The mixture was allowed to warm slowly to 0 ° C over 3.5 hours and then methanol (80 mL) was added dropwise. The mixture was poured into water (1000 mL) and acidified to pH ~ 3 with oxalic acid and then extracted with ethyl acetate (2 x 500 mL). The organic extracts were combined and washed with water (2 x 100 mL), brine (100 mL), dried (MgSO ₄ ) and concentrated to a white residue. Flash chromatography on silica gel, eluting with 20% ethyl acetate in hexanes, gave 13.5 g of a clear oil which solidified on standing. Melting point 45-47 ° C.

Preparation 108

4- (2,2,2-trifluoroethoxy) -benzonitrile

To a solution of 4-cyanophenol (5.0 g, 42.0 mmol) in HMPT (40 mL) was added sodium hydride (1.68 g, 42.0 mmol) and the mixture was stirred at room temperature for 15 minutes. 2,2,2-Trifluoroethyl methanesulfonate (8.98 g, 50.4 mmol) was added via syringe and the mixture was stirred at 140 ° C overnight. The mixture was then cooled to room temperature, diluted with 300 mL of ice water and 50 mL of 2 N hydrochloric acid and extracted with diethyl ether. The combined extracts were washed with water, 1 N sodium hydroxide and

Sodium chloride, dried over Na ₂ SO ₄ , filtered and concentrated to an oil which was purified by flash chromatography on silica gel using 25% diethyl ether in hexane as eluent to give an oil (2.68 g). Synthesis 727 (1980).

Preparation 109

1- (5-chloro-thiophen-2-yl) -ethylamine

A solution of 1- (5-chlorothiophen-2-yl) -ethanone (5.0 g, 31.0 mmol) in formamide (5 mL, 150.0 mmol) was stirred at 160 ° C for 18 h. The mixture was poured into 200 ml of water and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgSO ₄ , filtered, and concentrated to an oil which was purified by flash chromatography on silica gel eluting with 20% ethyl acetate in hexane to give an oil. This oil is taken up in 26 ml of 6 N NaOH, 20 ml of methanol and 5 ml of tetrahydrofuran and heated at reflux for 3 hours. The mixture was poured into 200 ml of water and extracted with diethyl ether. The combined extracts were concentrated to give a dark oil (2.3 g). MW 161.67; MS (m / e) 161 (M ^& lt ^{; +} & gt ^; ).

Preparation 109 was prepared to prepare compounds 110-111, but 1- (5-chlorothiophen-2-yl) -ethanone was replaced with the corresponding aldehyde or ketone. The reaction time is between 30 minutes and 24 hours.

Preparation 110

C- (5-methylthiophen-2-yl) -methylamine Molecular Weight 127.23, MS (m / e) 127 (M ⁺ ).

Preparation 111

C- (3-methylthiophen-2-yl) -methylamine Molecular Weight 127.23, MS (m / e) 127 (M ⁺ ).

-105-

Preparation 112

5-Aminomethyl-1,3-dihydroindol-2-one

To a solution of 2-oxo-2,3-dihydro-1H-indole-5-carbonitrile (1.3 g) in methanol (30 mL) was added 10% PtO ₂ (0.200 g). The mixture was shaken under 50 psi of hydrogen overnight. The catalyst was removed by filtration and the mixture was dried over Na ₂ SO ₄ . The solution was concentrated to give a yellow solid (1.1 g). Molecular Weight 162, MS (m / e) 162 (M ^& lt ^{; +} & gt ^; ).

Preparation 113

2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

A solution of 3,3-dibromo-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile (10.5 g, 33.3 mmol) and zinc dust (22.0 g, 338.5 mmol) in acetic acid (250 mL) was stirred at room temperature for 45 minutes. The mixture was filtered through Celite and concentrated to dryness. The resulting oil was diluted with 300 mL of water and extracted with ethyl acetate. The combined extracts were washed with 1 N sodium hydroxide and brine, dried over MgSO ₄ , filtered and concentrated to give a white solid (1.9 g). Molecular Weight 158.

Preparation 114

3,3-dibromo-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

To a solution of 1H-indole-5-carbonitrile (5.0 g, 35.2 mmol) in tert-butanol (300 mL) was added pyridinium bromide perbromide (37.5 g, 105.6 mmol) over 10 min. Stir at room temperature for 2 hours. The mixture was concentrated to an orange oil. The resulting oil was diluted with 500 mL of water and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated to give a yellow solid (10.37 g). Molecular Weight 315.95, MS (m / e) 316 (M ⁺ +1).

Preparations 115 · · · · ··· · ··· · ···

6-amino-3H-benzoxazol-2-one

A solution of 6-nitro-3H-benzoxazol-2-one (8.4 g, 46.0 mmol) and tin (16.0 g) in concentrated hydrochloric acid (100 mL) was stirred at 60 ° C for 2 hours . The mixture was diluted with water, basified to pH 12 and extracted with ethyl acetate. The combined extracts were dried over Na ₂ SO ₄ , filtered and concentrated to give an orange solid (2.45 g). Molecular Weight 150, MS (m / e) 151 (M @ ⁺ +1).

Preparation 116

6-nitro-3 H -benzoxazol-2-one

A solution of 3H-benzoxazol-2-one (10.0 g) in concentrated HNO ₃ (100 mL) was stirred at 40 ° C. A precipitate formed and the reaction temperature rose. The mixture was cooled below 50 ° C in an ice bath. The mixture was diluted with ice water and the precipitate collected by filtration. The product was washed with water to give a white solid (8.4 g). Mp 239-241 ° C.

Preparation 117

5-Aminomethyl-1H-indole-2-carboxylic acid ethyl ester

A solution of 5-cyano-1H-indole-2-carboxylic acid ethyl ester (1.8 g, 8.4 mmol) and Bu ₄ N ⁺ BH ₃ "in methylene chloride (80 mL) was heated at reflux for 4 hours. . The mixture was concentrated to a brown oil, which was dissolved in 10% hydrochloric acid (50 mL) and heated to reflux for 1 hour. The mixture was extracted with ethyl acetate (removed) and the pH was neutralized. The aqueous phase was extracted with ethyl acetate. The combined extracts were dried over Na ₂ SO ₄ , filtered and concentrated to give a solid (0.920 g). Molecular Weight 218,258, MS (m / e) 218 (M ⁺ ).

Preparation 118

3,5-di-tert-butyl-4-hydroxybenzonitrile

A solution of 3,5-di-tert-butyl-4-hydroxybenzaldehyde oxime (3.0 g, 8.4 mmol) in acetic anhydride (6 mL) was heated at reflux for 2 hours. The mixture was cooled to 0 ° C and saturated sodium bicarbonate solution was added. The mixture was extracted with methylene chloride. The combined extracts were washed with saturated NaHCO ₃ , dried over Na ₂ SO ₄ , filtered and concentrated to give a solid. This was dissolved in diethyl ether and extracted with 1 N sodium hydroxide, then acidified to pH 1 and extracted with ethyl acetate. The extract was dried and concentrated to give a yellow solid, which was recrystallized from ethyl acetate-hexane to give white crystals (1.05 g). Molecular Weight 231, MS (m / e) 249 (M @ ⁺ + NH4 _@ ⁺ ).

Preparation 119

3,5-di-tert-butyl-4-hydroxybenzaldehyde oxime

A solution of 3,5-di-tert-butyl-4-hydroxybenzaldehyde (10.0 g,

42.67 mmol), NH ₂ OH.HCl (14.83 g, 213.3 mmol) and 40% KOH (80 mL) in methanol (100 mL) was stirred at room temperature over the weekend. The mixture was concentrated to remove methanol. The aqueous phase was acidified and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated to give a yellow solid (8.9 g). M.p. 122-124 ° C, MW 249, MS (m / e) 249 (M ⁺ ).

The compound of Preparation 120 was prepared according to the procedure of Preparation 119, but the 3,5-di-tert-butyl-4-hydroxybenzaldehyde was replaced with the corresponding aldehyde. The duration of the reaction is between 1 and 48 hours.

Preparation 120

4-hydroxy-3,5-dimethylbenzaldehyde oxide MW 165, MS (m / e) 166 (M ⁺ +1).

Preparation 121 • ·

-1084-aminomethyl-2,6-dimethylphenol

A solution of 4-hydroxy-3,5-dimethylbenzaldehyde oxime (1.0 g, 6.06 mmol) in acetic acid (30 mL) and zinc dust (4.0 g, 61.2 mmol) were stirred at ~ 60 ° C. for 2 hours. The mixture was filtered through Celite, basified with aqueous ammonium hydroxide and extracted with chloroform. The combined extracts were dried over MgSO ₄ , filtered and concentrated to give a foam (0.90 g). Molecular Weight 151, MS (m / e) 151 (M ^& lt ^{; +} & gt ^; ).

Preparation

1- (2-chlorophenyl) ethane-1,2-diol

To a vigorously stirred mixture of AD-mix (1.4 g) in water (5 mL) and tert-butanol (5 mL) at 0 ° C was added 1-chloro-2-vinylbenzene (0.140 g, 1.0 mmol). and the mixture was stirred at 0 ° C for 2 hours. Sodium sulfite (1.5 g) was added to the mixture and allowed to warm to room temperature over 1 hour. The mixture was extracted with methylene chloride. The combined extracts were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give a colorless oil (0.190 g). Molecular Weight 172,61, MS (m / e) 190 (M ^{+ +} 18).

Preparation 123

4-Chloro-5- (1-hydroxy-1-methylethyl) -thiophene-2-carboxylic acid amide

A solution of 4-chloro-5- (1-hydroxy-1-methylethyl) thiophene-2-carboxylic acid methyl ester (2.4 g) in liquid NH ₃ (20 mL) and methanol (10 mL) was stirred at room temperature in a sealed tube for 3 days. The solvent was evaporated to give a solid which was purified by flash chromatography on silica gel using 5% methanol in methylene chloride as eluent to give a light brown solid. This was triturated in diethyl ether to give a white solid (1.6).

g). Molecular Weight 219,71, MS (m / e) 237 (M ^{+ +} 18) 220 (M ⁺ +1).

The compound of Preparations 124 to 125 was prepared according to the procedure of Preparation 123, but the 4-chloro-5- (1-hydroxy-1-methyl-ethyl) -thiophene-2-carboxylic acid methyl ester was replaced with the corresponding ester. The duration of the reaction is between 1 and 72 hours.

Preparation 124

5- (1-Ethyl-1-hydroxypropyl) -thiophene-2-carboxylic acid amide

Molecular Weight 213.33, MS (m / e) 213 (M ⁺ ).

Preparation 125

3-Chloro-5- (1-hydroxy-1-methylethyl) -thiophene-2-carboxylic acid amide

MW 186.63, ^{Χ Η} NMR (CDC1 ₃₎ d 1.63 (6H, s), 6.85 (1H, s).

Preparation 126

4-Chloro-5- (1-hydroxy-1-methylethyl) -thiophene-2-carboxylic acid methyl ester

To a solution of diisopropylamine (6 mL, 38.9 mmol) in tetrahydrofuran (15 mL) at 0 ° C was added dropwise 2.5M nBuLi (16 mL), and the mixture was stirred at 0 ° C for 10 minutes. The mixture was cooled to -78 ° C and 4-chlorothiophene-2-carboxylic acid (3.0 g, 18.5 mmol) in tetrahydrofuran (15 mL) was added dropwise and stirred for 20 min before the addition. acetone (1.6 mL, 22.2 mmol) and allowed to warm to room temperature over 1 hour. The mixture was poured into 200 ml of water and extracted with diethyl ether. The aqueous phase was acidified to pH 4 with oxalic acid and extracted with methylene chloride. The combined extracts were washed with water, dried over MgSO ₄ , filtered and concentrated to give a solid. This was taken up in diethyl ether (100 mL) and treated with CH ₂ N ₂ at

-no-.: ...... ’.... *.

temperature 0 ° C. Quench the reaction with acetic acid, dilute with diethyl ether (300 mL) and wash with saturated NaHCO ₃ , water, and brine, dry over MgSO ₄ , filter and concentrate to give an oil which is purified by flash chromatography on silica gel 20% ethyl acetate / hexane gave a solid (2.42 g). Molecular Weight 234.72, MS (m / e) 234/236 (M ⁺ +1).

Preparation 126 was prepared according to Preparation 127-129, but the 4-chlorothiophene-2-carboxylic acid was replaced with the corresponding acid. The duration of the reaction is between 1 and 24 hours.

Preparation 127

5- (1-Hydroxy-1-methylethyl) -furan-2-carboxylic acid amide

MW 184.21; MS (m / e) 184 (M ^& lt ^{; +} & gt ^; ).

Preparation 128

5- (1-Ethyl-1-hydroxypropyl) -thiophene-2-carboxylic acid methyl ester

Molecular Weight 228.34, MS (m / e) 228 (M ⁺ ).

Preparation 129

3-Chloro-5- (1-hydroxy-1-methylethyl) -thiophene-2-carboxylic acid methyl ester

MW 234.70, ^{Τ Η} NMR (CDC1 ₃₎ d 1.62 (6H, s), 3.85 (3H, s), 6.84 (1H, s).

Preparation

5-Aminopentanoic acid ethyl ester

A solution of 5-aminopentanoic acid (1.06 g, 9.0 mmol) and thionyl chloride (20.0 mL) was stirred at room temperature for 2 hours. Evaporate the solvent and add ethanol (26.5 mL) and heat gently. After 2 hours, the solution was concentrated to give a solution.

A yellow solid (0.580 g) was obtained. MW 145.22, MS (m / e) 146 (M ⁺ +1).

Following the procedure of Preparation 130, the compound of Preparation 131 was prepared, but the 5-aminopentanoic acid was replaced with the corresponding acid. The duration of the reaction is between 1 and 24 hours.

Preparation 131

Trans -4-Aminomethyl-cyclohexanecarboxylic acid ethyl ester

Molecular Weight 185.28, MS (m / e) 186 (M ⁺ +1).

Preparation 132

Methyl ester of the acid

To the solution

Of 5- (1-hydroxy-1-methylethyl) furan-2-carboxydiisopropylamine (7.6 mL), 54.0 mmol) in tetrahydrofuran (20 mL) at 0 ° C was added 2.5 M n-butyllithium (22 mL, 54.0 mmol). The mixture was cooled to -78 ° C and a solution of furan-2-carboxylic acid (3.0 g, 27.0 mmol) in tetrahydrofuran (20 mL) was added dropwise and the mixture was stirred for 20 minutes and acetone was added. (2.4 mL, 32.0 mmol). The mixture was stirred at -78 ° C for 10 minutes and allowed to warm to room temperature over 1 hour. The mixture was poured into 200 ml of water, acidified to pH 2 with oxalic acid and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgSO ₄ , filtered and concentrated to give a solid (0.580 g). Molecular Weight 145.22, MS (m / e) 146 (M ⁺ +1).

Preparation

3-Chloro-4- (1-hydroxy-1-methylethyl) -benzonitrile To a solution of 3-chloro-4-cyanobenzoic acid methyl ester (2.0 g, 10.0 mmol) in tetrahydrofuran (30 mL) at - 40 ° C was added dropwise 3.0 M CH ₃ MgCl (8 mL, 22.0 mmol). The mixture was allowed to warm to room temperature over 1 hour. The reaction is quenched by the dropwise addition of 10 ml of methanol, poured into 200 ml of water, acidified with oxalic acid and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over MgSO ₄ , filtered and concentrated to give an oil (2.1 g). Molecular Weight 195,60, MS (m / e) 195/197 (M ⁺ ).

The compound of Preparation 134 was prepared according to the procedure of Preparation 133 but the 3-chloro-4-cyanobenzoic acid methyl ester was replaced with the corresponding ester. The duration of the reaction is between 1 and 24 hours.

Preparation 134

2-chloro-4- (1-hydroxy-1-methylethyl) -benzonitrile Molecular Weight 195,60, MS (m / e) 195/197 (M ⁺ ).

Preparation 135

2-Chloro-4-cyanobenzoic acid methyl ester

A solution of 4-bromo-2-chlorobenzoic acid methyl ester (3.1 g, 12.0 mmol), Zn (CN) ₂ (0.875 g, 7.0 mmol) and Pd (PPh ₃ ) ₄ (0.555 g, 48.0) mmol) in dimethylformamide (30 mL) was heated at 90 ° C overnight. The reaction mixture was poured into 200 ml of saturated sodium bicarbonate solution and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgSO ₄ , filtered and concentrated to give an oil which was purified by flash chromatography on silica gel eluting with 20% ethyl acetate in hexane to afford a white solid. (2.1 g). MW 195.61, MS (m / e) 195/197 (M ^& lt ^{; +} & gt ^; ).

Following the procedure of Preparation 135, the compound of Preparation 136 was prepared, but the 4-bromo-2-chloro-benzoic acid methyl ester was replaced with 3-chloro-4-trifluoromethanesulfonyloxy-benzoic acid methyl ester. The duration of the reaction is between 1 and 24 hours.

V · 9 9

9 · · 9

9 »·

-113Preparation 136

4-Trifluoroacetylbenzonitrile Molecular Weight 199.13, MS (m / e) 199 (M ⁺ ).

Preparation 137 (S) - (+) - Trans-1- (4-Aminomethyl-cyclohexyl) -ethanol

Prepared in analogy to Preparation 253 from (S) - (+) - (trans-4- (1-hydroxyethyl) cyclohexylmethyl) carbamic acid benzyl ester, which was obtained from (trans-4-acetylcyclohexylmethyl) -carbamic acid benzyl ester using (R). 2-methyl-CBS-oxazaborolidine monohydrate analogously to Preparation 254.

Preparation 138

1- (4-Aminomethylphenyl) -2,2,2-trifluoroethanol

To a solution of 4-trifluoroacetylbenzonitrile (0.840 g, 4.49 mmol) in tetrahydrofuran (20 mL) was added dropwise 1.0 M lithium aluminum hydride (15 mL, 14.8 mmol), the mixture was stirred at 0 ° C for 10 min. minutes and reflux for 30 minutes. The mixture was cooled to 0 ° C, 10 mL of methanol was added dropwise and diluted with chloroform (300 mL). The mixture was washed with water, dried over MgSO ₄ , filtered and concentrated to an oil which was purified by flash chromatography on silica gel using 5% methanol in methylene chloride as eluent to give a solid (0.350 g). Molecular Weight 205.20, MS (m / e) 205 (M ⁺ ).

Following the procedure of Preparation 138, the compound of Preparation 139 was prepared, but the 4-trifluoroacetylbenzonitrile was replaced with the corresponding nitrile. The duration of the reaction is between 30 minutes and 24 hours.

Preparation 139

7-Aminomethylchroman-4-ol Molecular Weight 179.24, MS (m / e) 179 (M ⁺ ).

· »» »»

-1144 *% * • · »»

Preparation 140

4-Oxochroman-7-carbonitrile

A solution of trifluoromethanesulfonic acid 4-oxochroman-7-yl ester (2.0 g, 6.80 mmol), Zn (CN) ₂ (0.476 g, 4.1 mmol) and Pd (PPh ₃ ) ₄ (0.314 g, 0.27) mmol) in dimethylformamide (20 mL) was heated at 80 ° C overnight. The reaction mixture was poured into 200 ml of a mixture of saturated NaHCO ₃ and water 1/1 and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgSO ₄ , filtered and concentrated to give an oil which was purified by flash chromatography on silica gel eluting with 30% ethyl acetate in hexane to afford a solid (m.p. 1.02 g). MS (m / e) 173 (M ^& lt ^{; +} & gt ^; ).

The compound of Preparation 141 was prepared according to the procedure of Preparation 140, but the trifluoromethanesulfonic acid 4-oxochroman-7-yl ester was replaced with the corresponding triflate. The duration of the reaction is between 30 minutes and 24 hours.

Preparation 141

3-Chloro-4-cyanobenzoic acid methyl ester Molecular weight 195.61, MS (m / e,%) 195 (M ⁺ , 25), 164 (100).

Preparation 142

4- (1-hydroxycyclobutyl) -benzonitrile

To a solution of 4-bromobenzonitrile (2.0 g, 10.99 mmol) in tetrahydrofuran (30 mL) at -100 ° C was added dropwise 2.5 M nBuLi (4.8 mL) and stirred at - 100 ° C. 100 ° C for 15 minutes. Cyclobutanone (0.965 g, 13.19 mmol) was added dropwise and stirred for 10 minutes and allowed to warm to room temperature over 1 hour. The mixture was poured into 200 ml of water and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgSO ₄ , filtered, and concentrated to an oil which was purified by flash chromatography on silica gel using 40% ethyl acetate in ethyl acetate. • ··· · · · · * · <

-1-11- · · ········

Hexane as eluent to give a clear oil (1.5 g). MW 173.23; MS (m / e) 173 (M ^& lt ^{; +} & gt ^; ).

Preparation 143

4- (1-hydroxyprop-2-ynyl) -benzonitrile

To a solution of 4-formylbenzonitrile (1.5 g, 10.0 mmol) in tetrahydrofuran (20 mL) at -78 ° C was added 0.5 M ethinylmagnesium bromide (26 mL, 13.0 mmol) dropwise. The mixture was stirred at -78 ° C for 30 minutes and allowed to warm to room temperature over 1 hour. The reaction mixture is cooled to 0 ° C, 10 ml of methanol are added, poured into 200 ml of water, acidified with oxalic acid and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgSO ₄ , filtered, and concentrated to an oil which was purified by flash chromatography on silica gel using 30% ethyl acetate in hexane as eluent to give a solid (1. 6 g). MW 157.18; MS (m / e) 157 (M ^& lt ^{; +} & gt ^; ).

Preparation 144

3-Chloro-4-trifluoromethanesulfonyloxy-benzoic acid methyl ester

To a solution of 3-chloro-4-hydroxybenzoic acid methyl ester (15.0 g, 80.0 mmol), triethylamine (20.2 g, 200 mmol) and DMAP (1.0 g, 8.0 mmol) in methylene chloride (200 mL). mL) was added dropwise triflic anhydride (17 mL, 100.0 mmol) at 0 ° C. The mixture was allowed to warm to room temperature and stirred for 4 hours. Dilute with methylene chloride (600 mL), wash with water, dry over MgSO ₄ , filter and concentrate to an oil which is purified by flash chromatography on silica gel eluting with 20% ethyl acetate in hexane to give an oil (20 mL). 9 g). MW 322.05, MS (m / e) 322 (M ^& lt ^{; +} & gt ^; ).

Preparation 145 • «• · · ·

-116 ·········

4- (1-azetidinyl) -benzonitrile

A mixture of 6.34 g (52.5 mmol) of 4-fluorobenzonitrile, 3.00 g (52.5 mmol) of azetidine, 7.26 g (52.5 mmol) of K ₂ CO ₃ and 50 ml of methylsulfoxide is heated to 60 ° C for 16 hours. The cooled mixture was diluted with 200 mL of water and extracted with EtOAc (2 x 150 mL). The combined organic extracts were washed with water (1 x 150 mL), brine (1 x 150 mL), dried (Na ₂ SO ₄ ) and evaporated to 5.65 g of a white solid. Trituration in hexane gave 3.85 g (56% yield) of the title compound as a white solid, mp 98-99 ° C. 1 H NMR (CDCl ₃ ) d 2.39-2.45 (2H, m), 3.96 (4H, t, J = 7Hz), 6.32 (2H, d, J = 9Hz), 7 41 (2H, d, J = 9Hz); AMPI MS (m / e) 159 (M ^& lt ^; + &^gt; +1).

Following the procedure of Preparation 145, the compounds of Formula I were prepared

Preparations 146 to 151, but azetidine se replaces corresponding amine Temperatures are in the range 90 to 115 ° C. For preparation amines used in preparations 54a and 54f, see S.H . Rosenberg a j. J. Copper. Chem. 1993, 36. 460 and S. . D. Goldberg, J. Am. Chem.

Soc. , 1939, 61, 3526. Temperatures range from 60 to 115 ° C.

Mass spectra were determined by AMPI.

Preparation

4- (3-Hydroxyazetidin-1-yl) -benzonitrile

M.p. 78 ° C, 1 H NMR (CDCl ₃ ) d 2.37 (1H, d, J = 7 Hz), 4.04 (4H, ABX characteristic feature, J _M = 8 Hz, J _M = 7 Hz, J _bx = 4 Hz), 4.77-4.88 (1H, m), 6.36 (2H, d, J = 8Hz), 7.41 (2H, d, J = 8Hz) MS (m / e) 175 (M @ ⁺ +1).

Preparation 147

4-Pyrrolidin-1-yl-benzonitrile

Mp 75-76 ° C, ^X 1 HNMR (CDCl ₃₎ d 2.01-2.04 (4H, m)

3.29-3.33 (4H, m), 6.49 (2H, d, J = 8Hz), 7.43 (2H, d J = 8Hz),

MS (m / e) 173 (M ^& lt ^; + &^gt; +1).

Preparation 148

-1174-piperidin-1-yl-benzonitrile ^X 1 HNMR (CDCl ₃₎ d 1.63-1.69 (6H, m), 3.29-3.33 (4H, m), 6.83 (2H, d, J = 9 Hz), 7.44 (2H, d, J = 9 Hz).

Preparation 149

4-Morpholin-4-yl-benzonitrile

Mp 81-82 ° C, ^X 1 HNMR (CDCl ₃₎ d 3.25-3.27 (4H, m), 3.82-3.85 (4H, m), 6.85 (2H, d, J = 9 Hz), 7.49 (2H, d, J = 9 Hz), MS (m / e) 189 (M ^& lt ^; + &^gt; +1).

Preparation 150

(1,4-dioxa-8-aza-spiro [4,5] dec-8-yl) -benzonitrile, m.p. 133-134 ° C. Analysis for C ₁₄ H ₁₆ N ₂ O ₂ calculated: C 68.83 H, 6.60; N, 11.47. Found: C, 69.21; H, 6.64; N, 11.61.

Preparation

4 - [(2-hydroxy-2-methyl-propyl) -methyl-amino] -benzonitrile ^X 1 HNMR (CDCl ₃₎ d 1.27 (6H, s), 1.56 (1H, s), 3.09 (3H, s 3.39 (2H, s), 6.79 (2H, d, J = 9Hz), 7.44 (2H, d, J = 9Hz), MS (m / e) 205 (M ⁺ +1) ).

Preparation

1- [4- (Aminomethyl) phenyl] azetidine

To a solution of 2.00 g (12.6 mmol) of the compound of Preparation 145 in 50 mL of tetrahydrofuran was added portionwise 479 mg (12.6 mmol) of lithium aluminum hydride. After the addition was complete, the mixture was stirred at room temperature for 4 hours. Subsequently, 2 ml of water, 2 ml of 15% aqueous sodium hydroxide solution and 6 ml of water are added to the mixture. The precipitate was removed by filtration and sufficient washing with tetrahydrofuran. The filtrate was dried (Na ₂ SO ₄ ) and evaporated to give a yellow solid, which was purified by flash chromatography using EtOAc then 76: 20: 4 CHCl ₃ : MeOH: conc. NH ₃ (aq) as eluent to give 1.22 g of a semi-solid. Trituration in hexane yields the following:

-, - _n · · »· ......

-Him- "······· ·· ·· ·· ··

815 mg (40% yield) of the title compound as a yellow solid, mp 58-60 ° C. ¹ H NMR (CDCl ₃ ) d

1.60 (2H, s), 2.29-2.37 (2H, m), 3.73 (2H, s), 3.83 (4H, t,

J = 7Hz), 6.42 (2H, d, J = 8Hz), 7.13 (2H, d, J = 8Hz).

Preparation 55 yields compounds 153-158, but the compound of Preparation 145 is replaced with the corresponding substrate. Mass spectra were determined by AMPI.

Preparation

1- (4-aminomethylphenyl) -azetidin-3-ol 1 H NMR (CDCl 3) d 2.65 (3H, broad s), 3.54-3.61 (2H, m), 3.70 (2H, s) 4.08-4.12 (2H, m), 4.68-4.79 (1H, m), 6.40 (2H, d,

J = 8Hz), 7.09 (2H, d, J = 8Hz) MS (m / e) 162 (M ⁺ + 2-18 (H ₂ O)).

Preparation

1- (4-Aminomethyl-phenyl) -azetidin-3-ol

M.p. 110 ⁰ C ^X H NMR (CDC1 ₃₎ d 1.87 (2 H, s), 1.96-1.99 (4H, m), 3, 25 (4H, t, J = 7) Hz), 3.73 (2H, s) 6.52 (2H, d, J = 8Hz), 7.15 (2H , d, J = 8Hz) MS (m / h) 160 (M ^& lt ^; + & gt ^; + 2-18).

Preparation 155

4-Piperidin-1-yl-benzylamine

Mp 108-110 ° C, ^X 1 HNMR (CDCl ₃₎ d 1.52-1.58 (2H, m)

1.68-1.72 (4H, m), 1.80 (2H, s), 3.08-3.12 (4H, m), 3.76 (2H,

s), 6.89 (2H, d, J = 9Hz), 7.17 (2H, d, J = 9Hz).

Preparation 156

4-Morpholin-4-yl-benzylamine

Melting point to 54 ° c, 1 H NMR (CDCl ₃ ) d 1.51 (2H, s), 3.11-3.14 (4H, m) , 3.78 (2H, s), 3.83-3.86 (4H, m), 6.88 (2H, d, J = 8 Hz), 7.22 (2H, d, J = 8 Hz).

Preparation 157

TTQ · J · LJ7 · «········································

4- (1,4-dioxa-8-aza-spiro [4,5] dec-8-yl) -benzylamine, m.p. 107-111 ° C. 1 H NMR (CDCl ₃ ) d 1.81 (4H, t, J = 6 Hz), 3.07 (2H, broad s), 3.29 (4H, t, J = 6 Hz), 3.80 (2H, s), 3.98 (4H, s), 6, 89 (2H, d, J = 8Hz), 7.22 (2H, d, J = 8Hz).

Preparation 158

1- [(4-aminomethyl-phenyl) methylamino] -2-methylpropan-2-ol ^X 1 HNMR (CDCl ₃₎ d 1.26 (6H, s), 1.97 (3H, br s), 2.97 ( 3H, s), 3.25 (2H, s), 3.78 (2H, s), 6.80 (2H, d, J = 9Hz), 7.20 (2H, d, J = 9Hz) .

Preparation 159

2- (4-Fluorophenoxy) -3-pyridinecarboylic acid methyl ester

A mixture of 20.0 g (89.6 mmol) of 2- (4-fluorophenoxy) -3-pyridinecarboxylic acid (for preparation see: FJ Villani et al., J. Med. Chem., 1975, 18.3), 300 ml of methanol and 5.5 ml of concentrated sulfuric acid are heated to reflux for 2 hours. The cooled mixture was poured into 500 ml of ice cold saturated aqueous sodium bicarbonate solution and the resulting precipitate was filtered off, washed with water and dried under reduced pressure to give 12.9 g (yield 64%) of the title compound as a white solid. m.p. 97-99 ° C. Analysis for C ₁₃ H ₁₀ NO ₃ F calculated: C

H, 4.08; N, 5.67. Found: C, 62.80; H, 4.08; N, 5.50.

Preparation 160

2- (4-fluorophenoxy) -3-pyridine-methanol

A solution of 10.00 g (40.45 mmol) of the compound of Preparation 56 in 200 mL of anhydrous toluene was cooled to -78 ° C and treated dropwise with 84.95 mL (84.95 mmol) of a 1 M solution of diisobutylaluminum hydride in CH ₂ Cl _{2 2} . After the addition was complete, 200 mL of water was added followed by 200 mL of EtOAc and the mixture was allowed to warm to room temperature. After adjusting the aqueous layer to pH 4 with aqueous solution 1 · ·

The organic layer is separated and combined with 200 ml of backwashing of the aqueous layer. The organic extracts were washed with saturated aqueous sodium bicarbonate solution, brine, dried (Na ₂ SO ₄ ) and evaporated to give 9.00 g (yield 90%) of the title compound as an off-white solid, m.p. mp 70-72 ° C. ¹ H NMR (CDCl ₃ ) d 1.59 (1H, s), 4.84 (2H, d, J = 6Hz), 6.99-7.13 (5H, m), 7.76-7, 80 (1H, m), 8.07 (1H, dd, J = 2.5Hz).

Preparation 161

2- (4-fluorophenoxy) -3-pyridinecarboxaldehyde

A mixture of 932 mg (4.25 mmol) of the compound of Preparation 57, 2.00 g (23.0 mmol) of manganese dioxide and 30 ml of benzene was heated at reflux for 3 hours with water separation. The cooled mixture was filtered, evaporated to give a white solid and purified by flash chromatography using 15% EtOAc in hexane as eluent to give 735 mg (80% yield) of the title compound as a white solid, m.p. Mp 61-62 ° C. ¹ H NMR (CDCl ₃ ) d 7.08-7.21 (5H, m), 8.19-8.32 (2H, m), 10.55 (1H, s).

Preparation 162

3- [2- (4-Fluorophenoxy) -3-pyridinyl] -3-hydroxypropenoic acid tert-butyl ester

At -78 ° C, 115.3 mL (115.3 mmol) of a solution of 1 M bis (trimethylsilyl) amide in tetrahydrofuran was treated dropwise with 15.43 mL (13.39 g, 115.3 mmol) of tert-butyl acetate. After the addition was complete, the mixture was stirred for 15 minutes and then treated with a solution of 9500 g (38.43 mmol) of the compound of Preparation 56 in 50 mL of THF. After the addition was complete, the mixture was stirred for 15 minutes and then 230 mL of aqueous 1 N hydrochloric acid was added. After warming to room temperature, the organic layer was extracted with ether (2 x 500 mL) and combined.

-121-

organic layers wash with i saturated water solution bicarbonate sodium (i X 100 ml), solution chloride sodium hydroxide (1 x 200 ml), dried (Na ₂ SO ₄ ) a evaporates, , thereby 13.8 g light yellow substances. Cleaning fast Chromatography use 15 to 85% ether in hexane as eluent is obtained 11.7 g semi-solids, which is

triturated in hexane to give 6.124 g (48% yield) of the title compound as a white solid,

melting 87 to 89 ° C . 1 H NMR (CDC1 ₃ ) d 1.54 (9H, s), 6.12 (1 H, s), 7,01-7,16 (5H, m) 8.14 (1H, dd, J = 2 5 Hz) 8.30 (1 H, dd, J = 2.8 Hz) 12.99 (1 H, s). NMR also proves presence <10% tautomer keto. After standing AFTER 12 days with mother liquor recrystallize i pulverize se v hexane, thereby others are obtained

2.21 g (17% yield) of the title compound.

Preparation 163

Α - [(2-chlorophenyl) methyl] -2- (4-fluorophenoxy) -β-οχο-3-pyridinepropanoic acid tert-butyl ester

The sodium hydride obtained after washing with 28.9 mg (0.604 mmol) of 50% sodium hydride dispersion in mineral oil with pentane (3 x 5 mL) was suspended in 5 mL of THF, cooled to 0 ° C and treated dropwise with 200 mL solution. mg (0.604 mmol) of the compound of Preparation 59 in 5 mL of THF. After stirring for 15 minutes, 2-chlorobenzyl bromide (0.078 mL, 124 mg, 0.604 mmol) was added and the mixture was allowed to warm to room temperature, stirred for 4 hours and then heated at reflux for 16 hours. The cooled mixture was partitioned between 100 mL of saturated aqueous NH ₄ Cl solution and 200 mL of EtOAc. The separated organic layer was washed with saturated aqueous sodium bicarbonate solution (100 mL), brine (100 mL), dried (Na ₂ SO ₄ ) and evaporated to an oil. Purification by flash chromatography using 60% CH ₂ C1 ₂ in hexane as eluent gave 226 mg (82% yield) of the title compound as an oil. ³ 1 HNMR (CDCl ₃₎ d 1.54 (9H, s), 3.32-3.52 «• · · · · · • • ·

-122- ............ (2H, m), 5.09 (1H, dd, J = 7.8 Hz), 7.02-7.30 (9H) m), 8.05 (1H, dd, J = 2.8 Hz), 8.22 (1H, dd, J = 2.5 Hz). NMR also demonstrates the presence of <10% onol tautomer.

The compound of Preparations 164-168 was prepared according to the procedure of Preparation 163, but the 2-chlorobenzyl bromide was replaced with the corresponding benzyl halide. For preparations 165-168, one equivalent of KI is added immediately after the addition of the benzyl halide. All compounds are oils. Mass spectra were determined by thermospray method.

Preparation 164

2- (4-Fluorobenzyl) -3- [2- (4-fluorophenoxy) -pyridin-3-yl] -3-oxopropionic acid tert-butyl ester

MS (m / e) 440 (M ⁺⁺ 1), 1 H NMR (CDCl 3) d 1.27 (9H, s), 3.17-3.44 (2H, m), 4.80 (1H, dd, J = 7.8 Hz), 6.85-7.30 (9H, m), 8.08 (1H, dd, J = 2.8 Hz), 8.23-8.25 (1H, m).

Preparation 165

3- [2- (4-Fluorophenoxy) -pyridin-3-yl] -3-oxo-2- (4-trifluoromethyl-benzyl) -propionic acid tert-butyl ester

MS (m / e) 490 (M ⁺ l), ^X 1 HNMR (CDCl ₃₎ d 1.24 (9H, s), 3.36 (2H,

ABX pattern, J = 14 Hz _M J _M = 7Hz, J _BX = 8 Hz), 4.83 (1H, dd, J = 7.8 Hz), 6.99-7.50 (9H, m 8.02-8.22 (2H, m).

Preparation 166

3- [2- (4-Fluorophenoxy) -pyridin-3-yl] -3-oxo-2- (4-trifluoromethoxy-benzyl) -propionic acid tert-butyl ester

MS (m / e) 506 (M ⁺⁺ 1), ⁴ H NMR (CDCl ₃ ) d 1.25 (9H, s), 3.32-3.46 (2H, m), 4.82 (1H, t, J = 7Hz), 7.03-7.28 (9H, m), 8.09 (1H, dd, J = 2.8Hz), 8.24 (1H, dd, J = 2.5) Hz).

Preparation 167

2- (3,5-Difluorobenzyl) -3- [2- (4-fluorophenoxy) -pyridin-3-yl] -3-oxopropionic acid tert-butyl ester

-123 -...

MS (m / e) 458 (M ⁺ +1) ³ H NMR (CDCl ₃ ) d 1.25 (9H, s), 3.28 (2H,

ABX characteristic, δ = 14 Hz, J _M = 7 Hz, J _BX = 8 Hz), 4.79 (1H, dd, J = 7.8 Hz), 6.55-7.18 (8H, m ), 8.09 (1H, dd, J = 2.8Hz,

8.23 (1H, dd, J = 2.4Hz).

Preparation 168

3- [2- (4-Fluorophenoxy) -pyridin-3-yl] -3-oxo-2- (2,4,6-trifluorobenzyl) -propionic acid tert-butyl ester MS (m / e) 476 (M ⁺⁺ ) 1), ¹ HNMR (CDCl ₃ ) d 1.22 (9H, s), 3.22-3.35 (2H, m), 4.82 (1H, J = 8 Hz), 6.56 (2H, m, t, J = 8Hz), 7.02-7.12 (5H, m), 8.11 (1H, dd, J = 2.8Hz), 8.22 (1H, dd, J = 2.5) Hz).

Preparation 169

4- (1-hydroxy-1-methylethyl) -benzenepropanoic acid

A mixture of KOH (12.61 g, 224.7 mmol), water (73 mL) and ethanol (425 mL) was combined with 3- [4- (1-oxoethyl) phenyl] propionic acid ethyl ester (15.00 g, 68.10 mmol) (preparation). see E. Marechal,

J.P. Quere, Bull. Chem. Soc. Fr, 1971, 2227) and the resulting mixture was stirred at room temperature for 2 hours. The mixture is concentrated and the residue is dissolved in 100 ml of water, cooled to 0 ° C and acidified with concentrated aqueous hydrochloric acid. The precipitate was filtered and recrystallized from methanol / water to give 10.11 g (77% yield) of 3- [4- (1-oxoethyl) phenyl] propionic acid as a white solid, m.p. 118-119 °. C. H, 6.06. Found: C, 68.74; H, 6.29.

A solution of the above acid (5.000 g, 26.01 mmol) in tetrahydrofuran (500 mL) was cooled to -17 ° C and a 3 M solution of methylmagnesium iodide in ether (21.67 mL, 65.03 mmol) was added dropwise. Additional Grignard reagent solution was added in three portions, 5, 5 and 10 mL, over several hours, monitoring the progress of the reaction by NMR. The mixture was cooled to -30 ° C, 200 mL of saturated aqueous NH ₄ Cl solution was added and allowed to warm to room temperature.

• • •

-124- ···· ···· .e .. .. ..

The aqueous layer was adjusted to pH 1 with aqueous 1 N hydrochloric acid, and the organic layer was extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine (3 x 500 mL), dried (Na ₂ SO ₄ ) and evaporated to give 5.62 g of a yellow solid. Recrystallization from hexane / EtOAc gave 2.20 g (40% yield) of the title compound as a light yellow solid, mp 92-94 ° C. ¹ H NMR (CDCl ₃ ) d 1.36 (6H, s), 2.47 (2H, t, J = 7Hz), 2.74 (2H, t, J = 7Hz), 4.90 (1H , s), 7.21 (4H, AB quartet, J = 7Hz),

12.09 (1 H, s).

Preparation 170

N-methoxy-N-methyl-4-fluorobenzenepropionamide

Suspension 10.00 g (59.46 mmol) of 3- (4-fluorophenyl) propionic acid, 12.54 g (65.41 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, 6.381 g (65.41 mmol) mmol) of N, O-dimethylhydroxylamine hydrochloride in 300 mL of CH ₂ Cl ₂ was cooled to 0 ° C and treated with 18.23 mL (13.23 g, 130.8 mmol) of triethylamine. The mixture was stirred for 16 hours with gentle warming to room temperature. The mixture was concentrated and the residue was partitioned between 300 mL EtOAc and 200 mL aqueous 1 N hydrochloric acid. The separated organic layer was washed with aqueous 1 N hydrochloric acid solution (1 x 100 mL), saturated aqueous sodium bicarbonate solution (2 x 200 mL), brine (1 x 100 mL), dried (Na ₂ SO ₄ ) and evaporated. to give 9.56 g (yield 76 the title compound as an oil. ^'L 1 HNMR (CDCl ₃₎ d 2.70 (2H, t,

J = 8Hz), 2.91 (2H, t, J = 8Hz), 3.15 (3H, s), 3.59 (3H, s),

6.92-6.97 (2 H, m), 7.15-7.19 (2 H, m), APCI MS (m / e) 212 (M ⁺ +1).

Preparation 170 was used to prepare compounds 171-180, but 3- (4-fluorophenyl) propionic acid was replaced with the corresponding carboxylic acid. The carboxylic acid in Preparation 174 is the compound of Preparation 163,

-125 while all other carboxylic acids are commercially available. Mass spectra were determined by the APCI method.

Preparation 171

N-methoxy-N-methyl-3-phenylpropionamide Anal. Calcd for C _{1: 1} H _{1 S} NO ₂ : C 68.37, H 7.82, N 7.25. Found: C 68.65, H 8.11, N, 7.18.

Preparation 172

N-methoxy-2, N-dimethyl-3 -fenylpropionamid ^X 1 HNMR (CDCl ₃₎ d 1.16 (3H, d, J = 7Hz), 2.83-3.28 (2H, ABX pattern,? = 13 Hz, Hz, J _BX = 8 Hz), 3.08-3.18 (1H, m), 3.14 (3H, s), 3.48 (3H, s), 7,15-7, 32 (5H, m); MS (m / e) 208 (M ^& lt ^; + &^gt; +1).

Preparation 173

N-methoxy-N-methyl-3-phenylbutyramide ¹ H NMR (CDCl 3) d 1.31 (3H, d, J = 7 Hz), 2.59-2.78 (2H, m), 3.14 (3H) s, 3.32-3.44 (1 H, m), 3.58 (3H, s), 7.14-7.32 (5 H, m), MS (m / e) 208 (M ⁺⁺ ) l).

Preparation 174

3- [4- (1-hydroxy-methylethyl) phenyl] -N-methoxy-N-methylpropionamide ^X 1 HNMR (CDCl ₃₎ d 1.56 (6H, s), 1.71 (1H, s) 2.72 (2H, t, J = 8)

Hz), 2.93 (2H, t, J = 8 Hz), 3.17 (3H, s), 3.60 (3H, s), 7.30 (4H, AB quartet, J = 8 Hz), MS (m / e) 234 (m ⁺ + L-18 (H ₂ O)).

Preparation 175

N-methoxy-N-methyl-2-phenylacetamide 1 H NMR (CDCl ₃ ) d 3.18 (3H, s), 3.54 (3H, s), 3.78 (2H, s),

7.20-7.34 (5H, m); MS (m / e) 180 (M ^& lt ^; + &^gt; +1).

Preparation 176 »· · · · ·

-127-. · ·. ·· ··

^{N-methoxy-N-methyl-2-phenoxy-X} 1 HNMR (CDCl ₃₎ d 3.22 (3H, s), 3.74 (3H, s), 4.79 (2H, s)

6.92-6.97 (3H, m); 7.24-7.29 (2H, m); MS (m / e) 196 (M @ ⁺ +1).

Preparation 177

N-methoxy-N-methyl-3-phenyl-acrylamide, mp 40-42 ° C, ^X 1 HNMR (CDCl ₃₎ d 3.30 (3H, s), 3.76 (3H, s), 7.02 (1H d, J = 16 Hz), 7.34-7.39 (3H, m), 7.55-7.57 (2H, m), 7.72 (1H, d, J = 16 Hz), MS (m / e) 192 (M @ ⁺ +1).

Preparation 178

Benzofuran-3-carboxylic acid methoxymethylamide 1 H NMR (CDCl 3) d 3.41 (3H, s), 3.82 (3H, s), 7.24-7.43 (2H, m),

7.50 (1H, d), 7.59 (1H, dd, J = 1.8 Hz), 7.66 (1H, dd, J = 1.8)

Hz), MS (m / e) 206 (M @ ⁺ +1).

Příprvá 179

1H-Indole-3-carboxylic acid methoxymethylamide, m.p. 136-137 ° C. Anal. Calcd for C ₁₁ H ₁₂ N ₂ O ₂ : C

H, 5.94; N, 13.72. Found: C, 64.97; H, 5.81; N, 13.65.

Preparation 180

2- (2-chlorophenoxy) -N-methoxy-N-methylacetamide ^X H NMR (CDCl3) d 3.21 (3H, s), 3.74 (3H, s), 4.88 (2H, s), 6 89-6.93 (2H, m), 7.15-7.19 (1H, m), 7.34-7.36 (1H, m).

Preparation 181

1- [2-fluoro-3-pyridinyl] -3- (4-fluorophenyl) -1-propanone

A solution of 5.90 mL (4.56 g, 45.0 mmol) of diisopropylamine in 20 mL of tetrahydrofuran was cooled to -78 ° C and treated dropwise with 18.0 mL (45.0 mmol) of a 2.5 M solution. n-butyllithium in hexane. Once the addition is complete, the mixture is stirred for 0.5 hour at -78 ° C and then 3.88 ml (4.37 g, 45.0 mmol) of freshly distilled 2-fluoro is added dropwise.

-127pyridine. After the addition was complete, the resulting yellow suspension was stirred at -78 ° C for 0.5 h. A solution of 9.51 g (45.0 mmol) of the compound of Preparation 62 in 200 mL of tetrahydrofuran was added dropwise. The mixture was stirred for 16 hours with slow warming to room temperature as the dry ice / acetone bath melted. 50 ml of aqueous 1 N hydrochloric acid solution were added to the mixture, and THF was removed by partial evaporation. The residue was partitioned between EtOAc (300 mL) and aqueous 1 N hydrochloric acid solution (100 mL). The separated organic layer was washed with aqueous 1 N hydrochloric acid solution (100 mL), saturated aqueous sodium bicarbonate solution (100 mL), brine (100 mL), dried (Na ₂ SO ₄ ) and evaporated to give a solid. , 6 g of yellow oil. Purification by flash chromatography using 25% EtOAc in hexane as eluent gave 7.11 g of a yellow oil which solidified on standing. Trituration in hexane gave 6.87 g (62% yield) of the title compound as a pale yellow solid, mp 73-74 ° C. ¹ H NMR (CDCl ₃ ) d 3.02 (2H, t, J = 7Hz), 3.29-3.26 (2H, m), 6.91-6.99 (2H, m), 17-7.33 (3H, m), 8.29-8.38 (2H, m) APCI MS (m / e) 248 (M ^& lt ^; + &^gt; +1).

The compound of Preparation 182-190 was prepared according to the procedure of Preparation 181, but the compound of Preparation 170 was replaced with the corresponding N-methoxy-N-methylamide or ester. For preparations 185 and 191, an additional equivalent is used

Of 2-fluoro-3-lithiopyridine prepared in situ. The products are purified by direct grinding and / or flash chromatography. Mass spectra were determined by the APCI method.

Preparation 182

1- (2-fluoropyridin-3-yl) -3-phenylpropan-1-one 1 H NMR (CDCl ₃ ) d 3.05 (2H, t, J = 7 Hz), 3.32-3.64 (2H, m), 7.17-7.33 (6H, m), 8.29-8.38 (2H, m).

Preparations 183 · · · _{v v v v v v v v v v v v v v v v v v v} v

-128- ·· ·· ·· ··

1- (2-fluoropyridin-3-yl) -2-methyl-3-phenylpropan-1-one ^X H NMR _(CDCl3) d 1.18 (3H, d, J = 7Hz), 2.88 (2H ABX characteristic, λ = 14 Hz, J _M = 6 Hz, J _bx = 8 Hz), 3.63-3.72 (1Η, m), 7.14-7.29 (6H, m), 8 14-8.19 (1H, m); 8.33-8.35 (1H, m); MS (m / e) 244 (M @ ⁺ +1).

Preparation 184

1- (2-Fluoropyridin-3-yl) -3-phenylbutan-1-one M.p. 51-53 ° C. Analysis for C ₁₅ H ₁₄ FNO calculated: C

H, 6.00; N, 5.76. Found: C, 73.82; H, 5.83; N, 5.90.

Preparation 185

1- (2-Fluoropyridin-3-yl) -3- [4- (1-hydroxy-1-methylethyl) phenyl] propan-1-one

1 H NMR (CDCl 3) d 1.56 (6H, s), 3.03 (2H, t, J = 7Hz), 3.31-3.36 (2H, m), 7.20-7.25 ( 2H, m), 7.30-7.34 (1H, m), 7.40-7.42 (2H,

m), 8.30-8.38 (2H, m) MS (m / e) 270 (M ⁺ + L-18 (H ₂ O)).

Preparation 186

1- (2-fluoropyridin-3-yl) -2-phenylethanone 1 H NMR (CDCl 3) d 4.31 (2H, s), 7.19-7.34 (6H, m), 8.27-8.37 MS (m / e) 216 (M ^& lt ^; + &^gt; +1).

Preparation 187

1- (2-Fluoropyridin-3-yl) -2-phenoxyethanone

M.p. 82-83 ° C, 1 H NMR (CDCl ₃ ) d 5.21 (2H, d, J = 3 Hz), 6.91-7.01 (3H, m), 7.27-7.31 ( 2H, m), 7.37-7.40 (1H, m), 8.41-8.45 (2H, m), MS (m / e) 232 (M ⁺ +1).

Preparation 188

2- (2-chlorophenoxy) -1- (2-fluoropyridin-3-yl) -ethanone, mp 84-86 ° C ^{Τ Η} NMR (CDC1 ₃₎ d 5.34 (2H, d, J = 3Hz) 6.85-7.45 (5H, m); 8.42-8.50 (2H, m); MS (m / e) 266.268 (M ⁺ +1).

-129Preparation 189

1- (2-fluoropyridin-3-yl) -3-phenyl-propenone, mp 83 to 84 ° C, ^X 1 HNMR (CDCl ₃₎ d 7.34-7.37 (1H, m)

7.41-7.47 (4H, m), 7.62-7.65 (2H, m), 7.90 (1H, d, J = 15Hz),

8.29- 8.31 (1H, m); 8.38-8.41 (1H, m).

Preparation 190

Benzofuran-3-yl- (2-fluoropyridin-3-yl) -methanone, m.p. 110-111 ° C. Anal _. Calcd for C ₁₄ H ₈ FNO ₂ : C 69.71, H 3.34, N 5.81. Found: C 69.84, H 3.36, N 6.12.

Preparation 191 (2-Fluoropyridin-3-yl) - (1H-indol-3-yl) -methanone M.p. 195-198 ° C. Anal _. Calcd for C ₁₄ H ₉ FN ₂ O ₂ : C 70.00, H 3.78, 11.66. Found: C 69.69, H 3.60, N 11.59.

Preparation 192

1- (2-fluoropyridin-3-yl) -ethanone ^{: 1} H NMR (CDCl ₃ ) d 2.67 (3H, d, J = 0.5 Hz), 7.30-7.33 (1H, m),

8.30-8.38 (2 H, m).

Preparation 193

1- (2-fluoropyridin-3-yl) -2- (methylphenylamino) -ethanone 1 H NMR (CDCl ₃ ) d 3.10 (3H, s), 4.72 (2H, d, J = 3 Hz), 6 63.6.74 (3H, m), 7.18-7.24 (2H, m), 7.32-7.36 (1H, m), 8.30-8.42 (2H,

m), MS (m / e) 245 (M @ ⁺ +1).

Preparation 194

1- [2- (4-fluorophenoxy) -3-pyridinyl] -ethanone 1 H NMR (CDCl ₃ ) d 2.75 (3H, s), 7.07-7.12 (5H, m), 8.20 ( 1H, dd, J = 2.7Hz), 8.24 (1H, dd, J = 2.5Hz).

Preparation 195

1- [2- (3-pyridinyloxy) -3-pyridinyl] -ethanone

-130 ° C NMR (CDCl ₃ ) d 2.76 (3H, s), 7.13-7.15 (1H, m), 7.39 (1H, dd, J = 5.9 Hz), 7, 53-7.56 (1 H, m), 8.22-8.24 (2 H, m), 8.50-8.53 (2 H, m).

Preparation

-fluoro-α-phenyl-3-pyridinmethanol 1 H NMR (CDCl ₃ ) d 2.61 (1H, broad s), 6.03 (1H, s), 7.14-7.38 (6H, m), 7 , 97-8.08 (2 H, m).

Preparation 197 (2 - fluoro-3-pyridinyl) phenyl-methanone ^T H NMR (CDCl3) d 7.32-7.38 (1H, m), 7.47-7.50 (2H, m)

7.61-7.67 (1H, m), 7.78-7.82 (2H, m), 7.98-8.07 (1H, m),

8.38-8.42 (1 H, m).

Preparation 198

4- (1-hydroxy-1-methylethyl) -benzonitrile

To a stirred suspension of anhydrous cerium chloride (3.8 g, 16 mmol) in 20 mL of anhydrous tetrahydrofuran was slowly added dropwise at 0 ° C a solution of 3.0 M methylmagnesium chloride in tetrahydrofuran (10 mL, 31 mmol) dropwise. The mixture was stirred at 0 ° C for 30 minutes and then a solution of methyl 4-cyanobenzoate (2.0 g, 12.4 mmol) in 20 mL of anhydrous tetrahydrofuran was slowly added dropwise. The mixture was stirred for an additional 30 minutes at 0 ° C and then 2.0 M acetic acid (~ 10 mL) was added slowly dropwise. The mixture was poured into 200 mL of water and extracted with ethyl acetate (2 x 200 mL). The organic extracts were combined, washed with sodium bicarbonate solution (1 x 40 mL), water (2 x 40 mL), brine (1 x 40 mL), dried (MgSO ₄ ), and concentrated under reduced pressure to a residue. oil. This oil was absorbed into silica gel (10 g) and washed with ethyl acetate / hexane (1: 2, 1500 mL). Concentration of the washings under reduced pressure gave 1.75 g (88%) of 4- (1-hydroxy-1-methylethyl) -benzonitrile as a clear liquid.

-131 «·« · · ··· · ·

• f c · c c oleje oleje oleje oleje oleje oleje oleje oleje oleje oleje oleje. ¹ H NMR (CDCl ₃ ) δ 7.60 (m, 4H),

%): 161 (M ^& lt ^{; +} & gt ^; , 2), 146 (100).

1.58 (m,

6C), GC-MS (m / e,

Preparation 199

-fluoro-5-hydroxybenzonitrile

To a solution of 2-fluoro-5-methoxybenzonitrile (4.0 g, 26.5 mmol) in CH ₂ C1 ₂ (100 mL) at 0 ° C was added 1.0 M BBr ₃ (29 mL, 29 mmol ), warm to room temperature and stir overnight. The mixture was poured into 300 ml of ice water and stirred for 10 minutes. It is then poured into 100 ml of methylene chloride and the layers are separated. The mixture was washed with water, dried over MgSO ₄ , filtered and concentrated to give a solid (2.8 g). MW 137.12; MS (m / e) 137 (M ^& lt ^{; +} & gt ^; ).

Following the procedure of Preparation 199, the compound of Preparation 200 was prepared, but the 2-fluoro-5-methoxybenzonitrile was replaced with the corresponding ether. The duration of the reaction is between 1 and 24 hours.

Preparation 200

3-hydroxy-N, N-dimethylbenzamide

MW 165.21, MS (m / e),%) 165 (M ⁺ , 30), 121 (100).

Preparation 201

- fluoro-5-methoxybenzonitrile

A solution of 2-chloro-1-fluoro-4-methoxybenzene (10.4 g, 65.0 mmol), CuCN (6.4 g, 71.0 mmol) and N-methylpyrrolidinone (100 mL) was heated to reflux. condenser for 18 hours. An additional 2.3 g of CuCN was added and the mixture was heated to reflux for 40 hours. The mixture was poured into 300 ml of ice water and stirred for 10 minutes. It is then poured into 100 ml of methylene chloride and the layers are separated. The mixture was washed with water, dried over MgSO ₄ , filtered, and concentrated to give a residue.

-132 solids (2.8 g) (M ⁺ ).

Molecular Weight 137.12, MS (m / e) 137

Preparation 202

1,4-dioxa-spiro [4,5] decane-8-carbonitrile

To a solution of 1,4-dioxa-spiro [4.5] decan-8-one (2.0 g, 12.8 mmol) and tosylmethylisocyanate (5.0 g, 25.6 mmol) in dimethylformamide (25 mL) was added. at 0 ° C, 1.0 M tBuOK in tert. butanol (25.6 mL) and stirred at 0 ° C for 1 hour and at room temperature overnight. The mixture was diluted with water and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgSO ₄ , filtered and concentrated to give a solid which was purified by flash chromatography on silica gel using 30% ethyl acetate in hexane as eluent to give a solid (m.p. 1.45 g). Molecular Weight 167,209, MS (m / e) 168 (M ⁺ +1).

Preparation 203

C- (4,5-dichlorothiophen-2-yl) -methylamine

To a stirred suspension of 2- (4,5-dichlorothiophen-2-ylmethyl) -isoindole-1,3-dione (0.770 g, 2.47 mmol) in methanol (30 mL) and tetrahydrofuran (10 mL) was added at room temperature. hydrazine hydrate (0.395 g, 12.3 mmol) and stirred at room temperature overnight. A precipitate formed and the mixture was concentrated to about 15 ml and filtered. The filtrate is poured into 100 ml of water and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgSO ₄ , filtered and concentrated to give an oil which was purified by flash chromatography on silica gel eluting with 5% methanol in methylene chloride to give an oil (0.341 g). ). MW 182.08, MS (m / e) 183 (M ⁺ +1).

Preparation 204

2- (4,5-dichlorothiophen-2-ylmethyl) -isoindole-1,3-dione

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

-133- »» ··

Κ a stirred solution of (4,5-dichlorothiophen-2-yl) -methanol (0.660 g, 3.60 mmol), phthalimide (0.636 g, 4.32 mmol) and triphenylphosphene (1.1 g, 4.32 mmol) in tetrahydrofuran (20 mL) was added diethyl azodicarboxylate (0.395 g, 12.3 mmol) at room temperature and stirred at room temperature overnight. The mixture was poured into 100 ml of water and extracted with diethyl ether. The combined extracts were washed with 1 N NaOH, water and brine, dried over MgSO ₄ , filtered, and concentrated to an oil from which triphenylphosphine crystallized using a mixture of diethyl ether and hexane. The mother liquor was concentrated to give a solid which was purified by flash chromatography on silica gel using 30% ethyl acetate in hexane as eluent to give a yellow solid. This material was triturated in hexane to give a white solid (0.772 g). Molecular Weight 312,18, MS (m / e) 313 (M ⁺ +1).

Preparation 205 (4,5-Dichloro-thiophen-2-yl) -methanol

A solution of 4,5-dichlorothiophene-2-carboxylic acid (0.500 g, 2.53 mmol) and thionyl chloride (1.0 mL) in methylene chloride (10 mL) was heated at reflux for 3 hours. The mixture was concentrated to remove the solvent and diluted with 15 mL dioxane and sodium borohydride (0.143 g, 3.8 mmol) was added and refluxed for 3 hours. The mixture was cooled to 0 ° C and 3 mL of water was added dropwise. The mixture was poured into 100 ml of water. Extract with diethyl ether, wash with 1 N NaOH, water and brine, dry over MgSO ₄ , filter, and concentrate to an oil which is purified by flash chromatography on silica gel using 30% ethyl acetate in hexane as eluent to give to give an oil (0.671 g). Molecular Weight 183.06, MS (m / e) 184 (M ⁺ +1).

Preparation 206

-134 • · ·········· «#

4,5-dichlorothiophene-2-carboxylic acid

A solution of sodium hydroxide (19.2 g, 48.0 mmol) in water (30 mL) and ice (120 g) was bubbled through C ₂ gas at -10 ° C until 14.4 g was obtained. 50 ° C and 1- (4,5-dichlorothiophen-2-yl) -ethanone (8.5 g, 40.0 mmol) in dioxane (40 mL) is added dropwise to rise to 80-90 ° C . This temperature was maintained for 30 minutes. The mixture was poured into 500 ml of water. It is extracted with diethyl ether and the aqueous phase is treated with NaHSO ₃ then acidified to pH 1 with concentrated HCl. The resulting precipitate was filtered off and dried to give a white solid (5.7 g). Molecular Weight 197,04. ¹ H NMR (DMSO-d ⁶ ) d 7.731 (1H, s).

Preparation 207

1- (4,5-dichloro-thiophen-2-yl) -ethanone

To a solution of 1-thiophen-2-yl-ethanone (5.0 g, 40.0 mmol) in chloroform (50 mL) at 20 ° C was added portionwise aluminum chloride (15.9 g, 119.0 mmol). . The mixture was stirred at 20 ° C for 10 minutes and added dropwise with 1 M Cl ₂ in carbon tetrachloride (120 mL). The mixture was stirred at room temperature for 30 minutes and diluted with methylene chloride (300 mL) and washed with 1 N sodium hydroxide and water and dried over magnesium sulfate and concentrated to give a solid (8.5 g). Molecular Weight 195.07, MS (m / e) 196 (M ⁺ +1).

Preparation 208

2-bromomethyl-3,5-dichlorothiophene

A solution of 3,5-dichloro-2-methylthiophene (1.3 g, 7.8 mmol), NBS (1.4 g, 7.8 mmol) and benzoyl peroxide (0.065 g) in carbon tetrachloride (40 mL) was heated to reflux. under reflux for 18 hours. The mixture is cooled to 0 ° C, diluted with 40 mL of hexane and filtered. The filtrate was concentrated to an oil which was purified by flash chromatography on silica gel to afford the title compound as a white solid.

Use of hexane as eluent to give an oil (1.06 g). Molecular Weight 245.95, MS (m / e) 246 (M ⁺ +1).

Preparation 209

3,5-dichloro-2-methylthiophene

To a solution of 2-methylthiophene (7.0 g, 70.0 mmol) in methylene chloride (50 mL) was added SO ₂ Cl ₂ dropwise at room temperature. The mixture was stirred at room temperature overnight, diluted with hexane (300 mL), washed with 1 N NaOH, water and brine, dried over MgSO ₄ , filtered, and concentrated to an oil which was purified by vacuum distillation to afford oils. This oil was further purified by silica gel chromatography eluting with hexane to give an oil (1.32 g). Molecular Weight 167.06, MS (m / e) 166 (M ⁺ -1).

Preparation 210

2- (3-carbamoylphenoxy) -N- (2-chlorobenzyl) -nicotinic acid

A solution of 2- (3-carbamoylphenoxy) -N- (2-chlorobenzyl) -nicotinic acid ethyl ester (4.31 g, 16.08 mmol) in ethanol (100 mL) and 1 N sodium hydroxide (40.21 mL) was heated. to reflux for 4 hours. Concentrate to 1/3 volume, dilute to 300 mL with water, acidify to pH 3 with 1 N hydrochloric acid and filter to isolate a white solid which is recrystallized from ethyl acetate / hexane (3.8 g) . Mp 220-224 ° C. Analysa pro

C ₁₃ H ₁₀ N ₂ O ₄ requires C, 60.45; H, 3.91; N, 10.85. Found: C, 61.70; H, 3.61; N, 10.69.

Preparation 211

3-methoxy-N, N-dimethylbenzamide

Gaseous gas was bubbled through a solution of 3-methoxybenzoyl chloride (5.0 g) in methylene chloride (50 mL) at 0 ° C.

-136- dimethylamine for 5 minutes. The mixture was stirred at 0 ° C for 30 minutes, diluted with 300 mL of methylene chloride, washed with water, dried over MgSO _4; Filter and concentrate to give an oil (4.8 g). MW 179.24; MS (m / e) 179 (M ^& lt ^{; +} & gt ^; ).

Preparation 212

2- [3- (2,2,2-Trifluoro-1-hydroxyethyl) -phenoxy] -nicotinic acid ethyl ester

To a solution of 2- (3-formylphenoxy) -nicotinic acid ethyl ester (2.0 g, 7.4 mmol) in 0.5 M trimethyl (trifluoromethyl) silane (18 mL) in tetrahydrofuran (20 mL) at 0 ° C add tetrabutylammonium fluoride (0.050 g). The mixture was stirred at 0 ° C for 1 hour. To the mixture was added 1.0 N hydrochloric acid (10 mL) and stirred at room temperature for 30 minutes. The mixture was poured into 200 ml of water and extracted with diethyl ether. The combined extracts were washed with saturated NaHCO ₃ and water, dried over magnesium sulfate and concentrated to give an oil which was purified by flash chromatography on silica gel using 60% ethyl acetate in hexane to give an oil (1.97 g) . Molecular Weight 341.31, MS (m / e) 341 (M ⁺ ).

Preparation 213

2-fluoro-4- (1-hydroxy-1-methylethyl) -benzonitrile

To a stirred suspension of cerium chloride (4.7 g, 19.0 mmol) in tetrahydrofuran (30 mL) at 0 ° C was added dropwise 3.0 M methylmagnesium chloride (6.0 mL, 19.0 mmol). The mixture was stirred at 0 ° C for 45 minutes and 4-acetyl-2-fluorobenzonitrile (2.5 g, 15.0 mmol) in tetrahydrofuran (20 mL) was added dropwise. The mixture was stirred at 0 ° C for 1 hour and 5 mL of 2 N acetic acid was added dropwise. The mixture was poured into 200 mL of water, acidified to pH 2 with 2 N acetic acid, and extracted with ethyl acetate.

• · • ·

-137- .... ·. ·· ·· ·· ·· ··

The combined extracts were washed with water and brine, dried over magnesium sulfate and concentrated to an oil, which was purified by flash chromatography on silica gel using 50% ethyl acetate in hexane as eluent to give an oil (1.95 g) . MW 179.21; MS (m / e) 179 (M ^& lt ^{; +} & gt ^; ).

Preparation 214

4-Acetyl-2-fluorobenzonitrile

A mixture of 4-bromo-2-fluorobenzonitrile (5.0 g, 20.0 mmol), butyl vinyl ether (12.5 g, 124.0 mmol), triethylamine (4.0 g, 40.0 mmol), dppp (0.453 g) , 1.1 mmol), thallium acetate (5.8 g, 22.0 mmol) and Pd (OAc) ₂ (0.224 g, 1.0 mmol) in dimethylformamide (50 mL) were heated to 90 ° under a nitrogen atmosphere. C for 3 hours. An additional 0.453 g of dpp and 0.244 g of Pd (OAc) _{2 were} added and the mixture was heated at 90 ° C for 4 hours. The mixture was cooled to room temperature, 25 ml of 2 N hydrochloric acid was added and the mixture was stirred at room temperature for 30 hours. The mixture was poured into 300 ml of water and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over magnesium sulfate and concentrated to an oil which was purified by flash chromatography on silica gel eluting with 30% ethyl acetate in hexane to give an oil (2.5 g). . ¹ H NMR (CDCl ₃ ) δ 2.63 (s,

3H), 7.73 (m, 2H), 7.81 (m, 1H).

Preparation

4-Oxocyclohexanecarbonitrile

A solution of 1,4-dioxa-spiro [4,5] decane-8-carbonitrile (2.0 g,

12.8 mmol) and 2 N hydrochloric acid (21.0 g, 42.0 mmol) in tetrahydrofuran (30 mL) were stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with water and brine, dried over MgSO ₄ , filtered and concentrated to give an oil which was purified by flash chromatography to give a residue.

Silica gel using 10% ethyl acetate in hexane as eluent to give an oil (0.800 g). Molecular Weight 123.15.

Preparation 216

2- [4- (1-hydroxy-1-methylethyl) -cyclohex-1-enylmethyl] -isoindole-1,3-dione

To a stirred solution of 2- (4-hydroxymethylcyclohex-3-enyl) -propan-2-ol (5.765 g, 34.270 mmol), phthalimide (6.50 g, 44.208 mmol) and triphenylphosphene (11.60 g, 44.208 mmol) in tetrahydrofuran (200 mL) was added dropwise DIAD (9.010 g, 44.552 mmol) at room temperature and the peach-colored mixture was stirred at room temperature overnight. To the mixture was added 150 mL of water and extracted with 2 x 100 mL of ethyl acetate. The mixture was then concentrated to a yellow residue. This residue was taken up in diethyl ether, diluted with hexane, cooled and filtered. The crude product was purified by flash chromatography on silica gel using 50% ethyl acetate in hexane as eluent to give a yellow gum (5.73 g). Molecular Weight 299,373, MS (m / e) 279 (M ⁺ -18).

Preparation 217

2- (Benzo [1,3] dioxol-5-yloxy) -nicotinic acid ethyl ester

A solution of 2-chloronicotinic acid ethyl ester (5.0 g, 27.0 mmol), cesium carbonate (2.96 g, 67.5 mmol) and benzo [1,3] dioxol-5-ol (4.19 g, 29%). , 7 mmol) in dimethylformamide (80 mL) was heated at 65 ° C for 10 hours. The mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over MgSO ₄ , filtered and concentrated to give a solid (7.0 g). Molecular Weight 287,275.

Preparation 218

-1392- [4- (1-hydroxy-1-methylethyl) -cyclohex-1-enylmethyl] -isoindole-1,3-dione

To a stirred solution of 2- (4-hydroxymethylcyclohex-3-enyl) -propan-2-ol (5.765 g, 34.270 mmol), phthalimide (6.50 g, 44.208 mmol) and triphenylphosphene (11.60 g, 44.208 mmol) in tetrahydrofuran (200 mL) was added dropwise DIAD (9.010 g, 44.552 mmol) at room temperature and the peach-colored mixture was stirred at room temperature overnight. To the mixture was added 150 mL of water and extracted with 2 x 100 mL of ethyl acetate. It is then concentrated to give a yellow residue. This residue was taken up in diethyl ether, diluted with hexane, cooled and filtered. The crude product was purified by flash chromatography on silica gel using 50% ethyl acetate in hexane as eluent to give a yellow gum (5.73 g). Molecular Weight 299,373, MS (m / e) 279 (M ⁺ -18).

Preparation 219

2- (4-Aminomethyl-cyclohex-3-enyl) -propan-2-ol

A solution of 0.3 M methanolic hydrazine hydrate was prepared by adding hydrazine hydrate (1.39 g) to 204 mL of methanol. This solution was added to 2- [4- (1-hydroxy-1-methylethyl) -cyclohex-1-enylmethyl] -isoindole-1,3-dione (5.73 g, 19, 140 mmol) and stirred at temperature room overnight. 5% Hydrochloric acid was added and a precipitate formed over two hours, which was filtered through Celite and washed with water. The filtrate was poured into water and extracted with diethyl ether. The aqueous layer was basified to pH 9 with sodium hydroxide and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgSO ₄ , filtered and concentrated to an oil which solidified on standing (0.188 g). Melting point 95-97 ° C, molecular weight 169,269.

Analogously to Preparation 23, the compounds of Preparations 220-228 were prepared but substituting for the phenol.

• ·

-140Preparation 220

2- (3-Oxo-indan-5-yloxy) -nicotinic acid ethyl ester Prepared using 6-hydroxyindan-1-one (Phialas et al. J. Chem. Soc. Perkin trans. 1, 4, 1984, 687-68). 695). MS (m / h)

297 (M ^& lt ^{; +} & gt ^; ).

Preparation 221

2- (2-Methyl-benzothiazol-5-yloxy) -nicotinic acid ethyl ester

Prepared using 2-methyl-5-benzothiazolol. MS (m / e) 314 (M ^& lt ^{; +} & gt ^; ).

Preparation 222

2- (2-Methyl-benzothiazol-6-yloxy) -nicotinic acid ethyl ester

Prepared using 2-methyl-6-benzothiazolol (Tardieu et al. Helv. Chim. Acta, 75, 4, 1992, 1185-1197). MS (m / e) 314 (M ^& lt ^{; +} & gt ^; ).

Preparation 223

2- (Benzothiazol-6-yloxy) -nicotinic acid ethyl ester Prepared using benzothiazol-6-ol (El'tsov et al. Gen. Chem. USSR 51, 1981, 1822-1831). MS (m / e) 301 (M @ ⁺ +1, 100).

Preparation 224

2- (Benzooxazol-6-yloxy) -nicotinic acid ethyl ester Prepared using benzoxazol-6-ol (Cole et al., Aust. J. Chem. 39, 2, 1986, 295-301). MS (m / e) 284 (M ^& lt ^{; +} & gt ^; ).

Preparation 225

2- (3-Acetyl-4-chlorophenoxy) -nicotinic acid ethyl ester Prepared using 3-acetyl-4-chlorophenol. MS (m / e) 319 (M ^& lt ^{; +} & gt ^; ).

• · · · · · ·

-141-

Preparation 226

2- (3-Acetyl-5-chloro-phenoxy) -nicotinic acid ethyl ester Prepared using 1- (3-chloro-5-hydroxy-phenyl) -ethanone. MS (m / e) 319 (M ^& lt ^{; +} & gt ^; ).

Preparation 227

2- (3-Methylbenzo- (d) isoxazol-5-yloxy) -nicotinic acid ethyl ester

Prepared from 5-hydroxy-3-methylbenzo (d) isoxazole. MS (m / e) 299 (M ^& lt ^; + &^gt; +1, 100).

Preparation 228

2- (3-Methylbenzo (d) isoxazol-7-yloxy) -nicotinic acid ethyl ester

Prepared from 7-hydroxy-3-methylbenzo (d) isoxazole. MS (m / e) 298 (M ^& lt ^{; +} & gt ^; ).

Preparation 229

2- (2,3-Dihydro-benzo [1,4] dioxin-6-yloxy) -nicotinic acid ethyl ester

Prepared from 2,3-dihydro-benzo [1,4] dioxin-6-ol (Biosci. Biotech. Biochem., 56 (4), 1992, 630-635). MS (m / e) 302 (M @ ⁺ +1).

Preparation 230

3-Acetyl-4-chlorophenol

A mixture of 3-acetyl-4-chloroanisole (6.3 g, 0.03 mol) (Atkinson et al., J. Med. Chem., 26, 10, 1983, 1353-1360) and pyridine hydrochloride (19.4 g, (0.17 mol) was heated to 220 ° C for 2 hours. The mixture was poured into water (200 mL) and extracted with ethyl acetate (2 x 200 mL). The organic extracts were combined, washed with water (40 mL), brine (40 mL), dried (MgSO ₄ ) and concentrated to an oil. Chromatography • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

-142- on silica gel eluting with ethyl acetate / hexanes (1: 1) to give

5.1 g oil. MS (m / e) 172/170 (M ^& lt ^{; +} & gt ^; , 100).

Preparation 231

7-hydroxy-3-methyl-benz (d) isoxazole

A mixture of 7-methoxy-3-methyl-benz (d) isoxazole (2.9 g, 0.017 mmol) (Borsche et al., Justus Liebigs Ann. Chem. 570, 1950, 155, 163) in glacial acetic acid (15 mL) ) and 48% hydrobromic acid (15 ml) were heated at reflux for 6 hours. The mixture was concentrated to give 4.0 g of a solid. MS (m / e) 227/229 (M ^& lt ^; + & gt ^; + HBr), 149 (M ^& lt ^{; +} & gt ^; ).

Preparation 232

1- (3-chloro-5-hydroxyphenyl) -ethanone

A mixture of 1- (3-chloro-5-methoxyphenyl) -ethanone (14.3 g, 0.08 mol) and pyridine hydrochloride (44.8 g, 0.39 mol) was heated at 220 ° C for 2 hours. The mixture was poured into water (200 mL) and extracted with ethyl acetate (2 x 200 mL). The organic extracts were combined, washed with water (40 mL), brine (40 mL), and concentrated to an oil. Flash chromatography on silica gel eluting with ethyl acetate / hexanes (1: 1) afforded 6.6 g of a solid. MS (m / e) 170/172 (M ^& lt ^{; +} & gt ^; ).

Preparation 233

1- (3-chloro-5-methoxyphenyl) -ethanone

A mixture of trifluoromethanesulfonic acid 3-chloro-5-methoxyphenyl ester (26.5 g, 0.091 mol), butyl vinyl ether (59 mL, 0.46 mol), 1,3-bis (diphenylphosphinopropane) (1.1 g, 0.003 mol) , palladium acetate (0.51 g, 0.002 mol) and triethylamine (28 ml, 0.20 mol) in dimethylformamide (90 ml) were heated at 80 ° C for 4 hours. The mixture was poured into water (400 mL) and extracted with diethyl ether (2 x 400 mL). The organic extracts were combined, washed with 1 N hydrochloric acid (80 mL), 1 N sodium hydroxide (80 mL), water (80 mL), chloride solution.

-143sodného (80 mL), dried (MgSO ₄₎ and concentrated to an oil. Flash chromatography on silica gel eluting with ethyl acetate / hexanes (1: 9) gave 14.3 g of a solid. MS (m / e) 184/186 (M ^& lt ^{; +} & gt ^; ).

Preparation 234

Trifluoromethanesulfonic acid 3-chloro-5-methoxyphenyl ester

To a stirred solution of 3-chloro-5-methoxyphenol (15 g, 0.09 mol), triethylamine (31 mL, 0.23 mol) and 4-dimethylaminopyridine (1.1 g, 0.009 mol) in methylene chloride (200 mL) was added. trifluoromethanesulfonic anhydride (20 mL, 0.118 mol) was added dropwise at -78 ° C. The mixture was allowed to warm slowly to room temperature over 2 hours, then diluted with methylene chloride (400 mL) and washed with water (100 mL), dried (MgSO ₄ ) and concentrated to an oil. Flash chromatography on silica gel eluting with ethyl acetate / hexanes (1: 9) afforded 26.6 g of an oil. MS (m / e) 290 (M ^& lt ^{; +} & gt ^; ).

Preparation 235

5-hydroxy-3-methyl-benzo (d) isoxazole

A mixture of 5-methoxy-3-methyl-benzo (d) isoxazole (4.9 g, 0.03 mol) in 48% hydrobromic acid (20 mL) and acetic acid (20 mL) was heated to reflux for 18 hours. for 4 hours. The mixture was concentrated to give 6.2 g of solid. MS (m / e) 149 (M ^& lt ^{; +} & gt ^; ).

Preparation 236

5-methoxy-3-methyl-benzo (d) isoxazole

A mixture of 1- (2-hydroxy-5-methoxyphenyl) -ethanone-O-acetyloxime (15.3 g, 0.069 mol) in pyridine (50 mL) was heated at reflux for 4 hours. The mixture was poured into water (800 mL), acidified with concentrated hydrochloric acid to pH 1, then extracted with ethyl acetate (2 x 800 mL). Organic extracts were combined, washed with 1 N hydrochloric acid (100 mL). 1.0 N sodium hydroxide (100 ml), water (100 ml), brine (100 ml), dried (MgSO ₄ ) and concentrated to an oil. Flash chromatography on silica gel eluting with ethyl acetate / hexanes (1: 2) afforded 5.9 g of a solid. MS (m / e) 163 (M ^& lt ^{; +} & gt ^; ).

Preparation 237

1- (2-hydroxy-5-methoxyphenyl) -ethanone-O-acetyloxime

A mixture of 1- (2-hydroxy-5-methoxyphenyl) -ethanone oxime (13.7 g, 0.076 mol) and acetic anhydride (50 mL) was heated at 50 ° C for 10 minutes. The mixture was cooled to 0 ° C, filtered, and the filtrate was washed with water (50 mL) and dried to give 15.5 g of a solid. MS (m / e) 224 (M ^& lt ^; + &^gt; +1), 164 (100).

Preparation 238

1- (2-hydroxy-5-methoxyphenyl) -ethanone oxime

A mixture of 2-hydroxy-5-methoxyacetophenone (15.0 g, 0.09 mol), potassium hydroxide (23.6 g, 0.36 mol) and hydroxylamine hydrochloride (9.4 g, 0.14 mol) in water (3 (00 ml) was heated to reflux for 2 hours. The mixture was poured onto ice and acidified to pH 1 with 1 N hydrochloric acid. The resulting precipitate was filtered off and dried to give 13.7 g of a solid. MS (m / e) 182 (M ^& lt ^; + &^gt; +1, 100).

Analogously to Preparation 45, the compounds of Preparations 238-247 were prepared.

Preparation 239

2- (3-oxo-indan-5-yloxy) -nicotinic acid MS (m / e) 269 (M ^& lt ^{; +} & gt ^; ).

Preparation 240

2- (2-methyl-benzothiazol-5-yloxy) -nicotinic acid MS (m / e) 287 (M ⁺ +1, 100).

• ·

-145-

Preparation 241

2- (2-methyl-benzothiazol-6-yloxy) -nicotinic acid MS (m / e) 287 (M ⁺ +1, 100).

Preparation 242

2- (Benzothiazol-6-yloxy) -nicotinic acid MS (m / e) 273 (M ⁺ +1).

Preparation 243

2- (benzooxazol-6-yloxy) -nicotinic acid MS (m / e) 256 (M ^& lt ^{; +} & gt ^; ), 211 (100).

Preparation 244

2- (3-acetyl-4-chlorophenoxy) -nicotinic acid MS (m / e) 292/290 (M ^& lt ^{; +} & gt ^; , 100).

Preparation 245

2- (3-acetyl-5-chlorophenoxy) -nicotinic acid MS (m / e) 292/290 (M ^& lt ^{; +} & gt ^; , 100).

Preparation 246

2- (3-methylbenzo (d) isoxazol-5-yloxy) -nicotinic acid MS (m / e) 270 (M ⁺ +1, 100).

Preparation 247

2- (3-methylbenzo (d) isoxazol-7-yloxy) -nicotinic acid MS (m / e) 270 (M ⁺ +1, 100).

Preparation 248

2- (2,3-Dihydro-benzo [1,4] dioxin-6-yloxy) -nicotinic acid

MS (m / e) 274 (M @ ⁺ +1).

Preparation 249 • ·

-146- (S) - (-) - 1- (4-aminomethylphenyl) -ethanol

To a stirred solution of (S) - (-) - 4- (1-hydroxyethyl) -benzonitrile (2.2 g, 0.015 mol) in tetrahydrofuran (20 mL) at 0 ° C was added dropwise a 1.0 M solution. lithium aluminum hydride in tetrahydrofuran (45 mL, 0.045 mol). The mixture was heated to reflux for 30 minutes, then cooled to 0 ° C and methanol (5 mL) was added dropwise. The mixture was diluted with chloroform (300 mL) and washed with water (40 mL). The resulting suspension was filtered through Celite and the organic extract of the filtrate was separated, dried (MgSO 4 and concentrated to give 2.0 g of solid) and _D (CDCl ₃ ) -40.3 °.

Preparation 250 (S) - (-) - 4- (1-Hydroxyethyl) -benzonitrile

To a stirred solution of 4-acetylbenzonitrile (3.0 g, 0.021 mol) and a solution of 1.0 M (R) -2-methyl-CBS-oxazaborolidine in toluene (1.0 mL, 0.001 mol) in tetrahydrofuran (50 mL) 2.0 M borane-dimethylsulfide complex in tetrahydrofuran (9.0 mL, 0.017 mol) was added dropwise over 30 minutes at room temperature. The mixture was stirred at room temperature for 1 hour, cooled to 0 ° C, then methanol (10 mL) was added dropwise. Reduce the volume by half, dilute with diethyl ether (300 mL) and wash with pH 4 buffer (40 mL), water (40 mL), brine (40 mL), dry (MgSO 4) and then concentrate to an oil. Flash chromatography on silica gel, eluting with ethyl acetate / hexane (2: 3), gave 2.2 g of a clear oil, cc _D (CDCl ₃ ) -40.0 °.

Preparation 251 (R) - (+) - 1- (4-Aminomethylphenyl) -ethanol

Prepared in analogy to Preparation 247 starting from (R) - (+) - 4- (1-hydroxyethyl) -benzonitrile, which was obtained from 4-acetylbenzonitrile using 1.0 M @ -1.

9 · ♦

-147 (S) -2-methyl-CBS-oxazaborolidine in toluene analogously to Preparation 248.

Preparation 252

Trans-2- (aminomethylcyclohexyl) propan-2-ol

A mixture of trans- (4- (1-hydroxy-1-methylethyl) -cyclohexylmethyl) -carbamic acid benzyl ester (8.3 g, 0.027 mol) and Pearlman catalyst (400 mg) in ethyl acetate (100 mL) and methanol (25 mL) is shaken in a Parr apparatus under hydrogen pressure

275.8 kPa at room temperature for 1 hour. The mixture was filtered through Celite and the filtrate was concentrated to give 5.1 g of a white solid. MS (m / e) 171 (M ^& lt ^{; +} & gt ^; , 100).

Preparation 253

Trans- (4- (1-Hydroxy-1-methylethyl) -cyclohexylmethyl) -carbamic acid benzyl ester

A mechanically stirred suspension of anhydrous cerium chloride (29.8 g, 0.12 mol) in tetrahydrofuran was heated to reflux for 10 minutes, cooled to 0 ° C, and a solution of trans -4- (benzyloxycarbonylamino) ethyl ester was added dropwise. -methyl) cyclohexanecarboxylic acid (35.8 g, 0.11 mol) in tetrahydrofuran (20 mL) and then dropwise a solution of 3.0 M methylmagnesium chloride (121 mL, 0.363 mol) in tetrahydrofuran. The mixture was stirred at 0 ° C for 1 hour, then 2 N acetic acid was added dropwise. The volume of the mixture was reduced in half, poured into water (800 mL) and acidified with 2 N acetic acid to pH 3 and then extracted with ethyl acetate (2 x 800 mL). The organic extracts were combined, washed with sodium bicarbonate (100 mL), water (100 mL), brine (100 mL), dried (MgSO ₄ ) and concentrated to an oil. Flash chromatography on silica gel eluting with ethyl acetate / hexanes (2: 3) afforded 8.34 g of a solid. MS (m / e) 323 (M ⁺ + NH _3, 100).

-148 * • v v v v v v v v v v v v

Preparation 254

Trans-4- (Benzyloxycarbonylamino-methyl) -cyclohexanecarboxylic acid ethyl ester

To a stirred solution of trans -4-aminomethyl-cyclohexanecarboxylic acid ethyl ester (23.8 g, 0.11 mol) and triethylamine (34 mL, 0.24 mol) in dioxane (100 mL) was added N- (benzyloxycarbonyloxy) succinimide ( 26.7 g, 0.11 mol). The mixture was stirred at room temperature for 18 hours, poured into water (800 mL) and extracted with ethyl acetate (2 x 800 mL). The organic extracts were combined, washed with 0.5 N sodium hydroxide (100 mL), 0.5 N hydrochloric acid (100 mL), water (100 mL), brine (100 mL), dried (MgSO ₄ ) and dried (MgSO ₄ ). concentrate to give 36.0 g of a solid. MS (m / e) 337 (M ⁺ + NH _3, 100).

Preparation 255 (R) - (-) - trans-1- (4-Aminomethyl-cyclohexyl) -ethanol

A mixture of (R) - (-) - (trans -4- (1-hydroxyethyl) -cyclohexylmethyl) -carbamic acid benzyl ester (870 mg, 2.98 mmol) and Pearlman catalyst (100 mg) in ethyl acetate (100 mL) and methanol ( 25 ml) was shaken in a Parr apparatus at 50 psi hydrogen at room temperature for 1 hour. The mixture was filtered through Celite and the filtrate was concentrated to give 484 mg of an oil. [α] _D (CDCl ₃ ) -1.6 °.

Preparation 256

(R) - (-) - (trans-4- (1-hydroxyethyl) -cyclohexylmethyl) -carbamic acid benzyl ester

To a stirred solution of (trans-4-acetylcyclohexylmethyl) -carbamic acid benzyl ester (1.0 g, 3.46 mmol) and (S) -2-methyl-CBS-oxazaborolidine monohydrate (102 mg, 0.34 mmol) in tetrahydrofuran ( 15 ml) at 0 ° C was added dropwise a 2.0 M solution of borane-dimethylsulfide complex (1.4 ml, 2.77 mmol) in tetrahydrofuran over 20 minutes. The mixture was stirred

-149-

• ♦ · ·

9 ° F at 0 ° C for 30 minutes and then methanol (10 mL) was added. The volume of the mixture was reduced in half, poured into water (200 mL) and extracted with ethyl acetate (2 x 200 mL). The organic extracts were combined, washed with pH 4 buffer (40 mL), water (40 mL), brine (40 mL), dried (MgSO ₄ ) and concentrated to an oil. Flash chromatography on silica gel eluting with ethyl acetate / hexanes (1: 1) afforded 870 mg of a solid. and _D (CDCl ₃ ) -0.8 °.

Preparation 257

(Trans -4-Acetyl-cyclohexylmethyl) -carbamic acid benzyl ester

To a stirred solution of (trans -4- (methoxymethylcarbamoyl) -cyclohexylmethyl) -carbamic acid benzyl ester (5.8 g, 0.017 mol) in tetrahydrofuran (100 mL) was added dropwise a solution of 3.0 M methylmagnesium chloride in tetrahydrofuran at 0 ° C. (13 mL, 0.038 mol). The mixture was stirred at 0 ° C for 1 hour and then 2 N acetic acid was added dropwise. The mixture was poured into water (300 mL) and extracted with ethyl acetate (2 x 300 mL). The organic extracts were combined, washed with 0.5 N hydrochloric acid (80 mL), water (80 mL), brine (80 mL), dried (MgSO ₄ ) and concentrated to an oil. Flash chromatography on silica gel eluting with ethyl acetate / hexanes (2: 3) gave 2.0 g of a solid. MS (m / e) 307 (M ⁺ + NH _3, 100).

Preparation 258

(Trans -4- (Methoxymethylcarbamoyl) -cyclohexylmethyl) -carbamic acid benzyl ester

To a stirred solution of trans-4- (benzyloxycarbonylaminomethyl) -cyclohexanecarboxylic acid (16.7 g, 0.057 mol), N, O-dimethylhydroxylamine hydrochloride (6.2 g, 0.063 mol), triethylamine (9 mL, 0.063 mol) and 1-hydroxybenzotriazole hydrate (8.5 g, 0.063 mol) in dimethylformamide (200 mL) at RT

Add 1- (3-dimethylamino) propyl) -3-ethylcarbodiimide hydrochloride (13.1 g, 0.068 mol) was added to the room. The mixture was stirred at room temperature for 72 hours, poured into water (800 mL) and extracted with ethyl acetate (2 x 800 mL). The organic extracts were combined, washed with 1 N sodium hydroxide (80 mL), 1 N hydrochloric acid (80 mL), water (80 mL), brine (80 mL), dried (MgSO ₄ ) and concentrated to give oils. Flash chromatography on silica gel eluting with ethyl acetate / hexanes (3: 2) gave 5.8 g of an oil. MS (m / e) 352 (M ⁺ + NH _3, 100).

Preparation 259

Trans-4- (benzyloxycarbonylamino-methyl) -cyclohexanecarboxylic acid

To a stirred solution of trans-4- (aminomethyl) -cyclohexanecarboxylic acid (10.0 g, 0.063 mol) and potassium carbonate (30.5 g, 0.22 mol) in dioxane (200 mL) and water (200 mL) was added at room temperature. Benzyl chloroformate (11 mL, 0.08 mol) was added at room temperature. The mixture was stirred at room temperature for 18 hours, poured into water (800 mL) and washed with diethyl ether (800 mL). The aqueous extract was acidified and the resulting precipitate was filtered off and dried, yielding 16.7 g of a white solid. MS (m / e) 309 (M ⁺ + NH _3, 100).

• *

-151- ..............

Mass spectra were determined by GC-MS, AMPI, APCI or thermospray method. ¹ H NMR was measured on a 400 MHz device.

Example 1

2- (4-Fluorophenoxy) -N-thiophen-2-ylmethyl-nicotinamide

To a stirred solution of 2- (4-fluorophenoxy) -nicotinic acid (0.300 g, 1.29 mmol) and NMM (0.137 g, 1.35 mmol) in anhydrous methylene chloride (15 mL) at -10 ° C was added isobutyl chloroformate ( 0.164 g, 1.35 mmol). After 30 min, 2-aminomethylthiophene (0.152 g, 1.35 mmol) was added at -10 ° C and the mixture was allowed to warm to room temperature overnight. The mixture was poured into water and extracted with ethyl acetate. The combined organic extracts were washed with 1 N sodium hydroxide and water, dried over MgSO ₄ , filtered and concentrated to give a clear oil which was purified by silica gel chromatography eluting with 30% ethyl acetate in hexane to give a solid. Recrystallization from ethyl acetate / hexane gave white crystals (0.326 g). Mp 89-91 ° C, MS (m / e) 329 (M ⁺ +1).

Following the procedure of Example 1, the compounds of Examples 2 to 9 were prepared, but the 2-aminomethylthiophene was replaced with the corresponding amine. The duration of the reaction is between 1 and 24 hours.

Example 2

2- (4-fluorophenoxy) -N-furan-2-ylmethyl-nicotinamide, m.p. 71-73 ° C. Anal. Calcd for C ₁₇ H ₁₃ N ₂ O ₃ F: C

H, 4.20; N, 6.97. Found: C, 65.53; H, 4.34; N, 9.31.

EXAMPLE 3 (R) - (-) - 2- (4-Fluorophenoxy) -N- [1- (4-methoxyphenyl) ethyl] -nicotinamide · «··· · · · · · · · A · r«. · · · · · · · ·

-152- ............ ·· ··

Mp 101-103 ° C. Anal. Calcd for C ₂₁ H ₁₉ N ₂ O ₃ F: C

H, 5.23; N, 7.65. Found: C, 68.46; H, 5.20; N, 7.62.

Example 4 (S) - (+) - 2- (4-fluorophenoxy) -N- [1- (4-methoxyphenyl) ethyl] -nicotinamide

Melting point 97-99 ° C. Anal. Calcd for C ₂₁ H ₁₉ N ₂ O ₃ F: C

H, 5.23; N, 7.65. Found: C, 68.84; H, 5.17; N, 7.71. ? _D = +54.2 (c = 0.2, chloroform).

Example 5

N- (2-chloro-6-fluorobenzyl) -2- (4-fluorophenoxy) nicotinamide, m.p. 115-118 ° C. Analysis for C ₁₉ H ₁₃ N ₂ O ₂ F ₂ C1 calculated:

H, 3.45; N, 7.38. Found: C, 60.63; H, 3.45;

Example 6 (S) - (-) - 2- (4-fluorophenoxy) -N- (1-thiophen-2-ylethyl) nicotinamide

Mp 59-61 ° C. Anal. Calcd for C ₁₈ H ₁₅ N ₂ SO ₂ F: C 63.14, H 4.42, N 8.18. Found: C 63.21, H 4.34, N 8.16. alpha _D = -26.5 ⁰ (c = 0.3, chlorofrom).

Example 7 (R) - (+) - 2- (4-Fluorophenoxy) -N- (1-thiophen-2-ylethyl) nicotinamide

Melting point 60-62 ° C. Analysis for C ₁₈ H ₁₅ N ₂ SO ₂ F requires C, 63.14; H, 4.42; N, 8.18 Found: C 62.75, H 4.27, N 8.06. α _D = - + 26.2 ° (c = 0.4, chloroform).

Example 8

N- [1- (5-chloro-thiophen-2-yl) -ethyl] -2- (4-fluoro-phenoxy) -nicotinamide

Mp 87-89 ° C. Anal. Calcd for C ₁₈ H ₁₄ N ₂ SO ₂ ClF: C 57.37, H 3.74, N 7.43. Found: C 57.51, H 3.68, N 7.48.

-153 • ·

Example 9

N- (2-chlorobenzyl) -2- (4-fluorophenoxy) nicotinamide, m.p. 118-120 ° C. Analysis for C ₁₉ H ₁₄ N ₂ O ₂ C1F Calculated: C, 63.96, H, 3.95, N, 7.85 Found: C 63.54, H 3.96, N 7.72.

Example 10

N- (2-chlorobenzyl) -2- (2,4-difluorophenoxy) -nicotinamide

To a stirred solution of 2- (2,4-difluorophenoxy) -nicotinic acid (0.300 g, 1.19 mmol) and NMM (0.133 g, 1.31 mmol) in anhydrous methylene chloride (15 mL) was added at -10 ° C. isobutyl chloroformate (0.202 g, 1.31 mmol). After 20 minutes at -10 ° C, 2-chlorobenzylamine (0.202 g, 1.43 mmol) was added and the mixture was allowed to warm to room temperature overnight. The mixture was poured into water and extracted with ethyl acetate. The combined organic extracts were washed with 1 N NaOH, water and brine, dried over MgSO ₄ , filtered and concentrated to give a clear oil which was purified by silica gel chromatography eluting with 30% ethyl acetate in hexane to give a solid. Recrystallization from ethyl acetate / hexane gave a solid (0.295 g). Melting point 122-124 ° C. Analysis for C ₁₉ H ₁₃ N ₂ O ₂ F ₂ C1 Calculated: C 60.89, H 3.50, N 7.47 Found: C, 60.77; H, 3.44; N, 7.38.

Example 11

N- (2-chlorobenzyl) -2- (3-fluorophenoxy) nicotinamide

To a stirred solution of 2- (3-fluorophenoxy) -nicotinic acid (0.300 g, 1.29 mmol) and NMM (0.144 g, 1.41 mmol) in anhydrous methylene chloride (15 mL) at -10 ° C was added isobutyl chloroformate ( 0.193 g, 1.41 mmol). After 20 minutes at -10 ° C, 2-chlorobenzylamine (0.219 g, 1.5 mmol) was added and the mixture was allowed to warm to room temperature overnight. The mixture was poured into water and extracted with ethyl acetate. The combined organic extracts were washed with 1 N NaOH, water and brine, dried over MgSO ₄ , filtered, and concentrated under vacuum. ··· «· · · · · · · · · · · · · · · · · · ·

-154-. ···. ··. Formation of a solid which was purified by silica gel chromatography eluting with 30% ethyl acetate in hexane to give a solid. Recrystallization from ethyl acetate / hexane gave a white solid (0.328 g). Melting point 115-117 ° C.

Analysis for C ₁₉ H ₁₄ N ₂ O ₂ C1F Calculated: C, 63.96, H, 3.95, N, 7.85 Found: C 64.04, H 3.92, N 7.85.

Example 12

N- (2-chlorobenzyl) -2- (pyridin-3-yloxy) -nicotinamide To a stirred solution of 2- (pyridin-3-yloxy) -nicotinic acid (0.300 g, 1.39 mmol), o-chlorobenzylamine (0.216 g) ,

1.53 mmol) and 1-hydroxybenzotriazole hydrate (0.207 g, 1.53 mmol) in anhydrous dimethylformamide (15 mL) were added.

3- (dimethylamino) -propyl) -3-ethylcarbodiimide hydrochloride (0.319 g, 1.67 mmol) and stirred overnight. The mixture was diluted with 200 mL of ethyl acetate, washed with 1 N NaOH, water and brine, dried over MgSO ₄ , filtered and concentrated to give an oil which was purified by silica gel chromatography eluting with 5% methanol in methylene chloride. Recrystallization from ethyl acetate / hexane gave a white solid (0.275 g). Melting point 123-125 ° C. Anal. Calcd for C ₁₈ H ₁₄ N ₃ O ₂ Cl: C 63.63, H 4.15, N 12.37. Found: C 63.19, H 3.85, N 11.67.

Following the procedure of Example 12, the compounds of Examples 13 to 44 were prepared, but the o-chlorobenzylamine was replaced with the corresponding amine. The duration of the reaction is between 1 and 24 hours.

Example 13

N- (4-methylbenzyl) -2- (pyridin-3-yloxy) -nicotinamide, m.p. 91-93 ° C. Anal _. Calcd for C ₁₉ H ₁₇ N ₃ O ₂ : C

H, 5.37; N, 13.16. Found: C, 71.51; H, 5.40; N, 13.26.

Example 14 • ·

-155N- [1- (5-chloro-thiophen-2-yl) -ethyl] -2- (pyridin-3-yloxy) -nicotinamide

Mp 74-76 ° C. Anal. Calcd for C ₁₇ H ₁₄ N ₃ SO ₂ Cl: C

H, 3.92; N, 11.68. Found: C, 56.54; H, 4.06; N, 11.80.

Example 15

N-furan-2-ylmethyl-2- (pyridin-3-yloxy) -nicotinamide, m.p. 84-86 ° C. Anal _. Calcd for C ₁₆ H ₁₃ N ₃ O ₃ : C

H, 4.44; N, 14.23. Found: C, 65.04; H, 4.50; N, 14.55.

Example 16

N- (5-chlorothiophen-2-ylmethyl) -2- (pyridin-3-yloxy) -nicotinamide

Melting point 110-112 ° C. Anal _. Calcd for C ₁₆ H ₁₂ N ₃ SO ₂ Cl: C 55.57, H 3.50, N 12.15. Found: C 55.23, H 3.57, N 12.45.

Example 17

N- [1- (5-methylthiophen-2-yl) ethyl] -2- (pyridin-3-yloxy) nicotinamide

Mp 162-164 ° C, MS (m / e) 340 (M ⁺ +1).

Example 18

N- (5-methylthiophen-2-ylmethyl) -2- (pyridin-3-yloxy) -nicotinamide

Melting point 111-113 ° C. Analysis for C ₁₇ H ₁₅ N ₃ SO ₂ calculated: C

H, 4.65; N, 12.91. Found: C, 62.77; H, 4.67; N, 12.50.

Example 19

N- (5-Methylfuran-2-ylmethyl) -2- (pyridin-3-yloxy) -nicotinamide

Melting point 65-67 ° C. Anal. Calcd for C ₁₇ H ₁₅ N ₃ O ₃ C

H, 4.89; N, 13.28. Found: C, 65.77; H, 4.90;

Example 20

-156-. ·. ·. ·

N- (3-methylthiophen-2-ylmethyl) -2- (pyridin-3-yloxy) -nicotinamide

Mp 89-91 ° C. Analysis for C ₁₇ H ₁₅ N ₃ SO ₂ calculated: C

H, 4.65; N, 12.91. Found: C, 62.71; H, 4.64; N, 12.80.

Example 21

N- (4-chlorothiophen-2-ylmethyl) -2- (pyridin-3-yloxy) -nicotinamide

Melting point 118-120 ° C. Anal. Calcd for C ₁₈ H ₁₂ N ₃ SO ₂ Cl: C 55.57, H 3.50, N 12.15. Found: C 55.50, H 3.89, N 11.37.

Example 22

N-benzo [b] thiophen-2-ylmethyl-2- (pyridin-3-yloxy) -nicotinamide

Melting point 93-95 ° C. Analysis for C ₂₀ H ₁₅ N ₃ SO ₂ calculated: C

H, 4.18; N, 11.63. Found: C, 66.00; H, 4.19; N, 11.66.

Example 23

N- (5-chlorofuran-2-ylmethyl) -2- (pyridin-3-yloxy) -nicotinamide

Melting point 80-82 ° C. Anal _. Calcd for C ₁₆ H ₁₂ N ₃ O ₃ Cl: C 58.28, H 3.67, N 12.74. Found: C 58.52, H 3.73, N 12.80.

Example 24

2- (pyridin-3-yloxy) -N-thiazol-2-ylmethyl-nicotinamide, m.p. 94-96 ° C, MS (m / e) 313 (M ⁺ +1).

Example 25

2- (pyridin-3-yloxy) -N- [4- (2,2,2-trifluoroethoxy) -benzyl] -nicotinamide

Melting point 98-100 ° C. Anal _. Calcd for C ₂₀ H ₁₆ N ₃ O ₃ F ₃ : C 59.55, H 4.00, N 10.42. Found: C 59.74, H 3.92, N 10.53.

Example 26 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ··· aa and · aa ··

N- (2-fluorobenzyl) -2- (pyridin-3-yloxy) -nicotinamide, m.p. 90-92 ° C. Anal. Calcd for C ₁₈ H ₁₄ N ₃ O ₂ F: C

H, 4.36; N, 13.00. Found: C, 67.08; H, 4.23;

Example 27

N- (4-difluoromethoxybenzyl) -2- (pyridin-3-yloxy) nicotinamide

Mp 91-93 ° C. Analysis for C ₁₉ H ₁₅ N ₃ O ₃ F _2: Calculated: C 61.46, H 4.07, N 11.32 Found: C 61.47, H 3.84, N 11.24.

Example 28

N- (4-fluorobenzyl) -2- (pyridin-3-yloxy) -nicotinamide, m.p. 129-131 ° C. Analysis for C ₁₈ H ₁₄ N ₃ O ₂ F: Calculated: C 66.87, H 4.36, N 13.00 Found: C 66.63, H 4.42, N 13.04.

Example 29

N- (4-methoxybenzyl) -2- (pyridin-3-yloxy) -nicotinamide Temperature 62-64 ° C. Analysis for C ₁₉ H ₁₇ N ₃ O ₃ calculated: C 68.05,

H, 5.11; N, 12.53. Found: C, 68.20; H, 4.96; N, 12.58.

Example 30

2- (pyridin-3-yloxy) -N- (5-trifluoromethylthiophen-2-ylmethyl) -nicotinamide

Melting point 122-124 ° C. Analysis for C ₁₇ H ₁₂ N ₃ O ₂ SF ₃ calculated:

H, 3.19; N, 11.08. Found: C, 54.44; H, 3.22; N, 11.10.

Example 31

N- (2-chlorobenzyl) -2- (pyridin-3-yloxy) -nicotinamide, m.p. 174-176 ° C. Analysis for C ₁₈ H ₁₄ N ₃ O ₂ C1. H, 4.02; N, 11.17. Found: C, 57.16; H, 4.11; N, 11.09.

Example 32 • ·

-158N- (5-fluoro-thiophen-2-ylmethyl) -2- (pyridin-3-yloxy) -nicotinamide

Melting point 99-101 ° C. Anal _. Calcd for C ₁₆ H ₁₂ N ₃ O ₂ SF: C 58.35, H 3.67, N 12.76. Found: C 58.35, H 3.55, N 12.71.

Example 33

N- (2-oxo-2,3-dihydro-1H-indol-5-ylmethyl) -2- (pyridin-3-yloxy) -nicotinamide

M.p. 109-111 ° C. Anal _. Calcd for C ₂₀ H ₁₆ N ₄ O ₃ : C 66.66, H 4.47, N 15.55. Found: C 65.92, H 4.56, N 14.84.

Example 34

N- (3,5-di-tert-butyl-4-hydroxybenzyl) -2- (pyridin-3-yloxy) -nicotinamide

Mp 42-44 ° C. Anal. Calcd for C ₂₆ H ₃₁ N ₃ O ₃ : C

H, 7.21; N, 9.69. Found: C, 71.19; H, 7.22; N, 9.79.

Example 35

N- [5- (1-hydroxy-1-methylethyl) -thiophen-2-ylmethyl] -2- (pyridin-3-yloxy) -nicotinamide

Melting point 110-112 ° C. Anal _. Calcd for C ₁₉ H ₁₉ N ₃ SO ₃ : C 61.77, H 5.18, N 11.37. Found: C 61.63, H 5.40, N 10.60.

Example 36

N- [4- (1-hydroxy-1-methylethyl) -benzyl] -2- (pyridin-3-yloxy) -nicotinamide

Mp 79-81 ° C. Anal. Calcd for C ₂₁ H ₂₁ N ₃ O ₃ : C

H, 5.82; N, 11.56. Found: C, 69.19; H, 5.85; N, 11.58.

Example 37

4 - ({[2- (Pyridin-3-yloxy) -pyridine-3-carbonyl] amino} -methyl) -benzoic acid methyl ester

Melting point 125-127 ° C. Anal _. Calcd for C ₂₀ H ₁₇ N ₃ O ₄ : C 66.11, H 4.72, N 11.56. Found: C 65.83, H 4.52, N 11.39.

-159Example 38

N- [3-chloro-4- (1-hydroxy-1-methylethyl) -benzyl] -2-pyridin-3-yloxy) nicotinamide

M.p. 139-141 ° C. Anal. Calcd for C ₂₁ H ₂₀ N ₃ O ₃ Cl: C

H, 5.07; N, 10.56. Found: C, 63.24; H, 4.85; N, 10.21.

Example 39

N- [2-chloro-4- (1-hydroxy-1-methylethyl) -benzyl] -2- (pyridin-3-yloxy) -nicotinamide

MS (m / e) 400/398 (M ⁺⁺ 1), ⁴ H NMR (400 MHz, CDCl ₃ ) d 1.54 (s, 6H), 4.73 (d, 2H), 7.16-7 56 (m, 6H), 8.16 (d, 1H), 8.34 (m, 1H), 8.49 (dd, 2H), 8.61 (d, 1H).

Example 40

2- (pyridin-3-yloxy) -N- [4- (2,2,2-trifluoro-1-hydroxyethyl) -benzyl] -nicothiamide

MS (m / e) 404 (M ⁺⁺ 1), 1 H NMR (400 MHz, CDCl ₃ ) d 4.70 (dd, 2H), 4.98 (dd, 1H), 7.16-7.56 ( m, 7H), 8.00 (m, 1 H), 8.18 (dd, 1 H),

8.28 (d, 1H), 8.43 (m, 1H), 8.60 (dd, 1H).

Example 41

N- (4-Hydroxy-chroman-7-ylmethyl) -2- (pyridin-3-yloxy) -nicotinamide

Melting point 134-136 ° C. Anal. Calcd for C ₂₁ H ₁₉ N ₃ O ₄ C

H, 5.07; N, 11.13. Found: C, 66.50; H, 4.90; N, 11.60.

Example 42

N- [4- (1-hydroxycyclobutyl) -benzyl] -2- (pyridin-3-yloxy) nicotinamide

Melting point 116-118 ° C. Anal. Calcd for C ₂₂ H ₂₁ N ₃ O ₃ : C

H, 5.63; N, 11.19. Found: C, 70.41; H, 5.67; N, 10.97.

Example 43 · · · · * ·

-160 ^- · ············

N- [4- (1-hydroxyprop-2-ynyl) -benzyl] -2- (pyridin-3-yloxy) -nicotinamide

MS (me) 360/344 (M @ ⁺ +1), ^X H NMR (400 MHz, CDC1 ₃ ) d 4.69 (d, 2H) , 5.19 (m, 1H), 7.15-7.53 (m, 8H), 7.99 (m, 1 H) , 8.18 (dd, 1H) , 8.35 (dd, 1 H), 8.49 (d, 1H), 8.63 (dd, 1H).

Example 44

N- [3-chloro-5- (1-hydroxy-1-methylethyl) -thiophen-2-ylmethyl] -2- (pyridin-3-yloxy) -nicotinamide

Mp 74-76 ° C. Anal _. Calcd for C ₁₉ H ₁₈ N ₃ O ₃ SC 1: C 56.50, H 4.49, N 10.40. Found: C 56.79, H 4.68, N 9.64.

Example 45

2- (pyridin-3-yloxy) -N- (1-thiophen-2-ylethyl) -nicotinamide

To a stirred suspension of 2- (pyridin-3-yloxy) -nicotinic acid (0.300 g, 1.39 mmol) and NMM (0.155 g, 1.53 mmol) in anhydrous methylene chloride (15 mL) was added at -10 ° C. isobutyl chloroformate (0.208 g, 1.53 mmol). After 20 minutes at -10 ° C, 1-thiophen-2-ylethylamine (0.195 g, 1.53 mmol) was added and the mixture was allowed to warm to room temperature overnight. The mixture was diluted with 200 mL of ethyl acetate, washed with 1 N sodium hydroxide and water, dried over MgSO ₄ , filtered and concentrated to give an oil which was purified by silica gel chromatography eluting with 5% methanol in methylene chloride to give a solid. Recrystallization from ethyl acetate / hexane gave a white solid (0.191 g). Melting point 90-92 ° C.

Anal. Calcd for C ₁₇ H ₁₅ N ₃ O ₂ S: C 62.75, H 4.65, N 12.91. Found: C 62.51, H 4.69, N 13.10.

Following the procedure of Example 45, the compounds of Examples 46 to 47 were prepared, but the 1-thiophen-2-ylethylamine was replaced with the corresponding amine. The duration of the reaction is between 1 and 24 hours.

Example 46

-161-

(S) - (+) -2- (Pyridin-3-yloxy) -N- (1-thiophen-2-ylethyl) nicotinamide

Melting point 196-198 ° C. Analysis for C ₁₇ H ₁₅ N ₃ O ₂ S. HCl: Calculated: C 56.43, H 4.46, N 11.61 Found: C 59.48, H 5.49, N 10.04. [α] _D = +28.3 ° (c = 0.2, methanol).

Example 47 (R) - (-) - 2- (Pyridin-3-yloxy) -N- (1-thiophen-2-ylethyl) nicotinamide

Melting point 197-199 ° C. Analysis for C ₁₇ H ₁₅ N ₃ O ₂ S. HCl: Calculated: C 56.43, H 4.46, N 11.61 Found: C 57.55, H 5.12, N 10.62. rt _D = + 17.9 ⁰ (c = 0.1, methanol).

Example 48

2- (5-chloropyridin-3-yloxy) -N- (4-methylbenzyl) nicotinamide

To a stirred solution of 2- (5-chloropyridin-3-yloxy) -nicotinic acid (0.180 g, 0.78 mmol), 4-methylbenzylamine (0.104 g, 0.86 mmol) and 1-hydroxybenzotriazole hydrate (0.116 g, 0 , 86 mmol) in anhydrous dimethylformamide (5 mL) was added 1- (3- (dimethylamino) -propyl) -3-ethylcarbodiimide hydrochloride (0.165 g, 0.86 mmol) and stirred for 18 hours. The mixture was poured into 100 ml of water and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over MgSO ₄ , filtered, and concentrated to an oil which was purified by silica gel chromatography eluting with 5% methanol in methylene chloride. Recrystallization from ethyl acetate / hexane gave pale pink crystals (0.211 g). Melting point 119-121 ° C. Analysis for C ₁₉ H ₁₆ N ₃ O ₂ C1 Calculated: C 64.50, H 4.56, N 11.88 Found: C 64.44, H 4.47, N 11.94.

Following the procedure of Example 48, the compounds of Examples 49 to 60 were prepared, but the 4-methylbenzylamine was replaced with the corresponding amine. The duration of the reaction is between 1 and 24 hours.

• · ·

Example 162

2- (5-Chloro-pyridin-3-yloxy) -N- [1- (5-chloro-thiophen-2-yl) -ethyl] -nicotinamide

Melting point 110-112 ° C. Analysis for C ₁₇ H ₁₄ N ₃ 0 _{2 2} SCl Calculated: C 51.66, H 3.57, N 10.63 Found: C, 51.49; H, 3.51; N, 10.41.

Example 50

2- (5-chloropyridin-3-yloxy) -N- [1- (5-methylthiophen-2-yl) ethyl] nicotinamide

Mp 75-77 ° C. Analysis for C ₁₈ H ₁₆ N ₃ O ₂ SC 1 calculated: C

H, 4.31; N, 11.24. Found: C, 57.88; H, 4.42; N, 11.42.

Example 51

2- (5-chloro-pyridin-3-yloxy) -N- (5-chloro-thiophen-2-ylmethyl) -nicotinamide

Melting point 125-127 ° C. Analysis for C ₁₆ H ₁₁ N ₃ O ₂ SC1 ₂ Calculated: C 50.54, H 2.92, N 11.05 Found: C 50.42, H 2.99, N 11.07.

Example 52

2- (5-chloropyridin-3-yloxy) -N- (5-methylthiophen-2-ylmethyl) -nicotinamide

Mp 81-83 ° C. Anal. Calcd for C ₁₇ H ₁₄ N ₃ O ₂ SC 1: C 56.75, H 3.92, N 11.68. Found: C 56.94, H 4.07, N 11.19.

Example 53

2- (5-chloropyridin-3-yloxy) -N- (5-methylfuran-2-ylmethyl) nicotinamide

Melting point 103-105 ° C. Anal. Calcd for C ₁₇ H ₁₄ N ₃ O ₃ Cl: C

H, 4.10; N, 12.22. Found: C, 59.50; H, 4.15; N, 12.08.

Example 54

2- (5-chloropyridin-3-yloxy) -N- (3-methylthiophen-2-ylmethyl) -nicotinamide

-163 • · · · · · ·

Melting point 115-117 ° C. Analysis for C ₁₇ H ₁₄ N ₃ SO ₂ C1 calculated:

C 56.75, H 3.92, N 11.68. Found: C 56.75, H 4.02, N 11.37.

Example 55

2- (5-Chloro-pyridin-3-yloxy) -N- (4-chloro-thiophen-2-ylmethyl) -nicotinamide

Mp 94-96 ° C; MS (m / e) 380/382 (M ⁺ +1).

Example 56

N-benzo [b] thiophen-2-ylmethyl-2- (5-chloropyridin-3-yloxy) -nicotinamide

Mp 160-162 ° C. Anal _. Calcd for C ₂₀ H ₁₄ N ₃ SO ₂ Cl: C 60.68, H 3.56, N 10.61. Found: C 60.90, H 3.67, N 10.49.

Example 57

N- (5-chloro-furan-2-ylmethyl) -2- (5-chloro-pyridin-3-yloxy) -nicotinamide

Melting point 111-113 ° C. H, 3.04; N, 11.54. Found: C, 53.04; H, 3.16; N, 11.21.

Example 58

2- (5-chloropyridin-3-yloxy) -N-cyclohexylmethyl-nicotinamide, m.p. 95-97 ° C. Anal. Calcd for C ₁₈ H ₂₀ N ₃ O ₂ Cl: C 62.52, H 5.83, N 12.15. Found: C 62.51, H 5.80, N 12.10.

Example 59

2- (5-chloropyridin-3-yloxy) -N- [4- (1-hydroxy-1-methylethyl) -benzyl] -nicotinamide

Mp 78-80 ° C. Anal. Calcd for C ₂₁ H ₂₀ N ₃ O ₃ Cl: C

H, 5.07; N, 10.65. Found: C, 63.24; H, 5.00; N, 10.33.

Example 60

N- [3-Chloro-5- (1-hydroxy-1-methylethyl) -thiophen-2-ylmethyl] -2- (5-chloropyridin-3-yloxy) -nicotinamide m.p. 72-74 ° C. Analysis for C ₁₉ H ₁₇ N ₃ O ₃ SC1 ₂ Calculated: C 52.66, H 3.91, N 9.59 Found: C 50.27, H 4.10, N 9.01.

Combined with an organic chloride solution

Example 61

N- (5-chlorothiophen-2-ylmethyl) -2- (4-fluorophenoxy) nicotinamide

To a stirred solution of 2- (4-fluorophenoxy) -nicotinic acid (0.200 g, 1.02 mmol), C- (5-chlorothiophen-2-yl) -methylamine (0.151 g, 1.02 mmol) and 1-hydroxybenzotriazole- hydrate (0.138 g, 1.02 mmol) in anhydrous dimethylformamide (3 mL) was added 1- (3-dimethylamino) -propyl) -3-ethylcarbodiimide hydrochloride (0.212 g, 1.11 mmol) and stirred overnight. The mixture was poured into 100 ml of water and extracted with ethyl acetate.

The extracts were washed with 1 N NaOH, water and sodium, dried over MgSO ₄ , filtered and concentrated to an oil which was purified by silica gel chromatography eluting with 30% ethyl acetate in hexane. Recrystallization from ethyl acetate / hexane gave a white solid (0.216 g). Mp 91-93 ° C. Anal. Calcd for C ₁₇ H ₁₂ N ₂ O ₂ SFC 1: C 56.28, H 3.33, N 7.72. Found: C 56.34, H 3.36, N 7.41.

Following the procedure of Example 61, the compounds of Examples 62 to 91 were prepared, but C- (5-chlorothiophen-2-yl) -methylamine was replaced with the corresponding amine. The duration of the reaction is between 1 and 24 hours.

Example 62

N- (4-chlorothiophen-2-ylmethyl) -2- (4-fluorophenoxy) nicotinamide

Melting point 99-101 ° C. Analysis for C ₁₇ H ₁₂ N ₂ SO ₂ FC1 Calculated: C 56.28, H 3.33, N 7.72 Found: C 56.40, H 3.38, N 7.60.

Example 63

N- (5-chloro-furan-2-ylmethyl) -2- (4-fluorophenoxy) -nicotinamide · - · - · - · - · - · * · • ······ · ·

-1 r Γ- · · ········ - lO J “········ ·· ·· ·· ··

Melting point 116-118 ° C. Analysis for C ₁₇ H ₁₂ N ₂ O ₃ FC1 calculated:

C 58.89, H 3.49, N 8.08. Found: C 59.07, H 3.53, N 7.97.

Example 64

N- (2,3-difluorobenzyl) -2- (4-fluorophenoxy) -nicotinamide, m.p. 71-73 ° C. Analysis for C ₁₅ H ₁₃ N ₂ O ₂ F ₃ calculated: C

H, 3.66; N, 7.82. Found: C, 63.60; H, 3.64; N, 7.70.

Example 65

N-benzo [b] thiophen-2-ylmethyl-2- (4-fluorophenoxy) -nicotinamide

M.p. 109-111 ° C. Anal. Calcd for C ₂₁ H ₁₅ N ₂ O ₂ SF: C 66.65, H 4.00, N 7.40. Found: C 66.52, H 4.02, N 7.24.

Example 66

N- (3,5-difluorobenzyl) -2- (4-fluorophenoxy) nicotinamide, m.p. 116-118 ° C. Anal. Calcd for C ₁₅ H ₁₃ N ₂ O ₂ F ₃ : C 63.69, H 3.66, N 7.82. Found: C 65.57, H 4.24, N 7.73.

Example 67

2- (4-fluorophenoxy) -N- (2,4,6-trifluorobenzyl) -nicotinamide, m.p. 128-130 ° C. Analysis for C ₁₉ H ₁₂ N ₂ O ₄ F _2: Calculated: C 60.64, H 3.21, N 7.44 Found: C 60.83, H 3.15, N 7.25.

Example 68

N- (3,4-Dichlorothiophen-2-ylmethyl) -2- (4-fluorophenoxy) -nicotinamide

M.p. 132-134 ° C. H, 2.79; N, 7.05. Found: C, 51.36; H, 2.86.

N, 7.05.

Example 69

N- (3-chlorothiophen-2-ylmethyl) -2- (4-fluorophenoxy) -nicotinamide

M.p. 134-136 ° C. Analysis for C ₁₇ H ₁₂ N ₂ SO ₂ C1F calculated:

C 56.28, H 3.33, N 7.72. Found: C 56.17, H 3.30, N 7.70.

Example 70

N- (2-chlorobenzyl) -2- (4-fluorobenzyloxy) nicotinamide, m.p. 64-66 ° C. Anal. Calcd for C ₂₀ H ₁₆ N ₂ O ₂ ClF: C 64.78, H 4.35, N 7.55. Found: C 64.88, H 4.36, N 7.48.

Example 71

2- (4-Fluorophenoxy) -N- (1H-indol-5-ylmethyl) -nicotinamide M.p. 128-130 ° C. Anal. Calcd for C ₂₁ H ₁₆ N ₃ O ₂ F: C 69.80, H 4.46, N 11.63. Found: C 69.46, H 4.29, N 11.55.

Example 72

2- (4-Fluorophenoxy) -N- (4-nitrobenzyl) -nicotinamide, m.p. 155-157 ° C. Analysis for C ₁₉ H ₁₄ N ₃ O ₄ F ^X H NMR (400 MHz, CDC1 ₃₎ d 4.80 (d, J = 6.02 Hz, 2H), 7.21 (m, 5H), 7, 51 (m, 2H), 8.20 (m, 3H), 8.35 (broad s, 1H), 8.65 (m, 1H).

Example 73

2- (4-Fluorophenoxy) -N- (2-oxo-2,3-dihydro-1H-indol-5-ylmethyl) nicotinamide

Melting point 180-182 ° C. Anal. Calcd for C ₂₁ H ₁₆ N ₃ O ₃ F: C

H, 4.27; N, 11.13. Found: C, 66.31; H, 4.31; N, 10.76.

Example 74

- (4-Fluorophenoxy) -N- (2-oxo-2,3-dihydrobenzoxazol-6-yl) -nicotinamide

Melting point 289-291 ° C. Anal _. Calcd for C ₁₉ H ₁₂ N ₃ O ₄ F: C 62.47, H 3.31, N 11.50. Found: C 61.83, H 3.08, N 11.56.

Example 75

5 - ({[2- (4-Fluorophenoxy) -pyridine-3-carbonyl] -amino} -methyl) -1H-indole-2-carboxylic acid ethyl ester

-168 • · · 4

Mp 185-187 ° C. Anal. Calcd for C ₂₄ H ₂₀ N ₃ O ₄ F: C

H, 4.65; N, 9.98. Found: C, 66.61; H, 4.66; N, 9.55.

• · · · · · · · · · · · · · · · · · · · ·

Example 76

N- (3,5-di-tert-butyl-4-hydroxybenzyl) -2- (4-fluorophenoxy) -nicotinamide

Melting point 45-47 ° C. Anal. Calcd for C ₂₇ H ₃₁ N ₂ O ₃ F: C 71.98, H 6.93, N 6.22. Found: C 72.05, H 7.08, N 6.28.

Example 77

2- (4-Fluorophenoxy) -N- [4- (1-hydroxy-1-methylethyl) -benzyl] -nicotinamide

Melting point 106-108 ° C. Analysis for C ₂₂ H ₂₁ N ₂ O ₃ F calculated: C 69.46, H 5.56, N 7.36. Found: C 69.39, H 5.48, N 7.16.

Example 78

2- (4-Fluorophenoxy) -N- (4-hydroxy-3,5-dimethylbenzyl) -nicotinamide

M.p. 142-144 ° C. Anal. Calcd for C ₂₁ H ₁₉ N ₂ O ₃ F: C

H, 5.23; N, 7.65. Found: C, 68.42; H, 5.23; N, 7.61.

Example 79

2- (4-Fluorophenoxy) -N- [5- (1-hydroxy-1-methylethyl) -furan-2-ylmethyl] -nicotinamide

Mp 88-90 ° C. Analysis for C ₂₀ H ₁₉ N ₂ O ₄ F calculated: C

H, 5.17; N, 7.56. Found: C, 64.50; H, 4.99; N, 7.69.

Example 80

N- [5- (1-ethyl-1-hydroxypropyl) -thiophen-2-ylmethyl] -2- (4-fluorophenoxy) nicotinamide

Melting point 95-97 ° C. Analysis calculated for C ₂₂ H ₂₃ N ₂ O ₃ SF: C 63.75, H 5.59, N 6.76. Found: C 63.42, H 5.27, N 7.07.

Example 81 • · • ♦ · ·

-168N- [4-chloro-5- (1-hydroxy-1-methylethyl) -thiophen-2-ylmethyl] -2- (4-fluorophenoxy) -nicotinamide

Melting point 115-117 ° C. Analysis for C ₂ oH ₁₈ N ₂ 0 ₃ SClF: Calculated: C 57.08, H 4.31, N 6.66 Found: C 57.03, H 4.10, N 6.75.

Example 82

N- [1- (4-Bromo-phenyl) -ethyl] -2- (4-fluoro-phenoxy) -nicotinamide

Melting point 120 to 122 Deň: 32 ° C. ¹ H NMR (CDCl ₃ ) d 1.60 (3H, d, J = 6.85 Hz), 5.25 (1H, m), 7.1-7.5 (9H, m), 8.10 (1H, wide s), 8.20 (1 H, m), 8.60 (1H, m).

Example 83

2- (4-Fluorophenoxy) -N- [4- (1-methoxy-1-methylethyl) -benzyl] -nicotinamide

Analysis for C ₂₃ H ₂₃ N ₂ O ₃ F MS (m / e) 395 (M ⁺ l) ^X H NMR _(CDCl3) d

1.50 (6H, s), 3.05 (3H, s), 4.72 (2H, d, J = 5.81 Hz), 7.1-7.4 (9H, m), 8.2 (9H, m) 8.65 (1 H, m).

Example 84

N- [3-chloro-5- (1-hydroxy-1-methylethyl) thiophen-2-ylmethyl] -2- (4-fluorophenoxy) nicotinamide

Mp 85-87 ° C. Analysis for C ₂₀ H ₁₈ N ₂ O ₃ SClF: Calculated: C 57.08, H 4.31, N 6.66 Found: C 57.30, H 4.36, N 6.46.

Example 85

2- (4-Fluorophenoxy) -N- [4- (1-hydroxy-cyclobutyl) -benzyl] -nicotinamide

Melting point 95-97 ° C. Anal. Calcd for C ₂₃ H ₂₁ N ₂ O ₃ F: C

H, 5.39; N, 7.14. Found: C, 70.28; H, 5.45; N, 7.03.

Example 86

N- [2-chloro-4- (1-hydroxy-1-methylethyl) -benzyl] -2- (4-fluorophenoxy) -nicotinamide

9 99 · 9

M.p. 102-104 ° C. Analysis for C ₂ H ₂₀ N ₂ O ₃ FCl calculated:

N, 6.75. Found: C, 63.69; H, 4.99; N, 6.72.

Example 87

N- (4-azetidin-1-ylbenzyl) -2- (4-fluorophenoxy) nicotinamide, m.p. 128-129 ° C. Anal. Calcd for C ₂₂ H ₂₀ N ₃ O ₂ F: C 70.01, H 5.34, N 11.13. Found: C 69.64, H 5.27, N 11.13.

Example 88

2- (4-Fluorophenoxy) -N- [4- (3-hydroxy-azetidin-1-yl) -benzyl] -nicotinamide

Melting point 157 až 159 ° C ^X H NMR (CDC1 ₃ ) d 2.08 (1 H, d, J = 7 Hz), 3.62-3, 65 (2H, m), 4.09-4.16 (2H, m) ), 4.59 (2H, d, J = 5 Hz), 4.70-4, 75 (1 H, m), 6.42 (2H, d, J = 8 Hz), 7.07-7.24 (7H, m), 8.03 (1H , wide s), 8.16-8.18 (1H, m) , 8.61-8.64 (1H, m),

MS (m / e) 394 (M ^& lt ^; + &^gt; +1).

Example 89

2- (4-Fluorophenoxy) -N- (4-pyrrolidin-1-ylbenzyl) -nicotinamide

Mp 127-128 ° C, ^X 1 HNMR (CDCl ₃₎ d 1.93-2.03 (4H, m) 3.21-3.30 (4 H, m), 4.59 (2H, d, J = 5Hz) 6.43-6.60 (2H, m), 7.06-7.24 (7 H, m), 8.00 (1 H, wide) 8,16-8,18 (1H, m),

8.62-8.64 (1 H, m)

MS (m / e) 392 (M ⁺ +1).

Example 90

2- (4-Fluorophenoxy) -N- (4-piperidin-1-ylbenzyl) -nicotinamide

M.p. 119 ⁰ C. ^X H NMR (CDCl3) d 1.51-1.74 (6H, (m) 3.09-3.15 (4 H, m), 4.61 (2H, d J = 5 Hz) 6.82-6.90 (2H, m), 7.05-7.24 (7 H, m), 8.04 (1H, wide) 8.17-8.18 (1 H, m),

8.62-8.64 (1 H, m), MS (m / e) 406 (M ⁺ +1).

Example 91

2- (4-fluorophenoxy) -N- (4-morpholin-4-ylbenzyl) -nicotinamide

-170 • € 9 · · f *

99999999 9 9 · 9

Mp 163-165 ° C. Analysis for C ₂₃ H ₂₂ N ₃ O ₃ F calculated: C 67.80, H 5.44, N 10.31. Found: C 67.42, H 5.38, N 10.37.

Example 92

2- (4-Fluorophenoxy) -N- [4- (4-oxo-piperidin-1-yl) -benzyl] -nicotinamide

The crude product was further treated in a boiling 2: 5 aqueous 1N hydrochloric acid / tetrahydrofuran solution for 2 days to hydrolyze the ketal, working up by partitioning the mixture between EtOAc and saturated aqueous sodium bicarbonate, drying the organic layer (MgSO ₄ ). and evaporation. Melting point 138-139 ° C. Analysis for C ₂₄ H ₂₂ N ₃ O ₃ F: Calculated: C 68.72, H 5.29, N 10.02 Found: C 68.60, H 5.22, N 10.01.

Example 93

2- (4-Fluorophenoxy) -N- {4 - [(2-hydroxy-2-methylpropyl) methylamino] -benzyl} -nicotinamide

1 H NMR (DMSO-d ⁶ ) d 1.04 (6H, s), 2.98 (3H, s), 3.32 (2H, s)

4.01 (2H, d, J = 6Hz), 7.01-7.11 (2H, m), 7.06-7.25 (7H, m),

8.07-8.16 (2H, m), 8.85 (1H, t J = 6Hz), MS (m / e) 424 (M ⁺ +1).

Example 94

2- (4-fluorophenoxy) -N- [4- (2-methyl- [1,3] dioxolan-2-yl) benzyl] nicotinamide

Mp 78-80 ° C, MS (m / e) 408 (M ⁺ ).

Example 95

N- (1,4-dioxa-spiro [4,5] dec-8-ylmethyl) -2- (4-fluorophenoxy) nicotinamide

Mp 88-90 ° C, MS (m / e) 487 (M ⁺ +1).

Example 96

-171 · · <r r a a * * * * * * *

N- (4,5-dichlorothiophen-2-ylmethyl) -2- (4-fluorophenoxy) -nicotinamide

127 DEG-129 DEG. Analysis for C ₁₇ H ₁₁ N ₂ O ₂ FSC1 ₂ Calculated: C 51.40, H 2.79, N 7.05 Found: C 51.65, H 3.01, N 6.93.

Example 97

N- (3,5-dichlorothiophen-2-ylmethyl) -2- (4-fluorophenoxy) -nicotinamide

Mp 132-134 ° C, MS (m / e) 397 (M ⁺ ).

Example 98

2- (5-chloropyridin-3-yloxy) -N-cyclopropylmethyl-nicotinamide

To a stirred solution of 2- (5-chloropyridin-3-yloxy) -nicotinic acid (0.200 g, 0.88 mmol), aminomethylcyclopropane hydrochloride (0.094 g, 0.88 mmol), triethylamine (0.089 g, 0.88 mmol) and 1-hydroxybenzotrazole hydrate (0.119 g, 0.88 mmol) in anhydrous dimethylformamide (3 mL) was added 1- (3-dimethylamino) propyl) -3-ethylcarbodiimide hydrochloride (0.164 g, 0.96 mmol) and Stir overnight. The mixture was poured into 100 ml of water and extracted with ethyl acetate. The combined organic extracts were washed with 1 N NaOH, water and brine, dried over MgSO ₄ , filtered and evaporated to give an oil which was purified by silica gel chromatography eluting with 2.5% methanol in methylene chloride. Recrystallization from ethyl acetate / hexane gave a white solid (0.163 g). Melting point 105-107 ° C. Anal. Calcd for C ₁₅ H ₁₄ N ₃ O ₂ Cl: C 59.31, H 4.65, N 13.83. Found: C 59.41, H 4.68, N 13.44.

Example 99

2- (3-cyano-4-fluorophenoxy) -N- [2-fluoro-4- (1-hydroxy-1-methylethyl) -benzyl] -nicotinamide

-172 · · · · · · · · · · ··············

Prepared from 2- (3-cyano-4-fluorophenoxy) -nicotinic acid and 2- (4-aminomethyl-3-fluorophenyl) -propan-2-ol in analogy to the procedure used in Example 318. Melting point 157-159 ° C MS (m / e) 422 (M ^& lt ^; + &^gt; +1).

Example 100

2- (5-Chloro-pyridin-3-yloxy) -nicotinic acid benzyl ester

To a 15 mL flask was charged 2- (5-chloropyridin-3-yloxy) -nicotinic acid (0.056 g, 0.22 mmol), benzyl alcohol (0.052 g, 0.44 mmol), 4-DMAP (~ 3 mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.048 g, 0.25 mmol), diethyl ether (4 mL) and pyridine (1 mL) and the mixture was stirred at room temperature. After 1 h, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography eluting with 9: 1 ethyl acetate / hexane to give 0.060 g of the title compound as a colorless oil. Analysis for C ₁₈ H ₁₃ C1N ₂ O ₃ MS m / z [M +] 341; ^X H NMR (CD ₃ OD) d 4.58 (s, 2H);

7.45 (m, 7H), 7.71 (s, 1H), 8.28 (m, 2H), 8.38 (m, 2H).

Following the procedure of Example 100, the compounds of Examples 101-102 were prepared, but the benzyl alcohol was replaced with the corresponding alcohol. The duration of the reaction is between 1 and 6 hours.

Example 101

2- (5-Chloro-pyridin-3-yloxy) -nicotinic acid 4-fluoro-benzyl ester

Analysis for C ₁₈ H ₁₂ N ₂ O ₃ C1F, MS m / z [M +] 359; ^X H NMR (CD ₃ OD) d

4.56 (s, 2H), 7.88 (m, 2H), 7.29 (m, 2H), 7.47 (m, 2H), 7.72 (s, 1H), 8.37 (m , 3H).

Example 102

2- (5-Chloro-pyridin-3-yloxy) -nicotinic acid 3,5-difluorobenzyl ester · ············· · · · ·

-173- ............ ·· ··

Analysis for C _1S H ₁₁ N ₂ O ₃ C1F ₂ MS m / z [M +] 77 3, ¹ H NMR (CD ₃ OD) d

4.59 (s, 2H), 6.77 (m, 2H), 6.85 (m, 3H), 7.07 (m, 1H), 7.30 (m, 1H), 8.35 (m) , 2H).

Example 103

2- (4-Fluorophenoxy) -N- (4-hydroxybenzyl) -nicotinamide To a solution of 2- (4-fluorophenoxy) -N- (4-methoxybenzyl) -nicotinamide (0.200 g, 0.568 mmol) in anhydrous methylene chloride at - A solution of 1M boron tribromide (1.7 mL, 1.7 mmol) in methylene chloride was added over 2 minutes at 78 ° C. The resulting suspension was allowed to warm to room temperature overnight. Water (5 mL) was added and the reaction mixture was diluted with ethyl acetate. The organic phase is filtered, washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated to an oil which is purified by chromatography on silica gel eluting with 60% ethyl acetate in hexane. Recrystallization from ethyl acetate / hexane gave white crystals (0.058 g)

187 ° C. Analysis for C ₁₉ H ₁₅ N ₂ O ₃ F calculated:

Found: C, 67.24; H, 4.45; N, 8.28.

Following the procedure of Example 103, the compound of Example 104 was prepared, but the 2- (4-fluorophenoxy) -N- (4-methoxybenzyl) -nicotinamide was replaced with the corresponding ether. The duration of the reaction is between 1 and 24 hours.

M.p .: 185 DEG-67.45, H 4.47, N

Example 104

N- (4-hydroxybenzyl) -2- (pyridin-3-yloxy) -nicotinamide, m.p. 156-158 ° C. Anal. Calcd for C ₁₈ H ₁₅ N ₃ O ₃ : C 67.28, H 4.70, N 13.08. Found: C 66.86, H 4.57, N 12.89.

Example 105

2- (3-nitrophenoxy) -N- [4- (2,2,2-trifluoroethoxy) -benzyl] -nicotinamide

To a stirred solution of 2- (3-nitrophenoxy) -nicotinic acid (0.200 g, 0.77 mmol), 4- (2,2,2-trifluoroethoxy) -benzylamine

** (0.173 g, 0.85 mmol) and 1-hydroxybenzotriazole hydrate (0.125 g, 0.92 mmol) in anhydrous dimethylformamide (4 mL) 1- (3-dimethylamino) -propyl) -3-ethylcarbodiimide hydrochloride (0.192 g, 1.00 mmol) was added and the mixture was stirred overnight. The mixture was diluted with 50 mL of water and extracted with ethyl acetate. The combined organic extracts were washed with 1 N NaOH, water and brine and concentrated to give a yellow solid which was purified by silica gel chromatography eluting with 35% methanol in methylene chloride. Recrystallization from ethyl acetate / hexane gave a white solid (0.340 g). Melting point 90-92 ° C. Analysis calculated for C ₂₁ H ₁₆ N ₃ O ₅ F ₃ : C 56.38, H 3.60, N 9.39. Found: C 56.35, H 3.60, N 9.47.

Following the procedure of Example 105, the compounds of Examples 106-109 were prepared, but 4- (2,2,2-trifluoroethoxy) -benzylamine was replaced with the corresponding amine. The duration of the reaction is between 1 and 24 hours.

Example 106

2- (3-nitrophenoxy) -N- (2-oxo-2,3-dihydro-1H-indol-5-ylmethyl) nicotinamide

Mp 190-192 ° C. Anal. Calcd for C ₂₁ H ₁₆ N ₄ O ₅ : C 62.17, H 3.99, N 13.85, Found: C 62.24, H 4.12, N 13.73.

Example 107

N- [4- (1-hydroxy-1-methylethyl) -benzyl] -2- (3-nitrophenoxy) -nicotinamide

Melting point 43-45 ° C. Anal. Calcd for C ₂₂ H ₂₁ N ₃ O ₅ C

H, 5.20; N, 10.31. Found: C, 64.14; H, 5.19; N, 10.23.

Example 108

N- (4-hydroxy-3,5-dimethylbenzyl) -2- (3-nitrophenoxy) nicotinamide

Mp 128-130 ° C. Anal. Calcd for C ₂₁ H ₁₉ N ₃ O ₅ : C 64.12, H 4.87, N 10.68. Found: C 63.86, H 4.71, N 10.90.

• «« ·

Example 109

N- (5-chlorothiophen-2-ylmethyl) -2- (3-nitrophenoxy) nicotinamide

Melting point 115-117 ° C. Analysis for C ₁₇ H ₁₂ N ₃ O ₄ SC1: Calculated: C 52.44, H 3.11, N 10.80 Found: C, 52.35; H, 3.06; N, 10.78.

Example 110

N- (2-chlorobenzyl) -2- (3-cyanophenoxy) nicotinamide

To a stirred solution of 2- (3-cyanophenoxy) -nicotinic acid (0.085 g, 0.35 mmol), 2-chlorobenzylamine (0.055 g, 0.38 mmol) and 1-hydroxybenzotriazole hydrate (0.057 g, 0.42 mmol) in anhydrous dimethylformamide (5 mL) was added 1- (3-dimethylamino) -propyl) -3-ethylcarbodiimide hydrochloride (0.046 g, 0.87 mmol) and the mixture was stirred overnight. The mixture was diluted with 50 mL of water and extracted with ethyl acetate. The combined organic extracts were washed with 1 N NaOH, water and brine, dried over Na ₂ SO ₄ , filtered and concentrated to give a white solid, which was purified by silica gel chromatography. Recrystallization from ethyl acetate / hexane gave a white solid (0.067 g). Melting point 135-137 ° C. Anal _. Calcd for C ₂₀ H ₁₄ N ₃ O ₂ Cl: C 66.03, H 3.88, N 11.55. Found: C 65.40, H 3.89, N 11.50.

Following the procedure of Example 110, the compounds of Examples 111 to 117 were prepared, but the 2-chlorobenzylamine was replaced with the corresponding amine. The duration of the reaction is between 1 and 24 hours.

Example 111

N- (5-chlorothiophen-2-ylmethyl) -2- (3-cyanophenoxy) nicotinamide, m.p. 145-147 ° C. Anal. Calcd for C ₁₈ H ₁₂ N ₃ O ₂ ClS: C 58.46, H 3.27, N 11.36. Found: C 58.43, H 3.06, N 11.30. Example 112

2- (3-cyanophenoxy) -N- (2-oxo-2,3-dihydro-1H-indol-5-ylmethyl) -nicotinamide

• · · · · · · · · · · · · · · · · · », ·······

-176- ········ ♦ · ·· ·· ··

Melting point 197-199 ° C. Anal. Calcd for C ₂₂ H ₁₆ N ₄ O ₃ : C 68.74, H 4.20, N 14.58. Found: C 67.71, H 4.09, N 14.50.

Example 113

2- (3-cyanophenoxy) -N- [4- (1-hydroxy-1-methylethyl) -benzyl] -nicotinamide

Melting point 97-99 ° C. Anal. Calcd for C ₂₃ H ₂₁ N ₃ O ₃ : C

H, 5.46; N, 10.65. Found: C, 70.43; H, 5.39; N, 10.75.

Example 114

N- [3-chloro-5- (1-hydroxy-1-methylethyl) thiophen-2-ylmethyl] -2- (3-cyanophenoxy) nicotinamide

Mp 71-73 ° C. Anal. Calcd for C ₂₁ H ₁₈ N ₃ O ₃ SC 1: C 58.95, H 4.24, N 9.82. Found: C 58.97, H 4.19, N 9.67.

Example 115

2- (3-cyanophenoxy) -N- [4- (1-hydroxy-cyclobutyl) -benzyl] -nicotinamide

Mp 161-163 ° C. Analysis for C ₂₆ H ₂₁ N ₃ O _3: Calculated: C 72.17, H 5.30, N 10.52 Found: C 72.23, H 5.13, N 10.46.

Example 116

N- [2-chloro-4- (1-hydroxy-1-methylethyl) benzyl] -2- (3-cyanophenoxy) nicotinamide

121-123 ° C. Analysis calculated for C ₂₃ H ₂₀ N ₃ O ₃ Cl: C 65.48, H 4.78, N 9.96. Found: C 65.35, H 4.89, N 9.83.

Example 117

2- (3-cyanophenoxy) -N- (1-cyclohexyl-3-ethyl-1H-indazol-5-ylmethyl) nicotinamide

Mp 56-58 ° C. ¹ H NMR (400 MHz, CDCl ₃ ) d 1.20-2.10 (m, 13H), 2.95 (q, J = 7.68 Hz, 2H), 4.30 (m, 1H), 4 80 (d,

J = 5.81 Hz, 2H), 6.05 (m, 1H), 7.10-7.70 (m, 8H), 8.0 (broad s, 1H), 8.20 (m, 1H) 8.70 (m, IH).

-1ΊΊ ···· · · ··

Example 118

N- (2-chlorobenzyl) -2- (3-dimethylamino-phenoxy) -nicotinamide To a stirred solution of 2- (3-dimethylaminophenoxy) -nicotinic acid (0.200 g, 0.775 mmol), 2-chlorobenzylamine (0.120 g, 0.85) mmol) and 1-hydroxybenzotriazole hydrate (0.126 g, 0.93 mmol) in anhydrous dimethylformamide (4 mL) were added 1- (3-dimethylamino) -propyl) -3-ethylcarbodiimide hydrochloride (0.193 g, 1.00 mmol). The mixture was stirred overnight. The mixture was diluted with 50 mL of water and extracted with ethyl acetate. The combined organic extracts were washed with 1 N NaOH, water and brine, dried over Na ₂ SO ₄ , filtered, and concentrated to an oil which was purified by silica gel chromatography. Recrystallization from ethyl acetate / hexane gave an oil. The product was dissolved in diethyl ether and hydrochloric acid was used to precipitate the salt, the salt was filtered off, dissolved in methylene chloride and concentrated to a solid (0.075 g). Mp 85-87 ° C. Analysis calculated for C ₂₁ H ₂₀ N ₃ O ₂ Cl · HCl: C 60.30, H 5.06, N 10.04. Found: C 60.58, H 5.60, N 9.28.

Example 119

N- (2-chlorobenzyl) -2- (4-cyanophenoxy) -nicotinamide To a stirred solution of 2- (4-cyanophenoxy) -nicotinic acid (0.130 g, 0.54 mmol), 2-chlorobenzylamine (0.083 g, 0.59) mmol) and 1-hydroxybenzotriazole hydrate (0.088 g, 0.65 mmol) in anhydrous dimethylformamide (4 mL) were added 1- (3-dimethylamino) propyl) -3-ethylcarbodiimide hydrochloride (0.134 g, 0.70 mmol). The mixture was stirred overnight. The mixture was diluted with 50 mL of water and extracted with ethyl acetate. The combined organic extracts were washed with 1 N NaOH, water and brine, dried over Na ₂ SO ₄ , filtered, and concentrated to an oil which was purified by silica gel chromatography eluting with 50:50 ethyl acetate / hexane. Recrystallization from ethyl acetate / hexane gave a white solid (0.139 g). Melting point 112

-178 up to 114 ° C. Anal _. Calcd for C ₂₀ H ₁₄ N ₃ O ₂ Cl: C 66.03, H 3.88, N 11.55. Found: C 65.90, H 3.92, N 11.67.

Following the procedure of Example 119, the compound of Example 120 was prepared, but the 2-chlorobenzylamine was replaced with the corresponding amine. The duration of the reaction is between 1 and 24 hours.

Example 120

2- (4-cyanophenoxy) -N- [4- (1-hydroxy-1-methylethyl) -benzyl] -nicotinamide

Melting point: 13 to 13 ° C. Anal. Calcd for C ₂₃ H ₂₁ N ₃ O ₃ : C 71.30, H 5.46, N 10.85. Found: C 70.95, H 5.69, N 10.96.

Example 121

N- (4-aminobenzyl) -2- (4-fluorophenoxy) nicotinamide

To a degassed solution of 2- (4-fluorophenoxy) -N- (4-nitrobenzyl) -nicotinamide (0.800 g, 2.17 mmol) in ethyl acetate was added 10% palladium on carbon (0.160 g). The mixture is shaken under a hydrogen pressure of 30 psi for 30 minutes. The catalyst was removed by filtration and the solution was concentrated to an oil which was purified by silica gel chromatography eluting with 4% methanol in methylene chloride. Recrystallization from ethyl acetate / hexane gave a solid (0.562 g). ¹ H NMR (400 MHz, CDCl ₃ ) d 3.64 (s, 2H), 4.58 (d, J = 5.60 Hz, 2H), 6.64 (d, J = 8.30 Hz, 2H 7.05 (m, 7H), 8.02 (broad s, 1H), 8.20 (m, 1H), 8.62 (d, 1H).

Example 123

N-allyl-2- (3-chlorophenoxy) nicotinamide

To a stirred solution of 2- (3-chlorophenoxy) -nicotinamide (0.084 g, 0.34 mmol) in methylsulfoxide (2 mL) was added powdered potassium hydroxide (0.074 g, 1.32 mmol) followed by allyl bromide (0.082 g, 0, 68 mmol). After 1 hour the mixture was poured into water and extracted with methylene chloride. The combined organic extracts were washed with brine, dried over MgSO ₄ .

-179- • · · · · · • · • · they are filtered and thicken to form a clear film (0.011 g) · ¹ H NMR (40 MHz, CD ₃ OD) d 4.37 (q, J = 7.26 Hz) 1H), 4.82 (d, J = 5.60 Hz, 1 H) 5.26 (d, J = 10.58 Hz, 1H), 5.40 (d, J = 17.0) Hz, 1H), 6.05 (m, 1H), 7.03 (m, 1H); 7.13 (m, 1H); 7.21 (m, 2H),

7.38 (t, J = 8.1 Hz, 1H), 8.30 (m, 2H).

Example 124

N- (4-acetylaminobenzyl) -2- (4-fluorophenoxy) -nicotinamide A solution of N- (4-aminobenzyl) -2- (4-fluorophenoxy) -nicotinamide (0.105 g, 0.31 mmol) and triethylamine (0.047 g, 0.46 mmol) in methylene chloride was cooled to 0 ° C and acetyl chloride (0.029 g, 0.37 mmol) was added. The mixture was stirred for 10 minutes and then allowed to warm to room temperature over 30 minutes. The mixture was diluted with water and extracted with methylene chloride. The combined organic extracts were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated to a solid. Recrystallization from ethyl acetate / hexane gave a white solid (0.082 g). Mp 128-130 ° C. Analysis calculated for C ₂₁ H ₁₈ N ₃ O ₃ F: C 66.48, H 4.78, N 11.08. Found: C 66.14, H 4.47, N 11.08.

Example 125

2- (3-Acetylaminophenoxy) -N- (2-chlorobenzyl) -nicotinamide To a stirred solution of 2- (3-acetylaminophenoxy) -nicotinic acid (0.400 g, 1.47 mmol), 2-chlorobenzylamine (0.228 g, 1.62) mmol) and 1-hydroxybenzotriazole hydrate (0.238 g, 1.76 mmol) in anhydrous dimethylformamide (10 mL) were added 1- (3-dimethylamino) -propyl) -3-ethylcarbodiimide hydrochloride (0.367 g, 1.91 mmol). ) and stir overnight. The mixture was diluted with water, extracted with ethyl acetate, and concentrated to give a product which was purified by silica gel chromatography eluting with 3% methanol in methylene chloride. Recrystallization gave a solid (0.351 g). Melting point: 177-179 ° C. Analysis for • · · ·

-ion · · ....--- “loU · ······· ·· ·· ·· ··

C ₂ H ₁₈ N ₃ O ₃ C1: Calculated: C 63.72 H 4.58 N 10.62 Found: C 63.47, H 4.55, N 10.56.

Following the procedure of Example 125, the compound of Example 126 was prepared, but the 2-chlorobenzylamine was replaced with the corresponding amine. The duration of the reaction is between 1 and 24 hours.

Example 126

2- (3-Acetylaminophenoxy) -N- [4- (1-hydroxy-1-methylethyl) -benzyl] -nicotinamide

Mp 155-157 ° C. Analysis calculated for C ₂₄ H ₂₅ N ₃ O ₄ : C 68.72, H 6.01, N 10.02. Found: C 67.98, H 6.04, N 9.92.

Example 127 (R) -2- (3-Chloro-phenoxy) -N- (2-hydroxy-1-phenylethyl) -nicotinamide

A solution of 2- (3-chlorophenoxy) -nicotinic acid (0.25 g, 1.0 mmol) in thionyl chloride (10 mL) was heated to reflux. After 1 hour, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was dissolved in tetrahydrofuran (5 mL) and added dropwise at 0 ° C to a solution of (S) -2-hydroxy-1-phenylethylamine (0.14 g, 1.0 mmol) in pyridine (5 mL). . After 30 minutes the mixture was warmed to room temperature. After 1 hour, the mixture was poured into 1 N hydrochloric acid and extracted with ethyl acetate. The combined organic extracts were washed with 1 N hydrochloric acid and then with brine and dried over Na ₂ SO ₄ . Concentration under reduced pressure gave a yellow oil which was purified by silica gel chromatography and eluted with 1: 1 ethyl acetate: hexane to give a colorless oil. Anal _. Calcd for C ₂₀ H ₁₇ N ₂ O ₃ Cl: C 65.13, H 4.65, N 7.60. Found: C 65.20, H 4.78, N 7.38. MS m / z [M +] 369. 1 H NMR (400 MHz, CDCl ₃ ) d 2.54 (br s, 1H), 3.95 (m, 2H), 5.32 (m, 1H), 7.23 (m, 10H), 8.22 (m, 1 H), 8.58 (m, 2 H).

· · · · ·

-181-

Example 128 (R) -2- (3-Chloro-phenoxy) -3- (4-phenyl-4,5-dihydro-oxazol-2-yl) -pyridine

A solution of (R) -2- (3-chlorophenoxy) -N- (2-hydroxy-1-phenylethyl) -nicotinamide (0.30 g, 0.813 mmol) and phosphorus oxychloride (10 mL) in toluene (10 mL) was stirred for 10 hours. The mixture was concentrated to dryness and dissolved in methanol (15 mL) and 1 N sodium hydroxide (5 mL) and heated at reflux for 2 hours. Methanol was evaporated and the residue was dissolved in water and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over Na ₂ SO ₄ and concentrated to give a product which was purified by silica gel chromatography eluting with 1: 3 ethyl acetate: hexane to give a colorless oil. Anal _. Calcd for C ₂₀ H ₁₇ N ₂ O ₂ Cl: C 68.48, H 4.31, N 7.99. Found: C 68.58, H 4.50, N 7.63. MS m / z [M +] 351, and _D = + 24.0 ^° C - 5.6 mg / ml in methylene chloride. ^: Ή

NMR (400 MHz, CDCl ₃ ) d 4.29 (dd, J = 8.4, 9.5 Hz, 1H), 5.43 (dd, J = 8.1, 10.1 Hz, 1H), 7 22 (m, 10H); 8.30 (m, 2H).

Using the procedure of Example 128, the compound of Example 129 was prepared, but substituting (R) -2- (3-chlorophenoxy) -N- (2-hydroxy-1-phenylethyl) nicotinamide for the corresponding hydroxynicotinamide. The duration of the reaction is between 1 and 24 hours.

Example 129 (S) -2-Phenoxy-3- (4-phenyl-4,5-dihydro-oxazol-2-yl) -pyridine

Analysis for C ₂₀ H ₁₆ N ₂ O ₂ calculated: C 75.93, H 5,10, N 8.85, found : C H, 5.44 N, 8.17. M.S. m / z [M +] 317, and _D = +21.3 ⁰ c = 8.3 mg / ml v methylene chloride. ¹ H NMR (400 MHz, CDCl ₃ ) d 4.30 (t, J = 8.3Hz, 1H), 4.82 (dd, J = 8.5) , 10.2 Hz, 1H), 5.43 (dd, J = 8.28 (m, 2 H). 8.2, 10.3 Hz, 1H), 7.06 (m, 1 H), 7.29 (m, 10H),

Example 130 • · · ·

-1824 - 2,2-Dimethylpropionic acid ({[2- (4-fluorophenoxy) -pyridine-3-carbonyl] -amino} -methyl) -phenyl ester

A solution of 2- (4-fluorophenoxy) -N- (4-hydroxybenzyl) -nicotinamide (0.050 g, 0.148 mmol), trimethylacetyl chloride (0.019 g, 0.163 mmol) and triethylamine (0.022 g, 0.222 mmol) in methylene chloride (5 mL) was added. Stir for 30 minutes. The mixture was diluted with 1N sodium hydroxide (50 mL) and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over Na ₂ SO ₄ , filtered, and concentrated to an oil which was purified by silica gel chromatography eluting with 40% ethyl acetate in hexane. Recrystallization from ethyl acetate / hexane gave a solid (0.043 g). Mp 91-93 ° C. Analysis for C ₂₄ H ₂₃ N ₂ O ₄ F: Calculated: C 68.24, H 5.49, N 6.63 Found: C 66.07, H 5.24, N 6.42.

Example 131

2- (4-Fluorophenoxy) -N- (4-methanesulfonylamino-benzyl) -nicotinamide

To a solution of N- (4-aminobenzyl) -2- (4-fluorophenoxy) -nicotinamide (0.150 g, 0.445 mmol) and triethylamine (0.089 g, 0.89 mmol) in methylene chloride (5 mL) was added methanesulfonic anhydride (0.100 g). g, 0.578 mmol) and stirred overnight. The mixture was concentrated to dryness, dissolved in methanol (10 mL) and 1 N sodium hydroxide (15 mL), and extracted with ethyl acetate. The product was purified by silica gel chromatography eluting with 5% methanol in methylene chloride. Recrystallization gave white crystals (0.043 g). Melting point 107-109 ° C. Analysis for C ₂₀ H ₁₈ N ₃ O ₄ SF calculated: C 57.82, H 4.37, N 10.11, found: C 57.88, H 4.39, N 9.78.

Example 132 (S) -2- (3-Chloro-phenoxy) -N- (2-hydroxy-1-phenylethyl) -nicotinamide

-183 * e t t 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 · · · ♦

A solution of 2- (3-chlorophenoxy) -nicotinic acid (0.500 g) in thionyl chloride (10 mL) was heated at reflux for 1 hour. The mixture is concentrated to dryness, dissolved in 10 ml of tetrahydrofuran and used immediately. To a solution of (S) -2-phenylglycinol (0.140 g, 1.0 mmol) in anhydrous pyridine (5 mL) at 0 ° C was added dropwise a solution of 2- (3-chlorophenoxy) nicotinoyl chloride (0.270 g, 1, 0 mmol) in tetrahydrofuran (5 mL), stirred at 0 ° C for 30 min and allowed to warm to room temperature overnight. The mixture was concentrated under reduced pressure. The resulting residue was taken up in ethyl acetate, washed with 1 N HCl, water and brine, dried over Na ₂ SO _4, and concentrated to an oil which was purified by silica gel chromatography eluting with 1: 3 ethyl acetate: hexane to afford gives a colorless oil. Anal _. Calcd for C ₂₀ H ₁₇ N ₂ O ₃ Cl: C 65.13, H 4.65, N 7.60. Found: C 65.16, H 4.63, N 6.95. [.alpha.] _D = -63.2 DEG C. = 11.0 mg / ml in methylene chloride. ¹ H NMR (400 MHz, CDCl ₃ ) d 2.47 (t, J = 5.9 Hz,

1H), 3.96 (m, 2H), 5.33 (m, 1H), 7.23 (m, 9H), 8.23 (m, 1H), 8.58 (m, 2H).

Following the procedure of Example 132, the compound of Example 133 was prepared, but the (S) -2-phenylglycinol was replaced with the corresponding amine. The reaction time is between 30 minutes and 3 hours.

Example 133

2- (3-chlorophenoxy) -N- (2-hydroxy-2-phenylethyl) nicotinamide, m.p. 118-119 ° C. Analysis calculated for C ₂₀ H ₁₇ N ₂ O ₃ Cl: C 65.13, H 4.65, N 7.59. Found: C 65.37, H 4.46, N 7.35.

Example 134 (S) -2- (3-Chloro-phenoxy) -3- (4-phenyl) -4,5-dihydro-oxazol-2-yl) -pyridine

A solution of (S) -2- (3-chlorophenoxy) -N- (2-hydroxy-1-phenylethyl) -nicotinamide (0.340 g, 0.922 mmol) and phosphorus oxychloride (0.7 mL) in toluene (10 mL) was stirred through night. The mixture is thickened to

-184 to dryness and dissolve in methanol (10 ml) and add potassium carbonate . The mixture was stirred for 2 hours at room temperature and heated to reflux for 30 minutes. The methanol was evaporated and the residue was taken up in ethyl acetate. Wash with water and brine, dry over Na ₂ SO ₄ and concentrate to give a product which is purified by silica gel chromatography eluting with 1: 3 ethyl acetate / hexane to give a pale yellow oil (0.013 g). HRMS 351.0917. Mp 78-80 ° C. Analysis for C ₂₀ H ₁₅ N ₂ O ₂ Cl calculated: C 57.37, H 3.74, N 7.42. Found: C 57.31, H 3.80, N 7.39.

Example 135

2- (3-chlorophenoxy) -3- (5-phenyl-4,5-dihydro-oxazol-2-yl-pyridine)

A solution of 2- (3-chlorophenoxy) -N- (2-hydroxy-2-phenylethyl) -nicotinamide (0.320 g, 0.868 mmol) and phosphorus oxychloride (0.7 mL) in toluene (10 mL) was stirred overnight. The mixture was concentrated to dryness and dissolved in methanol (10 mL) and potassium carbonate was added. The mixture was stirred for 2 hours at room temperature and heated to reflux for 30 minutes. The methanol was evaporated and the residue was taken up in ethyl acetate. Wash with water and brine, dry over Na ₂ SO ₄ and concentrate to give a product which is purified by silica gel chromatography eluting with 1: 3 ethyl acetate: hexane to give a pale yellow oil (0.102 g). HRMS 351.0897. ^{Χ Η} NMR (400 MHz, _CDCl3) d 4.06 (dd, J = 8, 15.0 Hz, 1H), 4.56 (dd, J = 10.3, 15.0 Hz, 1H) ,

5.66 (dd, J = 8.0, 10.3 Hz, 1H), 7.24 (m, 10H), 8.27 (m, 2H).

Example 136

2- (2-Chloro-phenyl) -N- [2- (4-fluoro-phenoxy) -pyridin-3-yl] -acetamide

To a stirred solution of 2-chlorobenzoic acid (0.228 g, 1.34 mmol), 2- (4-fluorophenoxy) -pyridin-3-ylamine (0.300 g, 1.47 mmol) and 1-hydroxybenzotriazole hydrate (0.217 g, 1 , 61 mmol) in · · · · · · · · · ♦ · ♦ · · · · · · · · · · · · · v · ···· ····

Anhydrous dimethylformamide (10 mL) was added 1- (3-dimethylamino) -propyl) -3-ethylcarbodiimide hydrochloride (0.335 g, 1.74). mmol) and stirred overnight. The mixture was diluted with 50 mL of water and extracted with ethyl acetate. The combined organic extracts were washed with 1 N NaOH, water and brine, dried over Na ₂ SO ₄ , filtered and concentrated to give an oil which was purified by silica gel chromatography. Recrystallization from ethyl acetate / hexane gave a solid (0.230 g). Mp 73-75 ° C. Analysis for C ₁₉ H ₁₄ N ₂ O ₂ C1F Calculated: C, 63.95, H, 3.95, N, 7.85 Found: C 63.64, H 3.85, N 8.41.

Following the procedure of Example 136, the compound of Example 137 was prepared, but the 2-chlorobenzoic acid was replaced with the corresponding carboxylic acid. The duration of the reaction is between 1 and 24 hours.

Example 137

2- (4-Acetylphenyl) -N- [2- (4-fluorophenoxy) pyridin-3-yl] acetamide

Melting point 118-120 ° C. Anal. Calcd for C ₂₁ H ₁₇ N ₂ O ₃ F: C 69.22, H 4.70, N 7.69. Found: C 68.90, H 5.75, N 8.54.

Example 138

N- (2-chlorobenzyl) -2- {3- [3- (2-methoxyphenyl) -ureido] -phenoxy} -nicotinamide

A solution of 2- (3-aminophenoxy) -N- (2-chlorobenzyl) -nicotinamide (0.100 g, 0.28 mmol) and 1-isocyanato-2-methoxybenzene (0.063 g, 0.42 mmol) in dioxane (10 mL) Heat to reflux overnight. The mixture was cooled to room temperature and concentrated to an oil which was purified by silica gel chromatography eluting with 2% methanol in methylene chloride to give a solid. Recrystallization from ethyl acetate / hexane gave a solid (0.083 g). Melting point 180-182 ° C. Analysis calculated for C ₂₇ H ₂₃ N ₄ O ₄ Cl: C 64.48, H 4.61, N 11.14. Found: C 64.55, H 4.60, N 10.74.

• · · · · · · ·

-186- ········ ·· ·· ·· ··

Following the procedure of Example 138, the compound of Example 139 was prepared, but the 1-isocyanato-2-methoxybenzene was replaced with the corresponding isocyanate. The duration of the reaction is between 1 and 24 hours.

Example 139

N- (2-chlorobenzyl) -2- [3- (3-naphthalen-1-yl-ureido) -phenoxy] -nicotinamide

121-123 ° C. Analysis for C ₂ oH _{3 4} 0 3 N ₃ Cl Calculated: C 68.90, H 4.43, N 10.71 Found: C 69.24, H 4.52, N 10.28.

Example 140 (-) - N- [1- (5-Chloro-thiophen-2-yl) -ethyl] -2- (4-fluoro-phenoxy) -nicotinamide

N- [1- (5-chlorothiophen-2-yl) -ethyl] -2- (4-fluorophenoxy) -nicotinamide (0.750 g) was separated on a Chiral Cel AS column eluting with 95% hexane in isopropanol. Mp 78-80 ° C. Anal. Calcd for C ₁₈ H ₁₄ N ₂ O ₂ ClSF: C 57.37, H 3.74, N 7.42, found: C

H, 3.68; N, 7.42. alpha _D = -53.9 ⁰ (c = 0.2, chloroform).

Following the procedure of Example 140, the compound of Example 141 was prepared.

Example 141 (+) -N- [1- (5-Chloro-thiophen-2-yl) -ethyl] -2- (4-fluoro-phenoxy) -nicotinamide

Melting point 78-90 ° C. Analysis for C ₁₈ H ₁₄ N ₂ O ₂ C1SF Calculated: C 57.37, H 3.74, N 7.42 Found: C, 57.31; H, 3.80; N, 7.39. [α] _D = +52.8 ° (c = 0.3, chloroform).

Example 142 cis-2- (3-chlorophenoxy) -3- (4-phenyl- [1,3] dioxolan-2-yl) -pyridine

A solution of 2- (3-chlorophenoxy) -pyridine-3-carbaldehyde (0.182 g, 0.8 mmol), (S) -1-phenylethane-1,2-diol (0.110 g, 0.8 mmol), and PTSA (0.005 g) in toluene (10 ml) was heated at reflux for 48 hours. The mixture was concentrated and purified by silica gel chromatography, eluting with 4: 1 hexane / diethyl ether to give a colorless oil. Anal _. Calcd for C ₂₀ H ₁₆ NO ₃ Cl Calculated: C 67.90, H 4.56, N 3.96. Found: C 68.57, H 5.16,

N, 3.52. [α] _D = +49.5 °. ¹ H NMR (400 MHz, CDCl ₃ ) d 3.97 (dd, J = 7.0,

7.8 Hz, 1H), 4.41 (dd, J = 7.1, 7.7 Hz, 1H), 5.24 (t, J = 7.0 Hz, 1H), 6.36 (s, 1H), 7.25 (m, 10H), 8.09 (m, 1H), 8.19 (m, 1H).

Following the procedure of Example 142, the compound of Example 143 was prepared, but the (S) -1-phenylethane-1,2-diol was replaced with the corresponding diol. The duration of the reaction is between 1 and 24 hours.

Example 143 trans-2- (3-chlorophenoxy) -3- (4-phenyl- [1,3] dioxolan-2-yl) -pyridine

Analysis for C ₂₀ H ₁₆ NO ₃ Cl. HRMS 354.0894. _D = +40.5 DEG, ^X H NMR (400 MHz, CDC1 ₃₎ d 3.91 (t, J = 8 Hz, 1H), 4.57 (dd, J = 6.2, 8, 3 Hz, 1H), 5.27 (t, J = 7.0 Hz, 1H), 6.52 (s, 1H), 7.25 (m, 10H), 8.05 (m, 1H), 8 17 (m, 1 H).

Example 144

2- (3-Aminophenoxy) -N- (2-chlorobenzyl) -nicotinamide To a solution of 2- (3-nitrophenoxy) -N- (2-chlorobenzyl) -nicotinamide (0.530 g, 1.38 mmol) in methanol (15 mL) ) and tetrahydrofuran (20 ml) were added 10% PtO ₂ (0.50 g). The mixture is shaken under hydrogen pressure for 1 hour and 40 minutes. The catalyst was removed by filtration and the solution was concentrated to an oil which was purified by silica gel chromatography eluting with 2.5% methanol in methylene chloride. Recrystallization from ethyl acetate / hexane gave crystals (0.327 g). Mp 101-103 ° C. Anal _. Calcd for C ₁₉ H ₁₆ N ₃ O ₂ Cl: C 64.5, H 4.56, N 11.88. Found: C 64.15, H 4.07, N 11.80.

«·« ·

-188 Example 145 (-) - N- [1- (5-Chloro-thiophen-2-yl) -ethyl] -2- (pyridin-3-yloxy) -nicotinamide

N- [1- (5-chloro-thiophen-2-yl) -ethyl] -2- (pyridin-3-yloxy) -nicotinamide (0.776 g) was separated on a Chiral Cel AD column eluting with 9: 1 heptane / isopropanol to give the product is obtained in the form of an oil. Recrystallization from ethyl acetate / hexane gave a white solid (0.217 g). Melting point 82-84 ° C. α _D = -51.5 ° (c = 0.2, CHCl ₃ ).

Following the procedure of Example 145, the compound of Example 146 was prepared.

Example 146 (+) - N- [1- (5-Chloro-thiophen-2-yl) -ethyl] -2- (pyridin-3-yloxy) -nicotinamide

Melting point 83-85 ° C. α _D = +49.8 ° (c = 0.3, CHCl ₃ ).

Example 147 (-) - 2- (5-Chloro-pyridin-3-yloxy) -N- [1- (5-chloro-thiophen-2-yl) -ethyl] -nicotinamide

2- (5-Chloro-pyridin-3-yloxy) -N- [1- (5-chloro-thiophen-2-yl) -ethyl] -nicotinamide (0.800 g) was separated on a Chiral Cel AD column eluting with 90: 9.9: 0.1 heptane, isopropanol and diethyl ether to give a solid. Recrystallization from ethyl acetate / hexane gave a solid (0.393 g). M.p. 133-135 ° C. α _D = -48.8 ° (c = 0.2).

Following the procedure of Example 147, the compound of Example 148 was prepared.

Example 148 (+) - 2- (5-Chloro-pyridin-3-yloxy) -N- [1- (5-chloro-thiophen-2-yl) -ethyl] -nicotinamide

Mp 133-135 ° C. and _D = +40,6 ⁰ (c = 0.2).

• ·

Example 149 (R) -N- (2-Hydroxy) -1-phenylethyl) -2- (pyridin-3-yloxy) nicotinamide

A solution of 2- (pyridin-3-yloxy) -nicotinic acid (0.250 g, 1.2 mmol) in thionyl chloride (10 mL) was heated to reflux. After 1 hour, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was suspended in tetrahydrofuran (10 mL) and added dropwise at 0 ° C to a solution of (R) -2-hydroxy-1-phenylethylamine (0.160 g, 1.2 mmol) in pyridine (5 mL). After 30 minutes, warm the mixture to room temperature, stir at room temperature for 1 hour, and concentrate to remove pyridine. The crude product was purified by silica gel chromatography and eluted with ethyl acetate to give a yellow oil. HRMS 336.1324. and _D = +63.9 °, 12.6 mg / ml in methylene chloride. ¹ H NMR (400 MHz, CDCl ₃ ) d 2.76 (broad s, 1H), 3.95-4.02 (m, 2H),

5.31-5.36 (m, 1H); 7.16-7.40 (m, 1H); 8.19 (dd, J = 2.1 Hz, 4.8)

Hz, 1H), 8.48-8.61 (m, 4H).

Example 150 (R) -3- (4-Phenyl-4,5-dihydro-oxazol-2-yl) -2- (pyridin-3-yloxy) -pyridine

A solution of (R) -N- (2-hydroxy-2-phenyl-ethyl) -2- (pyridin-3-yloxy) -nicotinamide (0.050 g, 0.16 mmol) and phosphorus oxychloride (150 μΐ, 1.6 mmol) in toluene (10 mL) was stirred overnight. The mixture was concentrated to dryness and dissolved in methanol (10 mL) and potassium carbonate (250 mL) was added. The mixture was stirred for 24 hours at room temperature. The methanol was evaporated and the residue was taken up in ethyl acetate. Wash with water and brine, dry over Na ₂ SO ₄ and concentrate to give a product which is purified by silica gel chromatography and eluting with 1: 1 ethyl acetate: hexane to give a colorless oil (0.020 g). HRMS 318.1227. cc _D = + 21.2 °, 9.5 mg / ml in methylene chloride. ¹ H NMR (400 MHz, CDCl 3) d 4.31 (t, J = 8.3 Hz, 1H), 4.83 (dd, J = 8.3 Hz,

-190 ·········

10.2 Hz, 1H), 5.46 (dd, J = 8.1 Hz, 10.2 Hz, 1H), 7.07-7.20 (m,

1H), 7.27-7.43 (m, 6H), 7.53-7.57 (m, 1H), 8.22-8.53 (m, 4H).

Using the procedure of Example 150, the compound of Example 151 was prepared, but substituting (R) -N- (2-hydroxy-2-phenylethyl) -2- (pyridin-3-yloxy) -nicotinamide for the corresponding hydroxynicotinamide. The duration of the reaction is between 1 and 24 hours.

Example 151 (S) -3- (4-Phenyl-4,5-dihydro-oxazol-2-yl) -2- (pyridin-3-yloxy) -pyridine

HRMS 318.1267. and _D = -19.2 °, 11.2 mg / ml in methylene chloride. ^X H

NMR (400 MHz, CDC1 ₃ ) d 4.31 (t, J = 8) , 3 Hz (1H), 4.83 (dd, J = = 10.2 Hz, 8.3 Hz, 1H), 5, 46 (dd, J = 10.2 Hz, 8.1 Hz, 1H), 7.09- -7.57 (m, 7H), 7,54-7,57 (m, 1 H), 8.23) dd, J = 4.8 Hz, 1.9 Hz, 1H),

8.32-8.53 (m, 3H).

Example 152 (S) -N- (2-Hydroxy-1-phenylethyl) -2- (pyridin-3-yloxy) nicotinamide

A solution of 2- (pyridin-3-yloxy) -nicotinic acid (0.500 g) in thionyl chloride (10 mL) was heated at reflux for 1 hour. The mixture is concentrated to dryness, dissolved in 10 ml of tetrahydrofuran and used immediately. To a solution of (S) -2-phenylglycinol (0.190 g, 1.4 mmol) in anhydrous pyridine (5 mL) at 0 ° C was added a solution of 2- (3-pyridin-3-yloxy) nicotinoyl chloride (0.325 g, 1 mL). (4 mmol) in tetrahydrofuran (5 mL) and pyridine (5 mL), stirred at 0 ° C for 30 min and allowed to warm to room temperature overnight. The mixture was concentrated under reduced pressure and the concentrated crude product was purified by silica gel chromatography and eluting with 1: 1 ethyl acetate: hexane to give a colorless oil. HRMS 336.1358. alpha _D = -69.2 °, c = 6.2 mg (ml methylene chloride. ^X H NMR (400 MHz, CDC1 ₃₎ d 2.77 (br s, 1H), 3.98-4.08 (m , 2H), •

-1915.31-5.36 (m, 1H), 7.14-7.40 (m, 7H), 7.57-7.60 (m, 1H), 8.19 (dd, J = 1, 9 Hz, 4.8 Hz, 1H), 8.44-8.61 (m, 4H).

By the procedure of Examples 153 corresponding hours.

according to Example 152, compounds of up to 156 were prepared, but (S) -2-phenylglycinol was replaced with an amine. The duration of the reaction is between 1 and 24

Example 153 (R) -N- (1-Hydroxymethyl-2-methyl-propyl) -2-pyridin-3-yloxy) -nicotinamide

HRMS 3 02.15050. cc _D = + 6.1 °, 8.7 mg / ml in methylene chloride. ^X H

NMR (400 MHz, CDClj) d 1.00 (dd, J = 14.9 Hz, 6.8 Hz, 6H) 1.98-2.07 (m, 1H), 2.99 (wide s, (1H), 3.73-3.83 (m, 2H) 4.01-4.11 (m, 1H), 7.18-7.24 (m, 1H), 7.38-7.42 (m, 1H)

7.55-7.58 (m, 1H), 7.98 (d, J = 6.6 Hz, 1H), 8.18 (dd, J = 4.8 Hz,

2.1 Hz, 1H), 8.52-8.62 (m, 3H).

Example 154 (S) -N- (1-Hydroxymethyl-2-methyl-propyl) -2- (pyridin-3-yloxy) -nicotinamide

HRMS 302.1475. and _D = -6.3 °, 10.4 mg / ml in methylene chloride. ^X H

NMR (400 MHz, CDC1 ₃ ) d 1.00 (dd, J = 14.9 Hz, 6.8 Hz, 6H), 2,00-2,07 (m, 1 H), 3 , 09 (wide s, 1H), 3.75-3.78 (m, 2H), 4.01-4.07 (m, 1 H), 7.18-7.25 (m, 1H), 7.38-7.41 (m, 1H), 7,54-7,57 (m, 1 H), 7, 98 (d, J = 6.8Hz) (1H), 8.17-8.19 (m. 1H),

8.48-8.53 (m, 2H); 8.59-8.61 (m, 1H).

Example 155 (S) -N- (1-Hydroxymethyl) -2-methyl-butyl) -2- (pyridin-3-yloxy) -nicotinamide

HRMS 316.1661. α _D = -10.8 °, 10.0 mg / ml in methylene chloride. ^X H

NMR (400 MHz, CDCl ₃ ) d 0.91 (t, J = 7.3 Hz, 3H), 0.99 (d, J = 8.8

Hz, 3H), 1.15-1.27 (m, 1H), 1.53-1.60 (m, 1H), 1.74-1.84 (m, 1H), 2.78 (broad s (1H), 3.74-3.87 (m, 2H), 4.08-4.14 (m,

1H), 7.19-7.24 (m, 2H), 7.41 (dd, J = 8.1 Hz, 4.57 Hz, 1H), 7.55-7.58 (m, 1H), 8.00 (d, J = 7.3Hz, 1H), 8.19 (dd, J = 4.8Hz,

1.9 Hz, 1H), 8.53 (s, 1H), 8.60-8.63 (m, 1H).

Example 156

N- (2-hydroxy-1,1-dimethyl-ethyl) -2- (pyridin-3-yloxy) -nicotinamide

HRMS 288.1376. ¹ H NMR (400 MHz, CDCl ₃ ) d 1.41 (s, 6H), 3.70 (d, J = 5.6 Hz, 2H), 4.54 (broad s, 1H), 7.19 ( dd, J = 6.6 Hz, 4.8 Hz, 1H), 7.39-7.42 (m, 1H), 7.55-7.58 (m, 1H), 7.94 (broad s, 1H), 8.18 (dd, J = 4.8Hz, 2.1Hz, 1H), 8.53-8.59 (m, 3H).

Example 157

N- (2-chlorobenzyl) -2- (1H-indol-4-yloxy) -nicotinamide

To a stirred solution of 2- (1H-indol-4-yloxy) -nicotinic acid (0.055 g, 0.216 mmol), 2-chlorobenzylamine (0.034 g, 0.238 mmol) and 1-hydroxybenzotriazole hydrate (0.035 g, 0.259 mmol) in anhydrous Dimethylformamide (5 mL) was added 1- (3-dimethylamino) -propyl) -3-ethylcarbodiimide hydrochloride (0.054 g, 0.281 mmol) and stirred overnight. The mixture was diluted with 100 mL of water and extracted with ethyl acetate. The combined organic extracts were washed with 1 N NaOH, water and brine, dried over Na ₂ SO ₄ , filtered and concentrated to give an oil which was purified by silica gel chromatography. Recrystallization from ethyl acetate / hexane gave a pink / white solid (0.053 g). Mp 185-187 ° C. Anal. Calcd for C ₂₁ H ₁₆ N ₃ O ₂ Cl: C 66.76, H 4.27, N 11.12. Found: C 66.42, H 4.14, N 10.95.

Following the procedure of Example 157, the compound of Example 158 was prepared, but the 2-chlorobenzylamine was replaced with the corresponding amine. The duration of the reaction is between 1 and 24 hours.

Example 158

-193 • ♦ ·· ····

N- (5-chlorothiophen-2-ylmethyl) -2- (1H-indol-4-yloxy) -nicotinamide

M.p. 157-159 ° C. Anal _. Calcd for C ₁₉ H ₁₄ N ₃ O ₂ ClS: C 59.45, H 3.68, N 10.9. Found: C 59.38, H 3.94, N 10.95.

Example 159

N- (5-acetylthiophen-2-ylmethyl) -2- (pyridin-3-yloxy) -nicotinamide

A solution of N- [5- (2-methyl- [1,3] dioxolan-2-yl) -thiophen-2-ylmethyl] -2- (pyridin-3-yloxy) -nicotinamide (0.680 g) in 2 N hydrochloric acid (20 mL) and methylene chloride (20 mL) were stirred at room temperature overnight. The mixture was extracted with chloroform, washed with water, dried over MgSO ₄ , filtered and concentrated to give a solid which was triturated in diethyl ether to give a white solid (0.480 g). Mp 201-203 ° C. Analysis for C ₁₈ H ₁₅ N ₃ O ₃ S Calculated: C 61.18, H 4.28, N 11.89 Found: C 60.09, H 4.25, N 11.61.

Example 160

N- [5- (1-hydroxy-ethyl) -thiophen-2-ylmethyl] -2- (pyridin-3-yloxy) -nicotinamide

To a stirred suspension of N- (5-acetyl-thiophen) -2-ylmethyl) -2- (pyridin-3-yloxy) -nicotinamide (0.300 g, 0.85 mmol) in methylene chloride (25 mL) and tetrahydrofuran (25 mL) Sodium borohydride (0.035 g, 0.93 mmol) was added at room temperature and stirred for 2 hours. Saturated NH ₄ Cl (~ 1 mL) was added to the mixture and concentrated under reduced pressure to about 15 mL. The mixture was poured into water and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over MgSO ₄ , filtered, and concentrated to an oil which was purified by silica gel chromatography eluting with 5% methanol in methylene chloride. Recrystallization from ethyl acetate / hexane gave a white solid (0.207 g).

· · · · · · · · ·

194 Melting point 92-94 ° C. Analysis for C ₁₈ H ₁₇ N ₃ O ₃ S Calculated: C 60.83, H 4.82, N 11.82 Found: C, 60.68; H, 4.77; N, 11.89.

Example 161

3- (5-Phenyl-4,5-dihydro-oxazol-2-yl) -2- (pyridin-3-yloxy) -pyridine

A solution of N- (2-hydroxy-2-phenylethyl) -2- (pyridin-3-yloxy) -nicotinamide (0.450 g, 1.3 mmol) and phosphorus oxychloride (1.25 mL, 13 mmol) in toluene (5 mL) is stirred overnight. The mixture was concentrated to dryness and dissolved in methanol (5 mL) and potassium carbonate (0.500 g) was added. The mixture was stirred at room temperature overnight. The mixture was poured into water and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over Na ₂ SO ₄ and concentrated to give an oil which was purified by silica gel chromatography to give a colorless oil (0.042 g) eluting with ethyl acetate. HRMS

318.1269. ¹ H NMR (400 MHz, CDCl ₃ ) d 4.09 (dd, J = 15.1 Hz, 8.1 Hz, 6H), 4.57 (dd, J = 15.1 Hz, 10.3 Hz, 1H), 5.67 (dd, J = 10.2)

Hz, 7.9 Hz, 1H), 7.09-7.13 (m, 1H), 7.32-7.39 (m, 6H),

7.54-7.57 (m, 1H), 8.20-8.22 (m, 1H), 8.29-8.31 (m, 1H), 8.46 (dd, J = 4.6) Hz, 1.0 Hz, 1H), 8.61-8.64 (m, 1H).

Example 162 (S) -3- (4-Isopropyl-4,5-dihydro-oxazol-2-yl) -2- (pyridin-3-yloxy) -pyridine

A solution of N- (1-hydroxy-2-methyl-propyl) -2- (pyridin-3-yloxy) -nicotinamide (0.090 g, 0.299 mmol) and phosphorus oxychloride (1.0 mL) in toluene (5 mL) was stirred through night. The mixture was concentrated to dryness and dissolved in methanol (5 mL) and potassium carbonate (0.250 g) was added. The mixture was stirred at room temperature overnight. The mixture was poured into water and extracted with ethyl acetate. The combined organic extracts were washed with brine and concentrated to give a product which was purified by silica gel chromatography to give ethyl acetate.

-195- 9 « • • 9 9 9 • «99 9999 9 9 · · · · 9 «« 99 9 9999 99 9 <99 9 9 9 9 9 colorless oil (0.053 g). MS m / z [M +] 2 84. and _D = + 47.1 °, 5.5 mg / ml in methylene chloride. ¹ H NMR (400 MHz, CDC1 ₃ ) d 0.98 (dd, J = 32.8 Hz, 6.6 Hz, 6H), 1.78 -1.89 (m, 1H), 4.12-4 19 (m, 2H);

4.39-4.46 (m, 1H), 7.07-7.10 (τη, 1H), 7.31-7.34 (m, 1H), 7.51-7.54 (m, 1H) 8.18-8.22 (m, 2H); 8.44-8.50 (m, 2H).

Following the procedure of Example 162, the compound of Example 163 was prepared, but N- (1-hydroxy-2-methyl-propyl) -2- (pyridin-3-yloxy) -nicotinamide was replaced with the corresponding hydroxynicotinamide. The duration of the reaction is between 1 and 24 hours.

Example 163 (R) -3- (4-Isopropyl-4,5-dihydro-oxazol-2-yl) -2- (pyridin-3-yloxy) -pyridine

HRMS 284.13915. α _D = -52.7 °, 10.0 mg / ml in methylene chloride. ^X H

NMR (400 MHz, CDCl ₃ ) d 0.98 (dd, J = 32.8 Hz, 6.6 Hz, 6H),

1.86-1.92 (m, 1H), 4.12-4.19 (m, 2H), 4.39-4.45 (m, 1H), 7.08 (dd, J = 7.5) Hz, 4.8 Hz, 1H), 7.31-7.34 (m, 1H), 7.51-7.5 (m,

1H), 8.18-8.22 (m, 2H), 8.44 (dd, J = 4.5Hz, 1.2Hz, 1H), 8.50 (d, J = 2.7Hz, 1H).

Example 164 (R) -3- (4-sec-Butyl-4,5-dihydro-oxazol-2-yl) -2- (pyridin-3-yloxy) -pyridine

A solution of N- (1-hydroxymethyl) -2-methyl-butyl) -2- (pyridin-3-yloxy) -nicotinamide (0.120 g, 0.400 mmol) and phosphorus oxychloride (400 μΐ, 4.0 mmol) in toluene (5 mL) ) was stirred overnight. The mixture was concentrated to dryness and dissolved in methanol (5 mL) and potassium carbonate (0.250 g) was added. The mixture was concentrated to give a crude product which was purified by silica gel chromatography and eluted with ethyl acetate to give a colorless oil (0.060 g). Anal. Calcd for C ₁₇ H ₁₉ N ₃ O ₂ : C 68.67, H 6.44, N 14.13. Found: C 68.28, H 6.82, N 13.33. HRMS 298.1530. and _D = -42.9 °, 11.2 mg / ml in methylene chloride. ¹ H NMR (400MHz, CDCl ₃ ) d 0.95 (t, J = 7.3 Hz, 3H), 1.19-1.30 (m, 1H), 1.54-1.62 (m, 1H ), • · · · · ·

-196 ·········

1.71-1.77 (m, 1H), 4,14-4,18 (m, 1H), 4.25-4.31 (m, 1H), 4.40 (dd, J = 9) 8 Hz , 7.1 Hz, 1H) 7.08 (dd, J = 7.5Hz, 5.0 Hz, 1H), 7.31-7.35 (m, 1H) , 7,51-7, 54 (m, 1 H), 8.18-8, 22nd (m, 2H), 8,44-8,50 (m, 2H).

Example 165

5 - ({[2- (4-Fluorophenoxy) -pyridine-3-carbonyl] -amino} -methyl) -1H-indole-2-carboxylic acid

A solution of 5 - ({[2- (4-fluorophenoxy) -pyridine-3-carbonyl] -amino} -methyl) -1H-indole-2-carboxylic acid ethyl ester (0.043 g, 0.099 mmol) in 1 N sodium hydroxide (0 (25 mL, 0.25 mmol) and ethanol (5 mL) was heated at reflux for 9 hours. The mixture was concentrated to dryness under reduced pressure and dissolved in water (2 mL). The mixture was acidified with 2N hydrochloric acid to give a white solid which was collected by filtration (0.032 g). Mp 236-238 ° C. Analysis calculated for C ₂₂ H ₁₆ N ₃ O ₄ F: C 65.18, H 3.98, N 10.37. Found: C 65.12, H 4.08, N 10.20.

Example 166 (R) -3- (4-Phenyl- [1,3] dioxolan-2-yl) -2- (pyridin-3-yloxy) -pyridine

A solution of 2- (pyridin-3-yloxy) -pyridine-3-carbaldehyde (0.150 g, 0.75 mmol), (R) -1-phenylethane-1,2-diol (0.105 g, 0.75 mmol) and pTSA (0.005 g) in toluene (10 mL) was heated at reflux overnight. The mixture was concentrated under reduced pressure and dissolved in ethyl acetate. The organic phase was washed with saturated bicarbonate and brine, dried over Na ₂ SO ₄ and purified by silica gel chromatography to give a yellow oil (cis / trans mixture) eluting with diethyl ether. HRMS 321.1260. and _D = -46.3 °, 9.2 mg / mL in methylene chloride. ^X H

NMR (400 MHz, CDCl ₃ ) d 3.93-4.00 (m, 1H), 4.42 (dd, J = 7.9 Hz, 7.0 Hz, 1 / 2H), 4.56-4 60 (m, 1H), 5.25-5.30 (m, 1H), 6.39

-197 (s, 1 / 2H), 6.56 (s, 1 / 2H), 7.10-7.12 (m, 1H), 7.30-7.40 (m,

6H), 7.49-7.55 (m, 1H), 8.02-8.16 (m, 2H), 8.43-8.52 (m, 2H).

Following the procedure of Example 166, the compounds of Examples 167-169 were prepared, but the (R) -1-phenyl-ethane-1,2-diol was replaced with the corresponding diol. The duration of the reaction is between 1 and 24 hours.

Example 167 (S) -3- (4-phenyl- [1,3] dioxolan-2-yl) -2- (pyridin-3-yloxy) -pyridine

Anal _. Calcd for C ₁₉ H ₁₆ N ₂ O ₃ : C 71.24, H 5.03, N 8.74. Found: C 71.02, H 5.32, N 8.03. and _D -48.8 °, 12.8 mg / ml in methylene chloride. ¹ H NMR (400 MHz, CDCl ₃ ) d 3.90-4.00 (m, 1H),

4.42 (dd, J = 7.9 Hz, 7.1 Hz, 1 / 2H), 4.56-4.58 (m, 1 / 2H),

5.20-5.28 (m, 1H), 6.40 (s, 1 / 2H), 6.57 (s, 1 / 2H), 7.08-7.12 (m, 1H), 7, 32-7.41 (m, 6H); 7.53-7.55 (m, 1H); 8.10-8.15 (m,

2H), 8.44-8.54 (m, 2H).

Example 168 (S) -3- [4- (2-Chloro-phenyl) - [1,3] dioxolan-2-yl] -2- (pyridin-3-yloxy) -pyridine

Analysis for C ₁₉ H ₁₅ N ₂ O ₃ C1. HRMS 355.0864. and _D = + 55.5 °, 12.1 mg / ml in methylene chloride. ^τ Η NMR (400 MHz, CDCl ₃ ) d 3.80-3.96 (m,

1H), 4.56-4.60 (m, 1 / 2H), 4.78-4.82 (m, 1 / 2H), 5.58-5.62 (m,

1H), 6.39 (s, 1 / 2H), 6.53 (s, 1 / 2H), 7.11-7.15 (m, 1H), 7.20-7.38 (m, 5H) 7.53-7.60 (m, 1H); 8.06-8.18 (m, 2H); 8.44-8.54 (m, 2H).

Example 169 (R) -3- [4- (2-Chloro-phenyl) - [1,3] dioxolan-2-yl] -2- (pyridin-3-yloxy) -pyridine

Mixture of cis and trans isomers: Anal _. Calcd for C ₁₉ H ₁₅ N ₂ O ₃ Cl: C 64.32, H 4.26, N 7.90, Found: C 64.31, H 4.42

N, 7.72. and _D = -61.1 °, 10.2 mg / ml in methylene chloride. @ ³ H NMR.

-198 (400MHz, CDC1 ₃₎ d 3.82 (dd, J = 8.2 Hz, 7.3 Hz, 1 / 2H), 3.95 (dd, J = 7.2 Hz, 6.2 Hz, 1 / 2H), 4.58 (dd, J = 8.0 Hz, 7.3 Hz, 1 / 2H),

4.80 (dd, J = 8.5 Hz, 6.4 Hz, 1 / 2H), 5.58-5.62 (m, 1H), 6.39 (s,

1 / 2H), 6.53 (s, 1H), 7.10-7.15 (m, 1H), 7.24-7.38 (m, 4H),

7.55-7.68 (m, 2H), 8.06-8.18 (m, 2H), 8.45-8.55 (m, 2H).

Example 170

2- [2- (pyridin-3-yloxy) -pyridin-3-yl] -3-oxa-1-aza-spiro [4.4] non-1-ene

A solution of N- (1-hydroxymethyl-cyclopentyl) -2- (pyridin-3-yloxy) -nicotinamide (0.045 g, 0.144 mmol) and phosphorus oxychloride in toluene (5 mL) was stirred overnight. The mixture was concentrated to dryness and dissolved in methanol (5 mL) and potassium carbonate was added. The mixture was concentrated to give a crude product which was purified by silica gel chromatography and eluted with ethyl acetate to give a yellow oil (0.021 g). HRMS 296.1417. ³ H NMR (400 MHz, CDC1 ₃₎ d

1.65 -1.74 (m, 4H), 1.86-1.91 (m, 2H), 1.96-2.03 (m, 2H), 4.25 (with, 2H), 7.08 (dd, J = 7.5Hz, 5.0 Hz, 1H), 7.32 (dd, J = 8.3Hz, 4.8 Hz, 1H) 7.51-7.54 (m, 1 H), 8.15-8.22 (m, 2H), 8.43-8.50

(m, 2H).

Example 171

N-propyl-2- (pyridin-3-yloxy) -nicotinamide

To a solution of 2- (pyridin-3-yloxy) -nicotinic acid (0.100 g, 0.462 mmol), BOP (0.205 g, 0.463 mmol) and DIEA (0.242 μΐ) in dimethylformoamide (5 mL) was added n-propylamine (40 μΐ). (0.486 mmol) and stirred at room temperature for 4 hours. Add 10 μΐ of water to the reaction mixture and extract with ethyl acetate. The combined organic extracts were washed with alternate portions of 5% citric acid and saturated bicarbonate solution, dried over Na ₂ SO ₄ , filtered and concentrated to give a product which was purified by silica gel chromatography and eluted with diethyl ether to give a white crystalline solid (0.068). g). Mp 55-56 ° C. ¹ H NMR (400 * ·

A • • • •

-199MHz, CDCl 3) 0.98 (t, J = 7.3 Hz, 3H), 1.61-1.70 (m, 2H),

3.45-3.50 (m, 2H), 7.19 (dd, J = 7.5Hz, 4.8Hz, 1H), 7.38-7.41 (m, 1H), 7.52 -7.55 (m, 1H), 7.72 (broad s, 1H), 8.16 (dd,

J = 4.8 Hz,

2.1 Hz, 1H), 8.52-8.63 (m, 3H).

Following the procedure of Example 171, the compounds of Examples 172-182 were prepared, but the n-propylamine was replaced with the corresponding amine. The duration of the reaction is between 1 and 24 hours.

Example 172

N-isopropyl-2- (pyridin-3-yloxy) -nicotinamide ^X H NMR (400 MHz, CDC1 ₃₎ d 1.27 (d, J = 6.4 Hz, 6H), 4.29-4.34 ( m,

1H), 7.18 (dd, J = 7.7Hz, 4.8Hz, 1H), 7.39-7.42 (m, 1H), 7.51 (broad s, 1H), 7.53 -7.57 (m, 1H), 8.16 (dd, J = 4.8Hz, 2.1Hz,

1H), 8.53-8.62 (m, 3H).

Example 173

N-isobutyl-2- (pyridin-3-yloxy) -nicotinamide

Analysis for C ₁₅ H ₁₇ N ₃ O ₂ . ^X H NMR (400 MHz, CDCl 3) d 0.97 (d, J = 6.6) Hz, 6H), 1.71-1.95 (m, 1H), 3.35 (dd, J = 6.6 Hz , 5.8 Hz, 2H) 7.19 (dd, J = 7.8 Hz, 4.8) Hz, 1H), 7.39 -7.42 (m, 1H), 7,53-7,56

(m, 1H), 7.76 (broad s, 1H), 8.16 (dd, J = 4.8 Hz, 1.9 Hz, 1H), 8.52-8.63 (m, 3H).

Example 174

N-butyl-2- (pyridin-3-yloxy) -nicotinamide, m.p. 55-56 ° C. Analysis for C ₁₅ H ₁₇ N ₃ O ₂ . ¹ H NMR (400 MHz, CDCl ₃ ) d 0.93 (t, J = 7.5 Hz, 3H), 1.37-1.44 (m, 2H), 1.57, -1.65 (m (2H), 3.48-6.53 (m, 2H), 7.16-7.19 (m, 1H), 7.38-7.42 (m,

1H), 7.52-7.55 (m, 1H), 7.70 (broad s, 1H), 8.15 (dd, J = 4.8)

Hz, 1.9 Hz, 1H), 8.51-8.63 (m, 3H).

Example 175

N-Pentyl-2- (pyridin-3-yloxy) -nicotinamide

-200 V w w 6 6 6 6 · <«« r r r r r r r r r r r r 200 200 • · «*« and · · · · · ···

Mp 61-62 ° C. Anal _. Calcd for C ₁₆ H ₁₉ N ₃ O ₂ : C

H, 6.71; N, 14.72. Found: C, 67.52; H, 6.88; N, 14.23.

Example 176 (S) -N-sec-Butyl-2- (pyridin-3-yloxy) -nicotinamide M.p. 64-65 ° C. Analysis for C ₁₅ H ₁₇ N ₃ O ₂ calculated: C

H, 6.32; N, 15.49. Found: C, 66.66; H, 6.48; N, 14.89. and _D = + 9.0 °, 10.9 mg / ml in methylene chloride.

EXAMPLE 177 (R) -N-sec-Butyl-2- (pyridin-3-yloxy) -nicotinamide, m.p. 55-56 ° C. Analysis for C ₁₅ H ₁₇ N ₃ O ₂ calculated: C

H, 6.32; N, 15.49. Found: C, 67.14; H, 6.37; N, 14.70. α _D = -8.48 °, 12.5 mg / ml in methylene chloride.

Example 178

2- (pyridin-3-yloxy) -N- (4-sulfamoyl-benzyl) -nicotinamide, m.p. 196-197 ° C. Anal. Calcd for C ₁₈ H ₁₆ N ₄ O ₄ S: C 56.24, H 4.20, N 14.75, found. C 54.95, H 4.30, N 14.11.

Example 179

2- (pyridin-3-yloxy) -N- (1-sulfamoyl-piperidin-4-ylmethyl) -nicotinamide

Melting point 165-166 ° C. HRMS 392.1382.

Example 180

N- (1H-indol-4-ylmethyl) -2- (pyridin-3-yloxy) -nicotinamide, m.p. 134-135 ° C. Anal _. Calcd for C ₂₀ H ₁₆ N ₄ O ₂ : C 69.76, H 4.68, N 16.27. Found: C 69.45, H 4.63, N 16.15. Example 181

N-pyridin-2-ylmethyl-2- (pyridin-3-yloxy) -nicotinamide, m.p. 118-119 ° C. Anal. Calcd for C ₁₇ H ₁₄ N ₄ O ₂ : C 66.66, H 4.61, N 18.29. Found: C 66.24, H 4.58, N 18.21.

9

-201 • · · · «« * *

Example 182

N-benzo [1,3] dioxol-5-ylmethyl) -2- (pyridin-3-yloxy) -nicotinamide

Melting point 130-131 ° C. Analysis for C ₁₉ H ₁₅ N ₃ O _4: Calculated: C 65.32, H 4.33, N 12.03 Found: C 64.62, H 4.41, N 11.87.

Example 183

N- [4- (1-hydroxy-1-methylethyl) -benzyl] -2- (3-trifluoromethyl-phenoxy) -nicotinamide

To a stirred solution of 2- (3-trifluoromethyl-phenoxy) -nicotinic acid (0.311 g, 1.1 mmol), 2- (4-aminomethyl-phenyl) -propan-2-ol (0.200 g, 1.21 mmol) and 1-hydroxybenzotriazole hydrate (0.178 g, 1.32 mmol) in anhydrous dimethylformamide (15 mL) was added 1- (3-dimethylamino) -propyl) -3-ethylcarbodiimide hydrochloride (0.275 g, 1.43 mmol) and stirred over night. The mixture was diluted with 250 mL of water and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over Na ₂ SO ₄ , filtered, and concentrated to an oil which was purified by silica gel chromatography eluting with 4% methanol in methylene chloride to give a foam (0.350 g). . Mp 37-39 ° C. ¹ H NMR (CDCl ₃ ) d 1.56 (6H, s), 4.69 (2H, d, J = 5.81 Hz), 7.2-7.6 (9H, m), 8.02 ( 1H, s),

8.20 (1H, m); 8.64 (1H, m).

Following the procedure of Example 183, the compound of Example 184 was prepared, but the 2- (4-aminomethyl-phenyl) -propan-2-ol was replaced with the corresponding amine. The duration of the reaction is between 1 and 24 hours.

Example 184

N- (2-chlorobenzyl) -2- (3-trifluoromethyl-phenoxy) -nicotinamide, m.p. 88-90 ° C. Anal _. Calcd for C ₂₀ H ₁₄ N ₂ O ₂ F ₃ Cl: C 59.05, H 3.47, N 6.89. Found: C 58.89, H 3.39, N 6.94.

Example 185

-2022- (2-Chloro-phenyl) -4- [2- (pyridin-3-yloxy) -pyridin-3-yl] -acetamide

To a stirred solution of 2-chlorobenzoic acid (0.200 g,

1.17 mmol) of 2- (pyridin-3-yloxy) -pyridin-3-ylamine (0.239 g,

1.28 mmol) and 1-hydroxybenzotriazole hydrate (0.190 g, 1.40 mmol) in anhydrous dimethylformamide (15 mL) were added 2-diethylaminoethyl chloride hydrochloride (0.292 g, 1.52 mmol) and stirred over the weekend. The mixture was diluted with 200 mL of water and extracted with ethyl acetate. The combined organic extracts were washed with 1 N NaOH, water and brine, dried over Na ₂ SO ₄ , filtered and concentrated to give an oil which was purified by silica gel chromatography. Recrystallization from ethyl acetate / hexane gave a solid (0.093 g). M.p. 137-139 ° C. Anal. Calcd for C ₁₈ H ₁₄ N ₃ O ₂ Cl: C 63.63, H 4.15, N 12.37. Found: C 63.30, H 4.30, N 12.34.

Following the procedure of Example 185, the compound of Example 186 was prepared, but the 2-chlorobenzoic acid was replaced with the corresponding carboxylic acid. The duration of the reaction is between 1 and 24 hours.

Example 186

2- (4-Acetylphenyl) -N- [2- (pyridin-3-yloxy) -pyridin-3-yl] -acetamide

Melting point 110-112 ° C. 1 H NMR (CDCl ₃ ) d 2.6 (3H, s), 3.90 (2H, s), 7.0-8.7 (12H, m).

Example 187

2- (3-chlorophenoxy) -N- [4- (1-hydroxy-1-methylethyl) -benzyl] -nicotinamide

To a stirred solution of 2- (3-chlorophenoxy) -nicotinic acid (0.301 g, 1.21 mmol), 2- (4-aminomethyl-phenyl) -propan-2-ol (0.200 g, 1.21 mmol) and 1- hydroxybenzotriazole hydrate (0.178 g, 1.32 mmol) in anhydrous dimethylformamide (15 mL) was added 1- (3-dimethylamino) -propyl) -3-ethylcarbodiimide hydrochloride

-203- (0.275 g, 1.43 mmol) and stirred overnight. The mixture was diluted with 200 mL of water and extracted with ethyl acetate. The combined organic extracts were washed with water, 1N sodium hydroxide and brine, dried over MgSO ₄ , filtered, and concentrated to an oil which was purified by silica gel chromatography to give a solid (0.258 g) eluting with 6% methanol in methylene chloride. ). Mp 57-59 ° C. Analysis calculated for C ₂₂ H ₂₁ N ₂ O ₃ Cl: C 66.50, H 5.33, N 7.06. Found: C 67.15, H 5.95, N 6.68.

Following the procedure of Example 188, the compound of Example 189 was prepared, but the 2- (4-aminomethyl-phenyl) -propan-2-ol was replaced with the corresponding amine. The duration of the reaction is between 1 and 3 hours.

Example 189

N- (2-chlorobenzyl) -2- (3-chlorophenoxy) nicotinamide Melting point 126-128 ° C. Analysis for C ₁₉ H ₁₄ N ₂ O ₂ C1 ₂ requires C, 61.14; H, 3.78; N, 7.51 Found: C 61.07, H 3.73, N 7.51.

Example 190 (S) -2- (4- {2- [2- (4-Fluorophenoxy) -pyridin-3-yl] - [1,3] dioxolan-4-yl} -phenyl) -propan-2-ol

To a solution of (S) -4- {2- [2- (4-fluorophenoxy) -pyridin-3-yl] - [1,3] dioxolan-4-yl} -benzoic acid ethyl ester (0.085 g, 0.2 mmol) ) in tetrahydrofuran (5 mL), 1.4 M methyllithium in diethyl ether (0.45 mL, 0.6 mmol) is added dropwise at -78 ° C, keeping the temperature below -60 ° C and then stirred at -60 ° C. at -78 ° C for 90 minutes. The mixture was warmed to 0 ° C, saturated NH ₄ Cl was added and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over MgSO ₄ , filtered and concentrated to give an oil which was purified by silica gel chromatography eluting with 1: 4 ethyl acetate / hexane to give a colorless oil (0.45 g). ). Analysis for C ₂₃ H ₂ 2NO ₄ F calculated: C · · ·············

-204- .i ······ ·· ··

69.86, Η 5.61, N 3.54. Found: C 70.85, H 6.22, N 3.15. ¹ H NMR (400 MHz, CDCl ₃ ) d 1.58 (s, 6H), 3.90-4.00 (m, 1H), 4.38-4.42 (m, 1 / 2H), 4, 54-4.58 (m, 1 / 2H), 5.21-5.28 (m, 1H), 6.37 (s, 1 / 2H), 6.55 (s, 1 / 2H), 6, 98-7.15 (m, 5H), 7.34-7.38 (m, 2H), 7.44-7.52 (τη, 2H), 7.99-8.16 (m, 2H).

Following the procedure of Example 190, the compounds of Examples 191-192 were prepared but (S) -4- {2- [2- (4-fluorophenoxy) -pyridin-3-yl] - [1,3] dioxolan-4-yl ethyl ester The benzoic acid is replaced by the corresponding ester. The duration of the reaction is between 1 and 3 hours.

Example 191 cis- (R) -2- (4- {2- [2- (4-fluorophenoxy) -pyridin-3-yl] - [1,3] dioxolan-4-yl} -phenyl) -propan-2 -ol

Analysis for C ₂₃ H ₂₂ NO ₄ F. 0C _D ~ -45.3 °, 15.2 mg / ml v methylene- chloride. @ ¹ H NMR (400 MHz, CDCl ₃ ) d 1.58 (s, 6H) 3.96-4.00 (m, 1H), 4.39-4.42 (m, 1H), 5,21-5,24 (m, 1H), 6.38 (s, 1 H), 7.04-7.14 (m, 5H), 7.40 (d, J = 8.1 Hz, 2H), 7.50 (d, J = 8.5 Hz, 2H), 8.05-8.16 (m, 2H).

Example 192 trans- (R) -2- (4- {2- [2- (4-fluorophenoxy) -pyridin-3-yl] - [1,3] dioxolan-4-yl} -phenyl) -propan-2 -ol

Analysis for C ₂₃ H ₂₂ NO ₄ F ^T H NMR (4 00 MHz, CDC1 ₃ ) d 1.58 (with, 6H), 3.92 (t, J = 7.9Hz, 1H), 4.55-4.58 (m, 1H), 5, 23 · -5.28 (m, 1H), 6.54 (s, 1H); 7.03-7.19 (m, 5H); 7.40 (d, J = 8) , 3 Hz, 2H), 7.51 (d, J = 8.1 Hz, 2H), 7.99-8.15 (m, 2H).

Example 193

2- (4-fluorophenoxy) -N- (4-sulfamoyl-benzyl) -nicotinamide To a solution of 2- (4-fluorophenoxy) -nicotinic acid (0.110 g,

0.470 mmol), BOP (0.205 g, 0.470 mmol) and DIEA (0.242 μΐ, 1.42 mmol) in dimethylformamide (5 mL) were added 4-aminomethylbenzenesulfonamide (0.105 g, 0.470 mmol) and stirred at • •

room overnight. Add water and extract with ethyl acetate. The combined organic extracts were washed alternately with portions of 5% citric acid and saturated bicarbonate, dried over Na ₂ SO ₄ , filtered and concentrated to give the product which was recrystallized from ethyl acetate to give white crystals (0.100 g). M.p. 222-223 ° C. Analysis for C ₁₉ H ₁₆ N ₃ O ₄ SF: Calculated: C 56.85 H 4.02 N 10.47 Found: C 55.52, H 4.14, N 10.16.

Following the procedure of Example 193, the compounds of Examples 194-195 were prepared, but the 4-aminomethylbenzenesulfonamide was replaced with the corresponding amine. The duration of the reaction is between 1 and 3 hours.

Example 194

2- (4-Fluorophenoxy) -N- (1-sulfamoyl-piperidin-4-ylmethyl) -nicotinamide

Mp 225-226 ° C. Analysis for C ₁₈ H ₂₁ N ₄ O ₄ SF: Calculated: C 52.93, H 5.18, N 13.72 Found: C, 52.73; H, 5.16; N, 13.72.

Example 195

N- (3,4-dihydro-2H-pyran-2-ylmethyl) -2- (4-fluorophenoxy) nicotinamide

Mp 55-57 ° C. HRMS 329.1324.

Example 196

2- (3-cyanophenoxy) -N- (4-sulfamoyl-benzyl) -nicotinamide

To a solution of 2- (3-cyanophenoxy) -nicotinic acid (0.140 g,

0.60 mol), BOP (0.260 g, 0.600 mmol) and DIEA (0.310 μam, 1.8 mmol) in dimethylformamide (5 mL) were added 4-aminomethylbenzenesulfonamide (0.135 g, 0.600 mmol) and stirred at room temperature overnight. Add water and extract with ethyl acetate. The combined organic extracts were washed alternately with 5% citric acid and saturated bicarbonate, dried over Na ₂ SO ₄ , filtered and concentrated to give a solid.

-206 • b · · · · · · · · · · · · · · · · · · · · · · · · · · · · · 1 · 1

The product was recrystallized from ethyl acetate to give a white solid (0.100 g). Mp 179-180 ° C.

Anal _. Calcd for C ₂₀ H ₁₆ N ₄ O ₄ S: C 58.81, H 3.95, N 13.72, Found: C 57.47, H 4.15, N 13.45.

Example 197

N- (4-sulfamoyl-benzyl) -2- (3-tetrazol-1-yl-phenoxy) -nicotinamide

To a stirred solution of 2- (3-tetrazol-1-yl-phenoxy) -nicotinic acid (0.050 g, 0.180 mmol), 4-aminomethyl-benzenesulfonamide (0.060 g, 0.26 mmol) and 1-hydroxybenzotriazole hydrate (0.031 g, 0 , 23 mmol) in anhydrous dimethylformamide (2 mL) was added 2-diethylaminoethyl chloride hydrochloride (0.044 g, 0.23 mmol) and stirred overnight. The mixture was diluted with 200 mL of water and extracted with ethyl acetate. The combined organic extracts were washed with water, 1N sodium hydroxide and brine, dried over MgSO ₄ , filtered and concentrated to give a product which was purified by silica gel chromatography eluting with 5% methanol in methylene chloride to give a white solid (m.p. 0.013 g). Melting point 72-74 ° C. ¹ H NMR (400 MHz, CDCl 3) d 4.55 (d, J = 6.0 Hz, 2H), 6.74-6.84 (m, 2H), 7.21-7.37 (m, 4H) ), 7.49 (d, J = 8.5 Hz, 2H), 7.72 (d, J = 8.3 Hz, 2H),

8.10-8.21 (m, 2H); 9.05 (t, J = 6.0 Hz, 1H).

Example 198

N- [4- (1-hydroxy-1-methylethyl) -cyclohexylmethyl] -2- (3-methoxyphenoxy) -nicotinamide

To a solution of 4 - ({[2- (3-methoxy-phenoxy) -pyridine-3-carbonyl] -amino} -methyl) -cyclohexanecarboxylic acid ethyl ester (0.26 g, 0.63 mmol) in tetrahydrofuran (5) mL) at -78 ° C was added dropwise 1.4 M methyllithium in diethyl ether (1.4 mL, 1.89 mmol) while maintaining the temperature below -60 ° C and then stirred at -78 ° C for 2 hours and then allowed to warm to room temperature over the weekend. • • • ·

-207- ·· ·> ·· ¹ saturated _NH4 C1, and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated to give a product which was purified by silica gel chromatography eluting with 1: 1 ethyl acetate: hexane to give a pale yellow oil. (0.077 g). ¹ H NMR (400 MHz, CDCl ₃ ) d 1.02-1.22 (m, 10H), 1.52-1.56 (m,

2H), 1.82 -1.88 (m, 4H), 3,32-3, 36 (m, 2H), 3.80 (with, 3H), 6.70-6.74 (m, 2H) 6,80-6, 83 (m, 1H), 7, 12-7,16 (m, 1H), 7.33 (t, J = 8.1 Hz, 1H) 7.93 (wide with, 1H) , 8,20-8,22 (m, 1H),

8.60-8.61 (m, IH).

Example 199

2- (3-chlorophenoxy) -N- [4- (1-hydroxy-1-methylethyl) -cyclohexylmethyl] -nicotinamide

To 4 - ({[2- (3-chloro-phenoxy) -pyridine-3-carbonyl] -amino} -methyl) -cyclohexanecarboxylic acid ethyl ester (0.220 g, 0.53 mmol) in tetrahydrofuran (5 mL) at -78 Add 1.4 M methyllithium in diethyl ether (1.13 mL, 1.58 mmol) dropwise while keeping the temperature below -60 ° C and then stir at -78 ° C for 2 hours and then leave warm to room temperature. Add saturated NH ₄ Cl and extract with ethyl acetate. The combined organic extracts were washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated to give a product which was purified by silica gel chromatography eluting with 2: 3 ethyl acetate: hexane to give an off-white oil. (0.040 g). ¹ H NMR (400 MHz, CDCl ₃ ) d

0.84-1.70 (m, 12H), 1.83-1.87 (m, 4H), 3,30-3,37 (m, 2H) 7.04-7.07 (m, 1H), 7.11-7.19 (m, 2H), 7.24-7.27 (m, 1H) 7.35-7.39 (m, 1H), 7.79 (wide s, 1H), 8,19-8,21 (m, 1H) 8.60-8.62 (m, 1H).

Example 200

2- (3-methoxyphenoxy) -N- (4-sulfamoyl-benzyl) -nicotinamide

-208 • ·

To a solution of 2- (3-methoxy-phenoxy) -nicotinic acid (0.200 g, 0.820 mmol), BOP (0.360 g, 0.820 mmol) and DIEA (425 μΐ, 2.45 mmol) in dimethylformamide (5 mL) was added 4 -aminomethylbenzenesulfonamide (0.182 g, 0.820 mmol) and stirred at room temperature overnight. Add water and extract with ethyl acetate. The combined organic extracts were washed alternately with portions of 5% citric acid and saturated bicarbonate, dried over Na ₂ SO ₄ , filtered and concentrated to give the product which was recrystallized from ethyl acetate to give a white solid (0.260 g). M.p. 142-143 ° C.

Anal _. Calcd for C ₂₀ H ₁₉ N ₃ O ₅ S: C 58.10, H 4.63, N 10.16. Found: C 58.11, H 4.91, N 9.83.

The compound of Example 201 was prepared according to the procedure of Example 200, but the 4-aminomethyl-benzenesulfonamide was replaced with the corresponding amine. The duration of the reaction is between 1 and 3 hours.

Example 201

N- [4- (1-hydroxy-1-methylethyl) -benzyl] -2- (3-methoxyphenoxy) -nicotinamide

Mp 69-71 ° C. Analysis for C ₂₃ H ₂₄ N ₂ O ₄ Calcd

H, 6.16; N, 7.14. Found: C, 69.42; H, 6.34; N, 7.17.

Example 202

2- (3-Fluorophenoxy) -N- [4- (1-hydroxy-1-methylethyl) -benzyl] -nicotinamide

To a stirred solution of 2- (3-fluorophenoxy) -nicotinic acid (0.250 g, 1.07 mmol), 2- (4-aminomethyl-phenyl) -propan-2-ol (0.195 g, 1.18 mmol) and 1- hydroxybenzotriazole hydrate (0.173 g,

1.28 mmol) in anhydrous dimethylformamide (15 mL) was added 1- (3-dimethylamino) -propyl) -3-ethylcarbodiimide hydrochloride (0.173 g, 1.28 mmol) and stirred overnight. The mixture was diluted with 300 mL of water and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over MgSO ₄ .

-209- ...............

Filter and concentrate to give an oil which is purified by silica gel chromatography. Recrystallization from ethyl acetate / hexane gave a solid (0.400 g). Melting point 106-108 ° C. Anal. Calcd for C ₂₂ H ₂₁ N ₂ O ₃ F: C 6.46, H 5.56, N 7.36. Found: C 69.05, H 5.68, N 7.25.

Example 203

N- [2- (4-Fluorophenoxy) -pyridin-3-yl] -2- [4- (1-hydroxy-1-methylethyl) -phenyl] -acetamide

To 2- (4-acetylphenyl) -N- [2- (4-fluorophenoxy) -pyridin-3-yl] -acetamide (0.270 g, 0.741 mmol) in tetrahydrofuran (15 mL) at -78 ° C via syringe. Add 1.0 M methyllithium in tetrahydrofuran (1.63 mL, 1.63 mmol) and stir at -78 ° C for 75 minutes. An additional 0.8 mL of methyllithium was added and the mixture was warmed to 0 ° C for 10 minutes and then cooled to -78 ° C. Add water, allow to warm to room temperature, and extract with ethyl acetate. The combined organic extracts were washed with water and brine, dried over MgSO ₄ , filtered and concentrated to give a white solid, which was purified by silica gel chromatography eluting with 2% methanol in methylene chloride to give a white solid. Recrystallization from ethyl acetate / hexane gave a solid (0.032 g). Melting point 135-137 ° C. Analysis for C ₂₂ H ₂₁ N ₂ O ₃ F: Calculated: C 69.46, H 5.56, N 7.36 Found: C 69.46, H 5.92, N 7.73.

Example 204 (-) - N- [5- (1-Hydroxyethyl) -thiophen-2-ylmethyl] -2- (pyridin-3-yloxy) -nicotinamide

N- [5- (1-hydroxyethyl) -thiophen-2-ylmethyl] -2- (pyridin-3-yloxy) -nicotinamide (0.287 g) was separated on a Chiral Cel OJ column eluting with 70:30 heptane / isopropanol to give product is obtained. Recrystallization from ethyl acetate / hexane gave a solid (0.070 g). Mp 85-87 ° C. Analysis • · ·

For C ₁₈ H ₁₇ N ₃ O ₃ S calculated: C 60.83, H 8.82, N 11.82, found: C

H, 4.68; N, 10.82. and _D = -7.02 °.

Following the procedure of Example 204, the compound of Example 205 was prepared.

Example 205 (+) - N- [5- (1-Hydroxyethyl) -thiophen-2-ylmethyl] -2- (pyridin-3-yloxy) -nicotinamide

Mp 88-90 ° C. Analysis for C ₁₈ H ₁₇ N ₃ O ₃ S calculated: C

H, 8.82; N, 11.82. Found: C, 57.80; H, 5.06; N, 11.21. α _D = +7.73 °.

Example 206

N- [4- (1-hydroxy-1-methylethyl) -benzyl] -2- (3-methylsulfanyl-phenoxy) -nicotinamide

To a stirred solution of 2- (3-methylsulfanyl-phenoxy) -nicotinic acid (2.5 g, 9.58 mmol), 2- (4-aminomethyl-phenyl) -propan-2-ol (1.896 g, 11.50 mmol) ) and 1-hydroxybenzotriazole hydrate (1.55 g, 11.5 mmol) in anhydrous dimethylformamide (60 mL) were added 1- (3-dimethylamino) propyl-3-ethylcarbodiimide hydrochloride (2.39 g, 12 mL). (45 mmol) and stirred overnight. The mixture was diluted with 300 mL of water and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over MgSO ₄ , filtered and concentrated to give a yellow oil, which was purified by silica gel chromatography and eluted with 3.5% methanol in methylene chloride to give a white solid. Recrystallization from ethyl acetate / hexane gave a solid (0.550 g). Melting point 107-109 ° C. Analysis calculated for: C ₂₃ H ₂₄ N ₂ O ₃ S: C 67.62, H 5.92, N 6.86. Found: C 67.53, H 5.76, N 6.91.

Example 207

N- [4- (1-hydroxy-1-methylethyl) -benzyl] -2- (3-methanesulfonyl-phenoxy) -nicotinamide

-211- «··· ·. ·. ·· ·· ·· ·

A solution of N- [4- (1-hydroxy-1-methylethyl) benzyl] -2- (3-methylsulfanyl-phenoxy) -nicotinamide (3.5 g, 8.5 mmol) and MCPBA (3.945 g, 18.8 mmol) ) in methylene chloride (40 mL) was stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate, washed with water, 1N sodium hydroxide and brine, dried over MgSO ₄ , filtered and concentrated to give a white solid which was purified by silica gel chromatography eluting with 2% methanol in methylene chloride to give a white solid. solid (1.64 g). Mp 51-53 ° C. Analysis for C ₂₃ H ₂₄ N ₂ O ₅ S calculated: C 62.71, H 5.49, N 6.38. Found: C 61.87, H 5.48, N 6.29.

Example 208

N-pyridin-4-ylmethyl-2- (pyridin-3-yloxy) -nicotinamide

A solution of 2- (pyridin-3-yloxy) -nicotinic acid (0.0664 g, 0.31 mmol) in thionyl chloride (1.12 mL, 15.4 mmol) was heated to 50 ° C. After 1.5 hours, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. Pyridine (2.5 mL) was added at room temperature followed by C-pyridin-4-ylmethylamine (47 μΐ, 0.47 mmol). After 2 hours, the mixture was concentrated to remove pyridine. The crude product was purified by silica gel chromatography eluting with 9: 1 ethyl acetate-methanol to give a solid (0.0331 g). M.p. 142-144 ° C. Anal. Calcd for C ₁₇ H ₁₄ N ₄ O ₂ : C 66.66, H 4.61, N

Found: C, 66.40; H, 4.56; N, 17.94.

Example 209

2- (4-Fluorophenoxy) -N- (5-methyl-pyrazin-2-ylmethyl) -nicotinamide

A solution of 2- (4-fluorophenoxy) -nicotinic acid (0.0766 g, 0.33 mmol) in thionyl chloride (2 mL) was heated to 50 ° C. After 1.5 hours, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was dissolved in pyridine (2 mL) and C- (5-methyl-pyrazin-2-yl) -methyl-212amine (0.14 g, 1.0 mmol) was added. After 1.5 h, the mixture was concentrated under reduced pressure and purified by silica gel chromatography eluting with 1: 1 ethyl acetate: hexane to give a white solid. Mp 159 ° C. Anal. Calcd for C ₁₈ H ₁₅ N ₄ O ₂ F: C 63.90, H 4.47, N 16.56. Found: C 63.78, H 4.39, N 16.26.

Following the procedure of Example 63, the compound of Example 63a was prepared, but (methyl-pyrazin-2-yl) -methylamine was replaced with the corresponding amine. The duration of the reaction is between 1 and 24 hours.

Example 210

5 - {[2- (4-Fluorophenoxy) -pyridine-3-carbonyl] amino} -pentanoic acid ethyl ester

Analysis for C ₁₉ H ₂₁ N ₂ O ₄ F: Calculated: C 63.32, H 5.87, N 7.77 Found: C, 62.42; H, 5.62; N, 7.52. ¹ H NMR (CDCl ₃ ) d 1.21 (3H,

t, J = 7.1 Hz), 1.69 (3H, m) , 2.33 (2H, t, J = 6.2 Hz), 3.49 (2H, m), 4.08 (2 H, q, J = 7.06, 14.11) 7.13 (4H, m), 7.86 (1 H, s), 8.17 (1 H, dd, J = 2.08, 4.77; ), 8.59 (1H, dd, J = 2.07, 7.67).

Example 211

2- [4- (1-hydroxy-1-methylethyl) -phenyl] -N- [2- (pyridin-3-yloxy) -pyridin-3-yl] -acetamide

To a solution of 2- (4-acetylphenyl) -N- [2- (pyridin-3-yloxy) -pyridin-3-yl] -acetamide (0.130 g, 0.374 mmol) in tetrahydrofuran (10 mL) at -78 °. C was added 1.0 M methyllithium in tetrahydrofuran (1.123 mL, 1.123 mmol) and stirred at -78 ° C for 30 minutes. It was then allowed to warm to room temperature for 30 minutes and recooled to -78 ° C. Add water and extract with ethyl acetate. The combined organic extracts were washed with water and brine, dried over MgSO ₄ , filtered and concentrated to give a product which was purified by silica gel chromatography eluting with 3% methanol in methylene chloride. Recrystallization from ethyl acetate / hexane gave a solid (0.045 g).

M.p. 122-124 ° C. Analysis calculated for C ₂₁ H ₂₁ N ₃ O ₃ : C 69.41, H 5.82, N 11.50. Found: C 69.02, H 6.12, N 11.30.

Example 212

2- (4-Fluorophenoy) -N- (5-hydroxy-5-methylhexyl) -nicotinamide

To a solution of 5 - {[2- (4-fluorophenoxy) -pyridine-3-carbonyl] -amino} -pentanoic acid ethyl ester (0.0321 g, 0.06 mmol) in tetrahydrofuran (1 mL) at -78 ° Add 1.4 M methyllithium in diethyl ether (186 μΐ, 0.26 mmol) via syringe and stir at -78 ° C for 2 hours. Add 200 μΐ of water and warm to room temperature. The reaction mixture was diluted with ethyl acetate, dried over MgSO ₄ , filtered and concentrated to give a clear oil. Analysis for C ₁₉ H ₂₃ N ₂ O ₃ F: Calculated: C 65.88, H 6.69, N 8.09 Found: C 63.17, H 5.73, N 7.46. ¹ H NMR (CDCl ₃ ) d 1.21 (6H, m), 1.51 (3H,

m), 1.67 (2H, m), 3.52 (2H, m), 4.10 (1H, q, J = 7.17, 14.30),

7.17 (4H, m), 7.86 (1H, s), 8.20 (1H, dd, J = 2.1, 4.89), 8.58 (1H, dd, J = 2.16) , 7.67).

Example 213

N- [2- (3-Acetyl-phenoxy) -pyridin-3-yl] -2- [4- (1-hydroxy-1-methylethyl) -phenyl] -acetamide

To a solution of 2- (4-acetylphenyl) -N- [2- (3-cyanophenoxy) -pyridin-3-yl] -acetamide (0.250 g, 1.484 mmol) in tetrahydrofuran (15 mL) was added at -78 ° C. 1.0 M methyllithium in tetrahydrofuran (5.2 mL, 5.2 mmol) and stirred at -78 ° C for 2 hours. An additional 2.0 mL of methyllithium was added and stirred for 5 minutes while allowing to warm to room temperature. Add water and extract with ethyl acetate. The combined extracts were washed with water and brine, dried over MgSO ₄ , filtered, and concentrated to an oil which was purified by silica gel chromatography eluting with 30% ethyl acetate in hexane. Recrystallization from ethyl acetate / hexane gave white crystals (0.082 g). Melting point 85 to 85 ° C

-21487 ° C. Analysis for C ₂₄ H ₂₄ N ₂ O ₄ calculated: C 71.27, H 5.98, N 6.93. Found: C 68.61, H 6.30, N 6.19.

Example 214

2- (3-cyanophenoxy) -N- [4- (1-hydroxy-1-methylethyl) -cyclohexylmethyl] -nicotinamide

To a solution of 4 - {[2- (3-cyanophenoxy) -pyridin-3-ylcarbamoyl] -methyl} -cyclohexanecarboxylic acid ethyl ester (0.180 g, 0.46 mmol) in tetrahydrofuran (6 mL) was added at -78 ° C. with a syringe of 1.4 M methyllithium in diethyl ether (980 μΐ, 1.37 mmol) and stir at -78 ° C for 2 hours. Add 200 μΐ of saturated NH ₄ Cl and warm to room temperature. The reaction mixture was diluted with ethyl acetate, dried over MgSO ₄ , filtered and concentrated to give a pale yellow oil which crystallized on standing. Mp 129-130 ° C. Anal. Calcd for C ₂₃ H ₂₇ N ₃ O ₃ : C 70.21, H 6.92, N 10.68. Found: C 69.23, H 6.88, N 10.37.

Example 215

3- {3- [4- (1-Hydroxy-1-methylethyl) -benzylcarbamoyl] -pyridin-2-yloxy} -benzoic acid methyl ester

To a stirred solution of 2- (3-methoxycarbonyl-phenoxy) -nicotinic acid (0.400 g, 1.463 mmol), phenyl) -propan-2-ol (0.266 g, 1.61 mmol) triazole hydrate (0.237 g, 1.755 mmol)

2- (4-Aminomethyl and 1-hydroxybenzyl anhydrous dimethylformamide (20 mL)) was added 2-diethylaminoethyl chloride hydrochloride (0.365 g, 1.90 mmol) and stirred overnight The mixture was diluted with water and extracted with ethyl acetate. washed with water and brine, dried over MgSO _4, filtered and concentrated to give a white foam (0.360 g). MS (m / e) 420 (m ⁺ l). ^X H NMR _(CDCl3) d 1.50 (6H, s), 3.90 (3H, s), 4.70 (2H, d, J = 5.60 Hz), 7.20-8.65 (12H, m).

Example 216

-215

2- (4-Fluorophenoxy) -N- (5-oxo-morpholin-2-ylmethyl) -nicotinamide

A solution of 6-aminomethyl-morpholin-3-one hydrochloride (0.200 g, 1.2 mmol) and triethylamine (0.150 g, 1.5 mmol) in dimethylformamide was stirred at room temperature for 30 minutes. To this stirred solution was added 2- (4-fluorophenoxy) -nicotinic acid (0.280 g, 1.2 mmol), 1-hydroxybenzotriazole hydrate (0.237 g, 1.755 mmol) and 2-diethylaminoethyl chloride hydrochloride (0.30 g, 1.56 mmol) and stirred overnight. The mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed with 1 N NaOH, water and brine, dried over MgSO ₄ , filtered and concentrated to give a white solid, which was purified by silica gel chromatography eluting with 5% methanol in methylene chloride. Recrystallization from ethyl acetate / hexane gave white crystals (0.175 g). M.p. 157-159 ° C. Analysis for C ₁₇ H ₁₆ N ₃ O ₄ F: Calculated: C 59.14, H 4.67, N 12.17 Found: C, 59.00; H, 4.69; N, 12.19.

Example 217

2- (3-cyanophenoxy) -N- (5-methyl-pyrazin-2-ylmethyl) -nicotinamide

2- (3-cyanophenoxy) -nicotinic acid solution (0.0067 g,

0.03 mmol) in thionyl chloride (500 μΐ, 6.9 mmol) was stirred at room temperature for 3 hours and concentrated under reduced pressure to give a white solid. Pyridine (300 μΐ) and C- (5-methylpyrazin-2-yl) -methylamine (0.0038 g, 0.03 mmol) were added to the residue. The mixture was allowed to stand at room temperature for 3 hours and then concentrated under reduced pressure to give a white solid (0.0093 g). Analysis for C ₁₉ H ₁₅ N ₅ O ₂ Calculated: C 66.08, H 4.38, N 20.26 Found: C 56.89, H 5.02, N 18.31.

Example 218 • · · · · ““ · · · · · · 218 218 218 218

-216- ............

N- [2- (3-cyanophenoxy) -pyridin-3-yl] -2- [4- (1-hydroxy-1-methylethyl) -phenyl] -acetamide

To a solution of 2- (4-acetylphenyl) -N- [2- (3-cyanophenoxy) -pyridin-3-yl] -acetamide (0.360 g, 0.96 mmol) in tetrahydrofuran (15 mL) at -78 °. C was added 1.0 M methyllithium (2.03 mL, 2.03 mmol) in tetrahydrofuran (20 mL) and stirred at -78 ° C for 1 hour. Water was added to the reaction mixture and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over MgSO ₄ , filtered and concentrated to give a white solid, which was purified by silica gel chromatography eluting with 40% ethyl acetate in hexane. Recrystallization from ethyl acetate / hexane gave white crystals (0.115 g). Melting point 97-99 ° C. Analysis for C 3 H ₂₁ N _{2 3} O3: Calculated: C 71.30, H 5.46, N 10.85 Found: C, 70.96; H, 5.30; N, 10.69.

Example 219

2- (pyridin-3-yloxy) -N- (4-trifluoroacetyl-benzyl) -nicotinamide

To a stirred solution of 2- (pyridin-3-yloxy) -N- [4- (2,2,2-trifluoro-1-hydroxyethyl) -benzyl] -nicotinamide (0.350 g, 0.87 mmol), NMO (0.153 g) (1.3 g) and molecular sieves 4 x 10 ^-1 nm (0.5 g) in methylene chloride were added TPAP (0.015 g, 0.04 mmol) and stirred at room temperature for 4 hours. The mixture was filtered through Celite, washed with water, dried over MgSO ₄ , filtered and concentrated under reduced pressure to give an oil which was purified by silica gel chromatography eluting with 5% methanol in methylene chloride to give a solid ( 0.151 g). Melting point 134-136 ° C. Anal _. Calcd for C ₂₀ H ₁₄ N ₃ O ₃ F ₃ : C 59.85, H 3.52, N 10.47. Found: C 59.56, H 3.63, N 10.20.

2- (3-acetylphenoxy) -N-pyridin-4-ylmethyl-nicotinamide

Example 220 ######################################

To a solution of 2- (3-acetylphenoxy) -nicotinic acid (0.356 g, 1.39 mmol), C-pyridin-4-yl-methylamine (0.150 g, 1.39 mmol) and 1-hydroxybenzotriazole hydrate (0.224 g, 1.66 mmol) in anhydrous dimethylformamide was added 1- (3-dimethylamino) -propyl) -3-ethylcarbodiimide hydrochloride (0.319 g, 1.66 mmol) and stirred overnight. The mixture was diluted with 100 mL of water and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over MgSO ₄ , filtered and concentrated to give a white solid, which was purified by silica gel chromatography and eluted with ethyl acetate to give a white solid. Recrystallization from ethyl acetate / hexane gave a white solid (0.220 g). M.p. 148-150 ° C. Anal _. Calcd for C ₂₀ H ₁₇ N ₃ O ₃ : C 67.15, H 4.93, N 12.10. Found: C 66.57, H 4.55, N 11.43.

Following the procedure of Example 220, the compounds of Examples 221-224 were prepared, but the C-pyridin-4-yl-methylamine was replaced with the corresponding amine. The duration of the reaction is between 1 and 24 hours.

Example 221

2- (3-acetylphenoxy) -N- [4- (1-hydroxy-1-methylethyl) -benzyl] -nicotinamide

52-54 ° C. Analysis for C ₂₄ H ₂₄ N ₂ O ₄ Calcd

H, 5.98; N, 6.93. Found: C, 69.78; H, 5.54; N, 6.83.

Example 222

2- (3-acetylphenoxy) -N- (2-chloro-benzyl) -nicotinamide, m.p. 140-142 ° C. Analysis calculated for C ₂₁ H ₁₇ N ₂ O ₃ Cl: C 66.23, H 4.50, N 7.36. Found: C 65.84, H 4.22, N 6.88.

Example 223

2- (3-acetylphenoxy) -N- [4- (1-hydroxyethyl) -benzyl] -nicotinamide

Mp 105-107 ° C, MS (m / e) 391 (M ⁺ +1).

• · * 218 ········ ·· ·· · ·

Example 224

2- (3-acetylphenoxy) -N- (4-sulfamoyl-benzyl) -nicotinamide, m.p. 162-164 ° C, MS (m / e) 425 (M ⁺ ), 1 H NMR (DMSO-d ⁶ ) d 2, 55 (3H, s), 4.56 (2H, d, J = 6.0 Hz), 7.2-9.2 (12H, m).

Example 225

2- [3- (1-hydroxy-1-methylethyl) -phenoxy] -N-pyridin-4-ylmethyl-nicotinamide

To a solution of 2- (3-acetylphenoxy) -N-pyridin-4-ylmethyl-nicotinamide (0.180 g, 0.51 mmol) in tetrahydrofuran (20 mL) was added 1.0 M methyllithium in THF at -78 ° C. cumene (1.14 mL, 1.14 mmol) and stirred at -78 ° C for 1 hour. Add water and dilute with ethyl acetate. The organic phase was washed with water and brine, dried over MgSO ₄ , filtered and concentrated to give a product which was purified by silica gel chromatography eluting with ethyl acetate to give a white foam. MS (m / e) 364 (M ⁺ +1), 1 H NMR (CDCl ₃ ) d 1.58 (6H, s),

4.70 (2H, d, J = 5.81 Hz), 7.0-8.7 (12H, m).

Example 226

N- (2-chlorobenzyl) -2- [3- (1-hydroxy-1-methylethyl) -phenoxy] -nicotinamide

To a solution of 2- (3-acetylphenoxy) -N- (2-chlorobenzyl) -nicotinamide (0.410 g, 1.307 mmol) in tetrahydrofuran (20 mL) at -78 ° C was added 1.0 M methyllithium (2.7 mL). (2.697 mmol) and stirred at -78 ° C for 1 hour and then allowed to warm to room temperature over 1 hour. Add water and dilute with ethyl acetate. The organic phase was washed with water and brine, dried over MgSO ₄ , filtered and concentrated to give an oil which was purified by chromatography on silica gel eluting with 2% methanol in methylene chloride.

to obtain an oil. MS (me) 397 (M @ ⁺ +1). H NMR (CDC1 ₃₎ d 1.60 (6H, s) 4.78 (2 H, d, J = = 6.01 Hz), 7,0-7,5 ( 9H, m), 8.20 (1H, m), 8.55 (1H, broad s), 8.62 (1H, m).

• · · · ·

-219 ···· ♦ · · ·

Following the procedure of Example 226, the compound of Example 227 was prepared, but 2- (3-acetylphenoxy) -N- [4- (1-hydroxy-1-methylethyl) -benzyl] -nicotinamide was replaced with the corresponding ketone. The duration of the reaction is between 1 and 24 hours.

Example 227

N- [4- (1-hydroxy- (1-methylethyl) -benzyl] -2- [3- (1-hydroxy-1-methylethyl) -phenoxy] -nicotinamide

MS (m / e) 421 (M ^& lt ^; + &^gt; +1). ¹ H NMR (CDCl ₃ ) d 1.54 (6H, s), 1.57 (6H, s),

s), 4.67 (2H, d), 7.0-7.5 (9H, m), 8.10-8.70 (3H, m).

Example 228

N- [4- (1-hydroxy-1-methylethyl) -benzyl] -2- (3-trifluoromethoxy-phenoxy) -nicotinamide

To a solution of 2- (3-trifluoromethoxy-phenoxy) -nicotinic acid (0.409 g, 1.366 mmol), 2- (4-aminomethyl-phenyl) -propan-2-ol (0.200 g, 1.24 mmol) and 1-hydroxybenzotriazole -hydrate (0.185 g, 1.366 mmol) in anhydrous dimethylformamide was added 1- (3-dimethylamino) -propyl) -3-ethylcarbodiimide hydrochloride (0.286 g, 1.50 mmol) and stirred overnight. The mixture was diluted with ethyl acetate and washed with water and brine, dried over MgSO _4, filtered and concentrated to an oil which was purified by silica gel chromatography to give an oil (0.430 g) eluting with 3.5% methanol in methylene chloride. MS (m / e) 447 (M ^{+ l)!} 1 H NMR (CDCl ₃ ) d 1.50 (6H, s), 4.70 (2H, d, J = 5.81 Hz), 7.0-7.5 (9H, m), 8.00 (1H , wide

s), 8.65 (1 H, m).

Example 229

N- (4-acetyl-cyclohexylmethyl) -2- (4-fluorophenoxy) -nicotinamide

To 4 - {[2- (4-fluorophenoxy) -pyridin-3-ylcarbamoyl] -methyl} -cyclohexanecarboxylic acid ethyl ester (3.01 g, 7.5 mmol) in tetrahydrofuran (40 mL) at -78 ° C slowly • · • · ·

Add 1.4 M methyllithium in diethyl ether (16.1 mL, 22.5 mmol), stir at -78 ° C for 1 hour and slowly warm to -30 ° C. Add 6 00 μΐ of saturated NH ₄ Cl and warm to room temperature. The reaction mixture was diluted with ethyl acetate, dried over MgSO ₄ , filtered and concentrated to give a pale yellow oil which was purified by silica gel chromatography and eluted with 3: 2 hexane / ethyl acetate to give a clear oil which solidified on standing (0.3500 g). Melting point 110-111 ° C. Anal. Calcd for C ₂₁ H ₂₃ N ₂ O ₃ F: C 68.09, H 6.26, N

7.56, found: C 67.32, H 6.26, N 7.40.

Example 230

2- (2,4-Difluorophenoxy) -N- [4- (1-hydroxy-1-methylethyl) -benzyl] -nicotinamide

To a solution of 2- (2,4-difluorophenoxy) -nicotinic acid (0.300 g, 1.19 mmol), 2- (4-aminomethyl-phenyl) -propan-2-ol (0.217 g, 1.31 mmol) and 1 -hydroxybenzotriazole hydrate (0.177 g, 1.31 mmol) in anhydrous dimethylformamide was added 1- (3-dimethylamino) -propyl) -3-ethylcarbodiimide hydrochloride (0.273 g, 1.43 mmol) and stirred overnight. The mixture was poured into 100 ml of water and extracted with ethyl acetate. The combined extracts were washed with 1 N NaOH, water and brine, dried over MgSO ₄ , filtered, and concentrated to an oil which was purified by silica gel chromatography eluting with 40% ethyl acetate in hexane to give a white solid. Recrystallization from ethyl acetate / hexane gave a white solid (0.336 g). Melting point 92-94 ° C. Analysis calculated for C ₂₂ H ₂₀ N ₂ O ₃ F ₂ : C 66.32, H 5.06, N 7.03. Found: C 66.28, H 4.92, N 6.89.

Example 231

2- (3,4-difluorophenoxy) -N- [4- (1-hydroxy-1-methylethyl) -benzyl] -nicotinamide

To a solution of 2- (2,3-difluorophenoxy) -nicotinic acid (0.300 g, 1.19 mmol), 2- (4-aminomethyl-phenyl) -propan-2-ol.

-221 (0.217 g, 1.31 mmol) and 1-hydroxybenzotriazole hydrate (0.177 g, 1.31 mmol) in anhydrous dimethylformamide were added 1- (3-dimethylamino) propyl) -3-ethylcarbodiimide hydrochloride (0.273 g) (1.43 mmol) and stirred overnight. The mixture was poured into 100 ml of water and extracted with ethyl acetate. The combined extracts were washed with 1 N NaOH, water and brine, dried over MgSO ₄ , filtered, and concentrated to an oil which was purified by silica gel chromatography eluting with 40% ethyl acetate in hexane to give an oil. Recrystallization from ethyl acetate / hexane gave a white solid (0.337 g). Mp 98-1000 ° C. Anal. Calcd for C ₂₂ H ₂₀ N ₂ O ₃ F ₂ : C 66.32, H 5.06, N 7.03. Found: C 66.40, H 4.94, N 6.89.

Following the procedure of Example 231, the compounds of Examples 232-233 were prepared, but the 2- (4-aminomethyl-phenyl) -propan-2-ol was replaced with the corresponding amine. The duration of the reaction is between 1 and 24 hours.

Example 232

2- (3,4-difluorophenoxy) -N- [4- (1-hydroxy-cyclobutyl) -benzyl] -nicotinamide

Mp 74-76 ° C. Analysis for C ₂₃ H ₂ oN ₂ 0 ₃ F ₃ Calculated C 67.31, H 4.91, N 6.83 Found: C 67.14, H 4.93, N 6.67.

Example 233

N- [2-chloro-4- (1-hydroxy-1-methylethyl) -benzyl] -2- (3,4-difluorophenoxy) -nicotinamide

Melting point 119-121 ° C. Anal. Calcd for C ₂₂ H ₁₉ N ₂ O ₃ F ₂ Cl: C 61.65, H 4.42, N 6.47. Found: C 61.31, H 4.56, N 6.65.

Example 234

4 - ({[2- (3-Acetyl-phenoxy) -pyridine-3-carbonyl] -amino} -methyl) -cyclohexanecarboxylic acid ethyl ester

4-Aminomethyl-cyclohexanecarboxylic acid ethyl ester hydrochloride solution (0.410 g, 1.853 mmol), n 99 9 9

-222-

2- (3-acetylphenoxy) -nicotinic acid (0.500 g, 1.946 mmol), 1-hydroxybenzotriazole hydrate (0.275 g, 2.04 mmol) and 1- (3-dimethylamino) propyl) -3-ethylcarbodiimide hydrochloride ( 0.330 g (2.22 mmol) in dimethylformamide (30 mL) was stirred for 10 minutes. To this stirred solution was added triethylamine (0.280 g, 2.78 mmol) and stirred overnight at room temperature. The mixture was diluted with water (200 mL) and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over MgSO ₄ , filtered and concentrated to give a yellow solid, which was purified by silica gel chromatography eluting with 40% ethyl acetate in hexane. Recrystallization from ethyl acetate / hexane gave white crystals (0.680 g). Melting point 118-120 ° C. 1 H NMR (CDCl 3) d 1.02 (2H, q, J = 12.866 Hz), 1.2 (3H, t), 1.4 (2H, q), 1.6 (1H, m), 1.85 ( 2H, d, J = 12.5Hz), 2.0 (2H, d, J = 12.5Hz), 2.2 (1H, m), 2.6 (3H, s), 3.4 ( 2H, m)

4.10 (2H, t); 7.2-8.7 (7H, m).

Following the procedure of Example 234, the compounds of Examples 235-237 were prepared, but the 4-aminomethyl-cyclohexanecarboxylic acid ethyl ester hydrochloride was replaced with the corresponding amine. The duration of the reaction is between 1 and 24 hours.

Example 235

2- (3-acetylphenoxy) -N- [2-chloro-4- (1-hydroxy-1-methylethyl) -benzyl] -nicotinamide

Melting point 102-104 ° C. Analysis calculated for C ₂₄ H ₂₃ N ₂ O ₄ Cl: C 65.68, H 5.28, N 6.38. Found: C 65.39, H 5.08, N 6.15.

Example 236

2- (4-acetylphenoxy) -N- [4- (1-hydroxy-1-methylethyl) -benzyl] -nicotinamide

Melting point 95-97 ° C. Analysis for C ₂ 4 H ₂₄ N ₂ O ₄ Calculated: C,

H, 5.93; N, 6.93. Found: C, 70.19; H, 5.93; N, 7.02.

Example 237 ··· »

-223ν · · • ♦ • • # # # # # # # # # # # # # # # # #

4 «·

2- (3-acetylphenoxy) -N- [2-fluoro-4- (1-hydroxy-1-methylethyl) -benzyl] -nicotinamide

Melting point 68-70 ° C. MS (m / e) 423 (M ⁺ +1).

Example 238

2- (3,5-difluorophenoxy) -N- [4- (1-hydroxy-1-methylethyl) -benzyl] -nicotinamide

To a solution of 2- (3,5-difluorophenoxy) -nicotinic acid (0.300 g, 1.19 mmol), 2- (4-aminomethyl) -propan-2-ol (0.197 g, 1.19 mmol) and 1-hydroxybenzotriazole -hydrate (0.177 g, 1.31 mmol) in anhydrous dimethylformamide was added 1- (3-dimethylamino) -propyl) -3-ethylcarbodiimide hydrochloride (0.273 g, 1.43 mmol) and stirred overnight. The mixture was poured into 100 ml of water and extracted with ethyl acetate. The combined extracts were washed with 1 N NaOH, water and brine, dried over MgSO ₄ , filtered, and concentrated to an oil which was purified by silica gel chromatography eluting with 40% ethyl acetate in hexane to give an oil. Recrystallization from ethyl acetate / hexane gave a white solid (0.328 g). Melting point 68-70 ° C. Analysis calculated for C ₂₂ H ₂₀ N ₂ O ₃ F ₂ : C 66.32, H 5.06, N 7.03. Found: C 67.30, H 5.39, N 6.56.

Example 239

Trans-2- (2,4-difluorophenoxy) -N- [4- (1-hydroxy-1-methylethyl) -cyclohexylmethyl] -nicotinamide

To trans-4 - ({[2- (2,4-difluorophenoxy (-pyridine-3-carbonyl) -amino} -methyl) -cyclohexanecarboxylic acid ethyl ester (0.516 g, 1.23 mmol) in tetrahydrofuran (20 mL), 3.0 M methylmagnesium chloride (1.2 mL, 3.7 mmol) was added dropwise at 0 ° C and stirred for 1 hour The reaction mixture was poured into 150 mL water, acidified with oxalic acid to pH 3 and The combined extracts were washed with Spojené1 N

HCl, 1N NaOH, water and brine, dried over MgSO ₄ , filtered, and concentrated to an oil which

Purification by silica gel chromatography eluting with 50% hexane in ethyl acetate gave an oil. Recrystallization from ethyl acetate / hexane gave a white solid (0.207 g). Melting point 92-94 ° C. Analysis calculated for C ₂₂ H ₂₆ N ₂ O ₃ F ₂ : C 65.33, H 6.48, N 6.93. Found: C 65.27, H 6.26, N 6.73.

Following the procedure of Example 239, the compound of Example 240 was prepared but the trans-4 - ({[2- (2,4-difluorophenoxy) -pyridine-3-carbonyl] -amino} -methyl) -cyclohexanecarboxylic acid ethyl ester was replaced with the corresponding ester. The duration of the reaction is between 1 and 24 hours.

Example 240

Trans-2- (3,4-difluorophenoxy) -N- [4- (1-hydroxy-1-methylethyl) -cyclohexylmethyl] -nicotinamide, m.p. 80-82 ° C, MS (m / e) 405 (M ⁺⁺ ) l).

Example 241

4 - ({[2- (3-Nitrophenoxy) -pyridine-3-carbonyl] -amino} -methyl) -cyclohexanecarboxylic acid ethyl ester

To a stirred solution of 4-aminomethyl-cyclohexanecarboxylic acid ethyl ester hydrochloride (0.500 g, 2.26 mmol), 2- (3-nitrophenoxy) -nicotinic acid (0.588 g, 2.26 mmol),

1-hydroxybenzotriazole hydrate (0.366 g, 2.71 mmol) and 1- (3-dimethylamino) -propyl) -3-ethylcarbodiimide hydrochloride (0.564 g, 2.93 mmol) in dimethylformamide (50 mL) were added triethylamine (0.456 g, 4.52 mmol) and stirred at room temperature over the weekend. The mixture was diluted with water (150 mL) and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over MgSO 4, filtered and concentrated to give an oil which was purified by silica gel chromatography eluting with 40% ethyl acetate in hexane to give an oil (1.05 g). MS (m / e) 428 (M ^& lt ^; + &^gt; +1). ¹ H NMR (CDCl ₃ ) d 1.01 (2H, m),

1.2 (3H, t), 1.4 (2H, q), 1.6 (1H, m), 1.90 (2H, d, J = 12.5 • • · · · · ^- 225 ^- · ······· ·· ·· ··

Hz), 2.0 (1H, d, J = 12.5Hz), 2.2 (1H, m), 3.4 (2H, m), 4.10 (2H, q), 7.20- 8.7 (7 H, m).

Example 242

2- (3-acetylphenoxy) -N- [4- (1-hydroxy-1-methylethyl) -cyclohexylmethyl] -nicotinamide

A solution of N- [4- (1-hydroxy-1-methylethyl) -cyclohexylmethyl] -2- [3- (2-methyl- [1,3] dioxolan-2-yl) phenoxy] -nicotinamide (0.400 g, 0, 88 mmol) in acetic acid (10 mL) was stirred at room temperature for 3 hours. The mixture was diluted with 250 mL of ethyl acetate, washed with 1 N NaOH, water and brine, dried over MgSO ₄ , filtered and concentrated to give an oil which was purified by silica gel chromatography eluting with 40% ethyl acetate and hexane. Recrystallization gave a solid (0.055 g). Melting point 105-107 ° C. Analysis for C ₂ 4 H ₃ oN ₂ 0 ₄ calculated: C 70.22, H 7.37, N 6.82 Found: C 68.43, H 7.32, N 6.71.

Example 243

2- (3-Cyano-4-fluorophenoxy) -N- [4- (1-hydroxy-1-methylethyl) -benzyl] -nicotinamide

To a solution of 2- (3-cyano-4-fluorophenoxy) -nicotinic acid (0.300 g, 1.16 mmol), 2- (4-aminomethyl-phenyl) -propan-2-ol (0.192 g, 1.16 mmol) and 1-hydroxybenzotriazole hydrate (0.172 g,

1.28 mmol) in anhydrous dimethylformamide was added 1- (3-dimethylamino) -propyl) -3-ethylcarbodiimide hydrochloride (0.267 g, 1.39 mmol) and stirred overnight. The mixture was poured into 100 ml of water and extracted with ethyl acetate. The combined extracts were washed with 1 N NaOH, water and brine, dried over MgSO ₄ , filtered and concentrated to give an oil which was purified by silica gel chromatography eluting with 50% ethyl acetate in hexane to give an oil. Recrystallization from ethyl acetate / hexane gave a white solid (0.276 g). Melting point 147 • ·

to 14 ° C. Analysis for C ₂₃ H ₂ ON ₃ 0 ₃ F: Calculated: C 68.14, H 4.97, N 10.36 Found: C 67.77, H 5.00, N 10.15.

Following the procedure of Example 243, the compound of Example 244 was prepared, but the 2- (4-aminomethyl-phenyl) -propan-2-ol was replaced with the corresponding amine. The duration of the reaction is between 1 and 24 hours.

Example 244

N- [2-chloro-4- (1-hydroxy-1-methylethyl) benzyl] -2- (3-cyano-4-fluorophenoxy) nicotinamide

Melting point 151-153 ° C. Analysis for C ₂₃ H ₁₉ N ₃ O ₃ FC1: Calculated: C 62.80 H 4.35 N 9.55 Found: C 63.16, H 4.44, N 9.49.

Example 245

2- (4-Fluorophenoxy) -N- [4- (1-hydroxy-1-methylethyl) -cyclohexylmethyl] -nicotinamide

To 4 - ({[2- (4-fluorophenoxy) -pyridine-3-carbonyl] -amino} -methyl) -cyclohexanecarboxylic acid methyl ester (0.0221 g, 0.06 mmol) in tetrahydrofuran (1 mL) at RT -78 ° C add 1.4 M methyllithium in diethyl ether (171 μΐ, 0.24 mmol) and stir at -78 ° C for 2 hours. Add 200 μΐ of saturated NH ₄ Cl to the reaction mixture and warm to room temperature. The reaction mixture was filtered through a magnesium sulfate column and concentrated to give a light brown foam which was purified by silica gel chromatography eluting with 1: 1 hexane: ethyl acetate to 95: 5 methylene chloride / methanol to give a clear film (0.0111 g). ). Mp 78-80 ° C. Anal. Calcd for C ₂₂ H ₂₇ N ₂ O ₃ F: C 68.37, H 7.04, N 7.25. Found: C 68.32, H 7.04, N 7.27.

Example 246

N- (2-chlorobenzyl) -2- (pyridin-3-ylmethoxy) nicotinamide

To a solution of 2- (pyridin-3-ylmethoxy) -nicotinic acid (0.300 g, 1.3 mmol), 2-chlorobenzylamine (0.202 g, 1.43 mmol), and · · · ··· ··························· .

1-hydroxybenzotriazole hydrate (0.210 g, 1.56 mmol) in anhydrous dimethylformamide (10 mL) was added 1- (3-dimethylamino) -propyl) -3-ethylcarbodiimide hydrochloride (0.324 g, 1.69 mmol) and stirred over night. The mixture was diluted with 50 mL of water and 50 mL of 1 N sodium hydroxide and extracted with ethyl acetate. The combined extracts were washed with 1 N NaOH, water and brine, dried over Na ₂ SO ₄ , filtered, and concentrated to an oil which was purified by silica gel chromatography eluting with 5% methanol in methylene chloride. Recrystallization from ethyl acetate / hexane gave white crystals (0.116 g). Mp 91-93 ° C. Analysis for C ₁₉ H ₁₆ N ₃ O ₂ C1 Calculated:

H, 4.56; N, 11.88. Found: C, 64.38; H, 4.58; N, 11.97.

Example 247

N - [[4- (dimethylamino) phenyl] methyl] -2- (4-fluorophenoxy) -3-pyridinecarboxamide

To a solution of 1.00 g (2.96 mmol) of N- (4-aminobenzyl) -2- (4-fluorophenoxy) -nicotinamide in 20 ml of acetonitrile was added 1.44 ml (17.8 mmol) of an aqueous 37% formaldehyde solution. and then 0.558 g (4.45 mmol) of NaCNBH ₃ . After stirring for 16 hours at room temperature, the mixture was acidified to quench excess NaCNBH ₃ and partially evaporated to remove acetonitrile. The residue was adjusted to pH 6-7 and then extracted with EtOAc (2 x 200 mL). The combined extracts were washed with saturated aqueous sodium bicarbonate solution (1 x 100 mL), brine (1 x 100 mL), dried (Na ₂ SO ₄ ) and evaporated to 1.55 g oil. Purification by flash chromatography using 40%

EtOAc-hexane gave 992 mg of an oil which slowly solidified. Trituration in hexane gave 872 mg (81% yield) of the title compound as a white solid, mp 99.5-101.5 ° C. Analysis for C ₂₁ H ₂₀ N ₃ O ₂ F calculated:

C 69.03, H 5.51, N 11.50. Found: C 69.32, N 5.52, N 11.58.

Example 248

-228-

2- (4-fluorophenoxy) -α- [2- (4-methoxyphenyl) ethyl] -3-pyridine-methanol

A solution of 0.250 g (1.15 mmol) of 2- (4-fluorophenoxy) -3-pyridinecarboxaldehyde in 5 mL of tetrahydrofuran was cooled to -78 ° C and 1.0 mL of a Grignard reagent solution prepared from 2.62 g was added dropwise. (15.3 mmol) of 1- (2-chloroethyl) -4-methoxybenzene and 0.559 g (23.0 mmol) of magnesium turnings in 13 mL of THF. After stirring for 2 hours, an additional 0.5 mL of Grignard reagent was added and 2 mL of a saturated aqueous NH ₄ Cl solution was added. After warming to room temperature, the mixture was partitioned between 50 mL water and 200 mL EtOAc, and the separated organic layer was washed with saturated aqueous sodium bicarbonate, brine, dried (Na ₂ SO ₄ ) and evaporated to give 0.53 g colorless. oils. Two purifications by flash chromatography using 25% EtOAc-hexane and 25% ether-toluene as eluents gave 339 mg (64% yield) of the title compound as an oil. Thermospray MS: m / e 354 (M @ ⁺ +1).

Example 249

1- [2- (4-Fluorophenoxy) -3-pyridinyl] -3- (4-methoxyphenyl) -1-propanone

A solution of 353 mg (1.00 mmol) of 2- (4-fluorophenoxy) -α- [2- (4-methoxyphenyl) ethyl] -3-pyridinomethanol in 5 mL of acetone was cooled to 0 ° C and treated with 1 6 mL (2.00 mmol) of a 1.25 M Jones reaction solution. The mixture was allowed to warm to room temperature and then 5 mL of isopropanol was added. The precipitate was removed by filtration and the filtrate was evaporated and partitioned between 50 mL of saturated aqueous sodium bicarbonate solution and 100 mL of EtOAc. The separated organic layer was combined with 100 mL of aqueous washes with EtOAc, washed with brine (50 mL), dried (Na ₂ SO ₄ ) and evaporated. Trituration of the residue in hexane gave 271 mg (yield 77%) of the title compound, mp 73-74 ° C. ¹ H NMR • ·

-229-. ··. .... (CDCl ₃ ) d 3.03 (2H, t, J = 7Hz), 3.43 (2H, t, J = 7Hz), 3.78 (3H,

s), 6.75-7.18 (9H, m), 8.17 (1H, dd, J = 2.8 Hz), 8.25 (1H, dd, J = 2.4 Hz). Analysis for C ₂₁ H ₁₈ NO ₃ F. 0.25 H ₂ O: Calculated: C 70.87, H

N, 3.94. Found: C, 70.88; H, 4.79; N, 3.79.

Example 250

3- (2-chlorophenyl) -1- [2- (4-fluorophenoxy) -3-pyridinyl] -1-propanone

A solution of 226 mg (0.496 mmol) of α - [(2-chlorophenyl) methyl] -2- (4-fluorophenoxy) -β-οχο-3-pyridinepropanoic acid tert-butyl ester in 5 ml of trifluoroacetic acid is stirred at room temperature for 4 hours. hours. The mixture was evaporated and the residue was dissolved in 5 ml of toluene, heated at reflux for 2 hours and evaporated. The residue was dissolved in EtOAc (100 mL), washed successively with saturated aqueous sodium bicarbonate (1 x 50 mL) and brine (1 x 50 mL), dried (Na ₂ SO ₄ ) and evaporated to give 125 mg of an oil. Purification by flash chromatography using 40% ether in hexane as eluent gave 120 mg (68% yield) of the title compound as a colorless oil. ¹ H NMR (CDCl ₃ ) d 3.20 (2H, t, J = 8Hz), 3.49 (2H, t, J = 8Hz), 7.06-7.32 (9H, m), 8 19 (1H, dd, J = 2.7Hz), 8.25 (1H, dd, J = 2.5Hz). Thermospray MS (m / e) 356.358 (M ⁺ +1).

Following the procedure of Example 250, the compounds of Examples 251 to 255 were prepared, but the compound of Preparation 60 was replaced with the indicated substrate. Mass spectra were determined by the thermospray method.

Example 251

1- [2- (4-fluorophenoxy) pyridin-3-yl] -3- (4-fluorophenyl) -propan-1 -one ^{Χ Η} NMR (CDC1 ₃₎ d 3.07 (2H, t, J = 7 Hz), 3.45 (2H, t, J = 7Hz),

6.92-7.20 (9H, m), 8.18 (1H, dd, J = 2.8Hz), 8.25 (1H, dd,

J = 2.5 Hz), MS (m / e) 340 (M @ ⁺ +1).

• ·

-230Example 252

1- [2- (4-Fluorophenoxy) -pyridin-3-yl] -3- (4-trifluoromethyl-phenyl) -propan-1-one

Mp 94-95 ° C. Analysis for C ₂₁ H ₁₅ F ₄ NO ₂ calculated: C

H, 3.88; N, 3.60. Found: C, 64.44; H, 3.93; N, 3.45.

Example 253

1- [2- (4-Fluorophenoxy) -pyridin-3-yl] -3- (4-trifluoromethoxy-phenyl) -propan-1-one

Mp 79-81 ° C. Analysis for C ₂₁ H ₁₅ F ₄ NO ₃ calculated: C

H, 3.73; N, 3.46. Found: 62.11; H, 3.77; N, 3.57.

Example 254

3- (3,5-Difluorophenyl) -1- [2- (4-fluorophenoxy) -pyridin-3-yl] -propan-1-one

Mp 69-70 ° C. Analysis for C ₂₀ H ₁₄ F ₃ NO ₂ calculated: C

H, 3.95; N, 3.92. Found: C, 67.19; H, 3.47; N, 3.92.

Example 255

1- [2- (4-Fluorophenoxy) -pyridin-3-yl] -3- (2,4,6-trifluorophenyl) -propan-1-one

Mp 84-85 ° C. Analysis for C ₂₀ H ₁₃ F ₄ NO ₂ calculated: C

H, 3.49; N, 3.73. Found: C, 64.07; H, 3.31; N, 3.66.

Example 256

1- [2- (4-Fluorophenoxy) -3-pyridinyl] -3-phenyl-1-propanone To the sodium hydrides obtained by washing 351 mg (7.73 mmol)

50% dispersion of sodium hydrides in mineral oil with pentane was added with 10 mL of dimethylformamide followed by 867 mg (7.73 mmol) of p-fluorophenol. When hydrogen evolution ceased, 886 mg (3.87 mmol) of 1- (2-fluoropyridin-3-yl) -3-phenyl-propan-1-one dissolved in a minimal amount of DMF was added. The mixture was heated at 80 ° C for 3 hours and the solvent was evaporated under high vacuum. The residue is partitioned between 200 ml of ether and 50 ml of ether. The residue is partitioned between 200 ml of ether and 50 ml. ·· · 31 · · -231- ········ ·· ·· ·· ··

N aqueous sodium hydroxide solution and the separated organic layer was washed with 1 N aqueous sodium hydroxide solution (1 x 50 mL), brine (1 x 100 mL), dried (Na ₂ SO ₄ ) and evaporated to give 1.16 g of white solid. Recrystallization from hexane gave 1.06 g (85% yield) of the title compound as a white solid, mp 82-83 ° C. Anal _. Calcd for C ₂₀ H ₁₆ FNO ₂ : C 74.75, H

N, 4.36. Found: C, 74.63; H, 4.97; N, 4.31.

Following the procedure of Example 256, the compounds of Examples 257-270 were prepared, but the compound of Preparation 63a was replaced with the indicated substrate and, in the indicated cases, p-fluorophenol with 3-hydroxypyridine. The products are purified by direct grinding and / or flash chromatography. Mass spectra were measured by the APCI method.

Example 257

3-Phenyl-1- [2- (pyridin-3-yloxy) -pyridin-3-yl] -propan-1-one M.p. 45-46 ° C. Anal _. Calcd for C ₁₉ H ₁₆ N ₂ O ₂ : C

H, 5.36; N, 9.20. Found: C, 74.80; H, 5.35; N, 9.11.

Example 258

3- (4-Fluorophenyl) -1- [2- (pyridin-3-yloxy) -pyridin-3-yl] -propan-1-one

Mp 62-64 ° C. Anal _. Calcd for C ₁₉ H ₁₅ FN ₂ O ₂ : C

H, 4.69; N, 8.69. Found: C, 70.55; H, 4.80;

Example 259

1- [2- (4-fluorophenoxy) -pyridin-3-yl] -2-methyl-3-phenyl-propan-1-one 1 H NMR (CDCl ₃ ) d 1.19 (3H, d, J = 7 Hz), 2.92 (2H, ABX characteristic, J _M = 13 Hz, J _M = 6 Hz, J _BX = 8 Hz), 3.87-3.94 (1H, m), 7.02-7 24 (10H, m), 7.95 (1 H, dd, J = 2.7 Hz), 8.19 (1 H, dd, J = 2.5 Hz), MS (m / e) 336 (M ⁺ + l).

• • •

-232 • · ··························

Example 260

2- methyl-3-phenyl-l- [2- (pyridin-3-yloxy) -pyridin-3-yl] -propan-1-one ^X 1 HNMR (CDCl ₃₎ d 1.20 (3H, d, J = 7 Hz), 2.93 (2H, ABX pattern, J = 14 Hz _m J _m = 7Hz, J _BX = 8 Hz), 3.86-3.95 (1H, m), 7.06 -7.49 (8H, m), 7.94-7.97 (1H, m), 8.16-8.18 (1H,

m), 8.47-8.50 (2 H, m), MS (m / e) 319 (M ⁺ +1).

Example 261

1- [2- (4-fluorophenoxy) pyridin-3-yl] -3-phenyl-butan-l-one ^X H NMR (CDCl3) d 1.31 (3H, d, J = 7Hz), 3, 30-3.52 (3 H, m),

7.02-7.27 (10H, m), 8.01 (1H, dd, J = 2.8Hz), 8.20 (1H, dd,

J = 2.5 Hz), MS (m / e) 336 (M ^& lt ^; + &^gt; +1).

Example 262

3-phenyl-l- [2- (pyridin-3-yloxy) -pyridin-3-yl] -butan-l-one ^X H NMR (CDCl3) d 1.31 (3H, d, J = 7Hz) 3.32-3.52 (3H, m), 7.06-7.53 (8H, m), 8.05 (1H, dd, J = 2.8Hz), 8.19 (1H, dd, J = 2.5 Hz, 8.49-8.51 (2H, m), MS (m / e) 319 (M ^& lt ^; + &^gt; +1).

Example 263

3- [4- (1-hydroxy-l-methylethyl) phenyl] -1- [2- (pyridin-3-yloxy) -pyridin-3-yl] -propan-l-one ^X H NMR (CDCl3) d 1.54 (6H, s), 1.88 (1H, broad s), 3.07 (2H, t, J = 8Hz), 3.44 (2H, t, J = 8Hz), 7.11 -7.55 (7H, m), 8.17-8.21 (2H, m), 8.21-8.49 (2H, m), MS (m / e) 345 (M ⁺ +1-18) (H ₂ O)).

Example 264

1- [2- (4-Fluorophenoxy) -pyridin-3-yl] -2-phenyl-ethanone M.p. 81-82 ° C. Analysis for C ₁₉ H ₁₄ FNO ₂ calculated: C

H, 4.59; N, 4.56. Found: C, 74.13; H, 4.61; n, 4.56.

Example 265

1- [2- (4-Fluorophenoxy) -pyridin-3-yl] -2-phenoxy-ethanone ···· ······ _o OO · »····· *. ·

-zoo- ··· * ···· · «. ·· ·· · <

105.5-106.5 ° C. ¹ H NMR (CDCl ₃ ) d 5.34 (2H, s),

6.73-7.28 (10H, m); 8.26-8.33 (2H, m). MS (m / e) 324 (M ^& lt ^; + &^gt; +1).

Example 266

2- (2-Chloro-phenoxy) -1- [2- (4-fluoro-phenoxy) -pyridin-3-yl] -ethanone

Melting point 92-93 ° C. Analysis for C ₁₉ H ₁₃ NO ₃ C1F: Calculated: C 63.79, H 3.66, N 3.91 Found: C 63.43, H 3.52, N 3.94.

Example 267

1- [2- (4-Fluorophenoxy) -pyridin-3-yl] -3-phenyl-propenone M.p. 110-111 ° C. ¹ H NMR (CDCl ₃ ) d 7.07-7.58 (11H,

m), 7.75 (1H, d, J = 16Hz), 8.13 (1H, dd, J = 2.7Hz), 8.27 (1H, dd, J = 2.5Hz), MS (m / e) 320 (M @ ⁺ +1).

Example 268

Benzofuran-2-yl- [2- (4-fluorophenoxy) -pyridin-3-yl] -methanone, m.p. 102-103 ° C. Analysis for C ₂ oH ₁₂ N03F Calculated: C 72.07 H 3.63 N 4.20 Found: C, 71.84; H, 3.43; N, 4.15.

Example 269 [2- (4-Fluorophenoxy) -pyridin-3-yl] - (1H-indol-2-yl) -methanone M.p. 169-170 ° C. ¹ H NMR (CDCl ₃ ) d 7.04-7.17 (7H, m),

7.36 (1H, dd, J = 1.8 Hz), 7.46 (1H, d, J = 8Hz), 7.67 (1H, d, J = 8 Hz), 7.95 (1H, dd, J = 2.8Hz) 8.28 (1H, dd, J = 2.5Hz), 9,20 (1H, s), MS (m / e) 333 (M ^& lt ^; + &^gt; +1).

Example 270

1- [2- (4-Fluorophenoxy) -pyridin-3-yl] -2- (methylphenylamino) -ethanone

Melting point 126-128 ° C. ¹ H NMR (CDCl ₃ ) d 3.10 (3H, s), 4.85 (2H, s), 6.61-6.73 (3H, m), 7.09-7.21 (7H, m) ), 8.22 ((1 H, dd,

J = 2.8 Hz), 8.27 (1H, dd, J = 2.5 Hz), MS (m / e) 337 (M ⁺ +1).

«-2 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34

Example 271

1- [2- (4-Fluorophenoxy) -3-pyridinyl] -3-hydroxy-3-phenyl-1-propanone

A solution of 0.114 mL (111 mg, 1.10 mmol) of diisopropylamine in 8 mL of tetrahydrofuran was cooled to -78 ° C and treated dropwise with 0.440 mL (1.10 mmol) of a 2.5 M solution of n-butyllithium in THF. hexane. The mixture was stirred for 30 minutes and then a solution of 231 mg (1.00 mmol) of 1- [2- (4-fluorophenoxy) -3-pyridinyl] -ethanone in 2 mL of tetrahydrofuran was added dropwise. After stirring for 30 minutes, benzaldehyde (0.112 mL, 1.07 mmol) was added dropwise and stirring was continued for 1 hour. The reaction was quenched by addition of 2 mL of saturated aqueous NH ₄ Cl solution and allowed to warm to room temperature. The mixture was partitioned between 50 mL of saturated aqueous NH ₄ Cl solution and 300 mL of EtOAc. The separated organic layer was washed with 50 mL of saturated aqueous sodium bicarbonate solution, 50 mL of brine, dried (Na ₂ SO ₄ ) and evaporated to give 259 mg of an oil. Purification by flash chromatography using 40% EtOAc in hexane as eluent gave 211 mg (63% yield) of the title compound as an oil. 1 H NMR (CDCl ₃ ) d 3.23 (1H, broad s), 3.54-3.56 (2H, m), 5.34-5.37 (1H, m), 7.07-7, 41 (10H, m), 8.21-8.26 (2 H, m). APCI MS (m / e) 338 (M ^& lt ^; + &^gt; +1).

Example 272

1- [2- (3-pyridyloxy) -3-pyridinyl] -3-hydroxy-3-phenyl-1-propanone ^{τ Η} NMR (CDC1 ₃₎ d 3.29 (1H, br s), 3,52-3 57 (2H, m), 5.35-5.38 (1H, m), 7.13-7.51 (8H, m), 8.23-8.26 (2H, m), 8.46 -8.49 (2H, m), APCI MS (m / e) 321 (M ^& lt ^; + &^gt; +1).

Example 273 α- [2- (2-Chloro-phenyl) -ethyl] -2- (4-fluoro-phenoxy) -3-pyridine-methanol · 9 ····

-2359999 999 ·

A solution of 3- (2-chlorophenyl) -1- [2- (4-fluorophenoxy) -3-pyridinyl] -1-propanone (76.0 mg, 0.214 mmol) in methanol (5 mL) was cooled to 0 ° C and allowed to stand at room temperature. react with 8.0 mg (0.21 mmol) of NaBH ₄ . The mixture was stirred at 0 ° C for 30 min and then 1 mL of aqueous 1 N hydrochloric acid was added. The mixture was evaporated and the residue was partitioned between 100 mL EtOAc and 50 mL saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried (Na ₂ SO ₄ ) and evaporated to give 79 mg (100%) of the title compound as an oil. ¹ H NMR (CDCl ₃ ) d 2.10-2.32 (2H,

m), 2.35 (1H, d, J = 6Hz), 2.83-3.08 (2H, m), 5.06-5.15 (1H,

m), 7.01-7.33 (9H, m), 7.85 (1H, dd, J = 2.7Hz), 8.05 (1H, dd,

J = 2.5 Hz). Thermospray method MS (m / e) 358 and 360 (M ⁺ +1).

Following the procedure of Example 273, the compounds of Examples 274-276 were prepared, but 3- (2-chlorophenyl) -1- [2- (4-fluorophenoxy) -3-pyridinyl] -1-propanone was replaced with the indicated substrate.

Example 274

1- [2- (4-Fluorophenoxy) -pyridin-3-yl] -3- (2,4,6-trifluorophenyl) -propan-1-ol

Melting point 90-91 ° C. 1 H NMR (CDCl ₃ ) d 2.00-2.20 (2H, m),

2.31 (1H, d, J = 5Hz), 2.71-2.90 (2H, m), 4.98-5.08 (1H, m), 6.56-6.61 (2H, m), 6.99-7.10 (5H, m), 7.81 (1H, dd, J = 1.8 Hz), 8.02 (1H, dd, J = 2.5 Hz). Thermospray MS (m / e) 378 (M @ ⁺ +1).

Example 275

1- [2- (4-Fluorophenoxy) -pyridin-3-yl] -3-phenyl-propan-1-ol

^{: 1} H NMR ( CDC1 ₃ ) d 2.10-2.25 (2H, m), 2.20 (1H, broad s), 2.72-2.92 (2H, m), 5.01-5.09 (1H, m), 6.99-7.30 (10H, m), 7.79 (1 H, dd, J = 1.7 Hz) , 8.03 (1H, dd, J = 2.5 Hz). AMPI MS m / e 324

(M @ ⁺ +1).

-236:

Example 276

3-phenyl-1- [2- (pyridin-3-yloxy) -pyridin-3-yl] -propan-1-ol ^{: 1} H NMR (CDCl 3) d 2.08-2.23 (2H, m), 2 60 (1H, broad s), 2.73-2.89 (2H, m), 5.07-5.12 (1H, m), 7.04-7.48 (8H, m), 7, 86-7.89 (1 H, m), 8.01 (1 H, dd, J = 2.5 Hz), 8.40-8.43 (2 H, m),

AMPI MS (m / e) 307 (M ^& lt ^; + &^gt; +1).

Example 277 (E) -2- (4-Fluorophenoxy) -3- [3- (4-methoxyphenyl) -1-propenyl] pyridine

A mixture of 0.97 g (2.7 mmol) of 2- (4-fluorophenoxy) -α- [2- (4-methoxyphenyl) ethyl] -3-pyridinmethanol, 0.93 g (3.9 mmol) of Burgess reagent and 20 ml of benzene was heated to reflux for 4 hours. The cooled mixture was partitioned between 300 mL EtOAc and 100 mL saturated aqueous sodium bicarbonate and the separated organic layer was washed with 100 mL brine, dried (Na ₂ SO ₄ ) and evaporated to give 1.10 g of an oil. Purification by flash chromatography using 15% EtOAc in hexane as eluent gave 0.39 g (42% yield) of the title compound.

name in form oils . ¹ H NMR (CDClj) d 3.60 (2 H, d, J = 7 Hz), 3, 82 (3H, s), 6.48 ( 1H, dt, J = 7.16 Hz), 6.78 (1H, d, J = 16 Hz), 6.86 -7.18 (9H, m) 7.79 (1 H, dd, J = 2.8 Hz), 7.99 (1H, dd,

J = 2.5 Hz).

Following the procedure of Example 277, the compound of Example 278 was prepared, but the 2- (4-fluorophenoxy) -α- [2- (4-methoxyphenyl) ethyl] -3-pyridinmethanol was replaced with the corresponding alcohol.

Example 278 (E) -2- (4-fluorophenoxy) -3- [3-phenyl-1-propenyl] -pyridine ^X 1 HNMR (CDCl ₃₎ d 3.62 (2H, d, J = 7 Hz), 6 51 (1H, dt, J = 7.16)

Hz), 6.81 (1H, d, J = 16Hz), 6.83-7.35 (10H, m), 7.78 (1H, dd,

J = 2.8 Hz), 8.00 (1H, dd, J = 2.5 Hz). AMPI MS (m / e) 306 (M ^& lt ^; + &^gt; +1).

• · · ·

-237 • · «· · ········ · ·

Example 279 syn-3- [1,2-dihydroxy-3- (4-methoxyphenyl) propyl] -2- (4-fluorophenoxy) pyridine

To a mixture of 161 mg (1.19 mmol) of N-methylmorpholine-N-oxide hydrate, 0.175 g (0.0175 mmol) of a 2.5% solution of OsO ₄ in tert-butanol, 0.6 mL of acetone and 0.4 mL 200 mg (0.596 mmol) of (E) -2- (4-fluorophenoxy) -3- [3-phenyl-1-propenyl] -pyridine dissolved in 2 ml of acetone and 0.5 ml of water are added. The mixture was stirred at room temperature for 16 hours, then 5 g solid sodium sulfite was added. The suspension was stirred for 5 minutes and the solids were removed by filtration and rinsed with 100 mL acetone. The filtrate was concentrated and the residue was partitioned between 100 mL EtOAc and 50 mL brine. The organic layer was separated, combined with 100 mL of aqueous layer washing with EtOAc, dried (Na ₂ SO ₄ ) and evaporated to give 195 mg of a solid. Recrystallization from toluene afforded 140 mg (64% yield) of the title compound as a white solid, mp 125-126 ° C. ^τ Η NMR (CDCl ₃ ) d 2.13 (1H, d, J = 4Hz), 2.87 (2H, d, J = 6Hz), 2.94 (1H, d, J = 6Hz), 3.78 (3H, s), 4.05-4.14 (1H, m), 5.02 (1H, t, J = 5 Hz), 6.80-7.16 (9H, m), 7 89 (1H, dd, J = 2.7Hz), 8.08 (1H, dd, J = 2.4Hz).

Following the procedure of Example 279, the compound of Example 280 was prepared, but the starting material was replaced with the corresponding starting material.

Example 280 syn-3- (1,2-dihydroxy-3-phenylpropyl) -2- (4-fluorophenoxy) pyridine

Melting point 125-126 ° C. Anal _. Calcd for C ₂₀ H ₁₈ NO ₃ F: C 70.78, H 5.35, N 4.13. Found: C 70.68, H 5.19, N 4.24.

Example 281

3 - [(benzyloxy) methyl] -2- (4-fluorophenoxy) pyridine

To a suspension of 122 mg (2.53 mmol) of a 50% dispersion of sodium hydride in mineral oil in 10 ml of dimethylformamide was added 500 mg (2.30 mmol) of 2- (4-fluorophenoxy) -3-pyridinmethanol followed by 0.343 ml (396 mg). , 2.53 mmol) of 4-methoxybenzyl chloride and 420 mg (2.53 mmol) of KI. The mixture was stirred at room temperature for 1 hour and then partitioned between 100 mL water and 100 mL EtOAc. The separated organic layer was washed with brine, dried (Na ₂ SO ₄ ) and evaporated to give 949 mg of a yellow oil. Purification by flash chromatography using 20% EtOAc in hexane as eluent gave 552 mg of a colorless oil which solidified on standing. Trituration in hexane gave 464 mg (59% yield) of the title compound as a white solid, mp 49-50 ° C. Anal _. Calcd for C ₂₀ H ₁₈ NO ₃ F: C 70.78, H 5.35, N 4.13. Found: C 70.79, H 5.09, N 4.03.

Example 282

1- [2- (4-Fluorophenoxy) -3-pyridinyl) -3- (4-methoxyphenyl) propane

To a solution of 60 mg (0.18 mmol) of (E) -2- (4-fluorophenoxy) -3- [3- (4-methoxyphenyl) -1-propenyl] pyridine in 50 mL of ethanol was added 50 mg of 10% Pd The mixture was hydrogenated at 50 psi on a Parr shaker for 2 hours. The catalyst was removed by filtration and the filtrate was concentrated to give 50 mg (83% yield) of the title compound as a colorless oil. 1 H NMR (CDCl ₃ ) d 1.92-2.06 (2H, m), 2.67 (2H, t, J = 8Hz), 2.75 (2H, t, J = 8Hz), 3 80 (3H, s), 6.82-7.14 (8H, m),

7.52 (1H, dd, J = 2.7Hz), 7.99 (1H, dd, J = 2.5Hz). Thermospray MS (m / e) 338 (M @ ⁺ +1).

Example 283

N- (2-chlorobenzyl) -2- (3-methoxyphenoxy) nicotinamide

To a solution of 2- (3-methoxyphenoxy) -nicotinic acid (0.300 g, 1.224 mmol), 2-chlorobenzylamine (0.166 g, 1.160 mmol) and

1-hydroxybenzotriazole hydrate (0.173 g, 1.283 mmol) in anhydrous dimethylformamide (30 mL) was added 1- (3-dimethylamino) -propyl) -3-ethylcarbodiimide hydrochloride (0.269 g, 1.399 mmol) and stirred overnight. The mixture was diluted with 200 mL of water and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over MgSO ₄ , filtered and concentrated to give an oil which was purified by silica gel chromatography and eluted with 30% ethyl acetate in hexane to give an oil which solidified on standing (0.300 g). Mp 71-74 ° C.

Anal _. Calcd for C ₂₀ H ₁₇ N ₂ O ₃ Cl: C 65.13, H 4.65, N 7.60. Found: C 64.94, H 4.69, N 7.63.

Example 284

N- [4- (1-hydroxy-1-methylethyl) -benzyl] -2- (1-oxo-indan-4-yloxy) -nicotinamide

To a solution of 2- (1-oxo-indan-4-ylmethoxy) -nicotinic acid (0.220 g, 0.818 mmol), 2- (4-aminomethylphenyl) -propan-2-ol (0.128 g, 0.779 mmol) and 1-hydroxybenzotriazole hydrate (0.116 g, 0.857 mmol) in anhydrous dimethylformamide (30 mL) was added 1- (3-dimethylamino) -propyl) -3-ethylcarbodiimide hydrochloride (0.1795 g, 0.935 mmol) and stirred overnight. The mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over MgSO ₄ , filtered and concentrated to give an oil which was purified by silica gel chromatography eluting with 60% ethyl acetate in hexane to give a yellow solid (0.078 g). Melting point 145-147 ° C. Analysis calculated for C ₂₅ H ₂₄ N ₂ O ₄ : C 72.10, H 5.81, N 6.73. Found: C 71.79, H 5.67, N 6.61.

Example 285

N- (4-acetylbenzyl) -2- (4-fluorophenoxy) nicotinamide

A solution of 2- (4-fluorophenoxy) -N- [4- (2-methyl- [1,3] dioxolan-2-yl) -benzyl] -nicotinamide (1.2 g, 2.9 mmol) in 2 N acid hydrochloric acid (3.7 mL, 7.35 mmol) and tetrahydrofuran (30 mL)

-240

About ·

9

is stirred at room temperature for 3 hours. The mixture was diluted with 100 mL of water and extracted with ethyl acetate. The combined extracts were washed with 1 N NaOH, water and brine, dried over MgSO ₄ , filtered and concentrated to a solid which was recrystallized from ethyl acetate-hexane to give a white solid (0.780 g). Melting point 106-108 ° C. Anal. Calcd for C ₂₁ H ₁₇ N ₂ O ₃ F: C 69.22, H 4.70, N 7.69. Found: C 68.87, H 4.70, N 7.55.

Following the procedure of Example 285, the compound of Example 286 was prepared, but 2- (4-fluorophenoxy) -N- [4- (2-methyl- [1,3] dioxolan-2-yl) -benzyl] -nicotinamide was replaced with the corresponding ketal. . The duration of the reaction is between 1 and 24 hours.

Example 286

2- (4-fluorophenoxy) -N- (4-oxo-cyclohexylmethyl) -nicotinamide, m.p. 157-159 ° C, MS (m / e) 343 (M ⁺ +1).

Example 287

2- (4-Fluorophenoxy) -N- [4- (1-hydroxyethyl) -benzyl] -nicotinamide

To a stirred solution of N- (4-acetylbenzyl) -2- (4-fluorophenoxy) -nicotinamide (0.300 g, 0.823 mmol) in methanol (10 mL) and tetrahydrofuran (10 mL) at room temperature was added sodium borohydride (0.121 g, 3.993 mmol) and stirred for 1 hour. The mixture was poured into ice water and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over MgSO _4, filtered, and concentrated to a solid. Recrystallization from ethyl acetate / hexane gave a solid (0.180 g). Melting point 112-114 ° C. Anal. Calcd for C ₂₁ H ₁₇ N ₂ O ₃ F: C 68.84, H 5.23, N 7.65. Found: C 68.58, H 5.15, N 7.44.

Following the procedure of Example 287, the compound of Example 288 was prepared, but the N- (4-acetylbenzyl) -2- (4-fluorophenoxy) -nico-241-quinamide was replaced with the corresponding ketone. The duration of the reaction is between 1 and 24 hours.

Example 288

2- (4-Fluorophenoxy) -N- (4-hydroxy-cyclohexylmethyl) -nicotinamide

Mp 110-112 ° C, MS (m / e) 345 (M ⁺ +1).

Example 289

2- (3-carbamoylphenoxy) -N- (2-chlorobenzyl) -nicotinamide To a stirred solution of 2- (3-carbamoylphenoxy) -N- (2-chlorobenzyl) -nicotinic acid (0.300 g, 1.25 mmol), o- chlorobenzylamine (0.195 g, 1.375 mmol) and 1-hydroxybenzotriazole hydrate (0.203 g, 1.50 mmol) in anhydrous dimethylformamide (3 mL) were added 1- (3-dimethylamino) propyl) -3-ethylcarbodiimide hydrochloride (0.311) g, 1.63 mmol) and stirred overnight. The mixture was diluted with 100 mL of water and extracted with ethyl acetate.

NaOH, water and brine, dried over Na ₂ SO ₄ , filtered and concentrated to give a white solid which was purified by silica gel chromatography eluting with 7 methylene chloride. Recrystallization from hexane gave a white solid (0.239 g), m.p. 153-155 ° C. Analysis for C ₂₀ H ₁₆ N ₃ O ₃ Cl: calculated: C 62.91, H 4.22, N 11.01 Found: C 62.92, H 4.30, N 11.09.

The combined extracts were washed with% methanol in ethyl acetate and

Example 290

2- (3-Dimethylcarbamoyl-phenoxy) -N- [4- (1-hydroxy-1-methylethyl) -benzyl] -nicotinamide

To a stirred solution of 2- (3-dimethylcarbamoylphenoxy) -N- [4- (1-hydroxy-1-methylethyl) -benzyl] -nicotinic acid (0.300 g, 1.05 mmol), 2- (4-aminomethylphenyl) -propane 2-ol (0.190 g, 1.15 mmol) and 1-hydroxybenzotriazole hydrate (0.155 g, 1.15 mmol) in anhydrous dimethylformamide (5 mL) were added 1- (3-dihydrochloride).

- · ··· »- 242- ................

methylamino) -propyl) -3-ethylcarbodiimide hydrochloride (0.242 g, 1.26 mmol) and stirred overnight. The mixture was poured into 100 ml of water and extracted with ethyl acetate. The combined extracts were washed with 1 N NaOH, water and brine, dried over MgSO ₄ , filtered, and concentrated to an oil which was purified by silica gel chromatography eluting with 2.5% methanol in methylene chloride (0.360 g). ³ H NMR (CDCl ₃ ) d 1.54 (6H, s), 3.00 (3H, s), 3.08 (3H, s), 4.66 (2H, d), 7.20 (3H, s), m), 7.29 (4H, m), 7.43 (2H, m), 8.08 (1H, m), 8.18 (1H, dd), 8.63 (1H, dd), MS ( m / e) 433 (M ^& lt ^{; +} & gt ^; ).

Example 291

N- [4- (1-hydroxy-1-methylethyl) -benzyl] -2- (3-trifluoroacetylphenoxy) -nicotinamide

To a stirred solution of N- [4- (1-hydroxy-1-methylethyl) -benzyl] -2- [3- (2,2,2-trifluoro-1-hydroxyethyl) -phenoxy] -nicotinamide (0.520 g, 1 , 13 mmol), NMO (0.192 g, 1.7 mmol) and molecular sieves 4 x 10 ^-1 nm (0.5 g) in methylene chloride (15 mL) were added TPAP (0.020 g, 0.06 mmol) and stirred at room temperature for 1 hour. The mixture was filtered through Celite and washed with methylene chloride. The filtrate was diluted with 150 mL of methylene chloride, washed with water, dried over MgSO ₄ , filtered and concentrated under reduced pressure to give an oil which was purified by chromatography on silica gel eluting with 2.5% methanol in methylene chloride to give a foam ( 0.506 g). ¹ H NMR (CDCl ₃ ) d 1.54 (6H, s), 4.69 (2H, d), 7.50-7.15 (9H, m), 8.16 (1H, m), 8, MS (m / e) 458 (M ^& lt ^{; +} & gt ^; ).

Example 292

N- [4- (1-hydroxy-1-methylethyl) -benzyl] -2- [3- (2,2,2-trifluoro-1-hydroxyethyl) phenoxy] -nicotinamide

To a stirred solution of N- [4- (1-hydroxy-1-methylethyl) -benzyl] -2- [3- (2,2,2-trifluoro-1-hydroxyethyl) -phenoxy] -nicotinic acid (0.400 g, 1 , 28 mmol), 2- (4-aminomethylphenyl)

- · · · · ».-- 243- ................

-propan-2-ol (0.232 g, 1.40 mmol) and 1-hydroxybenzotriazole hydrate (0.189 g, 1.40 mmol) in anhydrous dimethylformamide (5 mL) were added 1- (3-dimethylamino) -propyl) - 3-ethylcarbodiimide hydrochloride (0.294 g, 1.54 mmol) and stirred overnight. The mixture was poured into 100 ml of water and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over MgSO ₄ , filtered, and concentrated to an oil which was purified by silica gel chromatography eluting with 2.5% methanol in methylene chloride (0.550 g). ¹ H NMR (CDCl ₃ ) d 1.54 (6H, s), 3.53 (1H, d), 4.66 (2H, d), 4.92 (1H, m), 7.46-7, 15 (9H, m), 8.12 (1 H, m), 8.16 (1 H, dd), 8.62 (1 H, dd).

Molecular Weight 313.25, MS (m / e) 313 (M ⁺ ).

Example 293

2- (Benzo [1,3] dioxol-5-yloxy) -N- [4- (1-hydroxy-1-methylethyl) -benzyl] -nicotinamide

To a stirred solution of 2- (benzo [1,3] dioxol-5-yloxy) -nicotinic acid (0.300 g, 1.158 mmol), 2- (4-aminomethylphenyl) -propan-2-ol (0.182 g, 1.103 mmol) and 1-hydroxybenzotriazole hydrate (0.163 g, 1.20 mmol) in anhydrous dimethylformamide (15 mL) was added 1- (3-dimethylamino) -propyl) -3-ethylcarbodiimide hydrochloride (0.254 g, 1.32 mmol) and stirred over night. The mixture was diluted with 200 mL of water and extracted with ethyl acetate. The combined organic extracts were washed with water, 1N sodium hydroxide and brine, dried over MgSO ₄ , filtered, and concentrated to an oil which was purified by silica gel chromatography eluting with 30% ethyl acetate in hexane to give an oil. Recrystallization from ethyl acetate / hexane gave a white solid (0.323 g). Mp 118-120 ° C, MS 407 (M ⁺ +1).

Example 294

2- (3-carbamoylphenoxy) -N- [4- (1-hydroxy-1-methylethyl) -benzyl] -nicotinamide

-244- ................

To a stirred solution of 2- (3-carbamoylphenoxy) -N- [4- (1-hydroxy-1-methylethyl) -benzyl] -nicotinic acid (0.400 g, 1.549 mmol), 2- (4-aminomethylphenyl) -propan-2 -ol (0.243 g, 1.475 mmol) and 1-hydroxybenzotriazole hydrate (0.219 g, 1.623 mmol) in anhydrous dimethylformamide (15 mL) were added 1- (3-dimethylamino) -propyl-3-ethylcarbodiimide hydrochloride (0.3401) g, 1.77 mmol) and stirred overnight. The mixture was poured into water and extracted with ethyl acetate. The combined extracts were washed with 1 N NaOH, water and brine, dried over Na ₂ SO ₄ , filtered, and concentrated to an oil which was purified by silica gel chromatography eluting with 7% methanol in methylene chloride (0.250 g). Melting point 145-147 ° C. MS (m / e) 387 (M ^& lt ^{; +} & gt ^; -18).

Following the procedure of Example 294, the compound of Example 295 was prepared, but the 2- (4-aminomethylphenyl) -propan-2-ol was replaced with the corresponding amine. The duration of the reaction is between 1 and 24 hours.

Example 295

4 - ({[2- (3-Carbamoyl-phenoxy) -pyridine-3-carbonyl] -amino} -methyl) -cyclohexanecarboxylic acid ethyl ester M.p. 160-162 ° C. MS (m / e) 426 (M ^& lt ^; + &^gt; +1).

Example 296

2- (3-acetylphenoxy) -N- (4-sulfamoylbenzyl) -nicotinamide

A solution of 4-aminomethylbenzenesulfonamide (0.248 g, 1.11 mmol), 2- (3-acetylphenoxy) -nicotinic acid (0.300 g, 1.167 mmol), 1-hydroxybenzotriazole hydrate (0.165 g, 1.22 mmol) and 1- ( 3-Dimethylamino) -propyl) -3-ethylcarbodiimide hydrochloride (0.256 g, 1.33 mmol) in dimethylformamide (15 mL) was stirred for 10 minutes. To this stirred solution was added triethylamine (0.280 g, 2.78 mmol) and stirred overnight at room temperature. The mixture was diluted with ethyl acetate and washed with water and brine, dried over MgSO ₄ , filtered, and concentrated to a solid.

• · • ·

-245- ................

Recrystallization from ethyl acetate / hexane gave a solid (0.280 g). Mp 162-164 ° C, MS (m / e) 425 (M ⁺ ).

Example 297

2- (4-Fluorophenoxy) -N- [4- (1-hydroxy-1-methylethyl) -cyclohex-1-enylmethyl] -nicotinamide

To a solution of 2- (4-aminomethyl-cyclohex-3-enyl) -propan-2-ol (0.360 g, 2.127 mmol), 2-diethylaminoethyl chloride hydrochloride (0.530 g, 2.725 mmol), 2- (4-fluorophenoxy) - nicotinic acid (0.645 g, 2.755 mmol), 1-hydroxybenzotriazole hydrate (0.374 g, 2.755 mmol) was added triethylamine (0.430 g, 4.254 mmol) in methylene chloride (40 mL) and stirred overnight. The mixture was concentrated and partitioned between ethyl acetate and 1 N HCl. The organic extracts were washed with saturated sodium bicarbonate and brine, dried over MgSO ₄ , filtered, and concentrated to an oil which was purified by silica gel chromatography eluting with 50% ethyl acetate in hexane to 100% ethyl acetate to give a yellow oil. (0.080 g). MW 384.455; MS 385 (M ⁺ l).

Following the procedure of Example 183, the compounds of Examples 298-317 were prepared but using the carboxylic acid and amine.

Example 298

N- (4- (1-hydroxy-1-methylethyl) -benzyl) -2- (3-oxo-indan-5-yloxy) -nicotinamide

Prepared from 2- (3-oxo-indan-5-yloxy) -nicotinic acid and 2- (4-aminomethyl-phenyl) -propan-1-ol. MS (m / e) 435 (M ⁺ + NH ₃₎

417 (M ⁺ +1), 400 (100). NMR (CDCl ₃ ) 8.62 (dd, J = 2.8 Hz, 1H), 8.15 (dd, J = 2.5 Hz, 1H), 8.07 (m, 1H), 7.32 ( m, 8H), 4.67 (d,

J = 6Hz, 2H), 3.13 (t, J = 6Hz, 2H), 2.72 (dt, J = 2.4Hz, 2H), 1.53 (s, 6H).

Example 299

-246- ········

N- (4- (1-hydroxy-1-methylethyl) -benzyl) -2- (2-methylbenzothiazol-5-yloxy) -nicotinamide

Prepared from 2- (2-methyl-benzothiazol-5-yloxy) -nicotinic acid and 2- (4-aminomethyl-phenyl) -propan-2-ol. Melting point 124-126 ° C. Analysis for C ₂₄ H ₂₃ N ₃ SO ₃ calculated: C 66.49, H 5.35, N 9.69. Found: C 66.34, H 5.38, N 9.57.

Example 300

N- (4- (1-hydroxy-1-methylethyl) -benzyl) -2- (2-methylbenzothiazol-6-yloxy) -nicotinamide

Prepared from 2- (2-methyl-benzothiazol-6-yloxy) -nicotinic acid and 2- (4-aminomethyl-phenyl) -propan-2-ol. Melting point 131-133 ° C. Analysis for C ₂₄ H ₂₃ N ₃ SO ₃ calculated: C 66.49, H 5.35, N 9.69. Found: C 66.43, H 5.42, N 9.72.

Example 301

2- (Benzothiazol-6-yloxy) -N- (4- (1-hydroxy-1-methylethyl) -benzyl) -nicotinamide

Prepared from 2- (benzothiazol-6-yloxy) -nicotinic acid and 2- (4-aminomethylphenyl) -propan-2-ol. Mp 195-197 ° C. Anal. Calcd for C ₂₃ H ₂₁ N ₃ SO ₃ : C 65.85, H 5.05 N 10.02. Found: C 68.74, H 5.49, N 9.96.

Example 302

2- (Benzooxazol-6-yloxy) -N- (4- (1-hydroxy-1-methylethyl) -benzyl) -nicotinamide

Prepared from 2- (benzooxazol-6-yloxy) -nicotinic acid and 2- (4-aminomethylphenyl) -propan-2-ol. Melting point 92-94 ° C. Anal. Calcd for C ₂₃ H ₂₁ N ₃ O ₄ : C 68.47, H 5.25, N 10.42. Found: C 68.47, H 5.32, N 10.42.

Example 303

2- (3-acetyl-4-chlorophenoxy) -N- (4- (1-hydroxy-1-methylethyl) benzyl) nicotinamide • *

-247- ................

Prepared from 2- (3-acetyl-4-chlorophenoxy) -nicotinic acid and 2- (4-aminomethylphenyl) -propan-2-ol. MS (m / e) 456/458 (M ⁺ + NH _3, 100). NMR (CDC1 ₃₎ d 8.64 (dd, J = 2.8 Hz, 1H), 8.18 (dd, J = 2.5 Hz, 1H), 7.95 (m, 1H), 7.46 (m, 3H), 7.31 (m, 3H), 7.19 (m, 2H), 4.68 (d, J = 6Hz, 2H), 2.66 (s, 3H), 1.56 (s, 6 H).

Example 304

N- (4- (1-hydroxy-1-methylethyl) -benzyl) -2- (3-methyl-benzo (d) isoxazol-7-yloxy) -nicotinamide

Prepared from 2- (3-methyl-benzo- (d) isoxazol-7-yloxy) -nicotinic acid and 2- (4-aminomethyl-phenyl) -propan-2-ol. Mp 194-196 ° C. Analysis calculated for C ₂₄ H ₂₃ N ₃ O ₄ : C 69.05, H 5.55, N 10.07. Found: C 68.70, H 5.64, N 9.81.

Example 305

2- (3-acetyl-5-chlorophenoxy) -N- (4- (1-hydroxy-1-methylethyl) benzyl) nicotinamide

Prepared from 2- (3-acetyl-5-chlorophenoxy) -nicotinic acid and 2- (4-aminomethylphenyl) -propan-2-ol. Melting point 110-112 ° C. Analysis calculated for C ₂₄ H ₂₃ N ₂ O ₄ Cl: C 65.68, H 5.28, N 6.38. Found: C 65.69, H 5.35, N 6.35.

Example 306 (S) - (-) - 2- (3-Acetylphenoxy) -N- (4- (1-hydroxyethyl) -benzyl) -nicotinamide

Prepared from 2- (3-acetylphenoxy) -nicotinic acid and (S) - (-) - 1- (4-aminomethylcyclohexyl) -ethanol. Melting point 102-104 ° C. and _D (CHCl 3) -13.8 °. Analysis for C ₂₃ H ₂₂ N ₂ O ₄ calculated: C 70.75, H 5.68, N 7.17. Found: C 70.48, H 5.70, N 7.12.

Example 307 (R) - (+) - 2- (3-Acetylphenoxy) -N- (4- (1-hydroxyethyl) -benzyl) -nicotinamide

-248- ········ · · · ·

Prepared from 2- (3-acetylphenoxy) -nicotinic acid and (R) - (+) - 1- (4-aminomethylcyclohexyl) -ethanol. Melting point 104-106 ° C. [α] _D (CHCl ₃ ) + 14.0 °. Anal. Calcd for C ₂₃ H ₂₂ N ₂ O ₄ : C 70.75, H 5.68, N 7.17. Found: C 70.30, H 5.71, N 7.10.

Example 308

2- (3-Acetyl-5-chlorophenoxy) -N- (trans-4- (1-hydroxy-1-methylethyl) -cyclohexylmethyl) -nicotinamide

Prepared from 2- (3-acetyl-5-chlorophenoxy) -nicotinic acid and trans-2- (aminomethyl-cyclohexyl) -propan-2-ol. M.p. 133-135 ° C. Analysis for C ₂₄ H ₂₉ N ₂ O ₄ Cl calculated: C 64.78,

H, 6.57; N, 6.30. Found: C, 64.75; H, 6.57; N, 6.17.

Example 309

2- (3-Acetyl-4-chlorophenoxy) -N- (trans-4- (1-hydroxy-1-methylethyl) -cyclohexylmethyl) -nicotinamide

Prepared from 2- (3-acetyl-4-chlorophenoxy) -nicotinic acid and trans-2- (aminomethyl-cyclohexyl) -propan-2-ol. Melting point 106-108 ° C. Anal. Calcd for C ₂₄ H ₂₉ N ₂ O ₄ Cl: C 64.78,

H, 6.57; N, 6.30. Found: C, 64.66; H, 6.58; N, 6.11.

Example 310 (R) - (-) - 2- (3-Acetylphenoxy) -N- (trans-4- (1-hydroxyethyl) -cyclohexylmethyl) -nicotinamide

Prepared from 2- (3-acetylphenoxy) -nicotinic acid and (R) - (-) - trans-1- (4-aminomethyl-cyclohexyl) -ethanol. Mp 101-103 ° C, and _D (CDCl ₃ ) -1.5 °.

Example 311 (S) - (+) - 2- (3-Acetylphenoxy) -N- (trans-4- (1-hydroxyethyl) -cyclohexylmethyl) -nicotinamide

Prepared from 2- (3-acetylphenoxy) -nicotinic acid and (S) - (+) - trans-1- (4-aminomethyl-cyclohexyl) -ethanol. Melting point 103-105 ° C, and _D (CDCl ₃ ) +1.5 · ·

-249 »··· · · · ·

Example 312

2- (3-acetylphenoxy) -N- (2-fluoro-4- (1-hydroxy-1-methylethyl) benzyl) -nicotinamide

Prepared from 2- (3-acetylphenoxy) -nicotinic acid and 2- (4-aminomethyl-3-fluorophenyl) -propan-2-ol. Melting point 68-70 ° C. Analysis calculated for C ₂₄ H ₂₃ N ₂ O ₄ F: C 68.24, H 5.49, N 6.63. Found: C 67.17, H 5.93, N 5.97.

Example 313

2- (3-Acetyl-5-chlorophenoxy) -N- (2-chloro-4- (1-hydroxy-1-methylethyl) -benzyl) -nicotinamide

Prepared from 2- (3-acetyl-5-chlorophenoxy) -nicotinic acid and 2- (4-aminomethyl-3-chlorophenyl) -propan-2-ol. M.p. 58-60 ° C. Anal. Calcd for C ₂₄ H ₂₂ N ₂ O ₄ Cl ₂ : C 6.90, H 4.68, N 5.92, Found: C 60.73, H 4.79, N 5.78.

Example 314

2- (3-Acetyl-4-chlorophenoxy) -N- (2-chloro-4- (1-hydroxy-1-methylethyl) benzyl) nicotinamide

Prepared from 2- (3-acetyl-4-chlorophenoxy) -nicotinic acid and 2- (4-aminomethyl-3-chlorophenyl) -propan-2-ol. MS (m / e) 490/492 (M ⁺ + NH _3, 100). NMR (CDCl ₃ ) 8.60 (dd, J = 2.8 Hz, 1H),

8.31 (m, 1 H), 8.17 (dd, J = 2.5 Hz, 1 H), 7.46 (m, 3 H), 7.33 (m, 2 H), 7.20 (m, 2 H) 4.73 (d, J = 6Hz, 2H), 2.67 (s, 3H), 1.54 (s, 6H).

Example 315

N- (4- (1-hydroxy-1-methylethyl) -cyclohexylmethyl) -2- (3-methyl-benzo (d) isoxazol-5-yloxy) -nicotinamide

Prepared from 2- (3-methyl-benzo (d) isoxazol-5-yloxy) -nicotinic acid and trans-2- (aminomethyl-cyclohexyl) -propan-2-ol. Melting point 135-137 ° C. Analysis for C ₂₄ H ₂₉ N ₃ O _4: Calculated: C 68.07, H 6.90, N 9.92 Found: C, 68.07; H, 7.04; N, 9.64.

• · · ·

-250Example 316

N- (4- (1-hydroxy-1-methylethyl) -benzyl) -2- (3-methyl-benzo (d) isoxazol-5-yloxy) -nicotinamide

Prepared from 2- (3-methyl-benzo (d) isoxazol-5-yloxy) -nicotinic acid and 2- (4-aminomethyl-phenyl) -propan-2-ol. Mp 128-130 ° C. MS (m / e) 418 (M ^& lt ^; + &^gt; +1).

Example 317

N- (4- (1-hydroxy-1-methylethyl) -cyclohexylmethyl) -2- (3-methyl-benzo (d) isoxazol-7-yloxy) -nicotinamide

Prepared from 2- (3-methyl-benzo (d) isoxazol-7-yloxy) -nicotinic acid and trans-2- (aminomethyl-cyclohexyl) -propan-2-ol. Melting point 170-172 ° C. Analysis for C ₂₄ H ₂₉ N ₃ O4: Calculated: C 68.07, H 6.90, N 9.92 Found: C 68.04, H 6.89, N 9.80.

Example 318

N- [4- (1-hydroxy-1-methylethyl) -cyclohexylmethyl] -2- (3-nitrophenoxy) -nicotinamide

A solution of 2- (3-nitrophenoxy) -nicotinic acid (86.9 mg, 0.33 mmol), trans-2- (4-aminomethyl-cyclohexyl) -propan-2-ol (57.2 mg, 0.33 mmol) , benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate (148 mg, 0.33 mmol) and diisopropylethylamine (0.29 mL, 1.67 mmol) in 10 mL of anhydrous DMF were stirred overnight. The solution was then diluted with ethyl acetate and washed with water, 5% citric acid, saturated sodium bicarbonate, and brine, dried over magnesium sulfate and concentrated to an oil. Purify through a silica gel column eluting with ethyl acetate to give a clear oil (120 mg). ^{Χ Η} NMR (CDCl) δ 1.04 (4H, dd), 1.14

(6H, s), 1.55 (2 sec), 1.88 (4 m), 3.37 (2H, t), 7.23 (1 H, m), 7.51 (1 H, d), 7.64 (1 H, t), 8.07 (1 H, t), 8.16 (2H, m) 8.63 (1H, dd), MS (m / e) 414 (M @ ⁺ +1).

• · · · · · · · · · ·

Following the procedure of Example 318, the compounds of Examples 319 to 328 were prepared using the indicated carboxylic acid and amine.

Example 319 (+) - 2- (Benzo [1,3] dioxol-5-yloxy) -N- [4- (1-hydroxyethyl) -cyclohexylmethyl] -nicotinamide

Prepared from 2- (benzo [1,3] dioxol-5-yloxy) -nicotinic acid and (+) - trans-1- (4-aminomethyl-cyclohexyl) -ethanol.

¹ H NMR (CDCl 3)? ) δ 0, 97 (1, m), 1.10 (3, m), 1.17 (4 m), 1.19 (4, m) 3.23 (1, t), 3.44 (2, q), 6.00 (2, s), 6.58 (1, dd), 6.64 (1, s), 6.8 (1, d), 7 , 10 (1, m), 7 9 (1 , m), 8.18 (1, m), 8.53 (1, d), MS (me) 399 (M @ ⁺ +1).

Example 320 (-) - 2- (3-Cyano-4-fluorophenoxy) -N- [4- (1-hydroxyethyl) -cyclohexylmethyl] -nicotinamide

Prepared from 2- (3-cyano-4-fluorophenoxy) -nicotinic acid and (-) - trans-1- (4-aminomethyl-cyclohexyl) -ethanol.

Mp 134-135 ° C, MS (m / e) 398 (M ⁺ +1).

Example 321 (+) - 2- (3-Cyano-4-fluorophenoxy) -N- [4- (1-hydroxyethyl) -cyclohexylmethyl] -nicotinamide

Prepared from 2- (3-cyano-4-fluorophenoxy) -nicotinic acid and (+) - trans-1- (4-aminomethyl-cyclohexyl) -ethanol.

Mp 134-135 ° C, MS (m / e) 398 (M ⁺ +1).

Example 322

2- (3-Cyano-4-fluorophenoxy) -N- [4- (1-hydroxy-1-methylethyl) -cyclohexylmethyl] -nicotinamide

Prepared from 2- (3-cyano-4-fluorophenoxy) -nicotinic acid and 2-trans- (4-aminomethyl-cyclohexyl) -propan-2-ol. Mp 85-88 ° C, MS (m / e) 410 (M ⁺ +1).

• ·

-252 ···············

Example 323

- (2,3-Dihydro-benzo [1,4] dioxin-6-yloxy) -N- [4- (1-hydroxy-1-methylethyl) -benzyl] -nicotinamide

Prepared from 2- (2,3-dihydro-benzo [1,4] dioxin-6-yloxy) -nicotinic acid and 2- (4-aminomethyl-phenyl) -propan-2-ol. MS (m / e) 421 (M ⁺ l) ^X H NMR _(CDCl3) δ 1.51 (6H, s), 4.24 (4H, s)

4.66 (2H, d), 6.57 (1H, dd), 6.85 (1H, d), 7.11 (1H, dd), 7.28 (2H, d), 7.41 (2H d), 8.19 (2H, m), 8.61 (1H, d).

Example 324 (+) - 2- (2,3-Dihydro-benzo [1,4] dioxin-6-yloxy) -N- [4- (1-hydroxy-ethyl) -cyclohexylmethyl] -nicotinamide

Prepared from 2- (2,3-dihydro-benzo [1,4] dioxin-6-yloxy) -nicotinic acid and (+) - trans-1- (4-aminomethyl-cyclo-

hexy 1) -et: hanol u. MS (m / e) 413 (M ⁺ +1), ^X H NMR (CDC1 - ₃ ) δ 0.98 (4H, m), 1.11 (3H, m), 1.22 (2H, m), 1.70 (2H, m), 1.84 (2H, m), 3.33 (2H, m), 3.51 (LH, m), 4.25 (4H, s), 6.65 (1H, m), 6.87 (1H, d), 7.11 (1H, m), 7.90 (1 H, m), 8 , 20 (1H, m), 8.60 (1H,

d).

Example 325

2- (2,3-dihydro-benzo [1,4] dioxin-6-yloxy) -N- [4- (1-hydroxy-1-methylethyl) -cyclohexylmethyl] -nicotinamide

Prepared from 2- (2,3-dihydro-benzo [1,4] dioxin-6-yloxy) -nicotinic acid and 2-trans- (4-aminomethyl-cyclohexyl) -

-propane-2 -olu. MS (me) 427 (M ⁺ +1) NMR (CDCl ₃ ) δ 1.03 (4H, m), 1.13 (6H, s) 1.85 (4H, m), 3.33 (2H, t) 4.26 (4H, s) 6.61 (1 H, d), 6.70 (1H, s), 6.88 (1 H, d), 7.11 (1H, dd), 7.90 (LH, m), 8.20 (1 H, dd), 8.58 (1 H, dd).

Example 326 (-) - 2- (2,3-Dihydro-benzo [1,4] dioxin-6-yloxy) -N- [4- (1-hydroxyethyl) -cyclohexylmethyl] -nicotinamide

»* 9 9 ·· • ·

Prepared from 2- (2,3-dihydro-benzo [1,4] dioxin-6-yloxy) -nicotinic acid and (-) - trans-1- (4-aminomethyl-cyclohexyl) -ethanol. Mp 57-59 ° C, MS (m / e) 422 (M ⁺ +1).

Example 327

2- (Benzo [1,3] dioxol-5-yloxy) -N- [2-fluoro-4- (1-hydroxy-1-methylethyl) -benzyl] -nicotinamide

Prepared from 2- (benzo [1,3] dioxol-5-yloxy) -nicotinic acid and 2- (4-aminomethyl-3-fluorophenyl) -propan-2-ol.

Mp 94-95 ° C, MS (m / e) 425 (M ⁺ +1).

Example 328

N- [2-fluoro-4- (1-hydroxy-1-methylethyl) -benzyl] -2- (4-fluorophenoxy) -nicotinamide

Prepared from 2- (4-fluorophenoxy) -nicotinic acid and 2- (4-aminomethyl-3-fluorophenyl) -propan-2-ol. Mp 93-94 ° C, MS (m / e) 399 (M ⁺ +1).

Claims (22)

A compound of formula I or a pharmaceutically acceptable salt thereof, wherein the dotted line represents an optional double bond, m is 0 or 1, n is 0 or 1, o is 0, 1, 2, 3 or 4, p is 0 or 1, q is 0, 1, 2 or 3, r is 0, 1, 2, 3 or 4, t is 0 or 1, A is an oxygen atom,> NH or a sulfur atom, B is O or NH, D is oxygen or NR ⁹ wherein R ⁹ is hydrogen or C 1 -C 6 alkyl, E is CH ₂ , O, NH or S (O) _a , wherein a is 0, 1 or 2, R ¹ is hydrogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkenyl, C 6 -C 10 aryl, C 7 -C 9 bridged bicycloalkyl or a saturated or unsaturated, cyclic or bicyclic heterocyclic group of 3 to 7 carbon atoms, wherein said saturated or unsaturated, cyclic or bicyclic heterocyclic group of 3 to 7 carbon atoms * · · · · · · · · · · · · 255 · .... ···. It contains from one to four heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and NR ⁹ , wherein R ⁹ is as defined above, wherein said R ¹ group as cycloalkyl, cycloalkenyl, cycloalkanone, aryl , the bicycloalkyl group and the heterocyclic group are optionally substituted with one to three substituents independently selected from the group consisting of halogen, cyano, carboxy, amino, nitro, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, cycloalkyl (C až-C uhlíku) hydroxy, (C až-C hydroxy) hydroxyalkyl, (C až-C hydroxy) hydroxyalkylamino, (C až-C alko) alkoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C až-C ac) acyl C 1 -C 6 acyloxy C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino in each alkyl moiety, alkyl-NH- (C = O) -, wherein the alkyl moiety has 1 to 6 carbon atoms, (alkyl) ₂ -N- (C = O) -, wherein each alkyl moiety has 1 to 6 carbon atoms, an aminosulfonyl group, an alkylaminosulfonyl group having 1 to 6 carbon atoms, or a saturated or unsaturated, cyclic or bicyclic heterocyclic group having 3 to 7 carbon atoms; carbon atoms, wherein said saturated or unsaturated, cyclic or bicyclic heterocyclic substituents having 3 to 7 carbon atoms on said R ¹ as cycloalkyl, cycloalkenyl, aryl, bicycloalkyl and heterocyclic group contain from one to four heteroatoms independently selected from the group including oxygen, sulfur, nitrogen and NR ⁹ , wherein R ⁹ is as defined above, and wherein the heterocyclic groups are optionally substituted It may be substituted by one to three substituents independently selected from the group. -256 including halogen, cyano, carboxy, amino, nitro, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, acyl of 1 to 6 carbon atoms, aryl of 6 to 10 carbon atoms, acylamino of 1 to 6 carbon atoms, acyloxy of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms, C 1 -C 6 dialkylamino, C 1 -C 6 alkylsulfonyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminosulfonyl, C 1 -C 6 dialkylaminosulfonyl or C 2 heteroaryl up to 9 carbon atoms, wherein said alkyl, alkoxy or cycloalkyl substituents on said sk R ¹ as a cycloalkyl group, a cycloalkenyl group, an aryl group, a bicycloalkyl group or a heterocyclic group are optionally further independently substituted with one to three substituents independently selected from halogen, cyano, carboxy, amino, nitro, hydroxy, alkyl of 1 to 3 (C 1 -C 6) hydroxyalkyl, (C 1 -C 6) alkoxy, (C 1 -C 6) alkoxy, (C 1 -C 6) alkylthio, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C 1 -C 6) acyl group (C 10-C 10), (Cy-C ac) acylamino, (C 6-C ac) acyloxy, (C až-C alky) alkylamino (C až-C dial) alkylamino, (C až-C alkyl) alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl C 1 -C 6 dialkyl, C 1 -C 6 dialkylaminosulfonyl The carbon atoms in each alkyl moiety or C 2 -C 9 heteroaryl, or said R ¹ as cycloalkyl, cycloalkenyl, aryl, bicycloalkyl and heterocyclic are further optionally independently substituted one to three substituents of the general formula Wherein R ¹⁰ is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkenyl, C 6 -C 10 arylamino , (C 6 -C 10) aryl, (C 7 -C 9) bridged bicycloalkyl or saturated or unsaturated, cyclic or bicyclic C 3 -C 7 heterocyclic, wherein said R ¹⁰ as saturated or unsaturated, cyclic or bicyclic heterocyclic the C 3 -C 7 group contains one to four heteroatoms independently selected from oxygen, sulfur, nitrogen and NR ⁹ wherein R ⁹ is as defined above, wherein said R ¹⁰ as alkyl, alkoxy, cycloalkyl, cycloalkenyl an aryl group, a bicycloalkyl group, and a heterocyclic group is optionally substituted with one to two groups; substituents independently selected from the group consisting of halogen, cyano, carboxy, amino, nitro, hydroxy, C 1 -C 6 alkylalkoxy and C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, hydroxyalkyl C 1 -C 6 hydroxy, C 1 -C 6 hydroxyalkylamino, alkoxy (C 1 -C 6), difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C 1 -C 6) acyl, (C 1 -C 6) acylamino, C 1 -C 6 acyloxy, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino in each alkyl moiety, aminosulfonyl, C 1 -C 6 alkylaminosulfonyl or a saturated or unsaturated cyclic or bicyclic 3-cyclic heterocyclic group up to 7 carbon atoms, wherein said saturated or unsaturated, cyclic or bicyclic heterocyclic group of 3 to 7 carbon atoms contains from one to four heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and NR ⁹ , wherein R ⁹ is as defined above and wherein said heterocyclic group is optionally substituted with one to three substituents independently selected from the group consisting of at halogen, cyano, carboxy, amino, nitro, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, difluoromethyl, trifluoromethyl , difluoromethoxy, trifluoromethoxy, C 1 -C 6 acyl, C 6 -C 10 aryl, C 1 -C 6 acylamino, C 1 -C 6 acyloxy, C 1 -C 6 alkylamino, C 1 dialkylamino up to 6 carbon atoms in each alkyl moiety, an alkylsulfonyl group having 1 to 6 carbon atoms, an aminosulfonyl group, an alkylaminosulfonyl group having 1 to 6 carbon atoms, a dialkylaminosulfonyl group having 1 to 6 carbon atoms in each alkyl portion, or a heteroaryl group having 2 to 9 atoms alkyl, wherein the alkyl, alkoxy or cycloalkyl substituents on said R ¹⁰ as alkyl group, alkoxy, cycloalkyl, cycloalkenyl, aryl, bicycloalkyl or heterocyclic group • · • · -259-. Are optionally substituted by one to three substituents independently selected from the group consisting of halogen, cyano, carboxy, amino, nitro, hydroxy, alkyl of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms 6 carbon atoms, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, acyl of 1 to 6 carbon atoms, aryl of 6 to 10 carbon atoms, acylamino of 1 to 6 carbon atoms, acyloxy of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms 6 carbon atoms, C 1 -C 6 dialkylamino, each C 1 -C 6 alkylsulfonyl, aminosulfonyl, C 1 -C 6 alkylaminosulfonyl, dialkyls a C 1 -C 6 nosulfonyl group in each alkyl moiety or a C 2 -C 9 heteroaryl group, or R ¹ is a group of the formula wherein u is 0 or 1, and G, J, K and L are independently O, S, N, NR ⁹ , where R ⁹ is as defined above, carbonyl or CHR ¹⁶ , wherein the dotted lines indicate optional double bonds and where it is understood that when the double a bond exists between G and J, J and K or K and L that R ⁹ is absent,> CHR ¹⁶ is> CR ¹⁶ and G, J, K or L cannot be a carbonyl group where R ¹⁶ is hydrogen, halogen , cyano, carboxy, amino, nitro, hydroxy, C 1 -C 6 alkylalkoxy and C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl -260- ........ * ** carbon, hydroxyalkyl of 1 to 6 carbon atoms, hydroxyalkylamino of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, C 1 -C 6 acyl, C 1 -C 6 acylamino, C 1 -C 6 acyloxy, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino, aminosulfonyl, (C 1 -C 6) alkylaminosulfonyl or a saturated or unsaturated, cyclic or bicyclic (C 3 -C 7) heterocyclic group containing one to four heteroatoms independently selected from oxygen, sulfur, nitrogen and NR ⁹ , wherein R ⁹ has the above wherein said heterocyclic group is optionally substituted with one to three substituents independently selected from the group consisting of halogen n, cyano, carboxy, amino, nitro, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, C 1 -C 6 acyl, C 6 -C 10 aryl, C 1 -C 6 acylamino, C 1 -C 6 acyloxy, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino 6 carbon atoms in each alkyl moiety, an alkylsulfonyl group having 1 to 6 carbon atoms, an aminosulfonyl group, an alkylaminosulfonyl group having 1 to 6 carbon atoms, a dialkylaminosulfonyl group having 1 to 6 carbon atoms in each alkyl portion, or a heteroaryl group having 2 to 9 carbon atoms wherein said R ¹⁶ as alkyl, alkoxy or cycloalkyl substituents are optionally sub substituted with one to three substituents independently selected from the group consisting of halogen, cyano, carboxy, -261amino, nitro, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, acy C 1 -C 6 aryl, C 1 -C 6 aryl, C 1 -C 6 acylamino, C 1 -C 6 acyloxy, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino an alkyl moiety, an alkylsulfonyl group having 1 to 6 carbon atoms, an aminosulfonyl group, an alkylaminosulfonyl group having 1 to 6 carbon atoms, a dialkylaminosulfonyl group having 1 to 6 carbon atoms in each alkyl portion, or a heteroaryl group having 2 to 9 carbon atoms, wherein R ² , R ³ and R ⁴ are independently hydrogen, hydroxy, halo, cyano, carboxy, nitro, amino p 1, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino in each alkyl moiety, hydroxyamino, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, or formula Wherein R ¹⁰ is as defined above, or R ² and R ³ together with the carbon atom to which they are attached form a carbonyl group or R ² and R ³ together with the carbon atom to which they are attached form a cycloalkyl ring of 3 to 6 7 carbon atoms, or when mj, njel, o is lap is 0, A and R ² together together form a group of the formula Where the dotted lines indicate the optional double bonds aq, A, B, R ¹ , R ³ and R ⁴ are as defined above, and when the double bond comprises the carbon atom to which R ^{3 is} attached, then R ³ is absent, or when m is, n is 1, o and p is 0, A and R ² together and R ³ and - [R ⁴ ] _q -R ¹ together form a group of the formula R ⁵ is a saturated or unsaturated, cyclic or bicyclic heterocyclic group of 3 to 7 carbon atoms containing one to four heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and NR ⁹ , wherein R ⁹ is as defined above, wherein the heterocyclic group is optionally substituted with one to three substituents independently selected from the group consisting of halogen, cyano, carboxy, amino, nitro, hydroxy, C 1 -C 6 alkylalkoxy and C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl carbon atoms, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, C 1 -C 6 acyl, C 1 -C 6 acylamino, C 1 -C 6 acyloxy C 1 -C 6 alkylamino, dialk ylamino group with • · · · · · -263 ·········· 1 to 6 carbon atoms in each alkyl moiety, alkyl-NH- (C = O) - having 1 to 6 carbon atoms in the alkyl moiety, (alkyl) ₂ -N- (C = O) - having 1 to 6 carbon atoms in the moiety each alkyl moiety, an aminosulfonyl group, a C 1 -C 6 alkylaminosulfonyl group or a C 3 -C 7 saturated or unsaturated, cyclic or bicyclic heterocyclic group containing one to four heteroatoms independently selected from oxygen, sulfur, nitrogen and NR ⁹ wherein R ⁹ is as defined above, wherein the heterocyclic substituent on R ⁵ as a saturated or unsaturated, cyclic or bicyclic heterocyclic group of 3 to 7 carbon atoms is optionally substituted with one to three substituents independently selected from halogen, cyano, carboxy , amino, nitro, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, alkoxy (C 1 -C 6) alkyl group, (C 1 -C 6) alkylthio, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C 1 -C 6) acyl, (C 6 -C 10) aryl, (C 1 -C 6) acylamino, (C 1 -C 6) acyloxy, (C 1 -C 6) alkylamino, (C 1 -C 6) dialkylamino, (C 1 -C 6) alkylsulfonyl, aminosulfonyl, (C 1 -C 6) alkylaminosulfonyl, dialkylaminosulfonyl C 1 -C 6 alkyl in each alkyl moiety or C 2 -C 9 heteroaryl group wherein the alkyl, alkoxy or cycloalkyl substituents on R ⁵ as a saturated or unsaturated, cyclic or bicyclic C 3 -C 7 heterocyclic group are optionally substituted with one to three sub-substituents independently selected from the group including halogen, cyano, carboxy, amino, nitro, &quot;&quot; -264 hydroxy, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, acyl 1 (C 1 -C 6) aryl, (C 6 -C 10) aryl, (C 1 -C 6) acylamino, (C 1 -C 6) acyloxy, (C 1 -C 6) alkylamino (C 1 -C 6) alkylamino group, (C 1 -C 6) alkylsulfonyl, (C 1 -C 6) aminosulfonyl, (C 1 -C 6) alkylaminosulfonyl, (C 1 -C 6) dialkylaminosulfonyl (C 2 -C 9) heteroaryl, or R ⁵ as saturated or an unsaturated, cyclic or bicyclic heterocyclic group having 3 to 7 carbon atoms is optionally further substituted with wherein R ¹⁰ is as defined above, or R ⁵ is a group of the formula wherein R ¹¹ , R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ are independently selected from the group consisting of hydrogen, halogen, cyano, carboxy , amino, nitro, hydroxy, &quot;&quot; (C 1 -C 6) alkylalkoxy of (C 1 -C 6) alkoxy, (C 3 -C 7) cycloalkyl, (C 1 -C 6) hydroxyalkyl, (C 1 -C 6) alkoxy, difluoromethyl , trifluoromethyl, difluoromethoxy, trifluoromethoxy, C 1 -C 6 acyl, C 1 -C 6 acylamino, alkyl- (C = O) -NH- (C = O) - C 1-6 alkyl, aryl- (C = O) -NH- (C = O) - having 6 to 10 carbon atoms in the aryl moiety, acyloxy of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms, dialkylamino of 1 to 6 carbon atoms in each alkyl moiety, alkyl-NH- (C = O) - having 1 to 6 carbon atoms in the alkyl moiety, (alkyl) ₂ -N- (C = O) - having 1 to 6 carbon atoms in each alkyl moiety, an aminosulfonyl group , (C 1 -C 6) alkylaminosulfonyl, (C 1 -C 6) dialkylaminosulfonyl in each alkyl or a saturated or unsaturated, cyclic or bicyclic heterocyclic group of 3 to 7 carbon atoms containing one to four heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and NR ⁹ , wherein R ⁹ is as defined above, and wherein the heterocyclic group is optionally substituted with one to three substituents independently selected from the group consisting of halogen, cyano, carboxy, amino, nitro, hydroxy, (C 1 -C 6) alkyl, (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy , (C 1 -C 6) alkylthio, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C 1 -C 6) acyl, (C 1 -C 6) aryl, (C 1 -C 6) acylamino, (C 1 -C 6) acyloxy group , (C1 -C6) alkylamino, (C1 -C6) dialkylamino 6 carbon atoms in each alkyl part, alkylsulfonyl having 1 to 6 carbon atoms, aminosulfonyl, alkylaminosulfonyl 9 · • »» -266skupinu having 1 to 6 carbon atoms, dialkylaminosulfonyl having from 1 to 6 carbon atoms in each alkyl moiety, or a heteroaryl group having 2-9 carbon atoms or R ^11, R ^12, R ^13, R ¹⁴ and R ¹⁵ are optionally, independently on another a group of the formula _R 1 ° group a group wherein R ¹⁰ is as defined above, wherein the alkyl, alkoxy or cycloalkyl groups of R ^11, R ^12, R ^13, R ¹⁴ and R ¹⁵ are optionally substituted with one to three substituents independently selected from halogen, cyano, carboxy, amino, nitro, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, difluoromethyl , trifluoromethyl, difluoromethoxy, trifluoromethoxy, acyl of 1 to 6 carbon atoms, aryl of 6 to 10 carbon atoms, acylamino of 1 C 1 -C 6 acyloxy, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino in each alkyl moiety, C 1 -C 6 alkylsulfonyl, amine sulfonyl, C 1-6 alkylaminosulfonyl C 1 -C 6 dialkylaminosulfonyl or C 2 -C 9 heteroaryl, or R ¹² and R ¹³ together with the carbon atoms to which they are attached form a group of the formula * -267where u, G, J, K and L are as defined above, R ⁶ , R ⁷ and R ⁸ are independently hydrogen, halogen, cyano, carboxy, amino, nitro, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy C 6 -C 6 alkylthio, C 1 -C 6 alkylthio, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, C 1 -C 6 acyl, C 6 -C 10 aryl, C 1 -C 6 acylamino, C 1 -C 6 acyloxy C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino in each alkyl moiety, C 1 -C 6 alkylsulfonyl, aminosulfonyl, C 1 -C 6 alkylaminosulfonyl, C 1 -C 6 dialkylaminosulfonyl 6 carbon atoms in each alkyl moiety or a heteroaryl group having 2 to 9 carbon atoms, or R ⁷ and R ⁸ together with the carbon atoms to which they are attached form a fused bicyclic ring of formula II wherein the dotted lines represent optional double bonds, and Μ, P, Q and T are independently O, N or CR ¹⁷ , wherein R ¹⁷ is hydrogen or alkyl having 1 to 6 carbon atoms, -268 »· · · · · with the proviso that when mj, njel, ojel, p is 0, q is 0, r is 0, A is oxygen, B is NH, R ² and R ³ are hydrogen, R ¹ is phenyl substituted with methyl, methoxy, atom chlorine or fluorine, E is oxygen and ^R5 is phenyl optionally substituted with one or two fluorine or chlorine atoms, then R ¹ must be at least disubstituted with substituents other than methyl, methoxy or halogen, with the proviso that when t is one, the compound of formula I is a zwitterionic N-oxide, provided that the adjacent positions defined by G, J, K and L cannot both be oxygen, and with the proviso that when the dashed line in formula I represents a double bond, p is 0 and R ³ is absent. A compound according to claim 1, wherein m is, n is, o is, p is 0, q is 0, r is 0, A is oxygen or nitrogen, B is NH, R ² is hydrogen or C 1 -C 6 alkyl R @ ³ is hydrogen, R @ ¹ is aryl of 6 to 10 carbon atoms, cycloalkyl of 3 to 7 carbon atoms or saturated or unsaturated, cyclic or bicyclic heterocyclic of 3 to 7 carbon atoms containing one to four heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen or NR ⁹ , wherein R ⁹ is hydrogen or C 1 -C 6 alkyl, wherein the aryl, cycloalkyl and heterocyclic group are optionally substituted with halogen, C 1 -C 6 alkyl 6 6 atoms 6 atoms carbon, carbon, C 1 -C 6, C 1 -C 6 -alkoxy, C 1 -C 6 -alkyloxy, C 1 -C 6 alkylamino or C 1 -C 6 hydroxyalkylamino, E is O and R ⁵ is C 1 -C 6 group of formula • · Or R ⁵ is a saturated or unsaturated, cyclic or bicyclic heterocyclic group of 3 to 7 carbon atoms containing one to four heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen or NR ⁹ , wherein: R ⁹ is hydrogen or C 1 -C 6 alkyl. A compound according to claim 1, wherein m is 0, n is 0, o is 3, p is 0, q is 0, r is 0, R ^{2 and} R ³ are hydrogen, R ¹ is an aryl group of 6 to 10 carbon atoms optionally substituted by halogen , (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy, (C 1 -C 6) hydroxyalkyl, amino, (C 1 -C 6) alkylamino, (C 1 -C 6) dialkylamino, or hydroxyalkylamino having 1 to 6 carbon atoms, E is oxygen and ^R5 is a group of the formula or ^R5 is a saturated or unsaturated, cyclic or bicyclic heterocyclic group with 3-7 carbon atoms containing one to four heteroatoms independently selected from • · • · · · • • · * * * * • • • • • • Groups including an oxygen, sulfur, nitrogen or NR ⁹ atom, wherein R ⁹ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. A compound according to claim 1, wherein m 1, n is 0, o is 2, p is 0, q is 0, r is 0, A is an oxygen atom, R ² and R ³ are hydrogen, R ¹ is an aryl group of 6 to 10 carbon atoms, optionally substituted with halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 hydroxyalkyl, amino, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino in each alkyl or a C 1 -C 6 hydroxyalkylamino group, E is oxygen and R ⁵ is of the formula or R ⁵ is a saturated or unsaturated, cyclic or bicyclic C 3 -C 7 heterocyclic group containing one to four heteroatoms independently selected from the group consisting of an oxygen, sulfur, nitrogen or NR ⁹ atom, wherein R ⁹ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. A compound according to claim 1, wherein m is 0, n is 0, ojel, pjel, qjel, r is ⁰ , R ^{2 and} R ³ are hydrogen, D is oxygen, R ⁴ is hydrogen, R ¹ is aryl of 6 to 10 carbon atoms optionally substituted by halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 hydroxyalkyl, amino, C 1 -C 6 alkylamino; -271- .............. atoms, dialkylamino having 1 to 6 carbon atoms in each alkyl or hydroxy- 1 to 6 carbon atoms, E is oxygen and ^R5 is a group of formula or R ^{5 *} is saturated or unsaturated, cyclic or bicyclic heterocyclic group 3 from 1 to 4 heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen or NR ⁹ , wherein R ⁹ is hydrogen or C 1 -C 6 alkyl. A compound according to claim 1, wherein m is 0, n is 0, o is 3, p is 0, q is 0, r is 0, R ² is hydrogen or hydroxy, R ³ is hydrogen, R ¹ is aryl of 6 to 10 carbon atoms optionally substituted halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 hydroxyalkyl, amino, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino in each alkyl moiety hydroxy- or 1-6 is oxygen and ^R5 is a group of the formula alkyl, E • • · · · · · · · · · • · * Or R ⁵ is a saturated or unsaturated, cyclic or bicyclic heterocyclic group of 3 to 7 carbon atoms containing one to four heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen or NR ⁸⁹ , wherein R ⁹ is hydrogen or C 1 -C 6 alkyl. A compound according to claim 1, wherein m is 1, n is 0, o is 1, p is 1, q is 0, r is 0, A is oxygen, R ² and R ³ are hydrogen, D is oxygen, R ¹ is aryl of 6 to 10 carbon atoms optionally substituted with halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 atoms C 1 -C 6 dialkylamino, or C 1 -C 6 hydroxyalkylamino, E is oxygen and R ⁵ is of the formula or R ⁵ is a saturated or unsaturated, cyclic or bicyclic 3 to 7 heterocyclic group carbon atoms containing one to four heteroatoms independently selected from oxygen, sulfur, nitrogen or NR ⁹ , wherein R ⁹ is hydrogen or C 1 -C 6 alkyl. 8. A compound according to claim 1, wherein mjel, njel, fucked, p is zero, qjeO, r is zero, A is O, B is oxygen, R ² and R ³ are hydrogen, R ¹ is an aryl group having 6 to 10 carbon atoms, optionally substituted with halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy -273 to 6 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms in each alkyl moiety or hydroxyalkylamino of 1-6 carbon atoms, E is oxygen and R ⁵ is a radical of formula or R ⁵ is a saturated or unsaturated, cyclic or bicyclic heterocyclic group of 3 to 7 carbon atoms containing one to four heteroatoms independently selected from oxygen, sulfur, nitrogen or NR ⁹ , where R ⁹ is an atom hydrogen or an alkyl group having 1 to 6 carbon atoms. A compound according to claim 1, wherein m is, n is, o is 0, p is 1, q is 0, r is 0, A is oxygen, B is NH, D is NR ⁸ , wherein R ⁸ is hydrogen or alkyl with C 1 -C 6, R ¹ is C 6 -C 10 aryl, optionally substituted with halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 hydroxyalkyl, amino , (C 1 -C 6) alkylamino, (C 1 -C 6) dialkylamino or (C 1 -C 6) hydroxyalkylamino, E is O and R ⁵ is R ⁵ or R ⁵ is saturated or unsaturated, cyclic or a bicyclic heterocyclic group of 3 to 7 carbon atoms containing one to four heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen or NR ⁹ , wherein R ⁹ is hydrogen or alkyl of 1 to 6 carbon atoms. The compound of claim 1, wherein m is 0, n is 1, o is 1, p is 0, q is 1, r is 0, B is NH, R ² and R ³ together form a carbonyl group, R ⁴ is hydrogen, R ¹ is aryl of 6 to 10 carbon atoms optionally substituted with halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 atoms C 1 -C 6 dialkylamino, or C 1 -C 6 hydroxyalkylamino, E is oxygen and R ⁵ is of the formula or R ⁵ is a saturated or unsaturated, cyclic or bicyclic 3 to 7 heterocyclic group carbon atoms containing one to four heteroatoms independently selected from • Groups comprising an oxygen, sulfur, nitrogen or NR ⁹ atom, wherein R ⁹ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. A compound according to claim 1, wherein m is 1, n is 1, o is 1, p is 0, q is 0, r is 0, A and R ² together form a group of the formula wherein A is nitrogen, B is NH, R ¹ is alkyl with C 1 -C 6 or C 6 -C 10 aryl, the aryl being optionally substituted with halogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl , amino, (C 1 -C 6) alkylamino, (C 1 -C 6) dialkylamino or C 1 -C 6 hydroxyalkylamino, E is O and R ⁵ is or R ⁵ is saturated or unsaturated, a cyclic or bicyclic heterocyclic group of 3 to 7 carbon atoms containing one to four heteroatoms independently selected from • -276 are oxygen, sulfur, nitrogen or NR ⁹ , wherein R ⁹ is hydrogen or C 1 -C 6 alkyl. The compound of claim 1, wherein m is 0, n is 0, o is 1, p is 0, q is 2, r is 0, R ² is hydrogen or hydroxy, R ³ is hydrogen, R ⁴ is independently is hydrogen or hydroxy, R ¹ is an aryl group having 6 to 10 carbon atoms optionally substituted by halogen, alkyl having 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, hydroxyalkyl groups having 1 to 6 carbon atoms, amino, (C 1 -C 6) alkylamino, (C 1 -C 6) dialkylamino, or (C 1 -C 6) hydroxyalkylamino, E is O and R ⁵ is R ⁵ or R ⁵ is saturated or unsaturated, cyclic or bicyclic a C 3 -C 7 heterocyclic group containing one to four heteroatoms independently selected from oxygen, sulfur, nitrogen or NR ⁹ , wherein R ⁹ is hydrogen or C 1 -C 6 alkyl. A compound according to claim 1, wherein mjel, njel, o is 1, 2, 3 or 4, p is 0, qjel, 2 or 3, r is 0, A is an oxygen atom, B is an oxygen atom, R ² , R ³ , R ⁴ and R ¹ are hydrogen, E is oxygen and R ⁵ is a group of the formula -277- or R ⁵ is a saturated or unsaturated, cyclic or bicyclic heterocyclic group of 3 to 7 carbon atoms containing one to four heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen or NR ⁹ , wherein R ⁹ is hydrogen or alkyl C 1 -C 6. A compound according to claim 1, wherein m is 1, n is 1, o is 1, p is 0, q is 0, r is 0, A and R ² together form a group of the formula wherein A is nitrogen, B is oxygen, R ¹ is (C 1 -C 6) alkyl or (C 6 -C 10) aryl group, the aryl group being optionally substituted by halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino in each alkyl moiety or C 1 -C 6 hydroxyalkylamino, E is oxygen and R ⁵ is hydroxyalkylamino; -278- or R ⁵ is a saturated or unsaturated, cyclic or bicyclic heterocyclic group of 3 to 7 carbon atoms containing one to four heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen or NR ⁹ , wherein R ⁹ is hydrogen or alkyl C 1 -C 6. A compound according to claim 1, wherein m is 1, n is 1, o is 1, p is 0, q is 0, r is 0, A and R ² together form a group of the formula wherein A is oxygen, B is oxygen, R ¹ is an alkyl group having 1 to 6 carbon atoms or an aryl group having 6 to 10 carbon atoms, wherein the aryl group is optionally substituted with a halogen atom, an alkyl group with C 1 -C 6, C 1 -C 6, C 6 -C 6, C 1 -C 6 alkoxy, C 1 -C 6 dialkylamino in each alkyl moiety or C 1 -C 6 hydroxyalkylamino carbon atoms, E is oxygen and ^R5 is a group of formula • < Unsaturated, cyclic or bicyclic R is a saturated or heterocyclic group of 3 to 7 carbon atoms containing one to four heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen or NR ⁹ , wherein R ⁹ is hydrogen or alkyl of 1 to 6 carbon atoms. A compound according to claim 1, wherein m is 1, n is 0, o is 0, p is 0, q is 0, r is 0, A is oxygen, R ¹ is C 6 -C 10 aryl or saturated or unsaturated, cyclic or a bicyclic heterocyclic group of 3 to 7 carbon atoms containing as heteroatom one to four oxygen, sulfur, nitrogen and NR ⁹ , wherein R ⁹ is hydrogen or alkyl of 1 to 6 carbon atoms, wherein the aryl or heterocyclic group is optionally substituted a halogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 alkyl group, a hydroxyalkyl group C 6 -C 6 amino, amino, C 1 -C 6 alkylalkoxy, C 1 -C 6 dialkylamino or C 1 -C 6 hydroxyalkylamino, E is oxygen and R ⁵ is a general group formulas • « -280nebo R ⁵ is saturated or unsaturated, cyclic or bicyclic heterocyclic group with 3-7 carbon atoms containing one to four heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen or NR ⁹ wherein R ⁹ is hydrogen or alkyl 1 to 6 carbon atoms. The compound of claim 1, wherein m is, n is, o is 0, p is 0, q is 1, r is 0, A is oxygen, B is NH, R ⁴ is C 1 -C 6 hydroxyalkyl, R ¹ is an alkyl group having 1 to 6 carbon atoms, E is oxygen and ^R5 is a group of the formula or ^R5 is a saturated or unsaturated, cyclic or bicyclic heterocyclic group with 3-7 carbon atoms containing one to four heteroatoms independently selected from the group including oxygen, sulfur, nitrogen or NR ⁹ , wherein R ⁹ is hydrogen or C 1 -C 6 alkyl. A compound according to claim 1, selected from the group consisting of: N- (4- (1-hydroxy-1-methyl-ethyl) -benzyl) -2- (3-methyl-benzo (d) -isoxazol-7-yloxy) -nicotinamide, N- (4- (1-hydroxy-1-methyl-ethyl) -benzyl) -2- (3-oxo-indan-5-yloxy) -nicotinamide, 2- (3- (1-hydroxyimino-ethyl) -phenoxy) -N- (4- (1-hydroxy-1-methyl-ethyl) -benzyl) -nicotinamide, N- (4- (1-hydroxy-1-methyl-ethyl) -benzyl) -2- (4-oxo-chroman-6-yloxy) -nicotinamide, (+) -2- (3) -acetyl-phenoxy) -N- (1-hydroxy-indan-5-ylmethyl) -nicotinamide, 2- (2,3-dihydro-benzo (1,4) dioxin-6-yloxy) -N- (4- (1-hydroxy-1-methyl-ethyl) -benzyl) -nicotinamide, N- (4- (1-hydroxy-1-methyl-ethyl) -benzyl) -2- (3- (1-methoxyimino-ethyl) -phenoxy) -nicotinamide, N- (2-chloro-benzyl) -2- (4-fluoro-phenoxy) -nicotinamide, N- (5-chloro-thiophen-2-ylmethyl) - (2-pyridin-3-yloxy) -nicotinamide, 2- (4-fluoro-phenoxy) -N- [4- (3-hydroxy-azetidin-1-yl) -benzyl] -nicotinamide, N- [4- (1-hydroxy-1-methyl-ethyl) -benzyl] -2- (3-nitro-phenoxy) -nicotinamide, 2- (4-fluoro-phenoxy) -N- (2-oxo-2,3-dihydro-1H-indol-5-ylmethyl) -nicotinamide, N- [2- (3-acetyl-phenoxy) -pyridin-3-yl] -2- [4- (1-hydroxy-1-methyl-ethyl) -phenyl] -acetamide, 3- {3- [4-methyl-4-methyl-methyl ester] - (1-hydroxy-1-methyl-ethyl) -benzylcarbamoyl] -pyridin-2-yloxy} -benzoic acid, 2- (4-fluoro-phenoxy) -N- [4- (1-hydroxy-1-methyl-ethyl) -benzyl] -nicotinamide, 2- (4-fluoro-phenoxy) -N- (1-thiophen-2-yl-ethyl) -nicotinamide, N- [2-chloro-4- (1-hydroxy-1-methyl-ethyl) -benzyl] -2- (3-cyanophenoxy) -nicotinamide, 2- (3-cyano-4-fluoro-phenoxy) -N- [4- (1-hydroxy-1-methylethyl) -benzyl] -nicotinamide, N- [2-chloro-4- (1-hydroxy-1-methyl-ethyl) -benzyl] -2- (3,4-difluoro-phenoxy) -nicotinamide, N- [2-chloro-4- (1-hydroxy-1-methyl-ethyl) -benzyl] -2- (3-cyano-4-fluoro-phenoxy) -nicotinamide, 2- (3-acetyl-phenoxy) -N- [2-chloro-4- (1-hydroxy-1-methyl-ethyl) -benzyl] -nicotinamide, 2- (3-acetyl-phenoxy) -N- [4- (1-hydroxy-1-methyl-ethyl) -cyclohexylmethyl] -nicotinamide; -2822- (3-acetyl-phenoxy) -N- [4- (1-hydroxy-1-methyl-ethyl) -benzyl] -nicotinamide, 2- (3,4-difluoro-phenoxy) -N- [4- (1-hydroxy-1-methyl-ethyl) -benzyl] -nicotinamide, 2- (4-fluoro-phenoxy) -N- [4- (1-hydroxy-1-methyl-ethyl) -cyclohexylmethyl] -nicotinamide, 2- (3-cyanophenoxy) -N- [4- (1-hydroxy-1-methyl-ethyl) -cyclohexylmethyl] -nicotinamide, (+) - 2- (benzo [1,3] dioxol-5-yloxy) ) -N- [4- (1-hydroxy-ethyl) -cyclohexylmethyl] -nicotinamide, (-) - 2- (3-cyano-4-fluorophenoxy) -N- [4- (1-hydroxy-ethyl)] -cyclohexylmethyl] -nicotinamide, (+) - 2- (3-cyano-4-fluorophenoxy) -N- [4- (1-hydroxy-ethyl) -cyclohexylmethyl] -nicotinamide, (+) - 2- (2 (3-Dihydro-benzo [1,4] dioxin-6-yloxy) -N- [4- (1-hydroxy-ethyl) -cyclohexylmethyl] -nicotinamide, (-) - 2- (2,3-dihydro-benzo) [1,4] dioxin-6-yloxy) -N- [4- (1-hydroxy-ethyl) -cyclohexylmethyl] -nicotinamide, 2- (benzo [1,3] dioxol-5-yloxy) -N- [4- (1-hydroxy-1-methyl-ethyl) -benzyl] -nicotinamide, 2- (benzo [1,3] dioxol-5-yloxy) -N- [4- (1-hydroxy-1-methyl-ethyl) -cyclohexylmethyl] -nicotinamide, 2- (3-acetyl-phenoxy) -N- [4- (1-hydroxy-ethyl) -cyclohexylmethyl] -nicotinamide, and 2- (3-cyano-4-fluoro-phenoxy) -N- [2-fluoro-4- (1-hydroxy-1-methyl-ethyl) -benzyl] -nicotinamide, N- [4- (1-hydroxy-1-methyl-ethyl) -benzyl] -2- (3-methoxy-phenoxy) -nicotinamide, 2- (3-cyanophenoxy) -N- [4- (1-hydroxy-1-methyl-ethyl) -benzyl] -nicotinamide, N- [4- (1-hydroxy-1-methyl-ethyl) -benzyl] -2- (pyridin-3-yloxy) -nicotinamide and 2- (3-acetyl-phenoxy) -N- [4- (1-hydroxy-1-methyl-ethyl) -benzyl] -nicotinamide. • · -283 A pharmaceutical composition for the treatment of respiratory, allergic and rheumatic diseases, weight control disorders, inflammatory diseases and diseases of the central nervous system such as asthma, chronic obstructive pulmonary disease, adult respiratory disease syndrome, shock, fibrosis, pulmonary hypersensitivity, allergic rhinitis, atopic dermatitis, psoriasis, weight control, rheumatoid arthritis, cachexia, Crohn's disease, ulcerative colitis, arthritic conditions and other inflammatory diseases, depression, multi-infarct dementia and AIDS, in mammals, including humans, comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof in an amount effective to prevent or treat it, and a pharmaceutically acceptable carrier. 20. A method of treating respiratory, allergic and rheumatic diseases, weight control disorders, inflammatory diseases and diseases of the central nervous system such as asthma, chronic obstructive pulmonary disease, adult respiratory disease syndrome, shock, fibrosis, pulmonary hypersensitivity, allergic rhinitis, atopic dermatitis , psoriasis, weight control, rheumatoid arthritis, cachexia, Crohn's disease, ulcerative colitis, arthritic conditions and other inflammatory diseases, depression, multi-infarct dementia and AIDS, in mammals, including humans, characterized in that it is administered by the compound of claim 1, or a pharmaceutically acceptable salt thereof in an amount effective for such treatment. 21. A pharmaceutical composition for the selective inhibition of PDE4 D isozymes that regulate activation and degranulation of human eosinophils, useful in the treatment of respiratory, allergic and rheumatic diseases, weight control disorders, inflammatory diseases and central diseases. 9 9 -284 of the nervous system such as asthma, chronic obstructive pulmonary disease, adult respiratory disease syndrome, shock, fibrosis, pulmonary hypersensitivity, allergic rhinitis, atopic dermatitis, psoriasis, weight control, rheumatoid arthritis, cachexia, Crohn's disease, arthritis colitis and ulcerative colitis other inflammatory diseases, depression, multi-infarct dementia and AIDS, in mammals, including humans, comprising a compound inhibiting the PDE4 D isozyme or a pharmaceutically acceptable salt thereof in an amount effective for such treatment, and a pharmaceutically acceptable carrier. A method of selectively inhibiting PDE4 D isozymes that regulate activation and degranulation of human eosinophils, which is useful for treating respiratory, allergic and rheumatic diseases, weight control disorders, inflammatory diseases and central nervous system diseases such as asthma, chronic obstructive pulmonary disease adult respiratory disease syndrome, shock, fibrosis, pulmonary hypersensitivity, allergic rhinitis, atopic dermatitis, psoriasis, weight control, rheumatoid arthritis, cachexia, Crohn's disease, ulcerative colitis, arthritic conditions and other inflammatory diseases, depression, multiinfarct, mammals, including humans, characterized in that the PDE4 D isozyme inhibiting compound or a pharmaceutically acceptable salt thereof is administered in an amount effective for the treatment.